Effect of surgery versus chemotherapy in pancreatic cancer patients: a target trial emulation.

PURPOSE: To estimate the causal effect of surgery vs chemotherapy on survival in patients with T1-3NxM0 pancreatic cancer in a rigorous framework addressing selection bias and immortal time bias. METHODS: We used population-based Danish healthcare registries to conduct a cohort study emulating a hypothetical randomized trial to estimate the absolute difference in survival, comparing surgery with chemotherapy. We included pancreatic cancer patients diagnosed during 2008-2021. Exposure was surgery or chemotherapy initiated within a 16-week grace period after diagnosis. At the time of diagnosis, data of each patient was duplicated; one copy was assigned to the surgery protocol and one copy to the chemotherapy protocol of the hypothetical trial. Copies were censored when the assigned treatment deviated from the observed treatment. To account for informative censoring, uncensored patients were weighted according to confounders. For comparison, we also applied a more conventional analysis using propensity score-based inverse probability weighting. RESULTS: We included 1,744 patients with a median age of 68 years; 73.6% underwent surgery and 18.6% had chemotherapy without surgery. 7.8% received no treatment. The 3-year survival was 39.7% (95% CI 36.7% to 42.6%) after surgery and 22.7% (95% CI: 17.7% to 28.4%) after chemotherapy, corresponding to an absolute difference of 17.0% (95% CI: 10.8% to 23.1%). In the conventional survival analysis, this difference was 23.0% (95% CI: 17.0% to 29.0%). CONCLUSION: Surgery was superior to chemotherapy in achieving long-term survival for pancreatic cancer. The difference comparing surgery and chemotherapy was substantially smaller when using the clone-censor-weight approach than conventional survival analysis.

Beta-blocker use and survival after pancreatic cancer surgery: A nationwide population-based cohort study.

PURPOSE: We examined the association between use of beta-blockers and survival in pancreatic cancer patients after curative-intent surgery. METHODS: Using Danish healthcare registries, we conducted a population-based cohort study of all patients undergoing curative-intent surgery for pancreatic cancer in Denmark 1997-2021. We defined beta-blocker use according to exposure before surgery as current (≤90 days), recent (91-365 days), or former (366-730 days) use, requiring at least one filled prescription. Patients were followed from the date of surgery for up to 5 years. We used Cox regression to compute hazard ratios (HRs) of deaths with 95% confidence intervals (CIs), adjusting for age, sex, year of diagnosis, cardiovascular disease, diabetes, liver disease, alcohol, and smoking. We also conducted an active comparator analysis, where we used angiotensin-converting enzyme inhibitors/angiotensin-receptor blockers as comparators instead of nonusers. RESULTS: We included 2592 patients, of which 16.7% were beta-blocker users. Median survival for the entire population was 24.4 months. Beta-blocker use was associated with increased mortality (adjusted HR: 1.18; 95% CI: 1.04-1.34). This was evident in current (adjusted HR: 1.19; 95% CI: 1.02-1.38) and recent (adjusted HR: 1.29; 95% CI: 1.04-1.59) but not former (adjusted HR: 0.91; 95% CI: 0.64-1.43) users. In the active comparator analysis, the association between beta-blocker exposure and mortality attenuated slightly (adjusted HR: 1.12; 95% CI: 0.93-1.35). CONCLUSIONS: We observed an association between beta-blocker use and increased mortality in patients operated for pancreatic cancer. Findings are likely explained by confounding by indication.

Real-Time Identification of Pancreatic Cancer Cases Using Artificial Intelligence Developed on Danish Nationwide Registry Data.

PURPOSE: Pancreatic cancer is expected to be the second leading cause of cancer-related deaths worldwide within few years. Most patients are not diagnosed in time for curative-intent treatment. Accelerating the time of diagnosis is a key component of reducing pancreatic cancer mortality. We developed and tested a dynamic algorithm aiming at proactively identifying patients with a substantially elevated risk of having undiagnosed pancreatic cancer. METHODS: Machine learning methodology was applied to a live stream of nationwide Danish registry data. A hybrid case-control and prospective cohort design relying on incidence density sampling was used. Three models with minimal tuning were tested. All performance evaluation metrics were based on out-of-sample, out-of-time data in a monthly walk-forward strategy to avoid any temporal biases or inflation of performance metrics. Outcome was a diagnosis of pancreatic cancer. RESULTS: Subgroups identified had a 10.1% risk of being diagnosed with pancreatic cancer within 1 year, corresponding to a number needed to screen of 9.9. When considering competing, potentially computed tomography-detectable GI cancers, this number is reduced to 5.7. The time of diagnosis can be accelerated by up to 142 days. CONCLUSION: Currently available nationwide live data and computational resources are sufficient for real-time identification of individuals with at least 10.1% risk of having undiagnosed pancreatic cancer and 17.7% risk of any GI cancer in the Danish population. For prospective identification of high-risk patients, the area under the curve is not a useful indication of the positive predictive values achieved. Viable design solutions are demonstrated, which address the main shortfalls of the existing cancer prediction efforts in relation to temporal biases, leaks, and performance metric inflation. Efficacy evaluations with resection rates and mortality as end points are needed.

