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.

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.

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.

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.

Antihypertensive drugs and pancreatic cancer risk in patients with chronic pancreatitis: a Danish nationwide population-based cohort study.

BACKGROUND: Antihypertensives may inhibit pancreatic carcinogenesis. We examined the association between use of these drugs and pancreatic cancer in patients with chronic pancreatitis. METHODS: We conducted a nationwide population-based cohort study of all chronic pancreatitis patients diagnosed in Denmark during 1996-2012. Using a Cox proportional hazards model with time-varying exposure lagged by 1 year, we examined the risk of pancreatic cancer according to antihypertensive drug use. RESULTS: We included 8,311 patients with chronic pancreatitis and observed 153 pancreatic cancers during follow-up. At baseline, 2197 patients (26.4%) were exposed to at least one class of antihypertensive drugs. We did not observe any measurable associations between the use of antihypertensive drugs and pancreatic cancer. CONCLUSIONS: Our findings suggest little evidence of an association between the use of antihypertensive drugs and pancreatic cancer risk in patients with chronic pancreatitis. Confirmation is warranted in future studies.

Perturbations of urea cycle enzymes during posthepatectomy rat liver failure.

Posthepatectomy liver failure (PHLF) may occur after extended partial hepatectomy (PH). If malignancy is widespread in the liver, the size of PH and hence the size of the future liver remnant (FLR) may limit curability. We aimed to characterize differences in protein expression between different sizes of FLRs and identify proteins specific to the regenerative process of minimal-size FLR (MSFLR), with special focus on postoperative day (POD) 1 when PHLF is present. A total of 104 male Wistar rats were subjected to 30, 70, or 90% PH (MSFLR in rats), sham operation, or no operation. Blood and liver tissue were harvested at POD1, 3, and 5 (n = 8 per group). Protein expression was assessed by proteomic profiling by unsupervised two-dimensional polyacrylamide gel electrophoresis (2D-PAGE) liquid chromatography tandem mass spectrometry (LC-MS/MS), followed by supervised selected reaction monitoring (SRM)-MS/MS. In all, 1,035 protein spots were detected, 54 of which were significantly differentially expressed between groups and identifiable. During PHLF after PH(90%) at POD1, urea cycle and related proteins showed significant perturbations, including the urea cycle flux-regulating enzyme of carbamoyl phosphate synthase-1, ornithine transcarbamylase, and arginase-1, as well as the ornithine aminotransferase and propionyl-CoA carboxylase alpha chain. Plasma-ammonia increased significantly at POD1 after PH(90%), followed by a prompt decrease. At the protein level, we found perturbations of urea cycle and related enzymes in the MSFLR during PHLF. Our results suggest that these perturbations may augment urea cycle function, which may be pivotal for increased ammonia elimination after extensive PHs and potential PHLF.NEW & NOTEWORTHY Posthepatectomy liver failure (PHLF) is associated with high mortality. In a rat model of 90% hepatectomy, PHLF is present. Our results on liver tissue proteomics suggest that the ability of the liver remnant to sufficiently eliminate ammonia may be brought about by perturbation related to urea cycle proteins and that enhancing the urea cycle capacity may play a key role in surviving PHLF.

Acute Pancreatitis and Pancreatic Cancer Risk: A Nationwide Matched-Cohort Study in Denmark.

BACKGROUND & AIMS: Acute pancreatitis may be a risk factor for pancreatic cancer; however, findings from studies on this association are conflicting. We investigated the association between acute pancreatitis and increased risk of pancreatic cancer. METHODS: We conducted a nationwide, population-based, matched cohort study of all patients admitted to a hospital in Denmark with a diagnosis of acute pancreatitis from January 1, 1980, through October 31, 2012. As many as 5 individuals from the general population without acute pancreatitis were matched for age and sex to each patient with acute pancreatitis. Pancreatic cancer risk was expressed as hazard ratios (HRs) with 95% confidence intervals (CIs), calculated using the Cox proportional hazards model. Cox models were stratified by age, sex, and year of pancreatitis diagnosis and adjusted for alcohol- and smoking-related conditions, and Charlson Comorbidity Index score. RESULTS: We included 41,669 patients diagnosed with incident acute pancreatitis and 208,340 comparison individuals. Patients with acute pancreatitis had an increased risk of pancreatic cancer compared with the age- and sex-matched general population throughout the follow-up period. The risk decreased over time but remained high after more than 5 years of follow-up (adjusted HR 2.02; 95% CI 1.57-2.61). Two- and 5-year absolute risks of pancreatic cancer among patients with acute pancreatitis were 0.70% (95% CI 0.62%-0.78%) and 0.87% (95% CI 0.78%-0.97), respectively. CONCLUSIONS: In a nationwide, population-based, matched cohort study, we observed an association between a diagnosis of acute pancreatitis and long-term risk of pancreatic cancer.

Metastasis directed therapy for liver and lung metastases from colorectal cancer-A population-based study.

