P-suPAR may reflect the inflammatory response after pancreatic surgery.

BACKGROUND: Several different scoring systems have been developed to predict post-pancreatectomy complications. Currently used inflammatory markers are of only limited value in predicting complications after pancreatic surgery. Plasma soluble urokinase plasminogen activator receptor (P-suPAR) is a prognostic biomarker associated with different inflammatory conditions. The aim of this study was to investigate P-suPAR levels before and after pancreatic surgery. METHODS: One hundred and seventy-six patients evaluated for pancreatic surgery due to suspected malignant or premalignant lesion were recruited for this study at Tampere University Hospital between 2016 and 2021. P-suPAR was analyzed before the planned operation and on postoperative days (PODs) one and three. RESULTS: One hundred and thirty-three patients [median age 67 (range 33-84) years, 50 % male] underwent a pancreatic surgery procedure. Compared to preoperative values [median 3.7 (IQR 3.1-4.7) ng/mL], P-suPAR was significantly lower on PODs 1 [3.2 (2.5-3.9) ng/mL; p < 0.001] and 3 [3.2 (2.7-4.1) ng/mL; p < 0.001]. P-suPAR on POD 1 was significantly lower in patients with postoperative pancreatic fistula (POPF) [2.6 (2.1-3.4) ng/mL] than in patients with no POPF [3.2 (2.6-3.8) ng/mL; p = 0.007]. Similar decreases in P-suPAR values were seen in patients with postoperative acute pancreatitis (POAP) and surgical site infection (SSI). CONCLUSIONS: After pancreatic surgery, P-suPAR level on POD 1 is significantly lower in patients with POPF, POAP or SSI. P-suPAR is decreased after pancreatic resection in all patients. This type of postoperative P-suPAR profile has not previously been described, and may reflect the compensatory anti-inflammatory reaction following the initial systemic inflammatory reaction caused by surgical trauma.

Plasma soluble urokinase-type plasminogen activator receptor (P-suPAR) in the diagnostics between malignant and non-malignant pancreatic lesions.

BACKGROUND: Soluble urokinase-type plasminogen activator receptor (suPAR) is a biomarker elevated in several inflammatory conditions and cancers. It has recently been shown to be elevated in pancreatic ductal adenocarcinoma (PDAC). Plasma suPAR (P-suPAR) predicts the severity of the disease in first acute alcohol-induced pancreatitis (AAP) and ten-year mortality after recovery from first AAP. According to our previous results, P-suPAR is not elevated in chronic pancreatitis (CP) and could possibly be used in distinguishing pancreatic cancer (PC) from CP. When imaging creates a suspicion of a pancreatic lesion, the distinction between malignant and non-malignant disease is crucial. Additional tools are needed, and we still lack a sufficiently sensitive and specific biomarker. Our aim was to further investigate whether preoperatively measured P-suPAR is beneficial in distinguishing between malignant and non-malignant pancreatic lesions. METHODS: One hundred and seventy-six patients evaluated in Tampere University Hospital for pancreatic surgery for suspected malignant pancreatic lesion were recruited for the study. The final study group consisted of 113 patients. P-suPAR and other covariates were measured before the planned operation. RESULTS: P-suPAR was significantly higher in patients with pancreatic cancer (PC) [median 4.1 (IQR 3.3-5.1) ng/mL] than in patients with non-malignant [3.3 (2.9-4.4) ng/mL; p = 0.012] histology. ROC curve analysis resulted in an AUC of 0.65 (95% CI 0.55-0.76); p = 0.007 and a cutoff value of 3.2 ng/mL. Crosstabulation yielded sensitivity of 82% and specificity of 43%. A combination of positive P-suPAR and elevated plasma carbohydrate antigen 19-9 (P-CA19-9) tests did not improve sensitivity but elevated specificity up to 86-88%. CONCLUSIONS: Preoperative P-suPAR is elevated in patients with PC compared to patients with a non-malignant pancreatic lesion. Combining P-suPAR with P-CA19-9 may improve diagnostic accuracy.

Osteoporosis and sarcopenia are common and insufficiently diagnosed among chronic pancreatitis patients.