Impact of prior cancer diagnosis on pancreatic cancer outcomes: A Danish Nationwide, population-based Cohort study.

BACKGROUND: The overall survival of pancreatic cancer (PC) remains low, underlining the need of further research to improve PC directed therapy. Some patients with PC may have experienced a prior cancer, refraining them from inclusion in clinical trials, despite not knowing the precise effect of a prior cancer on disease course of PC. OBJECTIVE: To examine the influence of prior cancer on the disease course in patients with PC. METHODS: We conducted a cohort study including Danish patients diagnosed with PC between 2004 and 2020 crosslinking data from the Danish Cancer Registry, the Danish National Patient Registry among several other databases. Using the Kaplan-Meier estimator, we calculated the overall and American Joint Committee on Cancer (AJCC) disease stage stratified survival, comparing patients with and without prior cancer. Furthermore, using inverse probability of treatment weighting (IPTW), we presented a covariate-adjusted model of the average treatment effect in the treated (ATT) of prior cancer on the overall PC survival and stratified for AJCC disease stage. RESULTS: We included 11,147 patients diagnosed with PC, of which 906 (8.1%) had a prior cancer. Comparing patients with and without prior cancer, the IPTW-adjusted survival, indicated a slightly better survival (ATT: 1.5 months; 95% CI: 0.7; 2.2 months). After stratifying by PC tumor stage, the difference was restricted to patients with stage IV PC disease (ATT: 1.1 months; 95% CI: 0.5; 1.7 months). Patients with prior cancer were slightly less prone to present with stage IV PC disease and were more likely to not receive active treatment compared with patients without prior cancer. CONCLUSION: Prior cancer was associated with a slightly better survival in patients with PC, but only in patients with stage IV PC disease. This is likely explained by lead time bias.

Biochemical and morphological responses to post-hepatectomy liver failure in rats.

The upper limit for partial hepatectomy (PH) in rats is 90%, which is associated with an increased risk of post-hepatectomy liver failure (PHLF), correlating with high mortality. Sixty-eight rats were randomized to 90% PH, sham operation, or no surgery. Further block randomization was performed to determine the time of euthanasia, whether 12, 24, or 48 h after surgery. A general distress score (GDS) was calculated to distinguish between rats with reversible (GDS < 10) and irreversible PHLF (GDS ≥ 10). At euthanasia, the liver remnant and blood were collected. Liver-specific biochemistry and regeneration ratio were measured. Hepatocyte proliferation and volume were estimated using stereological methods. All rats subjected to 90% experienced biochemical PHLF. The biochemical and morphological liver responses did not differ between the groups until 48 h after surgery. At 48 h, liver regeneration and function were significantly improved in survivors. The peak mean regeneration ratio was 15% for rats with irreversible PHLF compared to 26% for rats with reversible PHLF. The 90% PH rat model was associated with PHLF and high mortality. Irreversible PHLF was characterized by impaired liver regeneration capacity and an insufficient ability to metabolize ammonia.

Clinical implications of multidisciplinary team pancreatic cyst evaluation.

