Live enteroviruses, but not other viruses, detected in human pancreas at the onset of type 1 diabetes in the DiViD study.

AIMS/HYPOTHESIS: Enterovirus (EV) infection of pancreatic islet cells is one possible factor contributing to type 1 diabetes development. We have reported the presence of EV genome by PCR and of EV proteins by immunohistochemistry in pancreatic sections. Here we explore multiple human virus species in the Diabetes Virus Detection (DiViD) study cases using innovative methods, including virus passage in cell cultures. METHODS: Six recent-onset type 1 diabetes patients (age 24-35) were included in the DiViD study. Minimal pancreatic tail resection was performed under sterile conditions. Eleven live cases (age 43-83) of pancreatic carcinoma without diabetes served as control cases. In the present study, we used EV detection methods that combine virus growth in cell culture, gene amplification and detection of virus-coded proteins by immunofluorescence. Pancreas homogenates in cell culture medium were incubated with EV-susceptible cell lines for 3 days. Two to three blind passages were performed. DNA and RNA were extracted from both pancreas tissue and cell cultures. Real-time PCR was used for detecting 20 different viral agents other than EVs (six herpesviruses, human polyomavirus [BK virus and JC virus], parvovirus B19, hepatitis B virus, hepatitis C virus, hepatitis A virus, mumps, rubella, influenza A/B, parainfluenza 1-4, respiratory syncytial virus, astrovirus, norovirus, rotavirus). EV genomes were detected by endpoint PCR using five primer pairs targeting the partially conserved 5' untranslated region genome region of the A, B, C and D species. Amplicons were sequenced. The expression of EV capsid proteins was evaluated in cultured cells using a panel of EV antibodies. RESULTS: Samples from six of six individuals with type 1 diabetes (cases) and two of 11 individuals without diabetes (control cases) contained EV genomes (p<0.05). In contrast, genomes of 20 human viruses other than EVs could be detected only once in an individual with diabetes (Epstein-Barr virus) and once in an individual without diabetes (parvovirus B19). EV detection was confirmed by immunofluorescence of cultured cells incubated with pancreatic extracts: viral antigens were expressed in the cytoplasm of approximately 1% of cells. Notably, infection could be transmitted from EV-positive cell cultures to uninfected cell cultures using supernatants filtered through 100 nm membranes, indicating that infectious agents of less than 100 nm were present in pancreases. Due to the slow progression of infection in EV-carrying cell cultures, cytopathic effects were not observed by standard microscopy but were recognised by measuring cell viability. Sequences of 5' untranslated region amplicons were compatible with EVs of the B, A and C species. Compared with control cell cultures exposed to EV-negative pancreatic extracts, EV-carrying cell cultures produced significantly higher levels of IL-6, IL-8 and monocyte chemoattractant protein-1 (MCP1). CONCLUSIONS/INTERPRETATION: Sensitive assays confirm that the pancreases of all DiViD cases contain EVs but no other viruses. Analogous EV strains have been found in pancreases of two of 11 individuals without diabetes. The detected EV strains can be passaged in series from one cell culture to another in the form of poorly replicating live viruses encoding antigenic proteins recognised by multiple EV-specific antibodies. Thus, the early phase of type 1 diabetes is associated with a low-grade infection by EVs, but not by other viral agents.

Prognostic Impact of Resection Margin Status in Distal Pancreatectomy for Ductal Adenocarcinoma.

BACKGROUND: Resection margin status is considered one of the few surgeon-controlled parameters affecting prognosis in pancreatic ductal adenocarcinoma (PDAC). While studies mostly focus on resection margins in pancreatoduodenectomy, little is known about their role in distal pancreatectomy (DP). This study aimed to investigate resection margins in DP for PDAC. METHODS: Patients who underwent DP for PDAC between October 2004 and February 2020 were included (n = 124). Resection margins and associated parameters were studied in two consecutive time periods during which different pathology examination protocols were used: non-standardized (period 1: 2004-2014) and standardized (period 2: 2015-2020). Microscopic margin involvement (R1) was defined as ≤1 mm clearance. RESULTS: Laparoscopic and open resections were performed in 117 (94.4%) and 7 (5.6%) patients, respectively. The R1 rate for the entire cohort was 73.4%, increasing from 60.4% in period 1 to 83.1% in period 2 (p = 0.005). A significantly higher R1 rate was observed for the posterior margin (35.8 vs. 70.4%, p < 0.001) and anterior pancreatic surface (based on a 0 mm clearance; 18.9 vs. 35.4%, p = 0.045). Pathology examination period, poorly differentiated PDAC, and vascular invasion were associated with R1 in the multivariable model. Extended DP, positive anterior pancreatic surface, lymph node ratio, perineural invasion, and adjuvant chemotherapy, but not R1, were significant prognostic factors for overall survival in the entire cohort. CONCLUSIONS: Pathology examination is a key determinant of resection margin status following DP for PDAC. A high R1 rate is to be expected when pathology examination is meticulous and standardized. Involvement of the anterior pancreatic surface affects prognosis.

Implementation and training with laparoscopic distal pancreatectomy: 23-year experience from a high-volume center.

BACKGROUND: Distal pancreatectomy is the most common procedure in minimally-invasive pancreatic surgery. Data in the literature suggest that the learning curve flattens after performing up to 30 procedures. However, the exact number remains unclear. METHODS: The implementation and training with laparoscopic distal pancreatectomy (LDP) in a high-volume center were studied between 1997 and 2020. Perioperative outcomes and factors related to conversion were assessed. The individual experiences of four different surgeons (pioneer and adopters) performing LDP on a regular basis were examined. RESULTS: Six hundred forty LDPs were done accounting for 95% of all distal pancreatectomies performed throughout the study period. Conversion was needed in 14 (2.2%) patients due to intraoperative bleeding or tumor adherence to the major vasculature. Overall morbidity and mortality rates were 35 and 0.6%, respectively. Intra- and postoperative outcomes did not change for any of the surgeons within their first 40 cases. Operative time significantly decreased after the first 80 cases for the pioneer surgeon and did not change afterwards although the proportion of ductal adenocarcinoma increased. Tumor size increased after the first 80 cases for the first adopter without affecting the operative time. CONCLUSIONS: In this nearly unselected cohort, no significant changes in surgical outcomes were observed throughout the first 40 LDPs for different surgeons. The exact number of procedures required to overcome the learning curve is difficult to determine as it seems to depend on patient selection policy and specifics of surgical training at the corresponding center.

Characterisation of enterovirus RNA detected in the pancreas and other specimens of live patients with newly diagnosed type 1 diabetes in the DiViD study.

AIMS/HYPOTHESIS: The Diabetes Virus Detection (DiViD) study is the first study to laparoscopically collect pancreatic tissue and purified pancreatic islets together with duodenal mucosa, serum, peripheral blood mononuclear cells (PBMCs) and stools from six live adult patients (age 24-35 years) with newly diagnosed type 1 diabetes. The presence of enterovirus (EV) in the pancreatic islets of these patients has previously been reported. METHODS: In the present study we used reverse transcription quantitative real-time PCR (RT-qPCR) and sequencing to characterise EV genomes present in different tissues to understand the nature of infection in these individuals. RESULTS: All six patients were found to be EV-positive by RT-qPCR in at least one of the tested sample types. Four patients were EV-positive in purified islet culture medium, three in PBMCs, one in duodenal biopsy and two in stool, while serum was EV-negative in all individuals. Sequencing the 5' untranslated region of these EVs suggested that all but one belonged to enterovirus B species. One patient was EV-positive in all these sample types except for serum. Sequence analysis revealed that the virus strain present in the isolated islets of this patient was different from the strain found in other sample types. None of the islet-resident viruses could be isolated using EV-permissive cell lines. CONCLUSIONS/INTERPRETATION: EV RNA can be frequently detected in various tissues of patients with type 1 diabetes. At least in some patients, the EV strain in the pancreatic islets may represent a slowly replicating persisting virus.

Laparoscopic distal pancreatectomy in patients with poor physical status.

BACKGROUND: Laparoscopic distal pancreatectomy (LDP) is advantageous over open surgery in the treatment of benign pancreatic lesions and low-grade malignancies. Yet the evidence on the relationship between comorbidities and the outcomes of LDP remains scarce. METHODS: Patients who had undergone LDP for all indications between April 1997 and December 2019 were included. Preoperative physical status was defined according to the American Society of Anesthesiology (ASA) criteria. Perioperative outcomes were compared between the patients with high (ASA III-IV) and low/moderate anesthetic risk (ASA I-II). RESULTS: A total of 605 patients were eligible for analysis including 190 with ASA III-IV and 415 with ASA I-II. The former was associated with older age, male gender, preexisting medical conditions, greater total number of comorbidities and red blood cell transfusion. The rate of medical complications was significantly higher in high-risk patients. Multivariable analysis identified ASA III-IV and operative time as independent predictors for medical complications. Overall/severe morbidity, surgical complications and mortality rates were similar. CONCLUSIONS: Poor physical status defined as ASA grades III-IV predicts medical complications, but has a limited impact on surgical complications and severe morbidity of LDP. Thus, it should not be considered as a contraindication for LDP.

Psychometric performance of the PAncreatic CAncer disease impact (PACADI) score.

BACKGROUND/OBJECTIVE: Pancreatic Cancer Disease Impact (PACADI) score measures the impact of pancreatic cancer (PC) on important health dimensions, selected by patients. The aim of this single center study was to test the psychometric performance of the Pancreatic Cancer Disease Impact (PACADI) score. METHODS: Patients with suspected pancreatic cancer (PC) completed PACADI, the EuroQol-5D (EQ-5D index) and Edmonton Symptom Assessment System (ESAS) in this longitudinal observational study. Measures were compared across patients with PC (n = 210), other malignant lesions (OML) (n = 109) and non-malignant lesions (NML) (n = 41). Associations, test-retest and internal consistency reliability, longitudinal changes, sensitivity to change and prediction of mortality during the first year were examined in patients with PC. RESULTS: The three measures discriminated between PC and OML. The PACADI score correlated strongly at baseline (n = 199)/after three months (n = 85) with the EQ-5D index and ESAS "sense of well-being" (0.64 and 0.66/0.73 and 0.69, p < 0.001, respectively), showed high test-retest reliability (ICC 0.84) and very good internal consistency reliability (Cronbach's alpha 0.81-0.85) across all visits. Scores improved over time at 3, 6, 9 and 12 months for survivors, and standardized response mean (SRM) for improvement between 2 and 3 months (n = 44) was 0.80 (PACADI), -0.59 (EQ-5D index) and 0.69 (ESAS "sense of well-being"). The PACADI score significantly predicted mortality within the first year (p = 0.02) in contrast to the EQ-5D index and ESAS "sense of well-being". CONCLUSION: This study showed satisfactory psychometric performance of the PACADI score. The results support its use in clinical practice and intervention trials.

Trends in management and outcome of cystic pancreatic lesions - analysis of 322 cases undergoing surgical resection.

Background: Several guidelines for the management of cystic pancreatic lesions (CPL) exists. From 2013, Oslo University Hospital adapted the European consensus guidelines (ECG) in the decision-making as to whether patients should be advised to have resection or observation for CPL. The aims of the study were to assess changes over time in the workup and diagnostic accuracy of resected CPL, and the short-term surgical outcome. Methods: Preoperative radiological workup, clinicopathological characteristics, and perioperative outcomes were retrospectively reviewed in three consecutive time periods (early: 2004-2008, intermediate: 2009-2012, late: 2013-2016). The rate of concordance between the ECG recommendations for resection (ECG+) or observation (ECG-) and the final histological diagnosis were assessed. Results: A total of 322 consecutive patients underwent resection for CPL (early: n = 89, intermediate: n = 108, late: n = 125). The most common diagnoses were intraductal papillary mucinous neoplasia (IPMN, 36.0%), serous cystic neoplasm (SCN, 23.9%), mucinous cystic neoplasm (10.6%), pseudocyst (9.6%), solid pseudopapillary neoplasm (7.8%), and cystic pancreatic neuroendocrine tumour (5.3%). The proportion of ECG+ CPL undergoing surgery increased significantly (42.7% vs. 60.7% vs. 70.4%, p < .001). The relative proportion of patients undergoing resection for SCN decreased (38.2% vs. 21.3% vs. 16.0%), whereas it increased for IPMN (31.5% vs. 30.6% vs. 44.0%). The use of magnetic resonance imaging and endoscopic ultrasound increased. There were no differences in postoperative severe complications (23.0% vs. 23.6%) or 90-day mortality (2.3% vs. 0.8%) between ECG+ and ECG- patients. Conclusion: Several changes in the management of CPL were revealed during time. Adherence to guidelines is important in order to avoid unnecessary surgery for CPL.

Survival, Complications and Patient Reported Outcomes after Pancreatic Surgery.

BACKGROUND: Long-term effects of complications in pancreatic surgery have not been systematically evaluated. The objectives were to assess potential effects of complications on survival and patient reported outcomes (PROs) as well as feasibility of PRO questionnaires in patients with periampullary and pancreatic tumors. METHODS: From October 2008 to December 2011, 208 patients undergoing pancreatic surgery were included in a prospective observational study. ESAS, EORTC QLQ-C30 and QLQ-PAN26 questionnaires were completed at inclusion, then every third month. Complications were recorded according to the Clavien-Dindo (CD) classification and Comprehensive Complication Index (CCI). RESULTS: 148 complications were registered in 100 patients (48%), 36 patients (17%) had CD IIIa or above. 125 patients (60%) completed baseline questionnaires, 80 (39%) responded after three and 54 (28%) after six months. Complications were associated with reduced long-term survival in patients with pancreatic ductal adenocarcinoma (PDAC) (p = 0.049) and other malignant diseases. No significant relationship was found between complications and PROs, except for anxiety, which was significantly increased in patients with complications. CONCLUSION: Postoperative complications led to increased anxiety at 3 months after surgery and were associated with reduced long-term survival in patients with malignancy. A short, patient derived, disease specific questionnaire is required in the clinical research context.

Demonstration of Tissue Resident Memory CD8 T Cells in Insulitic Lesions in Adult Patients with Recent-Onset Type 1 Diabetes.

Subtypes of CD8+ T cells in insulitic lesions in biopsy specimens from six subjects with recent-onset type 1 diabetes (T1D) and six nondiabetic matched controls were analyzed using simultaneous multicolor immunofluorescence. Also, insulitic islets based on accumulation of CD3+ T cells were microdissected with laser-capture microscopy, and gene transcripts associated with inflammation and autoimmunity were analyzed. We found a substantial proportion, 43%, of the CD8+ T cells in the insulitic lesions to display a tissue resident memory T cell (TRM) (CD8+CD69+CD103+) phenotype in T1D subjects. Most TRM cells were located in the insulitic lesion in the endocrine-exocrine interface. TRM cells were also sporadically found in islets of control subjects. Moreover, gene expression analysis showed a lack of active transcription of genes associated with acute inflammatory or cytotoxic T-cell responses. We present evidence that a substantial proportion of T cells in insulitic lesions of recent-onset T1D patients are TRM cells and not classic cytotoxic CD8+ T cells. Our findings highlight the need for further analysis of the T cells involved in insulitis to elucidate their role in the etiology of T1D.

Can standardized pathology examination increase the lymph node yield following laparoscopic distal pancreatectomy for ductal adenocarcinoma?

BACKGROUND: Lymph node yield (LNY) is an indicator of oncological adequacy of surgery in patients with pancreatic ductal adenocarcinoma (PDAC). Our hypothesis is that standardized pathology examination (SPE) aimed at accurate staging can increase the LNY without changing surgical technique. METHODS: After the introduction of SPE for distal pancreatosplenectomy specimens at Oslo University Hospital, prospective data were collected on patients with PDAC undergoing laparoscopic distal pancreatosplenectomy (LDP). Their data were compared with retrospective data from specimens examined in a non-standardized way (NSPE). RESULTS: SPE and NSPE were applied to 20 and 33 specimens, respectively. SPE was associated with a higher LNY and a higher median number of positive lymph nodes (PLN) in the specimen (18 vs 7, P = 0.001 and 4 vs 1, P = 0.005, respectively). In the stepwise regression model, SPE and younger age resulted in an increased LNY. In the logistic regression model, increased LNY and larger tumor size positively correlated with the presence of PLN. CONCLUSION: SPE of distal pancreatosplenectomy specimens is associated with higher LNY in patients with PDAC, which increases the likelihood of detecting PLN and reduces the risk of understaging. These findings also indicate that the LDP technique provides an adequate LNY in patients with PDAC.

Insulitis and characterisation of infiltrating T cells in surgical pancreatic tail resections from patients at onset of type 1 diabetes.

AIMS/HYPOTHESIS: It is thought that T cells play a major role in the immune-mediated destruction of beta cells in type 1 diabetes, causing inflammation of the islets of Langerhans (insulitis). The significance of insulitis at the onset of type 1 diabetes is debated, and the role of the T cells poorly understood. METHODS: In the Diabetes Virus Detection (DiViD) study, pancreatic tissue from six living patients with recent-onset type 1 diabetes was collected. The insulitis was characterised quantitatively by counting CD3(+) T cells, and qualitatively by transcriptome analysis targeting 84 T and B lymphocyte genes of laser-captured microdissected islets. The findings were compared with gene expression in T cells collected from kidney biopsies from allografts with ongoing cellular rejection. Cytokine and chemokine release from isolated islets was characterised and compared with that from islets from non-diabetic organ donors. RESULTS: All six patients fulfilled the criteria for insulitis (5-58% of the insulin-containing islets in the six patients had ≥ 15 T cells/islet). Of all the islets, 36% contained insulin, with several resembling completely normal islets. The majority (61-83%) of T cells were found as peri-insulitis rather than within the islet parenchyma. The expression pattern of T cell genes was found to be markedly different in islets compared with the rejected kidneys. The islet-infiltrating T cells showed only background levels of cytokine/chemokine release in vitro. CONCLUSIONS/INTERPRETATION: Insulitis and a significant reserve reservoir for insulin production were present in all six cases of recent-onset type 1 diabetes. Furthermore, the expression patterns and levels of cytokines argue for a different role of the T cells in type 1 diabetes when compared with allograft rejection.

Expression of human leukocyte antigen class I in endocrine and exocrine pancreatic tissue at onset of type 1 diabetes.

The cause of type 1 diabetes remains unknown. To dissect the link between hyperexpression of human leukocyte antigen (HLA) class I on the islet cells, we examined its expression in subjects with recent-onset type 1 diabetes. IHC showed seemingly pronounced hyperexpression in subjects with recent-onset type 1 diabetes, as well as in some nondiabetic subjects. In all subjects, HLA class I expression on exocrine tissue was low. However, no difference in the level of HLA class I expression was found between islet and exocrine tissue using Western blot, flow cytometry, real-time quantitative PCR, or RNA sequencing analyses. Also, the level of HLA class I expression on the messenger level was not increased in islets from subjects with recent-onset type 1 diabetes compared with that in nondiabetic subjects. Consistently, the HLA class I specific enhanceosome (NLRC5) and related transcription factors, as well as interferons, were not enhanced in islets from recent-onset type 1 diabetic subjects. In conclusion, a discrepancy in HLA class I expression in islets assessed by IHC was observed compared with that using quantitative techniques showing similar expression of HLA class I in islets and exocrine tissue in subjects with recent-onset type 1 diabetes, nor could any differences be found between type 1 diabetic and nondiabetic subjects. Results presented provide important clues for a better understanding on how this complex disease develops.

Impact of early disease progression and surgical complications on adjuvant chemotherapy completion rates and survival in patients undergoing the surgery first approach for resectable pancreatic ductal adenocarcinoma - A population-based cohort study.

BACKGROUND: Multimodality treatment (MMT) improves survival for patients with pancreatic ductal adenocarcinoma (PDAC). The surgery-first (SF) strategy is the most universally accepted approach. MATERIAL AND METHODS: Population-based retrospective cohort study of all cases of resectable PDAC from 2006 to 2012. Patients were planned for adjuvant chemotherapy (AC) with the Nordic 5-fluorouracil/leucovorin regimen. Reasons for and rates of failure to complete AC, postoperative major complications (PMC), and overall survival (OS) were analysed. RESULTS: Of 203 patients, 85 (41.9%) completed AC, 41 (20.2%) failed to complete AC, and 77 (37.9%) never initiated AC. Primary reasons for not initiating or completing AC were early disease progression (34.7%), postoperative complications/poor performance status (32.2%), and age > 75 years (24.6%). Median OS in the whole cohort was 17.0 months, and 20.0 months in patients who initiated AC. Median OS in patients who completed AC was higher than in patients who did not (25.0 months vs. 12.0 months, p < 0.001). PMC (n = 41) were associated with decreased initiation rate (p < 0.001) and completion rate (p = 0.007) of AC, and decreased median OS (11.0 months vs. 19.0 months, p = 0.028). Among patients with R1 resection, PMC again were associated with worse median OS (8.0 months vs. 16.0 months, p = 0.028). