Practice patterns in diagnostics, staging, and management strategies of gallbladder cancer among Nordic tertiary centers.

BACKGROUND AND OBJECTIVE: Gallbladder cancer (GBC) is a rare malignancy in the Nordic countries and no common Nordic treatment guidelines exist. This study aimed to characterize the current diagnostic and treatment strategies in the Nordic countries and disclose differences in these strategies. METHODS: This was a survey study with a cross-sectional questionnaire of all 19 university hospitals providing curative-intent surgery for GBC in Sweden, Norway, Denmark, and Finland. RESULTS: In all Nordic countries except Sweden, neoadjuvant/downstaging chemotherapy was used in GBC patients. In T1b and T2, majority of the centers (15-18/19) performed extended cholecystectomy. In T3, majority of the centers (13/19) performed cholecystectomy with resection of segments 4b and 5. In T4, majority of the centers (12-14/19) chose palliative/oncological care. The centers in Sweden extended lymphadenectomy beyond the hepatoduodenal ligament, whereas all other Nordic centers usually limited lymphadenectomy to the hepatoduodenal ligament. All Nordic centers except those in Norway used adjuvant chemotherapy routinely for GBC. There were no major differences between the Nordic centers in diagnostics and follow-up. CONCLUSIONS: The surgical and oncological treatment strategies of GBC vary considerably between the Nordic centers and countries.

Tumour-agnostic circulating tumour DNA analysis for improved recurrence surveillance after resection of colorectal liver metastases: A prospective cohort study.

PURPOSE: Nearly 50% of patients recur within two years after curatively intended resection of colorectal cancer liver metastasis (CRLM). The optimal surveillance strategy is unknown due to the lack of evidence. Here, we explored the potential for improving postoperative CRLM surveillance by performing serial circulating tumour DNA (ctDNA) assessments parallel to standard-of-care surveillance. EXPERIMENTAL DESIGN: 499 prospectively collected serial plasma samples from 96 patients undergoing CRLM resection were analysed using the tumour-agnostic methylation multiplex droplet-digital PCR test 'TriMeth'. RESULTS: Patients with ctDNA postoperatively or post adjuvant chemotherapy experienced a significant lower recurrence-free survival than patients without ctDNA (hazard ratio (HR) 4.5; P < 0.0001 and HR 8.4, P < 0.0001). ctDNA status was a stronger predictor of recurrence than standard clinical risk factors and carcinoembryonic antigen. Serial TriMeth analysis detected ctDNA before radiological recurrence in 55.6% of ctDNA-positive patients, with up to 10.6 months lead-time (median 3.1 months). During surveillance, 24% of patients had inconclusive CT scans, which was associated with a significant delay in recurrence diagnosis (median 3.5 months versus 1.0 month, P < 0.0001). Uniquely, ctDNA status at the time of inconclusive CT scans predicted recurrence with positive and negative predictive values of 100%, and 75% (P = 0.0003). Serial TriMeth analysis allowed ctDNA growth rate assessment and revealed that fast ctDNA growth was associated with poor overall survival (HR: 1.6, P = 0.0052). CONCLUSIONS: Serial postoperative ctDNA analysis has a strong prognostic value and is more sensitive for recurrence detection than standard-of-care CRLM surveillance tools. Altogether, TriMeth provides several opportunities for improving postoperative surveillance of CRLM patients.

Intra-observer agreements in multidisciplinary team assessments of pancreatic cancer patients.

BACKGROUND AND METHODS: Treatment strategies for pancreatic cancer patients are made by a multidisciplinary team (MDT) board. We aimed to assess intra-observer variance at MDT boards. Participating units staged, assessed resectability, and made treatment allocations for the same patients as they did two years earlier. We disseminated clinical information and CT images of pancreatic cancer patients judged by one MDT board to have nonmetastatic pancreatic cancer to the participating units. All units were asked to re-assess the TNM stage, resectability, and treatment allocation for each patient. To assess intra-observer variance, we computed %-agreements for each participating unit, defined as low (<50%), moderate (50%-75%), and high (>75%) agreement. RESULTS: Eighteen patients were re-assessed by six MDT boards. The overall agreement was moderate for TNM-stage (ranging from 50%-70%) and resectability assessment (53%) but low for treatment allocation (46%). Agreement on resectability assessments was low to moderate. Findings were similar but more pronounced for treatment allocation. We observed a shift in treatment strategy towards increasing use of neoadjuvant chemotherapy, particularly in patients with borderline resectable and locally advanced tumors. CONCLUSIONS: We found substantial intra-observer agreement variations across six different MDT boards of 18 pancreatic cancer patients with two years between the first and second assessment.

Initial treatment and survival in 4163 Danish patients with pancreatic cancer: A nationwide unselected real-world register study.

BACKGROUND: Nationwide register data on the effect of primary treatment on survival in an unselected population of patients with pancreatic cancer (PC) have not been reported before. The study aim was to investigate the overall survival (OS) related to initial treatment with resection, chemotherapy, or best supportive care (BSC) in all patients diagnosed with PC in Denmark from 2011 to 2016. METHODS: From 1 May 2011 to 30 April 2016, 4260 patients with PC were identified in the Danish Pancreatic Cancer Database. Ninety-seven patients (2%) were excluded, 56 because of treatment with preoperative chemotherapy, 39 because of incorrect registration of diagnosis or treatment, and 2 because of loss to follow-up; thus, 4163 patients were included. RESULTS: The 718 patients (17%) receiving resection had a median overall survival (mOS) of 21.9 months (range 20.0-24.2). In the chemotherapy group of 1746 patients (42%), those treated with FOLFIRINOX had the longest mOS of 10.0 months (9.2-11.0), whereas those treated with gemcitabine had the shortest mOS of 5.1 months (4.8-5.6). The 1697 patients (41%) receiving BSC had a mOS of only 1.6 months (1.5-1.7). CONCLUSIONS: The resected PC cohort had an OS comparable with that reported in randomised controlled trials (RCTs). The mOS of the chemotherapy-treated patients was slightly shorter compared with the results from RCTs and reflects the unselected population in this study. During the last decade, a larger fraction of patients received anticancer treatment, but the BSC group was still large and showed extremely poor OS.

Predictors of underlying pancreatic cancer in patients with acute pancreatitis: a Danish nationwide cohort study.

BACKGROUND: To identify demographic characteristics, comorbidities, medical procedures, and prescription drug use that may act as predictors of underlying pancreatic cancer in acute pancreatitis. METHODS: A cohort study of all patients admitted to Danish hospitals with incident acute pancreatitis during 1999-2015. The ability of age, sex, selected comorbidities, medical procedures, and prescription drug use to predict underlying pancreatic cancer in acute pancreatitis (i.e., pancreatic cancer diagnosed up to one year after acute pancreatitis) was examined. The absolute risk and odds ratio (OR) with 95% confidence interval (CI) of cancer was computed for each variable. RESULTS: 28,231 patients with incident acute pancreatitis, of which 283 (1.0%) had underlying pancreatic cancer, were included. Age >50 years was a predictor of pancreatic cancer with highest risk in patients aged 56-70 years. New-onset chronic pancreatitis (multivariable OR: 2.36 [95% CI: 1.35-4.14]) and new-onset diabetes (multivariable OR: 1.94 [95% CI: 1.30-2.92]) were also predictors of pancreatic cancer. Diagnoses of biliary or alcohol-related diseases were predictors of no underlying pancreatic cancer. Most variables examined had no or limited predictive ability. CONCLUSION: Age, new-onset chronic pancreatitis, new-onset diabetes, and absence of biliary or alcohol-related diseases were predictors of underlying pancreatic cancer in acute pancreatitis patients.

Positive predictive value of acute and chronic pancreatitis diagnoses in the Danish National Patient Registry: A validation study.

Aims: To examine the validity of the diagnoses of acute and chronic pancreatitis registered in the Danish National Patient Registry. Methods: We identified all patients in the Danish National Patient Registry admitted to two Danish hospitals with acute or chronic pancreatitis from 1996 to 2013. From this population, we randomly sampled 100 patients with acute pancreatitis and 100 patients with chronic pancreatitis. For each cohort, we computed the positive predictive values and associated 95% confidence intervals (CIs) for the discharge diagnosis of acute or chronic pancreatitis using medical records as the gold standard. Results: We identified 2617 patients with acute pancreatitis and 1284 patients with chronic pancreatitis discharged from either of the two hospitals during the study period. Of these, 776 (19.9%) had a diagnosis of both acute and chronic pancreatitis and are thus present in both cohorts. From the 200 sampled patients, a total of 138 (69.0%) medical records were available for review. The positive predictive value for a diagnosis of acute pancreatitis in the Danish National Patient Registry was 97.3% (95% CI 90.5-99.2%) and for chronic pancreatitis 83.1% (95% CI 72.2-90.3%). Conclusions: The validity of diagnoses of acute and chronic pancreatitis registered in the Danish National Patient Registry since 1996 is generally high.

Cholecystitis and risk of pancreatic, liver, and biliary tract cancer in patients undergoing cholecystectomy.

BACKGROUND: Cholecystitis before cholecystectomy may increase risk of cancers in the hepato-pancreato-biliary area. METHODS: A population-based cohort study of all patients undergoing cholecystectomy in Denmark during 1996-2015, using nationwide healthcare registries. We retrieved information on cholecystitis within two years before the date of surgery and information on pancreatic cancer, hepatocellular carcinoma (HCC), and biliary tract cancer. We examined cancer risk using a Cox model to calculate the hazard ratios (HRs). We also computed cumulative incidence functions with 95% CIs, comparing patients with and without cholecystitis before cholecystectomy. RESULTS: We included 132,794 patients, of which 73.0% were women. In the first five years of follow-up, we observed an increased risk of biliary tract cancer, but not pancreatic cancer or HCC, in patients with prior cholecystitis. After more than five years of follow-up, patients with prior cholecystitis had an increased risk of pancreatic cancer (adjusted HR: 1.26; 95% CI: 0.98-1.63) and possibly biliary tract cancer (adjusted HR: 1.33; 95% CI: 0.64-2.77). Long-term risk of HCC was decreased in patients with prior cholecystitis. For all cancers, the 20-year absolute risks were less than 1%. CONCLUSION: In patients undergoing cholecystectomy, prior cholecystitis was associated with increased risk of pancreatic and possibly biliary tract cancer.

Acute pancreatitis as an early marker of pancreatic cancer and cancer stage, treatment, and prognosis.

BACKGROUND: We aimed to examine the association between acute pancreatitis, a potential early symptom of pancreatic cancer, and pancreatic cancer stage, treatment, and prognosis. METHODS: We conducted a cohort study of patients diagnosed with pancreatic cancer during 2004-2017 using population-based registry data from Denmark and Surveillance, Epidemiology, and End Results (SEER) data linked with Medicare claims from the United States (US), which include individuals aged 65 + . We ascertained information on acute pancreatitis diagnoses up to 90 days before pancreatic cancer and followed them for a maximum of five years. We assessed overall survival difference at 30 days, six months, and one, three and five years, comparing patients with and without coexistence of acute pancreatitis. Secondary outcomes were cancer stage and treatment. RESULTS: We identified 12,522 Danish and 37,552 US patients with pancreatic cancer (median age 71 and 78 years, respectively). In the Danish cohort, 1.4 % had acute pancreatitis before pancreatic cancer vs. 5.9 % in the US cohort. After five years of follow-up, the survival difference was 6.1 % (95 % CI: [-0.4 %, 12.6 %]) in Danish and 1.7 % (95 % CI: [0.8 %, 2.7 %]) in US patients, comparing patients with and without acute pancreatitis. Patients with acute pancreatitis had lower prevalence of metastatic tumors at diagnosis (Denmark: 42.5 % vs. 48.7 %; US: 34.4 % vs. 45.9 %) and higher resection frequencies (Denmark: 20.1 % vs. 12.1 %; US: 16.1 % vs.11.3 %) than patients without acute pancreatitis. CONCLUSIONS: Pancreatic cancer patients with acute pancreatitis diagnosed up to 90 days before cancer diagnosis had earlier stage at diagnosis and better survival than patients without acute pancreatitis.

Clinical Implications of Monitoring Circulating Tumor DNA in Patients with Colorectal Cancer.

Purpose: We investigated whether detection of ctDNA after resection of colorectal cancer identifies the patients with the highest risk of relapse and, furthermore, whether longitudinal ctDNA analysis allows early detection of relapse and informs about response to intervention.Experimental Design: In this longitudinal cohort study, we used massively parallel sequencing to identify somatic mutations and used these as ctDNA markers to detect minimal residual disease and to monitor changes in tumor burden during a 3-year follow-up period.Results: A total of 45 patients and 371 plasma samples were included. Longitudinal samples from 27 patients revealed ctDNA postoperatively in all relapsing patients (n = 14), but not in any of the nonrelapsing patients. ctDNA detected relapse with an average lead time of 9.4 months compared with CT imaging. Of 21 patients treated for localized disease, six had ctDNA detected within 3 months after surgery. All six later relapsed compared with four of the remaining patients [HR, 37.7; 95% confidence interval (CI), 4.2-335.5; P < 0.001]. The ability of a 3-month ctDNA analysis to predict relapse was confirmed in 23 liver metastasis patients (HR 4.9; 95% CI, 1.5-15.7; P = 0.007). Changes in ctDNA levels induced by relapse intervention (n = 19) showed good agreement with changes in tumor volume (κ = 0.41; Spearman ρ = 0.4).Conclusions: Postoperative ctDNA detection provides evidence of residual disease and identifies patients at very high risk of relapse. Longitudinal surveillance enables early detection of relapse and informs about response to intervention. These observations have implications for the postoperative management of colorectal cancer patients. Clin Cancer Res; 23(18); 5437-45. ©2017 AACR.

Cholinergic PET imaging in infections and inflammation using 11C-donepezil and 18F-FEOBV.

INTRODUCTION: Immune cells utilize acetylcholine as a paracrine-signaling molecule. Many white blood cells express components of the cholinergic signaling pathway, and these are up-regulated when immune cells are activated. However, in vivo molecular imaging of cholinergic signaling in the context of inflammation has not previously been investigated. METHODS: We performed positron emission tomography (PET) using the glucose analogue 18F-FDG, and 11C-donepezil and 18F-FEOBV, markers of acetylcholinesterase and the vesicular acetylcholine transporter, respectively. Mice were inoculated subcutaneously with Staphylococcus aureus, and PET scanned at 24, 72, 120, and 144 h post-inoculation. Four pigs with post-operative abscesses were also imaged. Finally, we present initial data from human patients with infections, inflammation, and renal and lung cancer. RESULTS: In mice, the FDG uptake in abscesses peaked at 24 h and remained stable. The 11C-donepezil and 18F-FEOBV uptake displayed progressive increase, and at 120-144 h was nearly at the FDG level. Moderate 11C-donepezil and slightly lower 18F-FEOBV uptake were seen in pig abscesses. PCR analyses suggested that the 11C-donepezil signal in inflammatory cells is derived from both acetylcholinesterase and sigma-1 receptors. In humans, very high 11C-donepezil uptake was seen in a lobar pneumonia and in peri-tumoral inflammation surrounding a non-small cell lung carcinoma, markedly superseding the 18F-FDG uptake in the inflammation. In a renal clear cell carcinoma no 11C-donepezil uptake was seen. DISCUSSION: The time course of cholinergic tracer accumulation in murine abscesses was considerably different from 18F-FDG, demonstrating in the 11C-donepezil and 18F-FEOBV image distinct aspects of immune modulation. Preliminary data in humans strongly suggest that 11C-donepezil can exhibit more intense accumulation than 18F-FDG at sites of chronic inflammation. Cholinergic PET imaging may therefore have potential applications for basic research into cholinergic mechanisms of immune modulation, but also clinical applications for diagnosing infections, inflammatory disorders, and cancer inflammation.

Correlation between liver cell necrosis and circulating alanine aminotransferase after ischaemia/reperfusion injuries in the rat liver.

Circulating liver enzymes such as alanine transaminase are often used as markers of hepatocellular damage. Ischaemia/reperfusion (I/R) injury is an inevitable consequence of prolonged liver ischaemia. The aim of this study was to examine the correlation between liver enzymes and volume of liver cell necrosis after ischaemia/reperfusion injuries, using design-unbiased stereological methods. Forty-seven male Wistar rats were subjected to 1 h of partial liver ischaemia, followed by either 4 or 24 h of reperfusion. Within each group, one-third of animals were subjected to ischaemic preconditioning and one-third to ischaemic postconditioning. At the end of reperfusion, blood and liver samples were collected for analysis. The volume of necrotic liver tissue was subsequently correlated to circulating markers of I/R injury. Correlation between histological findings and circulating markers was performed using Pearson's correlation coefficient. Alanine transferase peaked after 4 h of reperfusion; however, at this time-point, only mild necrosis was observed, with a Pearson's correlation coefficient of 0.663 (P = 0.001). After 24 h of reperfusion, alanine aminotransferase was found to be highly correlated to the degree of hepatocellular necrosis R = 0.836 (P = 0.000). Furthermore, alkaline phosphatase (R = 0.806) and α-2-macroglobulin (R = 0.655) levels were also correlated with the degree of necrosis. We show for the first time that there is a close correlation between the volume of hepatocellular necrosis and alanine aminotransferase levels in a model of I/R injury. This is especially apparent after 24 h of reperfusion. Similarly, increased levels of alkaline phosphatase and α-2-macroglobulin are correlated to the volume of liver necrosis.

Analysis of circulating tumour DNA to monitor disease burden following colorectal cancer surgery.

OBJECTIVE: To develop an affordable and robust pipeline for selection of patient-specific somatic structural variants (SSVs) being informative about radicality of the primary resection, response to adjuvant therapy, incipient recurrence and response to treatment performed in relation to diagnosis of recurrence. DESIGN: We have established efficient procedures for identification of SSVs by next-generation sequencing and subsequent quantification of 3-6 SSVs in plasma. The consequence of intratumour heterogeneity on our approach was assessed. The level of circulating tumour DNA (ctDNA) was quantified in 151 serial plasma samples from six relapsing and five non-relapsing colorectal cancer (CRC) patients by droplet digital PCR, and correlated to clinical findings. RESULTS: Up to six personalised assays were designed for each patient. Our approach enabled efficient temporal assessment of disease status, response to surgical and oncological intervention, and early detection of incipient recurrence. Our approach provided 2-15 (mean 10) months' lead time on detection of metastatic recurrence compared to conventional follow-up. The sensitivity and specificity of the SSVs in terms of detecting postsurgery relapse were 100%. CONCLUSIONS: We show that assessment of ctDNA is a non-invasive, exquisitely specific and highly sensitive approach for monitoring disease load, which has the potential to provide clinically relevant lead times compared with conventional methods. Furthermore, we provide a low-coverage protocol optimised for identifying SSVs with excellent correlation between SSVs identified in tumours and matched metastases. Application of ctDNA analysis has the potential to change clinical practice in the management of CRC.