PURPOSE: Chronic pancreatitis (CP) leads to diabetes and pancreatic exocrine insufficiency (PEI). PEI may lead to maldigestion and malnutrition, which may cause fat-soluble vitamin deficiency, sarcopenia and abnormal bone density. We aim to study the prevalence of osteoporosis, sarcopenia and vitamin deficiency among CP patients. METHODS: Long-term (4-5 years) follow-up was implemented on CP patients. We recorded CP duration, BMI, smoking, alcohol consumption and medication. We determined the serum values for A, D and E vitamins, albumin, creatinine, haemoglobin, calcium and magnesium. Bone density measurement was taken from the proximal femur and lumbar spine. CT/MRI scans were used to measure for psoas muscle area. RESULTS: A total of 33 patients (median age 62 [39-81] years, 61% male) were included. None of these patients had earlier diagnosis of osteopathy, and none of them had known vitamin deficiency or were sarcopenic. Nineteen patients (57%) had pancreatic exocrine insufficiency and of these seven patients (37%) had no pancreatic enzyme replacement therapy (PERT) and one (5%) had inadequate enzyme therapy. During the study, osteoporosis was diagnosed in 20% and possible sarcopenia in 48% of patients. PEI and inadequate PERT was associated with low E vitamin levels (75% vs. 0%, p = 0.012), higher risk of osteoporosis (43% vs. 5.6%, p = 0.013) and sarcopenia (80% vs. 36%, p = 0.044). CONCLUSION: This study demonstrates that chronic pancreatitis is associated with osteoporosis, sarcopenia and vitamin deficiency. If untreated, pancreatic exocrine insufficiency is associated with increased risk of these outcomes. This highlights the importance of identifying and treating PEI in CP patients.

The association between appendicitis severity and patient age with appendiceal neoplasm histology-a population-based study.

PURPOSE: Recent studies have reported alarming appendiceal tumor rates associated with complicated acute appendicitis, especially in patients presenting with a periappendicular abscess. However, the data on histology of appendiceal tumors among acute appendicitis patients is limited, especially in patient cohorts differentiating between uncomplicated and complicated acute appendicitis. We have previously reported the association of increased appendiceal tumor prevalence with complicated acute appendicitis in this population-based study. The objective of this secondary analysis was to evaluate the association of both appendicitis severity and patient age with appendiceal tumor histology. METHODS: This nationwide population-based registry study (The Finnish Cancer Registry) was conducted from 2007 to 2013. All appendiceal tumors (n = 840) and available medical reports (n = 504) of these patients at eight study hospitals were previously evaluated, identifying altogether 250 patients with both acute appendicitis and appendiceal tumor. RESULTS: The severity of acute appendicitis was significantly associated with more malignant tumor histology. The risk of adenocarcinoma or pseudomyxoma was significantly higher among patients with periappendicular abscess (OR 15.05, CI 95% 6.98-32.49, p < 0.001) and patients presenting with perforated acute appendicitis (OR 4.09, CI 95% 1.69-9.90, p = 0.0018) compared to patients with uncomplicated acute appendicitis. Similarly, patient age over 40 years was significantly associated with the risk of adenocarcinoma and pseudomyxoma (OR 26.46, Cl 95% 7.95-88.09, p < 0.001). Patient sex was not associated with a more malignant appendiceal tumor histology (p = 0.67). CONCLUSION: More malignant appendiceal tumor histology of adenocarcinoma or pseudomyxoma was significantly associated with patient age over 40 years and complicated acute appendicitis, especially periappendicular abscess.

Pancreatic Secretory Trypsin Inhibitor (SPINK1) Gene Mutation in Patients with Acute Alcohol Pancreatitis (AAP) Compared to Healthy Controls and Heavy Alcohol Users without Pancreatitis.

Only 3-5% of heavy alcohol users develop acute alcohol pancreatitis (AAP). This suggests that additional triggers are required to initiate the inflammatory process. Genetic susceptibility contributes to the development of AAP, and SPINK1 mutation is a documented risk factor. We investigated the prevalence of the SPINK1(N34S) mutation in patients with AAP compared to heavy alcohol users who had never suffered an episode of pancreatitis. Blood samples for the mutational analysis from patients with first episode (n = 60) and recurrent AAP (n = 43) and from heavy alcohol users without a history of AAP (n = 98) as well as from a control population (n = 1914) were obtained. SPINK1 mutation was found in 8.7% of the patients with AAP. The prevalence was significantly lower in healthy controls (3.4%, OR 2.72; 1.32-5.64) and very low in alcoholics without pancreatitis (1.0%, OR 9.29; 1.15-74.74). In a comparison adjusted for potential cofounders between AAP patients and alcoholics, SPINK1 was found to be an independent marker for AAP. The prevalence of the SPINK1 mutation is overrepresented in AAP patients and very low in alcoholics without pancreatitis. This finding may play a role in understanding the variable susceptibility to AAP found in heavy alcohol users.