INTRODUCTION: The detection of incidental pancreatic cysts (PCs) is increasing due to frequent use of imaging. The aim of the present study was to evaluate the clinical consequences of regular multidisciplinary team (MDT) conferences for patients with PCs. METHODS: All patient data were obtained by review of patient medical records. PCs were assessed at the weekly MDT in accordance with the revised Fukuoka guidelines. RESULTS: A total of 455 patients were evaluated within 12 months. A large proportion of the cysts could not be characterised and was handled as branch duct (BD)-intraductal papillary mucinous neoplasia (IPMN). A total of 245 patients were included in a follow-up programme, whereas 175 patients were excluded. Further diagnostic work-up was recommended for 31 patients. A total of 66 patients were reviewed on MDT a second time during the study period, eight of whom received a diagnosis different from that given at the first MDT. A total of 35 patients with mucinous PC or cysts treated as BD-IPMN had either worrisome features (WF) or high-risk stigmata (HRS), four of these patients had a PC ≤ 10 mm. Indication for surgery was WF or HRS and, in the course of 12 months, six patients were recommended surgery taking their PS into account. Two patients had a malignant and two had a premalignant lesion. CONCLUSION: In all, 455 patients were evaluated to find 35 patients with suspected premalignant PCs. This means that almost 8% of the referred patients had suspicious lesions, which indicates a need for a regular MDT conference. FUNDING: None. TRIAL REGISTRATION: Not relevant.

Validation of a surgical model for posthepatectomy liver failure in rats.

BACKGROUND: The upper limit for liver resections in rats is approximately 90%. In the early postoperative phase, mortality increases. The aim of the present study was to validate the rat model of 90% partial hepatectomy (PH) as a model of post-hepatectomy liver failure (PHLF). Further, we wanted to test a quantitative scoring system as a detector of lethal outcomes caused by PHLF in rats. METHODS: Sixty-eight rats were randomized to 90% PH, sham operation, or no surgery. Further, block randomization was performed based on time of euthanization: 12, 24, or 48 h after surgery. A general distress score (GDS) ≥10 during the day or ≥6 at midnight prompted early euthanization and classification as nonsurvivor. Animals euthanized as planned were classified as survivors. During euthanization, blood and liver tissue were collected, and liver-specific biochemistry was evaluated. RESULTS: Based on the biochemical results, all animals subjected to 90% PH experienced PHLF. Seventeen rats were euthanized due to irreversible PHLF. The GDS increased for nonsurvivors within 12-18 h after surgery. The mean time for euthanization was 27 h after surgery. CONCLUSION: Based on the GDS and liver-specific biochemistry, we concluded that the model of 90% PH seems to be a proper model for investigating PHLF in rats. As a high GDS is associated with increased mortality, the GDS appears to be valuable in detecting lethal outcomes caused by PHLF in rats.

N-(4-[18F]fluorobenzyl)cholylglycine, a potential tracer for positron emission tomography of enterohepatic circulation and drug-induced inhibition of ileal bile acid transport. A proof-of-concept PET/CT study in pigs.

INTRODUCTION: Enterohepatic circulation (EHC) of conjugated bile acids is an important physiological process crucial for bile acids to function as detergents and signal carriers. Perturbation of the EHC by disease or drugs may lead to serious and life-threatening liver and gastrointestinal disorders. In this proof-of-concept study in pigs, we investigate the potential of N-(4-[18F]fluorobenzyl)cholylglycine ([18F]FBCGly) as tracer for quantitative positron emission tomography (PET) of the EHC of conjugated bile acids. METHODS: The biodistribution of [18F]FBCGly was investigated by PET/CT in domestic pigs following intravenous and intraileal administration of the tracer. Hepatic kinetics were estimated from PET and blood data using a 2-tissue compartmental model and dual-input of [18F]FBCGly. The ileal uptake of [18F]FBCGly was investigated with co-injection of nifedipine and endogenous cholyltaurine. Dosimetry was estimated from the PET data using the Olinda 2.0 software. Blood, bile and urine samples were analyzed for possible fluorine-18 labelled metabolites of [18F]FBCGly. RESULTS: [18F]FBCGly was rapidly taken up by the liver and excreted into bile, and underwent EHC without being metabolized. Both nifedipine and endogenous cholyltaurine inhibited the ileal uptake of [18F]FBCGly. The flow-dependent hepatic uptake clearance was estimated to median 1.2 mL blood/min/mL liver tissue. The mean residence time of [18F]FBCGly in hepatocytes was 4.0 ± 1.1 min. Critical organs for [18F]FBCGly were the gallbladder wall (0.94 mGy/MBq) and the small intestine (0.50 mGy/MBq). The effective dose for [18F]FBCGly was 36 µSv/MBq. CONCLUSION: We have shown that [18F]FBCGly undergoes EHC in pigs without being metabolized and that its ileal uptake is inhibited by nifedipine and endogenous bile acids. Combined with our previous findings in rats, we believe that [18F]FBCGly has potential as PET tracer for assessment of EHC of conjugated bile acids under physiological conditions as well as conditions with perturbed hepatic and ileal bile acid transport.