Chronic stress does not impair liver regeneration in rats.

BACKGROUND: Although wound healing is a simple regenerative process that is critical after surgery, it has been shown to be impaired under psychological stress. The liver has a unique capacity to regenerate through highly complex mechanisms. The aim of this study was to investigate the effects of chronic stress, which may induce a depression-like state, on the complex process of liver regeneration in rats. METHODS: Twenty rats were included in this study. The animals received either a standard housing protocol or were subjected to a Chronic Mild Stress (CMS) stress paradigm. All rats underwent a 70 % partial hepatectomy (PHx). The animals were evaluated on postoperative day 2 or 4. Blood samples were collected to examine circulating markers of inflammation and liver cell damage. Additionally, liver tissues were sampled to evaluate liver weight and regeneration rate. RESULTS: None of the animals died during the study. There were no differences between in body weight, liver weight, liver regeneration rate or biochemical markers at any time during the study. CONCLUSION: The results of this study indicate that stress and the induction of depression-like state do not affect the process of liver regeneration after 70 % hepatectomy in rats.

Malignant ascites in patients with terminal cancer is effectively treated with permanent peritoneal catheter.

BACKGROUND: Malignant ascites is a pathological condition caused by intra- or extra-abdominal disseminated cancer. The object of treatment is palliation. In search of an effective and minimally invasive palliative treatment of malignant ascites placement of a permanent intra peritoneal catheter has been suggested. PURPOSE: To evaluate our experiences with treatment of malignant ascites by implantation of a permanent PleurX catheter. MATERIAL AND METHODS: A retrospective study was conducted, comprising 20 consecutive patients with terminal cancer, who had a permanent PleurX catheter implanted because of malignant ascites in the period from February to November 2014. Using the patients' medical records, we retrieved data on patients and procedures. RESULTS: The technical success rate was 100%. Catheter patency was 95.2%, one catheter was removed due to dislocation. Ten patients (50.0%) experienced minor adverse events. No procedural difficulties were reported and there was no need for additional treatment of malignant ascites after catheter implantation. Median residual survival after catheter implantation was 27 days. CONCLUSION: Implantation of a permanent PleurX catheter is a minimally invasive and effective procedure with only minor adverse events and a high rate of catheter patency in patients with malignant ascites caused by terminal cancer disease.

Percutaneous cholecystostomy is an effective treatment option for acute calculous cholecystitis: a 10-year experience.

BACKGROUND: Percutaneous cholecystostomy (PC) can be used to treat patients with acute calculous cholecystitis (ACC) who are considered to be unfit for surgery. However, this procedure has been insufficiently investigated. This paper presents the results of a 10-year experience with this treatment modality. METHODS: A retrospective observational study of all consecutive patients treated with PC for ACC in the period from 1 May 2002 to 30 April 2012 was conducted. All data were collected from patients' medical records. RESULTS: A total of 278 patients were treated with PC for ACC. Of these, 13 (4.7%) died within 30 days, 28 (10.1%) underwent early laparoscopic cholecystectomy and three (1.1%) patients were lost from follow-up. Of the remaining 234 patients, 55 (23.5%) were readmitted for the recurrence of cholecystitis. In 128 (54.7%) patients, PC was the definitive treatment (median follow-up time: 5 years), whereas 51 (21.8%) patients were treated with elective laparoscopic cholecystectomy. The frequency of recurrence of cholecystitis in patients with contrast passage to the duodenum on cholangiography was lower than that in patients without contrast passage (21.1% versus 36.7%; P = 0.037). CONCLUSIONS: The present study, which is the largest ever conducted in this treatment area, supports the hypothesis that PC is an effective treatment modality for critically ill patients with ACC unfit for surgery and results in a low rate of 30-day mortality.