Long-term health-related quality of life in persons diagnosed with an insulinoma in Finland 1980-2010.

OBJECTIVE: Insulinomas are rare pancreatic neoplasms, which can usually be cured by surgery. As the diagnostic delay is often long and the prolonged hyperinsulinemia may have long-term effects on health and the quality of life, we studied the long-term health-related quality of life (HRQoL) in insulinoma patients. DESIGN, PATIENTS AND MEASUREMENTS: The HRQoL of adults diagnosed with an insulinoma in Finland in 1980-2010 was studied with the 15D instrument, and the results were compared to those of an age- and gender-matched sample of the general population. The minimum clinically important difference in the total 15D score has been defined as ±0.015. The clinical characteristics, details of insulinoma diagnosis and treatment, and the current health status of the subjects were examined to specify the possible determinants of long-term HRQoL. RESULTS: Thirty-eight insulinoma patients participated in the HRQoL survey (response rate 75%). All had undergone surgery with a curative aim, a median of 13 (min 7, max 34) years before the survey. The insulinoma patients had a clinically importantly and statistically significantly better mean 15D score compared with the controls (0.930 ± 0.072 vs 0.903 ± 0.039, P = .046) and were significantly better off regarding mobility, usual activities and eating. Among the insulinoma patients, younger age at the time of survey, higher level of education and smaller number of chronic diseases were associated with better overall HRQoL. CONCLUSIONS: In the long term, the overall HRQoL of insulinoma patients is slightly better than that of the general population.

Regulation of p38 MAPK and glucocorticoid receptor activation by hydrocortisone in mono-and co-cultured pancreatic acinar and stellate cells.

BACKGROUND/OBJECTIVES: Acute pancreatitis develops as an inflammatory response to pancreatic tissue injury. Postoperative pancreatitis has recently been associated with increased occurrence of complications. Activation of the mitogen-activated protein kinase p38 (p38 MAPK) pathway occurs early in acute pancreatitis and its inhibition has been suggested to alleviate pancreatic inflammation. Glucocorticoids are potent anti-inflammatory steroids whose use in the management of acute pancreatitis remains controversial. Our aim was to examine the effect of crosstalk between pancreatic acinar cells (PACs) and stellate cells (PSCs) on p38 MAPK and glucocorticoid receptor (GR) activation and to assess the impact of hydrocortisone on these events. METHODS: The long-term co-culture setting for mouse PACs and PSCs developed in our laboratory was used. Parallel 4d mono- and co-cultures with or without 10 nM hydrocortisone were performed followed by immunocytochemical analysis of nuclear GR and phospho-p38 MAPK (pp38 MAPK). RESULTS: Hydrocortisone inhibited pp38 MAPK up-regulation evoked by co-culture in PACs and PSCs and increased nuclear translocation of GR in PAC monocultures and in co-cultured PACs and PSCs. In PSC monocultures and co-cultured PACs, ligand-independent expression of nuclear GR was observed. In the former no change in nuclear GR but a significant decrease in total GR as analyzed by Western blot was caused by hydrocortisone. CONCLUSIONS: Cellular microenvironment plays a significant role on p38 MAPK and GR activation in PACs and PSCs. Hydrocortisone is an effective means to inhibit p38 MAPK activation in PACs and PSCs. Both ligand-dependent and -independent regulatory roles for GR are suggested in the exocrine pancreas.

Perioperative acinar cell count method works well in the prediction of postoperative pancreatic fistula and other postoperative complications after pancreaticoduodenectomy.

BACKGROUND: Earlier we have shown that high frequency of acinar cells in the pancreatic transsection line predicts postoperative pancreatic fistula after pancreaticoduodenectomy (PD). Acinar cell count method (ACM) is fast to perform during operation. In this study our aim was to validate the accuracy of ACM to compare it with other published risk prediction methods. METHODS: 87 patients who underwent PD without any trial including perioperative medications were collected from a single hospital. Data on demographics, surgical details, postoperative complications clinically relevant pancreatic fistulae (CR-POPF) and clinically relevant Clavien-Dindo complications (CR-CDC) were registered. Thirteen previously published risk prediction methods were included in the comparison, such as pancreatic duct diameter, palpable texture of pancreas, Braga score (BC), Fistula Risk Score, Modified Fistula Risk Score, Alternative Fistula Risk Score and multiple radiological parameters. ROC-curves were calculated to compare sensitivity and specificity for identifying high risk patients for CR-POPF and CR-CDC. RESULTS: The three most accurate risk prediction methods for CR-POPF were ACM (sensitivity 88.9%, specificity 52.6%; p = 0.043), BC (87.5%, 56.6%; p = 0.039) and visceral fat area to subcutaneous fat area ratio (75.5%, 80.0%; p = 0.032). In predicting CR-CDC the three most accurate methods were ACM (73.9%, 56.2%; p = 0.033), BC (68.4%, 59.5%; p = 0.036) and TPAI (78.3%, 41.7%; p = 0.012). CONCLUSION: ACM was shown to be as good as the more complicated risk scoring methods in the prediction of CR-POPF. It was good also in predicting all clinically relevant complications. ACM is easy to use during operation and can be recommended as a routine risk prediction method.