Trends in pancreatic cancer incidence, characteristics, and outcomes in Denmark 1980-2019: A nationwide cohort study.

OBJECTIVE: To describe time-trends in incidence, characteristics, treatments, and survival in pancreatic cancer patients in Denmark during 1980-2019. DESIGN: A nationwide population-based cohort study of all Danish patients diagnosed with exocrine pancreatic cancer during the study period. Data was obtained from individual-level cross linkage between Danish healthcare registries. We present descriptive characteristics and survival estimates, which was obtained using the Kaplan-Meier estimator and Cox proportional hazards regression models. RESULTS: During the study period, 32,107 patients were diagnosed with pancreatic cancer. In the most recent period, the age-standardized incidence rate was 17.7 per 100,000 person-years. Throughout the study period, between 18.4% and 27.5% of patients had no tumor staging performed, and approximately half of the patient were only offered best supportive care. The proportion of patients treated with surgery doubled during the study period, and the use of adjuvant and neoadjuvant oncological therapy increased substantially. Median survival after surgical resection also increased to 25.8 months in the most recent time period. CONCLUSION: Pancreatic cancer incidence is increasing in Denmark, and this increase is projected to continue. The proportion of patients offered curative-intent treatment increased, which translates into an increase in overall survival. All numbers are comparable to best international standards.

Circulating tumor DNA for prognosis assessment and postoperative management after curative-intent resection of colorectal liver metastases.

The recurrence rate of colorectal liver metastases (CRLM) patients treated with curative intent is above 50%. Standard of care surveillance includes intensive computed tomographic (CT) imaging as well as carcinoembryonic antigen (CEA) measurements. Nonetheless, relapse detection often happens too late to resume curative treatment. This longitudinal cohort study enrolled 115 patients with plasma samples (N = 439) prospectively collected before surgery, postoperatively at day 30 and every third month for up to 3 years. Droplet digital PCR (ddPCR) was used to monitor serial plasma samples for somatic mutations. Assessment of ctDNA status either immediately after surgery, or serially during surveillance, stratified the patients into groups of high and low recurrence risk (hazard ratio [HR], 7.6; 95% CI, 3.0-19.7; P < .0001; and HR, 4.3; 95% CI, 2.3-8.1; P < .0001, respectively). The positive predictive value (PPV) of ctDNA was 100% in all postoperative analyses. In multivariable analyses, postoperative ctDNA status was the only consistently significant risk marker associated with relapse (P < .0001). Indeterminate CT findings were observed for 30.8% (21/68) of patients. All patients (9/21) that were ctDNA positive at the time of the indeterminate CT scan later relapsed, contrasting 42.6% (5/12) of those ctDNA negative (P = .0046). Recurrence diagnoses in patients with indeterminate CT findings were delayed (median 2.8 months, P < .0001). ctDNA status is strongly associated with detection of minimal residual disease and early detection of relapse. Furthermore, ctDNA status can potentially contribute to clinical decision-making in case of indeterminate CT findings, reducing time-to-intervention.

Disparity in use of modern combination chemotherapy associated with facility type influences survival of 2655 patients with advanced pancreatic cancer.

AIM: Academic and high volume hospitals have better outcome for pancreatic cancer (PC) surgery, but there are no reports on oncological treatment. We aimed to determine the influence of facility types on overall survival (OS) after treatment with chemotherapy for inoperable PC. MATERIAL AND METHODS: 2,657 patients were treated in Denmark from 2012 to 2018 and registered in the Danish Pancreatic Cancer Database. Facilities were classified as either secondary oncological units or comprehensive, tertiary referral cancer centers. RESULTS: The average yearly number of patients seen at the four tertiary facilities was 71, and 31 at the four secondary facilities. Patients at secondary facilities were older, more frequently had severe comorbidity and lived in non-urban municipalities. As compared to combination chemotherapy, monotherapy with gemcitabine was used more often (59%) in secondary facilities than in tertiary (34%). The unadjusted median OS was 7.7 months at tertiary and 6.1 months at secondary facilities. The adjusted hazard ratio (HR) of 1.16 (confidence interval 1.07-1.27) demonstrated an excess risk of death for patients treated at secondary facilities, which disappeared when taking type of chemotherapy used into account. Hence, more use of combination chemotherapy was associated with the observed improved OS of patients treated at tertiary facilities. Declining HR's per year of first treatment indicated improved outcomes with time, however the difference among facility types remained significant. DISCUSSION: Equal access to modern combination chemotherapy at all facilities on a national level is essential to ensure equality in treatment results.