About 10-20% of patients with metastatic colorectal cancer (mCRC) are candidates for metastasis directed therapies such as surgical resection, ablation and stereotactic radiotherapy. We examined the temporal changes in use of metastasis directed therapies and established prognostic factors for survival in a nationwide cohort study. The Danish nationwide medical registries were used to retrieve data on treatment for liver and/or lung metastasis in patients with metastatic colorectal cancer in the period 2000-2013. Overall survival through 2014 was calculated from the time of treatment of metastases by Kaplan-Meier method and mortality between groups was assessed using Cox regression. We report 2,912 patients undergoing a total of 3,602 procedures with an increased use of all modalities during 14 calendar years. Median survival was 3.7 years (interquartile range (IQR) 2.0-9.7 years). In the multivariate analysis, the nodal stage of the primary tumor had the most pronounced association with survival with a hazard ratio for mortality of 1.56 (95% CI: 1.33-1.83) for N2 stage with reference to N0. Furthermore, female gender, age, comorbidity, surgical treatment, administration of chemotherapy, and left-sided primary tumors were associated with improved prognosis in the multivariate analysis.

Adaptive growth changes in the liver remnant are affected by the size of hepatectomy in rats.

In this study we investigated the dynamics of hepatocyte hyperplasia and hypertrophy in rats subjected to increasing sizes of partial hepatectomy (PH). A total of 104 rats were randomized according to the size of PH. On postoperative days (PODs) 1, 3 and 5, blood was drawn and the remnant liver removed for stereological analysis. Liver parameters and regeneration rate were significantly affected by size of PH. On POD 1, hepatocyte volumes had increased significantly in all PH groups. On POD 3, all groups showed hepatocyte volumes approximating baseline. On POD 5, hepatocyte volumes were significantly lower in PH (90) than in baseline, sham and PH (30) rats. Increasing hepatocyte proliferation was not observed following PH (30). Following PH (70), cell proliferation was significantly elevated on PODs 1 and 3, and following PH (90) on PODs 3 and 5. In conclusion, general hypertrophy of hepatocytes after different size of PH was followed by hepatocyte proliferation only in the liver remnant of PH (70) and PH (90).

Chronic Pancreatitis and Pancreatic Cancer Risk: A Systematic Review and Meta-analysis.

Chronic pancreatitis is a putative risk factor for pancreatic cancer. The aim of this study was to examine the magnitude and temporality of this association. We searched MEDLINE and EMBASE for observational studies investigating the association between chronic pancreatitis and pancreatic cancer. We computed overall effect estimates (EEs) with associated 95% confidence intervals (CIs) using a random-effects meta-analytic model. The EEs were stratified by length of follow-up from chronic pancreatitis diagnosis to pancreatic cancer (lag period). Robustness of the results was examined in sensitivity analyses. We identified 13 eligible studies. Pooled EEs for pancreatic cancer in patients with chronic pancreatitis were 16.16 (95% CI: 12.59-20.73) for patients diagnosed with pancreatic cancer within 2 years from their chronic pancreatitis diagnosis. The risk of pancreatic cancer in patients with chronic pancreatitis decreased when the lag period was increased to 5 years (EE: 7.90; 95% CI: 4.26-14.66) or a minimum of 9 years (EE: 3.53; 95% CI: 1.69-7.38). In conclusion, chronic pancreatitis increases the risk of pancreatic cancer, but the association diminishes with long-term follow-up. Five years after diagnosis, chronic pancreatitis patients have a nearly eight-fold increased risk of pancreatic cancer. We suggest that common practice on inducing a 2-year lag period in these studies may not be sufficient. We also recommend a close follow-up in the first years following a diagnosis of chronic pancreatitis to avoid overlooking a pancreatic cancer.

Gene Expression in the Liver Remnant Is Significantly Affected by the Size of Partial Hepatectomy: An Experimental Rat Study.

Extended hepatectomies may result in posthepatectomy liver failure, a condition with a high mortality. The main purpose of the present study was to investigate and compare the gene expression profiles in rats subjected to increasing size of partial hepatectomy (PH). Thirty Wistar rats were subjected to 30%, 70%, or 90% PH, sham operation, or no operation. Twenty-four hours following resection, liver tissue was harvested and genome-wide expression analysis was performed. Cluster analysis revealed two main groupings, one containing the PH(90%) and one containing the remaining groups [baseline, sham, PH(30%), and PH(70%)]. Categorization of specific affected molecular pathways in the PH(90%) group revealed a downregulation of cellular homeostatic function degradation and biosynthesis, whereas proliferation, cell growth, and cellular stress and injury were upregulated in the PH(90%) group. After PH(90%), the main upregulated pathways were mTOR and ILK. The main activated upstream regulators were hepatocyte growth factor and transforming growth factor. With decreasing size of the future liver remnant, the liver tended to prioritize expression of genes involved in cell proliferation and differentiation at the expense of genes involved in metabolism and body homeostasis. This prioritizing may be an essential molecular explanation for posthepatectomy liver failure.

Long-term outcome of peroral endoscopic myotomy for esophageal achalasia in patients with previous Heller myotomy.

BACKGROUND: Peroral endoscopic myotomy (POEM) is an emerging procedure in the treatment of esophageal achalasia, a primary motility disorder. However, the long-term outcome of POEM in patients, who have previously undergone a Heller myotomy, is unknown. METHODS: Using a local database, we identified patients with esophageal achalasia, who underwent POEM. We compared patients with a previous Heller myotomy to those, who had received none or only non-surgical therapy prior to the POEM procedure. We conducted follow-up examinations at 3, 12, and 24 months following the procedure. RESULTS: We included 66 consecutive patients undergoing POEM for achalasia, of which 14 (21.2 %) had undergone a prior Heller myotomy. In both groups, the preoperative Eckardt score was 7. Postoperatively, the non-Heller group experienced a more pronounced symptom relief at both 3-, 12-, and 24-month follow-up compared with the Heller group, and there was a tendency for the effect of POEM to reduce over time. We suggest that there is a correlation between preoperative measurements of gastroesophageal sphincter pressures and the chance of a successful POEM. CONCLUSIONS: POEM has a place in the treatment of esophageal achalasia in patients with a prior Heller myotomy and persistent symptoms as it is a safe procedure with acceptable long-term results.

Liver regeneration is dependent on the extent of hepatectomy.

BACKGROUND: The upper limit for the size of hepatectomy is approximately 90% in rats. The aim of the study was to assess quantitatively using stereological methods the impact on liver function, regeneration rate (RR), and hepatocyte proliferation of varying hepatectomy size in a rat model. MATERIALS AND METHODS: A total of 104 male Wistar rats were subjected to 30%, 70%, or 90% partial hepatectomy, sham operation, or no operation. Euthanization and harvesting of liver tissue and blood took place at postoperative days 1, 3, and 5 (n = 8 per group). Liver-specific biochemistry and RR were evaluated. Hepatocyte proliferation was estimated by immunohistochemical staining for Ki-67 antigen using unbiased stereological principles. RESULTS: Liver RR in the 90% group increased by a 6.6 fold during the 5 postoperative days compared with only a minor increase in both the 70% and 30% partial hepatectomy groups. The highest number of Ki-67-positive hepatocytes was observed in the 70% group at postoperative day 1 and for the 90% group at postoperative day 3. Prothrombin-proconvertin ratio was significantly lower in the 90% group 1 d after surgery compared with all other groups, however, nearly normalized at postoperative day 5. CONCLUSIONS: We show that liver RR and the number of proliferating hepatocytes increase, whereas the initial hepatic synthetic capacity decreases with increasing hepatectomy size.

Postoperative but not preoperative treatment with sorafenib inhibits liver regeneration in rats.

BACKGROUND: Sorafenib, a multikinase inhibitor, has been shown to halt the growth of hepatocellular carcinoma. The aim of the present study was to investigate the effect of Sorafenib on liver regeneration in healthy rats. METHODS: In two substudies we examined the effect of pre- or post-operative treatment with Sorafenib (15 mg/kg/d). Wistar rats (n = 120) received either Sorafenib (S) or placebo (P). After 70% partial hepatectomy, the rats were euthanized on postoperative days 2, 4, or 8. Body weight and liver weight were recorded and regeneration rate (RR) calculated. Hepatocyte proliferation was estimated by immunohistochemistry for Ki-67 antigen using unbiased stereological methods. RESULTS: Eleven animals (9%) died after surgery. In the preoperative substudy, lower body weight gains during the gavage period in the S group were found. No difference between groups S and P regarding liver weight gain, liver RRs, and hepatocyte proliferation on postoperative days 2 and 4 were found. In the postoperative substudy, significantly lower values of liver weight gain, liver RRs, and hepatocyte proliferation were found in the S group. CONCLUSIONS: In our rat model, Sorafenib did not increase posthepatectomy mortality. Postoperative treatment significantly impaired liver regeneration. Preoperative treatment impaired body weight during the gavage period, but was without effect on liver regeneration.

Peroral endoscopic myotomy (POEM) for nutcracker esophagus. Three cases with 12 months follow-up.

INTRODUCTION: Peroral endoscopic myotomy (POEM) has been introduced as a new treatment of achalasia, and studies are emerging on POEM treatment of other esophageal motility disorders. The effects of medical treatment, botox injections and dilatations are often limited in patients with severe nutcracker esophagus (NE). We therefore decided to perform POEM in three patients with severe NE. MATERIAL AND METHODS: Informed consent was provided. POEM was performed under general anesthesia on the distal esophagus and upper stomach. At 3 months, 6 months and 1 year postoperatively all patients had clinical follow-up, barium swallow and high-resolution manometry. RESULTS: All patients displayed marked improvement with a significant reduction in Eckardt score at follow-up after 1 year, from 10, 10 and 11 to 3, 1 and 1, respectively. During follow-up, the patients were diagnosed with increased reflux index and one patient was diagnosed with gastroparesis. CONCLUSION: Considering our results, treating severe NE with POEM has to be considered in the future; however, further studies have to confirm this.

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

BACKGROUND: 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 health-care 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 were 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 1744 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% confidence interval [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.