Plasma suPAR may help to distinguish between chronic pancreatitis and pancreatic cancer.

OBJECTIVES: SuPAR (soluble urokinase-type plasminogen activator receptor) is a biomarker reflecting the inflammatory state of the human body. Earlier studies suggest that urinary suPAR/creatinine ratio levels are elevated in chronic pancreatitis (CP), and that plasma suPAR (P-suPAR) level is elevated in pancreatic cancer (PC). Our aim was to study the levels of P-suPAR in CP in a long-term prospective follow-up setting to explore the possibility of distinguishing between PC and CP. MATERIALS AND METHODS: Two patient groups were compared. The first group included 83 patients who were prospectively followed up after their first acute alcohol-induced pancreatitis (AAP) for median 7.0 (range 0.3-9.8) years. Twelve patients in this group developed CP during follow-up, and two patients were further excluded from the CP cohort. The second group consisted of 25 patients operated on for suspicion of pancreatic malignancy and final pathological diagnosis of PC. P-suPAR levels were measured and compared within and between these groups. RESULTS: P-suPAR levels remained low during follow-up despite the development of CP. P-suPAR was significantly higher in PC patients [median 3.7 (IQR 3.1-4.4) ng/mL] than in CP patients [2.6 (1.8-3.6) ng/mL]; p = .014. A cutoff value of 2.8 ng/mL resulted from a ROC curve with area under curve (AUC) of 0.79 (95% CI 0.61-0.97), p = .009 in differentiation between PC and CP with a sensitivity and a specificity of 88% and 70% respectively. CONCLUSION: P-suPAR is higher in patients with PC than in patients with CP, and it could thus be used in differentiating between PC and CP.

A population-based study of chronic pancreatitis in Finland: Effects on quality of life.

BACKGROUND/OBJECTIVES: In Finland the incidence of chronic pancreatitis (CP) is high compared to that in most European countries. Recent epidemiological data is lacking. Our aim was to investigate the current epidemiologic and behavioural data on CP patients in Finland. METHODS: CP patients according to M-ANNHEIM criteria in Tampere University Hospital (TAUH) during 2014-2015 were included. Aetiology, time from diagnosis, pancreatic function, treatment, complications, smoking, alcohol consumption (AUDIT) and quality of life (QoL) (QLQ C30, PAN26) were gathered. RESULTS: 235 CP patients (57 (26-88) years, 65% men) were included. Time since diagnosis was 5.5 (1-41) years. Aetiology was alcohol in 67%, and smoking contributed in 54%. Of these patients 78% continued smoking and 58% continued to consume alcohol even after CP diagnosis. CP related complications were common. Pseudocysts were more common in alcohol related CP than in non-alcohol related CP (60% vs. 38%, p < 0.05). Reported QoL and pain were worse in the CP patients than in controls. Alcohol consumption differed from that of the Finnish population; the CP patients were either total abstainers or heavy alcohol consumers. CONCLUSIONS: CP constitutes a great burden on the health care system and on the patients. The patients frequently develop complications and symptoms and their QoL is inferior to that of controls. The most important measure to halt the progression of CP would be to prevent acute phases and for patients to stop smoking, which does not happen in many CP patients. It would be beneficial to increase awareness among CP patients and medical professionals.

The European evidence-based guidelines on pancreatic cystic neoplasms (PCN) in clinical practice: The development of relative and absolute indications for surgery during prospective IPMN surveillance.

