Plasma Osteopontin Reflects Tissue Damage in Acute Pancreatitis.

Several scoring systems for clinical prediction of the severity of acute pancreatitis (AP) have been proposed. Yet, there is still a need for an easy-to-measure biomarker. Osteopontin (OPN) may be released to the circulation early during tissue injury, but the significance of OPN in AP has not yet been established. We aimed to evaluate plasma levels of OPN in relation to the severity of AP. In 39 individuals with confirmed AP, plasma was collected on the day of admission and consecutively for three days thereafter. Sex- and age-matched healthy blood donors (n = 39) served as controls. Plasma OPN was measured by a commercial enzyme-linked immunosorbent assay. At admission, patients with AP displayed higher OPN, 156.4 ng/mL (IQR 111.8-196.2) compared to controls, 37.4 ng/mL (IQR 11.7-65.7) (p < 0.0001). However, OPN levels on admission could not discriminate between mild and moderate-to-severe disease (132.6 ng/mL vs. 163.4 ng/mL). Nevertheless, the changes in OPN within 24 h of admission and Day 2/3 were higher among patients with moderate/severe AP (33.7%) compared to mild AP (-8.1%) (p = 0.01). This indicates that OPN is a relevant biomarker reflecting tissue injury in AP. The increase in OPN over time suggests that serial OPN measurements could contribute to the early detection of at-risk patients. Prospective studies assessing OPN in relation to outcome in AP are warranted.

Laparoscopic distal pancreatectomy is more cost-effective than open resection: results from a Swedish randomized controlled trial.

BACKGROUND: Laparoscopic distal pancreatectomy is being implemented worldwide. The aim of this study was to perform a cost-effectiveness analysis from a health care perspective. METHODS: This cost-effectiveness analysis was based on the randomized controlled trial LAPOP, where 60 patients were randomized to open or laparoscopic distal pancreatectomy. For the follow-up of two years, resource use from a health care perspective was recorded, and health-related quality of life was assessed using the EQ-5D-5L. The per-patient mean cost and quality-adjusted life years (QALYs) were compared using nonparametric bootstrapping. RESULTS: Fifty-six patients were included in the analysis. The mean health care costs were lower, €3863 (95% CI: -€8020 to €385), for the laparoscopic group. Postoperative quality of life improved with laparoscopic resection and resulted in a gain in QALYs of 0.08 (95% CI: -0.09 to 0.25). The laparoscopic group had lower costs and improved QALYs in 79% of bootstrap samples. With a cost-per-QALY threshold of €50 000, 95.4% of the bootstrap samples were in favour of laparoscopic resection. CONCLUSION: Laparoscopic distal pancreatectomy is associated with numerically lower health care costs and improvements in QALYs compared with the open approach. The results support the ongoing transition from open to laparoscopic distal pancreatectomies.

Quality of life after open versus laparoscopic distal pancreatectomy: long-term results from a randomized clinical trial.

BACKGROUND: Pancreatic surgery is rapidly transitioning towards minimally invasive methods. Positive results have been published regarding the safety and efficacy of laparoscopic distal pancreatectomy, but postoperative quality of life after operation remains relatively unexplored. The aim of this study was to assess the long-term quality of life after open versus laparoscopic distal pancreatectomy. METHODS: A long-term analysis of quality-of-life data after laparoscopic and open distal pancreatectomy based on the LAPOP trial (a single-centre, superiority, parallel, open-label, RCT in which patients undergoing distal pancreatectomy were randomized 1 : 1 to either the open or laparoscopic approach). Patients received the quality-of-life questionnaires QLQ-C30 and PAN26 before surgery and at 5-6 weeks, 6 months, 12 months, and 24 months after surgery. RESULTS: Between September 2015 and February 2019, a total of 60 patients were randomized, and 54 patients (26 in the open group and 28 in the laparoscopic group) were included in the quality-of-life analysis. A significant difference was observed in six domains in the mixed model analysis, with better results among patients who underwent laparoscopic surgery. At the 2-year measurement, a statistically significant difference between groups was seen in three domains, and a clinically relevant difference of 10 or more was seen in 16 domains, with better results among the patients who underwent laparoscopic resection. CONCLUSION: Considerable differences were shown in postoperative quality of life after laparoscopic compared with open distal pancreatectomy, with better results among the patients who had undergone laparoscopic resection. Of note, some of these differences persisted up to 2 years after surgery. These results strengthen the ongoing transition from open to minimally invasive pancreatic surgery for distal pancreatectomy. Registration number: ISRCTN26912858 (http://www.controlled-trials.com).

Complications and chemotherapy have little impact on postoperative quality of life after pancreaticoduodenectomy - a cohort study.

BACKGROUND: With the poor prognosis of pancreatic cancer and the high rate of postoperative complications after pancreaticoduodenectomy, it is important to evaluate how the operation affects patients' quality of life. METHODS: This single-centre study included all patients undergoing pancreaticoduodenectomy from 2006 to 2016. Quality of life was measured with two questionnaires preoperatively, and at 6 and 12 months postoperatively. Comparisons between groups were made using a linear mixed models analysis. RESULTS: Of 279 patients planned for pancreaticoduodenectomy, 245 underwent the operation. The postoperative response rates were all 80% or more. Differences were found in one domain between the early and late time periods and three domains between patients receiving and not receiving adjuvant chemotherapy. No significant differences were found between patients with and without severe postoperative complications. However, the demographic variables of age group, sex, preoperative diabetes and smoking all exerted a significant impact on postoperative quality of life. CONCLUSION: While little or no impact was shown for the factors of postoperative complications, time period and adjuvant chemotherapy, demographic data, such as age, sex, preoperative diabetes and smoking, had considerable impacts on postoperative quality of life after pancreaticoduodenectomy.

Preoperative Biliary Drainage Does Not Independently Reduce Survival After Pancreaticoduodenectomy Among Patients With Pancreatic Ductal Adenocarcinoma: A National Registry Study.

Objective: This study aimed to explore a possible relationship between preoperative biliary drainage (PBD) and overall survival in a national cohort of Swedish patients who underwent pancreaticoduodenectomy (PD) for pancreatic ductal adenocarcinoma (PDAC). Background: PBD has been shown to increase postoperative complications after PD, but its use is steadily increasing. There are a few small studies that have indicated that PBD might in itself negatively affect overall survival after PD. Methods: Patients from the Swedish National Registry for tumors in the pancreatic and periampullary region diagnosed from 2010 to 2019 who underwent PD for PDAC were included. Kaplan-Meier curves, log-rank tests and Cox proportional hazards analyses were performed to investigate survival. Results: Out of 15,818 patients in the registry, 3113 had undergone PD, of whom 1471 had a histopathological diagnosis of PDAC. Patients who had undergone PBD had significantly worse survival, but the effect of PBD disappeared in the multivariable analysis when elevated bilirubin at any time was included. Conclusions: PBD does not independently influence survival after PD for PDAC, but this study implies that even a nominally increased preoperative bilirubin level might impair long-term survival.

Iterative reconstruction algorithm improves the image quality without affecting quantitative measurements of computed tomography perfusion in the upper abdomen.

OBJECTIVE: To investigate differences between reconstruction algorithms in quantitative perfusion values and time-attenuation curves in computed tomography perfusion (CTP) examinations of the upper abdomen. METHODS: Twenty-six CTP examinations were reconstructed with filtered back projection and an iterative reconstruction algorithm, advanced modeled iterative reconstruction (ADMIRE), with different levels of noise-reduction strength. Using the maximum-slope model, quantitative measurements were obtained: blood flow (mL/min/100 mL), blood volume (mL/100 mL), time to peak (s), arterial liver perfusion (mL/100 mL/min), portal venous liver perfusion (mL/100 mL/min), hepatic perfusion index (%), temporal maximum intensity projection (Hounsfield units (HU)) and temporal average HU. Time-attenuation curves for seven sites (left liver lobe, right liver lobe, hepatocellular carcinoma, spleen, gastric wall, pancreas, portal vein) were obtained. Mixed-model analysis was used for statistical evaluation. Image noise and the signal:noise ratio (SNR) were compared between four reconstructions, and statistical analysis of these reconstructions was made with a related-samples Friedman's two-way analysis of variance by ranks test. RESULTS: There were no significant differences for quantitative measurements between the four reconstructions for all tissues. There were no significant differences between the AUC values of the time-attenuation curves between the four reconstructions for all tissues, including three automatic measurements (portal vein, aorta, spleen). There was a significant difference in image noise and SNR between the four reconstructions. CONCLUSIONS: ADMIRE did not affect the quantitative measurements or time-attenuation curves of tissues in the upper abdomen. The image noise was lower, and the SNR higher, for iterative reconstructions with higher noise-reduction strengths.

There Is No Increase in Perioperative Mortality After Pancreaticoduodenectomy in Octogenarians: Results From the Swedish National Registry for Tumors in the Pancreatic and Periampullary Region.

Objective: The aim of this observational study was to compare postoperative mortality and complications between octogenarians and younger patients following pancreaticoduodenectomy (PD). Summary Background Data: With the growing elderly population and improved operative and postoperative results, PD is performed more frequently in octogenarians. Despite recent studies, it is uncertain whether elderly patients experience worse postoperative outcomes than younger patients. Methods: All patients registered in the Swedish National Registry for tumors in the pancreatic and periampullary region from 2010 to 2018 who underwent PD were included in the analysis. Results: Out of 13,936 patients included in the registry, 2793 patients underwent PD and were divided into the following age groups: <70 (n = 1508), 70-79 (n = 1137), and ≥80 (n = 148) years old. There was no significant difference in in-hospital, 30- or 90-day mortality among groups. The 2 older groups had a higher rate of medical and some surgical complications but not a significantly higher rate of complications ≥IIIa according to the Clavien-Dindo classification system. The 2 older groups had lower body mass index, higher American Society of Anesthesiologists and Eastern Cooperative Oncology Group scores, lower smoking rates, and a higher rate of preoperative biliary drainage than the <70-year-old group (all P < 0.001). The operation time was shorter in the oldest group. Conclusions: Despite the worse preoperative condition of octogenarians than younger patients, short-term mortality and serious complications were not increased. The shorter operation time, however, may indicate that patients in the oldest group were more strictly selected. With careful preoperative consideration, especially regarding cardiovascular morbidity, more octogenarians can potentially be safely offered PD.

Laparoscopic versus open distal pancreatectomy (LAPOP): study protocol for a single center, nonblinded, randomized controlled trial.

BACKGROUND: Earlier nonrandomized studies have suggested that laparoscopic distal pancreatectomy (LDP) is advantageous compared with open distal pancreatectomy (ODP) regarding hospital stay, blood loss, and recovery. Only one randomized study has been conducted showing reduced time to functional recovery after LDP compared with ODP. METHODS: LAPOP is a prospective randomized, nonblinded, parallel-group, single-center superiority trial. Sixty patients with lesions in the pancreatic body or tail that are found by a multidisciplinary tumor board to need surgical resection will be randomized to receive LDP or ODP. The primary outcome variable is postoperative hospital stay, and secondary outcomes include functional recovery (defined as no need for intravenous medications or fluids and as the ability of an ambulatory patient to perform activities of daily life), perioperative bleeding, complications, need for pain medication, and quality of life comparison. DISCUSSION: The LAPOP trial will test the hypothesis that LDP reduces postoperative hospital stay compared with ODP. TRIAL REGISTRATION: ISRCTN, 26912858 . Registered on 28 September 2015.

Digital twins to personalize medicine.

Personalized medicine requires the integration and processing of vast amounts of data. Here, we propose a solution to this challenge that is based on constructing Digital Twins. These are high-resolution models of individual patients that are computationally treated with thousands of drugs to find the drug that is optimal for the patient.

First results from the Swedish National Pancreatic and Periampullary Cancer Registry.

BACKGROUND: Despite improvements in therapy regimens over the past decades, overall survival rates for pancreatic and periampullary cancer are poor. Specific cancer registries are set up in various nations to regional differences and to enable larger prospective trials. The aim of this study was to describe the Swedish register, including possibilities to improve diagnostic work-ups, treatment, and follow-up by means of the register. METHODS: Since 2010, all patients with pancreatic and periampullary cancer (including also patients who have undergone pancreatic surgery due to premalignant or benign lesions) have been registered in the Swedish National Periampullary and Pancreatic Cancer registry. RESULTS: In total 9887 patients are listed in the registry; 8207 of those have malignant periampullary cancer. Approximately one-third (3282 patients) have had resections performed, including benign/premalignant resections. 30-day and 90-day mortality after pancreatoduodenectomy is 1.5% and 3.5%, respectively. The overall 3-year survival for resected pancreatic ductal adenocarcinoma is 35%. Regional variations decreased over the studied period, but still exist. CONCLUSION: Results from the Swedish National Registry are satisfactory and comparable to international standards. Trends over time show increasing resection rates and some improved results. Better collaboration and openness within pancreatic surgeons is an important side effect.

Scandinavian multicenter study on the safety and feasibility of the associating liver partition and portal vein ligation for staged hepatectomy procedure.

BACKGROUND: Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) has emerged as an additional tool to increase the size of the future liver remnant (FLR) in the settings of advanced tumor burden in the liver. Initial reports have indicated high feasibility but also high mortality and morbidity. The aim of this study was to assess the initial experience with ALPPS in Scandinavia regarding feasibility, morbidity, and mortality. MATERIALS AND METHODS: We conducted a retrospective analysis of all patients who underwent ALPPS since its introduction at 3 Scandinavian hepatobiliary centers. RESULTS: Thirty-six patients were identified, 21 male and 15 female. Median age was 67 years (22-83). Colorectal liver metastases (n = 25) were the most common indication for ALPPS followed by hepatocellular carcinoma (n = 4), cholangiocarcinoma (n = 4), and other (n = 3). Median growth of the FLR between the operations was 67% (-17 to 238) in 6 (5-13) days. All patients completed the second operation, and 71% of the resections were R0. Although the total percentage of patients with complication(s) was 92%, only 4 patients (11%) had a grade 3b complication according to the Clavien-Dindo classification, and no other severe complications were noted. There was no in-hospital mortality, but 1 (2.8%) patient died within 90 days of operation. CONCLUSION: ALPPS is a highly feasible method to stimulate FLR growth in patients with colorectal liver metastases as well as primary hepatobiliary malignancies. The treatment can be carried out with relative safety.

From palliative to curative treatment - stage IV mucinous adenocarcinoma, successfully treated with metronomic capecitabine in combination with Bevacizumab and surgery- a case report.

BACKGROUND: Mucinous adenocarcinoma (MAC) represents 6-19 % of all colorectal carcinoma. It is associated with poorer response to chemotherapy and chemoradiotherapy. CASE PRESENTATION: A 27-year-old Swedish woman presented with stomach pain and weight loss, and was diagnosed with locally advanced MAC in the transverse colon as well as 3 liver metastases. Neoadjuvant treatment with fluorouracil, folinic acid and oxaliplatin (FLOX) failed due to several infections, pulmonary embolism and deteriorated performance status. The patient was therefore considered palliative. Palliative treatment with metronomic capecitabine 500 mg × 2 daily and bevacizumab every other week were initiated. After 4 months of treatment the tumors had regressed and the patient was able to undergo radical surgery, thereby changing the treatment intention from palliative to curative. No adjuvant chemotherapy was given. There were no signs of recurrence 9 months later. CONCLUSIONS: The role of the combination of metronomic capecitabine and bevacizumab in patients with MAC merits further investigation.

Early endoscopic treatment of blunt traumatic pancreatic injury.

Blunt pancreatic trauma is a rare and challenging situation. In many cases, there are other associated injuries that mandate urgent operative treatment. Morbidity and mortality rates are high and complications after acute pancreatic resections are common. The diagnosis of pancreatic injuries can be difficult and often requires multimodal approach including Computed Tomography scans, Magnetic resonance imaging and Endoscopic retrograde cholangiopancreaticography (ERCP). The objective of this paper is to review the application of endoprothesis in the settings of pancreatic injury. A review of the English literature available was conducted and the experience of our centre described. While the classical recommended treatment of Grade III pancreatic injury (transection of the gland and the pancreatic duct in the body/tail) is surgical resection this approach carries high morbidity. ERCP was first reported as a diagnostic tool in the settings of pancreatic injury but has in recent years been used increasingly as a treatment option with promising results. This article reviews the literature on ERCP as treatment option for pancreatic injury and adds further to the limited number of cases reported that have been treated early after the trauma.

In situ split of the liver when portal venous embolization fails to induce hypertrophy: a report of two cases.

Introduction. Associated liver partition and portal vein ligation for staged hepatectomy (ALPPS) has been reported as an efficient alternative to portal vein embolization (PVE) to induce growth of the future liver remnant (FLR). This method combines portal vein ligation with splitting of the liver parenchyma. Although shown to be efficient in introducing growth of the FLR and allowing for resection of the deportalized part of the liver one to two weeks after the first operation, this approach carries a significant mortality. Presentation of Case. ALPPS was applied to two elderly patients where PVE failed to stimulate sufficient growth of the FLR. In both cases, subsequent growth of the FLR allowed for successful resection of the liver lesions. The postoperative course was uneventful for both patients. Discussion. In both cases, the growth of the FLR was similar to what was previously reported when ALPPS has been performed, both patients underwent radical resections that would probably not have been safe after only the PVE. Conclusion. ALPPS used as rescue technique when PVE fails to stimulate sufficient growth of the FLR can be expected to deliver similar results as ALPPS "Up front". These cases also suggest that ALPPS is applicable to the elderly population.

The Influence of a load of L-arginine on serum amino acids and pancreatic apoptosis/proliferation and ATP levels in the rat.

OBJECTIVES: Administration of high doses of amino acids like ethionine, methionine, and arginine causes pancreatic tissue damage. The initial mechanism behind these effects is not known. The aim of this study was to show the early effects of a load of L-arginine on programed cell death/proliferation and ATP levels in the pancreas. METHODS: We analyzed in rats the effects of intraperitoneal administration of L-arginine on serum amino acids, pancreatic cell apoptosis/proliferation, and ATP levels at 8, 16, and 24 hours. Serum amino acid concentrations were measured with HPLC, tissue ATP was measured fluorometrically, apoptosis was studied with caspase-3 activity and histone-associated DNA-fragments, and proliferation was studied with thymidine autoradiography. RESULTS: After a load of l-arginine, there were initially increased serum levels of L-arginine and L-citrulline, but these fell below control levels after 24 hours as well as amino acids in the glutamate family (ornithine, proline, histidine, and glutamine). Initially, increased ATP levels in the pancreatic tissue returned to control levels at 24 hours. The acinar cells proliferation was suppressed and the apoptosis rate strongly increased at 16 and 24 hours. Pancreatic histology showed vacuole formation in the acinar cells at 8 hours. At 16 hours, there was less vacuolization, but apoptotic bodies were seen, and at 24 hours there was cell degeneration but no necrosis. CONCLUSIONS: After a load of l-arginine, amino acid metabolism causes a high ATP production in the pancreatic tissue that may cause mitochondrial initiation of cell death.

Cholecystokinin-8-induced hypoplasia of the rat pancreas: influence of nitric oxide on cell proliferation and programmed cell death.

The background of cholecystokinin-8 (CCK-8)-induced hypoplasia in the pancreas is not known. In order to increase our understanding we studied the roles of nitric oxide and NF-kappaB in rats. CCK-8 was injected for 4 days, in a mode known to cause hypoplasia, and the nitric oxide formation was either decreased by means of N(omega)-nitro-L-arginine (L-NNA) or increased by S-nitroso-N-acetylpencillamine (SNAP). The activation of NF-kappaB was quantified by ELISA detection, apoptosis with caspase-3 and histone-associated DNA-fragmentation and mitotic activity in the acinar, centroacinar and ductal cells were visualized by the incorporation of [(3)H]-thymidine. Pancreatic histology and weight as well as protein- and DNA contents were also studied. Intermittent CCK injections reduced pancreatic weight, protein and DNA contents and increased apoptosis, acinar cell proliferation and nuclear factor kappaB (NF-kappaB) activation. It also caused vacuolisation of acinar cells. The inhibition of endogenous nitric oxide formation by L-NNA further increased apoptosis and NF-kappaB activation but blocked the increased proliferation and vacuolisation of acinar cells. The DNA content was not further reduced. SNAP given together with CCK-8 increased apoptosis and other pathways of cell death, raised proliferation of acinar cells and strongly reduced the DNA content in the pancreas. Histological examination showed no inflammation in any group. We conclude that during CCK-8-induced pancreatic hypoplasia, endogenously formed nitric oxide suppresses apoptosis but increases cell death along non-apoptotic pathways and stimulates regeneration of acinar cells. Exogenous nitric oxide enhances the acinar cell turnover by increasing both apoptotic and non-apoptotic cell death and cell renewal. In this situation NF-kappaB activation seems not to inhibit apoptosis nor promote cell proliferation.

Depletion of serum L-arginine in patients with acute pancreatitis.

INTRODUCTION: Acute pancreatitis may be initiated by interference with the pancreatic outflow to the duodenum. This flow is normally regulated by reflex relaxation of the sphincter of Oddi in which nitric oxide is an important mediator. AIM: To test the hypothesis that acute pancreatitis involves a depletion in serum L-arginine resulting in impaired production of nitric oxide. METHODS: We measured serum L-arginine and L-citrulline and urinary nitrite/nitrate concentrations 1 to 3 days after the onset of symptoms in 11 patients with gallstone pancreatitis, 10 patients with alcoholic pancreatitis, and 6 patients with idiopathic pancreatitis. We compared their results with those from control groups of 13 healthy blood donors, 9 patients fasting before hernia operations, 8 patients with acute cholecystitis, and 9 alcoholic subjects but no pancreatitis. Serum arginine and citrulline concentrations were measured with high performance liquid chromatography, and urinary nitrite/nitrate spectrophotometrically. RESULTS: Patients with acute pancreatitis, of whatever cause, had lower serum L-arginine and L-citrulline concentrations than controls. Patients with gallstone and idiopathic pancreatitis also have reduced urinary concentrations of nitrite and nitrate but this was not seen in patients with alcoholic pancreatitis. CONCLUSIONS: L-arginine and L-citrulline concentrations are depleted in the serum of patients with acute pancreatitis. Reduced urinary nitrite and nitrate in gallstone pancreatitis indicate that there is a defect formation of nitric oxide. This may cause a functional obstruction of the outflow of pancreatic juice to the duodenum and so may be involved in the pathophysiology of acute pancreatitis.

The influence of nitric oxide on basal and cholecystokinin-8-induced proliferation and apoptosis in the rat pancreas.

Nitric oxide (NO) is formed by different cell types in the pancreas. In this study, inhibition of endogenous nitric oxide by N(omega)-nitro-L-arginine (L-NNA) reduced the urinary excretion of NO(2)/NO(3) and raised serum L-arginine and the NO donator S-nitroso-N-acetylpenicillamine (SNAP) increased the urinary excretion of NO(2)/NO(3). The peptide cholecystokinin-8 (CCK-8) has a strong influence on exocrine pancreatic proliferation. Rat pancreas was excised and studied with regard to tissue weight, protein and DNA contents after 3 days of treatment with saline, L-NNA or SNAP given separately or combined with CCK-8. Further, proliferation of different pancreatic cells was studied with [3H]-thymidine incorporation and apoptotic activity was studied by analysing caspase-3 activity and histone-associated DNA fragments. The effects of L-NNA indicate that endogenous nitric oxide formation has a tonic inhibition on apoptosis in the pancreas during both basal condition and growth stimulation by CCK-8. In CCK-induced hyperplasia, NO inhibits the proliferation of acinar cells but stimulates ductal cells. Endogenous NO may regulate the balance between proliferation and apoptosis and in a situation of growth stimulation by CCK-8, it has a tonic inhibition on both mitogenesis and apoptosis thus slowing down the acinar cell turnover in the pancreas.