Surgical treatment of symptomatic simple liver cysts.

INTRODUCTION: Simple hepatic cyst (SHC) can cause symptoms due to compression of the surrounding structures. The aim of the present study was to evaluate symptoms, treatment, recurrence rate and post-operative complications of patients treated for symptomatic SHC. METHODS: Patients were identified from medical records. The inclusion criteria were symptomatic SHC, treatment with percutaneous aspiration or laparoscopic deroofing or both. Age, gender, symptoms, type of treatment, post-operative complications, recurrence of symptomatic liver cyst and time of symptomatic relief were recorded. RESULTS: A total of 66 patients were included. The most common symptom was abdominal discomfort and/or pain, which was reported in 88%. Nine patients received two, one received three and one received four cyst aspirations before further treatment or no recurrence of symptoms. A total of 84.7% had recurrence of symptoms after aspiration. Forty patients were treated with laparoscopic deroofing, 37 (92.5%) had relief of symptoms. Complications reported after cyst drainage was prolonged drainage (n = 1), dyspnoea (n = 1), bleeding (n = 2) and peritonitis (n = 2). After laparoscopic deroofing, the only post-operative complication was wound infection (n = 2). CONCLUSIONS: The present study showed that percutaneous aspiration of symptomatic SHC should be performed to ensure that the symptoms are related to the cyst. Laparoscopic deroofing has proven a definitive treatment for simple SHC and is associated with a low recurrence rate and few post-operative complications. FUNDING: none. TRIAL REGISTRATION: not relevant.

Aspirin as secondary prevention in colorectal cancer liver metastasis (ASAC trial): study protocol for a multicentre randomized placebo-controlled trial.

BACKGROUND: Colorectal cancer is one the most common cancers in the western world with increasing incidence. Approximately 50% of the patients develop liver metastases. Resection of liver metastases is the treatment of choice although almost half of the resected patients get recurrence in the liver. METHODS: The ASAC trial is a Scandinavian, multicentre, double-blinded, randomized, placebo-controlled study to determine whether adjuvant treatment with low-dose aspirin (acetylsalicylic acid (ASA)) can improve disease-free survival in patients treated for colorectal cancer liver metastases (CRCLM). Up to 800 patients operated for CRCLM will be randomized to Arm#1 ASA 160 mg once daily or Arm#2 Placebo, for a period of 3 years or until disease recurrence. The patients will be recruited at all major hepatobiliary surgical units in Norway, Sweden and Denmark and have follow-up according to standard of care and the National Guidelines. DISCUSSION: The ASAC trial will be the first clinical interventional trial to assess the potential beneficial role of ASA in recurrence of CRCLM and survival. ASA is an inexpensive, well-tolerated and easily accessible drug that will be highly potential as adjuvant drug in secondary prevention of CRCLM if the study shows a beneficial effect. We will also determine the effect of ASA as adjuvant treatment on Health-Related Quality of Life and the cost-effectiveness. TRIAL REGISTRATION: ClinicalTrials.gov NCT03326791 . Registered on 31 October 2017.

Splenectomy and risk of COVID-19 infection, hospitalisation, and death.

OBJECTIVES: Splenectomy is a common surgical procedure, and splenectomized patients have shown to be severely more affected by certain infections than patients with a preserved splenic function. We investigated the risk of COVID-19 infection and subsequent hospitalisation and death in splenectomized patients. METHODS: We conducted a case-control study of all individuals with a microbiologically verified COVID-19 infection in Denmark through December 31, 2020. To each case, we matched three controls on age, sex, and region of residence. We examined the association between previous splenectomy and the risk of COVID-19 infection, hospitalisation, and death using a logistic regression model. RESULTS: We identified 165,623 individuals with a positive COVID-19 test and 493,300 matched controls. Mean age was 38 years. 130 and 422 splenectomies were performed in the COVID-19 positive individuals and controls, respectively. Splenectomized patients did not have a higher risk of COVID-19 infection than non-splenectomized patients (adjusted OR: 0.89; 95% CI: 0.73-1.08). Among COVID-19 positive individuals, splenectomized patients may have an increased risk of hospitalisation or death (adjusted OR for combined endpoint: 1.44; 95% CI: 0.79-2.61). CONCLUSIONS: Splenectomized patients are not at an increased risk of COVID-19 infection, but they may have a higher risk of hospitalisation or death among COVID-19 positive individuals. This may be attributed to higher comorbidity levels.

Hepatic blood flow in adult Göttingen minipigs and pre-pubertal Danish Landrace x Yorkshire pigs.

The liver receives dual blood supply from the hepatic artery and portal vein. The pig is often used as an animal model in positron emission tomography (PET) and pharmacokinetic studies because of the possibility for extensive and direct blood sampling. In this study, we compared measurements of hepatic blood flow in 10 female adult Göttingen minipigs and 10 female pre-pubertal Danish Landrace x Yorkshire (DLY) pigs. Ultrasound transit time flow meter probes were placed around the hepatic artery and portal vein through open surgery, hepatic blood flow measurements were performed, and the liver was weighed. Total hepatic blood flow was on average 363 ± 131 mL blood/min in Göttingen minipigs and 988 ± 180 mL blood/min in DLY pigs (p < 0.001). The mean hepatic blood perfusion was 623 mL blood/min/mL liver tissue and 950 mL blood/min/mL liver tissue (p = 0.005), and the liver weight was 0.58 kg and 1.04 kg, respectively. The mean arterial flow fraction in Göttingen minipigs was 12 ± 7% and lower than in DLY pigs, where it was 24 ± 7% (p = 0.001). Using the gold standard for blood flow measurements, we found that both total hepatic blood flow and blood perfusion were significantly lower in Göttingen minipigs than in DLY pigs. The hepatic blood perfusion and arterial flow fraction in DLY pigs were comparable to normative values from humans. Differences in hepatic blood flow between adult Göttingen minipigs and humans should be considered when performing physiological liver studies in this model.

Low Interleukin-22 Binding Protein Is Associated With High Mortality in Alcoholic Hepatitis and Modulates Interleukin-22 Receptor Expression.

INTRODUCTION: In alcoholic hepatitis (AH), high interleukin (IL)-22 production is associated with disease improvement, purportedly through enhanced infection resistance and liver regeneration. IL-22 binding protein (BP) binds and antagonizes IL-22 bioactivity, but data on IL-22BP in liver disease suggest a complex interplay. Despite the scarcity of human data, IL-22 is in clinical trial as treatment of AH. We, therefore, in patients with AH, described the IL-22 system focusing on IL-22BP and associations with disease course, and mechanistically pursued the human associations in vitro. METHODS: We prospectively studied 41 consecutive patients with AH at diagnosis, days 7 and 90, and followed them for up to 1 year. We measured IL-22 pathway proteins in liver biopsies and blood and investigated IL-22BP effects on IL-22 in hepatocyte cultures. RESULTS: IL-22BP was produced in the gut and was identifiable in the patients with AH' livers. Plasma IL-22BP was only 50% of controls and the IL-22/IL-22BP ratio thus elevated. Consistently, IL-22-inducible genes were upregulated in AH livers at diagnosis. Low plasma IL-22BP was closely associated with high 1-year mortality. In vitro, IL-22 stimulation reduced IL-22 receptor (R) expression, but coincubation with IL-22BP sustained IL-22R expression. In the AH livers, IL-22R mRNA expression was similar to healthy livers, although IL-22R liver protein was higher at diagnosis. DISCUSSION: Plasma IL-22BP was associated with an adverse disease course, possibly because its low level reduces IL-22R expression so that IL-22 bioactivity was reduced. This suggests the IL-BP interplay to be central in AH pathogenesis, and in future treatment trials (see Visual abstract, Supplementary Digital Content 5, http://links.lww.com/CTG/A338).

Acute pancreatitis: 31-Year trends in incidence and mortality - A Danish population-based cohort study.

BACKGROUND: Objectives: Increasing incidence rates and declining mortality rates have made acute pancreatitis a common cause of hospitalization. We aimed to examine 31-year trends in first-time hospitalization for acute pancreatitis, the subsequent short-term and long-term mortality, and the prognostic impacts of age, sex, and comorbidity. METHODS: In this nationwide Danish population-based cohort study of 47,711 incident cases, we computed the annual sex-specific age-standardized incidence rates of acute pancreatitis for 1988-2018. Among patients with incident hospitalization for acute pancreatitis, we computed sex-specific 30-day and 31-365-day mortality rates, stratified them, and performed proportional-hazards regression to estimate mortality rate ratios adjusted for sex, age, and comorbidity, measured by Charlson Comorbidity Index categories. RESULTS: From 1988 to 2018, the standardized incidence rate of acute pancreatitis per 100,000 person-years increased by 29% for men (28.8-37.0%) and by 148% for women (15.7-38.9%). Among patients with pancreatitis, the 30-day mortality declined from 10.0% in those diagnosed in 1988-1992 to 6.3% for those diagnosed in 2013-2017. The corresponding 31-365 day mortality increased from 5.5% to 6.0%. In comparing periods 1988-1992 and 2013-17, the adjusted 30-day mortality rate ratio was 0.36 (95% confidence interval: 0.32-0.41) and the adjusted 31-365 day mortality rate ratio was 0.64 (95% confidence interval: 0.56-0.74). Comorbidity was a strong predictor of mortality among patients with pancreatitis. CONCLUSIONS: Over the 31 years of observations, annual rates of acute pancreatitis more than doubled among women, converging with those among men. The comorbidity burden was a strong prognostic factor for short and long-term mortality. Treatments for acute pancreatitis should focus on existing comorbidities.

Hepatic regeneration following radiation-induced liver injury is associated with increased hepatobiliary secretion measured by PET in Göttingen minipigs.

Normal liver tissue is highly vulnerable towards irradiation, which remains a challenge in radiotherapy of hepatic tumours. Here, we examined the effects of radiation-induced liver injury on two specific liver functions and hepatocellular regeneration in a minipig model. Five Göttingen minipigs were exposed to whole-liver stereotactic body radiation therapy (SBRT) in one fraction (14 Gy) and examined 4-5 weeks after; five pigs were used as controls. All pigs underwent in vivo positron emission tomography (PET) studies of the liver using the conjugated bile acid tracer [N-methyl-11C]cholylsarcosine ([11C]CSar) and the galactose-analogue tracer [18F]fluoro-2-deoxy-D-galactose ([18F]FDGal). Liver tissue samples were evaluated histopathologically and by immunohistochemical assessment of hepatocellular mitosis, proliferation and apoptosis. Compared with controls, both the rate constant for secretion of [11C]CSar from hepatocytes into intrahepatic bile ducts as well as back into blood were doubled in irradiated pigs, which resulted in reduced residence time of [11C]CSar inside the hepatocytes. Also, the hepatic systemic clearance of [18F]FDGal in irradiated pigs was slightly increased, and hepatocellular regeneration was increased by a threefold. In conclusion, parenchymal injury and increased regeneration after whole-liver irradiation was associated with enhanced hepatobiliary secretion of bile acids. Whole-liver SBRT in minipigs ultimately represents a potential large animal model of radiation-induced liver injury and for testing of normal tissue protection methods.

Statins and pancreatic cancer risk in patients with chronic pancreatitis: A Danish nationwide population-based cohort study.

Statins (HMG-CoA reductase inhibitors) have antiinflammatory and possibly anticancer properties. We hypothesized that statin use is associated with lower risk of pancreatic cancer in patients with chronic pancreatitis. This nationwide population-based cohort study included all Danish patients diagnosed with incident chronic pancreatitis from 1 January 1996 to 31 December 2012. We used the Danish National Prescription Registry to ascertain information on statin prescriptions for members of the study population before and after their pancreatitis diagnosis. We computed crude incidence rates, incidence rate ratios (IRRs) and adjusted hazard ratios (HRs) with associated 95% confidence intervals (CIs) for pancreatic cancer, comparing statin users with nonusers. We computed HRs using Cox proportional hazards regression with statins treated as a time-varying exposure lagged by 1 year, adjusting for age, sex, socioeconomic status and individual comorbidities. The study included 8,311 chronic pancreatitis patients with a median age of 54 years. We observed 153 pancreatic cancers during 60,365 person-years of follow-up. The unadjusted IRR comparing statin users with nonusers was 1.00 (95% CI: 0.60-1.60). Adjustment for potential confounders only had a small impact on the estimate (adjusted HR: 0.90; 95% CI: 0.56-1.44). Our findings suggest that statin use is not associated with pancreatic cancer risk in patients with chronic pancreatitis.