INTRODUCTION: The European evidence-based guidelines on PCN recommend surveillance for IPMN patients who are fit for surgery but who have no indication for immediate surgery. Our aim was to demonstrate the feasibility of the new guidelines in clinical practice. METHODS: This is a prospective cohort study of patients included in the IPMN register in Tampere University Hospital, Finland. IPMN was diagnosed from January 1, 2013 to December 31, 2018. Patients were analyzed for surveillance and indications for surgery according to the European guidelines on PCN. RESULTS: Out of 128 patients in register 23 was decided to operate upfront and 105 patients were included in the surveillance programme. Invasive carcinoma was found in 4/23 of operated patients. Median follow-up time was 26 months (6-69). Median size of the cyst at the beginning and end of the surveillance was 16 mm (4-58 mm). During surveillance 0/105 (0.0%) patients had or developed an absolute indication for surgery. Relative indication for surgery was present in 8/105 (7.6%) patients in the beginning surveillance and 9/105 (8.6%) patients developed at least one relative indication for surgery during surveillance. From the surveillance cohort 2/105 patients were operated. Surveillance was abandoned in 15/105 (14.1%) patients all due to poor general condition or other medical conditions. CONCLUSIONS: In clinical practice, surveillance of IPMN according to the European guidelines on PCN is feasible. Among our patients 16% were detected to have relative indications for surgery during the median 26 (range 3-135) months of surveillance. Nearly 15% became surgically unfit during surveillance period.

Wnt/ß-catenin signalling plays diverse functions during the process of fibrotic remodelling in the exocrine pancreas.

BACKGROUND/OBJECTIVES: Wnt/ß-catenin signalling plays vital roles in tissue homeostasis. Dysregulation of the pathway has been implicated in the pathogenesis of cancer and fibroses in numerous tissues, including the pancreas. We studied the effect of microenvironmental changes pertaining to fibrotic tissue remodelling on the expression of selected Wnt/ß-catenin pathway proteins in the human exocrine pancreas. The role of acinar/stellate cross-talk on the expression of the proteins was elucidated in a long-term mouse co-culture system. METHODS: Expression of ß-catenin, Wnt2, Wnt5a and SFRP4 was analysed immunohistochemically in normal and moderately or highly fibrotic human pancreata (n = 8). The effect of humoral interactions on the expression of the proteins was studied by immunocytochemical means in parallel mono- and co-cultures of mouse acinar and stellate cells (PSCs). RESULTS: In human pancreatic tissue, fibrotic microenvironment was associated with redistribution of the proteins in and between epithelial and stromal compartments, compared to acinar-rich tissue. In non-fibrotic and moderately fibrotic tissue the proteins appeared only in acinar cells whereas in highly fibrotic tissue stromal fibroblastoid/stellate cells and macrophages were their predominant locations. Subcellular changes in the expression of ß-catenin and Wnt5a were detected. Our in vitro data suggest potential involvement of acinar cell/PSC cross-talk in mediating the changes observed in tissue specimens. CONCLUSIONS: Wnt/ß-catenin pathway-associated proteins are abundantly expressed in the exocrine pancreas with prominent changes in their cellular and subcellular expression patterns along with increasing levels of fibrosis. Diverse functions for Wnt/ß-catenin signalling during the course of fibrotic remodelling in the exocrine pancreas are suggested.

Perioperative hydrocortisone treatment reduces postoperative pancreatic fistula rate after open distal pancreatectomy. A randomized placebo-controlled trial.

BACKGROUND: Postoperative pancreatic fistula (POPF) is the most common complication after distal pancreatectomy (DP). In a recent RCT on pancreaticoduodenectomy (PD), perioperative hydrocortisone (HC) treatment reduced Clavien-Dindo (C-D) III-V complications. The aim of this study was to investigate whether perioperative HC treatment reduces the overall complications and clinically significant POPF after distal pancreatectomy (DP). METHODS: Fourty consecutive patients undergoing DP were randomized to receive intravenous HC 100mg/placebo every eight hours until the second postoperative day. Thirty-one patients were completed with DP and received HC/placebo every 8 h for two days postoperatively. The primary endpoint was overall complications (C-D III-V) and the secondary endpoint was the development of clinically significant POPF. RESULTS: Pancreatic duct diameter, operative time and blood loss were similar in the groups. Ninety-day mortality was zero. With HC treatment the rates of C-D III-V complications tended to be lower compared to the placebo group (5.9% vs 21.4%, p = 0.034). The rate of grade B/C POPF was significantly reduced with HC treatment compared to the placebo group (5.9% vs. 42.9%, p = 0.028). CONCLUSION: Perioperative HC treatment may have a favourable effect on overall major complications after open DP. HC treatment reduces the incidence of clinically significant POPF after open DP.

Characteristics and long-term survival of resected pancreatic cystic neoplasms in Finland. The first nationwide retrospective cohort analysis.

BACKGROUND: Pancreatic cystic neoplasms (PCN) are being found increasingly in imaging studies. Even though the characteristics of PCN lesions have been studied extensively in single and multicentre settings, nationwide data is lacking. The aim of this study was to determine the nationwide epidemiologic characteristics and long-term survival of all resected PCNs. METHODS: For this retrospective cohort analysis, all PCNs operated on in Finland during the period 2000-2008 were identified. Data was collected from all patients: on demographics, comorbidities, symptoms, radiological findings, surgical procedures, complications, histopathological diagnoses and survival. Incomplete pathology reports and any uncertain diagnoses were re-assessed. Survival data was collected after a five-year follow-up period. RESULTS: The final database included 225 patients with operated PCN. After reviewing the incomplete pathology reports, in 44 cases the original diagnosis was changed, mostly from MCN to IPMN. The most common histopathological diagnoses were IPMN (94/225; 50/225 MD-IPMN, 30/225 MX-IPMN and 14/225 BD-IPMN), SCN (41/225) and MCN (40/225). Overall, 53/225 (23.6%) of the tumours were malignant. Malignancy was detected in MD-IPMN 29/50 (58%), MX-IPMN 10/30 (33.3%), MCN 12/40 (30%), BD-IPMN 2/14 (14.3%) patients. Median 5-year survival for all patients was 77%: 87% in patients without malignancy, 77% with HGD and 27% in patients with a malignant resected PCN. CONCLUSION: One fourth of the PCNs operated on nationwide were malignant, with a five-year survival of 27%, compared to overall survival of 87% in patients with non-malignant disease and 77% in those with HGD. Detecting - and operating on - a PCN before the malignant transfer remains a great challenge.

Appendiceal neoplasm risk associated with complicated acute appendicitis-a population based study.

PURPOSE: Appendiceal tumors are rare, but high neoplasm rates have been reported at interval appendectomy after periappendicular abscess. Non-operative management of uncomplicated acute appendicitis has shown promising results. The data on appendiceal tumor incidence and presentation among acute appendicitis patients is limited, especially in patient cohorts differentiating between uncomplicated and complicated acute appendicitis. Objective was to assess appendiceal tumor incidence and tumor association to appendicitis in patients with uncomplicated and complicated acute appendicitis. METHODS: This nationwide population-based registry study was conducted from 2007 to 2013. The Finnish Cancer Registry and the National Institute for Health Registry were used to combine data on all appendiceal tumors and acute appendicitis diagnosis with medical reports evaluated at eight study hospitals. RESULTS: Altogether, 840 appendiceal tumors were identified, and out of these, 504 patient reports were reviewed, including 472 patients in this study. Tumor was diagnosed at appendectomy for suspected acute appendicitis in 276 patients (58%). In the whole study, histologically acute appendicitis and tumor were both present in 53% (n = 250), and out of these, 41% (n = 102) were complicated and 59% (n = 148) uncomplicated acute appendicitis. The associated tumor risk was significantly higher in complicated acute appendicitis compared with uncomplicated cases (3.24% vs. 0.87%, p < 0.001). Overall tumor prevalence among acute appendicitis patients was 1.24%. CONCLUSIONS: Appendiceal tumor prevalence in acute appendicitis was low. Tumor risk was significantly higher in complicated acute appendicitis compared with uncomplicated acute appendicitis. The risk of missed appendiceal tumors related to antibiotic therapy of uncomplicated acute appendicitis is very low.

Long-term cardiovascular morbidity and mortality in patients treated for differentiated thyroid cancer.

OBJECTIVES: Thyroid hormone suppression therapy has been widely used in the treatment of thyroid cancer, but concerns have been raised about the cardiovascular risks of this treatment. The objective of this study was to evaluate long-term cardiovascular morbidity and mortality in patients treated for differentiated thyroid cancer (DTC) and to assess the effect of TSH suppression and radioiodine (RAI) treatment on the cardiovascular outcome. DESIGN: Retrospective cohort study. PATIENTS AND MEASUREMENTS: Patients (n = 901) treated for DTC between 1981 and 2002 at 2 Finnish University hospitals were compared with a randomly chosen reference group (n = 4485) matched for age, gender and the place of residence. Kaplan-Meier and Cox regression analyses were used to estimate the risk of morbidity or death due to different cardiovascular diseases (CVD) after the diagnosis of DTC. RESULTS: Morbidity due to any CVD (hazard ratio [HR] 1.16, 95% confidence interval [CI] 1.05-1.28) and due to all arrhythmias (HR 1.25, CI 1.06-1.48) and atrial fibrillation (AF) (HR 1.29, CI 1.06-1.57) was more frequent in the DTC patients than in the controls. The increased cardiovascular morbidity was confined to patients with a mean TSH level below 0.1 mU/L (HR 1.27, CI 1.03-1.58) and to those treated with RAI (HR 1.18, CI 1.05-1.31). Cardiovascular mortality, however, was lower among the patients than the controls (HR 0.73, CI 0.58-0.92), due to a lower mortality from coronary artery disease. CONCLUSIONS: Differentiated thyroid cancer patients have an increased CVD morbidity, which is mostly accountable to AF and to TSH suppression below 0.1 mU/L.

A pilot study of endoscopically inserted biodegradable biliary stents in the treatment of benign biliary strictures and cystic duct leaks.

BACKGROUND AND AIMS: Self-expanding biodegradable biliary stents (BDBSs) have recently become available for use in endoscopic retrograde cholangiography (ERC). The aim was to evaluate the effectiveness and safety of novel BDBSs in iatrogenic cystic duct leaks and benign biliary strictures (BBSs). METHODS: Patients providing informed consent were recruited for the prospective study. Braided self-expanding poly-dioxanone BDBSs were inserted using ERC during from 2014 to 2016. Repeated liver function tests and magnetic resonance imaging were performed during follow-up. The main outcomes were treatment success and adverse events. RESULTS: Thirteen patients, 5 women, median age 67 years (range, 43-79) underwent BDBS insertion for iatrogenic cystic duct leak (n = 7) or BBS (n = 6). Stent insertion using ERC was successful in all cases. All bile leaks were treated uneventfully with BDBSs. In BBSs, the clinical success rate of BDBS therapy was 83% in a median of 21 months of follow-up (range, 14-25). Early ERC-related adverse events included 1 cholangitis (8%) and 1 pancreatitis (8%), both in the stricture group. During the first 90 days, 23% of patients were readmitted for mild cholangitis. CONCLUSIONS: The short- and long-term safety of endoscopically inserted poly-dioxanone BDBSs was satisfactory. The management of cystic duct leaks and benign distal common bile duct strictures was highly successful. Episodes of mild cholangitis during stent indwelling seemed to be typical of BDBSs. The advantage of BDBSs is the avoidance of repeated endoscopy for stent removal. (Clinical trial registration number: NCT02353286.).

Biodegradable biliary stents preferable to plastic stent therapy in post-cholecystectomy bile leak and avoid second endoscopy.

BACKGROUND: The treatment of post-cholecystectomy bile leak is endoscopic retrograde cholangiography (ERC) with plastic stent (PS) insertion combined with external drainage. Self-expanding biodegradable biliary stents (BDBS) have only recently become available. AIM: The aim was to compare success rate, adverse events and costs of BDBS with PS in the treatment of post-cholecystectomy cystic duct leak Materials and methods: Patients recruited prospectively for treatment with BDBS during the period 2014-2017 were compared to a control group treated with PS in a non-randomized setting. RESULTS: Altogether 32 patients (median age 68, range 33-88, 59% male) were treated for Strasberg A bile leak over a period of 3.5 years, accounting for 1.8% of all ERCs. Eight patients were treated with BDBS and 24 with PS. Treatment with BDBS was safe; rate of readmissions and 30-day adverse events were 13% in both groups. There was no statistical difference in the clinical success rate. All cases with laparoscopic lavation or re-ERC with stent exchange occurred in the PS group. Total drain output was lower in BDBS patients (330ml vs 83ml, p=.002). All PS patients required another endoscopy for stent removal, whereas all BDBS patients were spared repeated endoscopy. CONCLUSION: Treatment of cystic duct leak with BDBS is highly successful and as safe as traditional treatment with PS. The most obvious benefit of BDBS is that it avoids stent removal. The lower drain output after ERC with a trend for fewer unplanned interventions may indicate more efficient leak resolution with the large bore BDBS.

Five-Year Follow-up of Antibiotic Therapy for Uncomplicated Acute Appendicitis in the APPAC Randomized Clinical Trial.

Importance: Short-term results support antibiotics as an alternative to surgery for treating uncomplicated acute appendicitis, but long-term outcomes are not known. Objective: To determine the late recurrence rate of appendicitis after antibiotic therapy for the treatment of uncomplicated acute appendicitis. Design, Setting, and Participants: Five-year observational follow-up of patients in the Appendicitis Acuta (APPAC) multicenter randomized clinical trial comparing appendectomy with antibiotic therapy, in which 530 patients aged 18 to 60 years with computed tomography-confirmed uncomplicated acute appendicitis were randomized to undergo an appendectomy (n = 273) or receive antibiotic therapy (n = 257). The initial trial was conducted from November 2009 to June 2012 in Finland; last follow-up was September 6, 2017. This current analysis focused on assessing the 5-year outcomes for the group of patients treated with antibiotics alone. Interventions: Open appendectomy vs antibiotic therapy with intravenous ertapenem for 3 days followed by 7 days of oral levofloxacin and metronidazole. Main Outcomes and Measures: In this analysis, prespecified secondary end points reported at 5-year follow-up included late (after 1 year) appendicitis recurrence after antibiotic treatment, complications, length of hospital stay, and sick leave. Results: Of the 530 patients (201 women; 329 men) enrolled in the trial, 273 patients (median age, 35 years [IQR, 27-46]) were randomized to undergo appendectomy, and 257 (median age, 33 years, [IQR, 26-47]) were randomized to receive antibiotic therapy. In addition to 70 patients who initially received antibiotics but underwent appendectomy within the first year (27.3% [95% CI, 22.0%-33.2%]; 70/256), 30 additional antibiotic-treated patients (16.1% [95% CI, 11.2%-22.2%]; 30/186) underwent appendectomy between 1 and 5 years. The cumulative incidence of appendicitis recurrence was 34.0% (95% CI, 28.2%-40.1%; 87/256) at 2 years, 35.2% (95% CI, 29.3%-41.4%; 90/256) at 3 years, 37.1% (95% CI, 31.2%-43.3%; 95/256) at 4 years, and 39.1% (95% CI, 33.1%-45.3%; 100/256) at 5 years. Of the 85 patients in the antibiotic group who subsequently underwent appendectomy for recurrent appendicitis, 76 had uncomplicated appendicitis, 2 had complicated appendicitis, and 7 did not have appendicitis. At 5 years, the overall complication rate (surgical site infections, incisional hernias, abdominal pain, and obstructive symptoms) was 24.4% (95% CI, 19.2%-30.3%) (n = 60/246) in the appendectomy group and 6.5% (95% CI, 3.8%-10.4%) (n = 16/246) in antibiotic group (P < .001), which calculates to 17.9 percentage points (95% CI, 11.7-24.1) higher after surgery. There was no difference between groups for length of hospital stay, but there was a significant difference in sick leave (11 days more for the appendectomy group). Conclusions and Relevance: Among patients who were initially treated with antibiotics for uncomplicated acute appendicitis, the likelihood of late recurrence within 5 years was 39.1%. This long-term follow-up supports the feasibility of antibiotic treatment alone as an alternative to surgery for uncomplicated acute appendicitis. Trial Registration: ClinicalTrials.gov Identifier: NCT01022567.

Quality of life in patients with pancreatic ductal adenocarcinoma undergoing pancreaticoduodenectomy.

INTRODUCTION: Survival for pancreatic ductal adenocarcinoma (PDAC) is relatively short even after complete resection. Pancreaticoduodenectomy (PD) carries a high risk for postoperative morbidity, and the effect on quality of life (QoL) is unclear. We aimed to study QoL in PDAC patients undergoing PD. PATIENTS AND METHODS: Sixty patients with suspected PDAC and planned PD were asked to complete EORTC QoL questionnaires QLQ-C30 and QLQ-PAN26 preoperatively and at 3-6-12-18-24 months postoperatively. RESULTS: 47 PDAC patients who underwent PD (66 (21-84) years, 53% men) were included. Follow-up was completed by 81% (6 months) and 45% (24 months) post-PD. Compared to preoperative level, QoL tended to improve or remained the same in 63% during the follow-up. At three months after PD patients had less hepatic symptoms (decreased by 100%; p < 0.001), pancreatic pain and sexuality symptoms tended to decrease by 33% and global and functional QoL tended to slightly improve. These parameters remained at the achieved level during the longer follow-up. A temporary rising tendency was seen in digestive symptoms at three months but this later reverted to the preoperative level. More altered bowel movements and sexuality symptoms tended to arise during the longer follow-up. A negative correlation was found between reported financial difficulties and length of survival. CONCLUSIONS: PD does not worsen the QoL in most of the patients with PDAC. The potentially beneficial effect on QoL is apparent already at three months after surgery. This information may be helpful for the clinician and patient, when deciding on the treatment for PDAC.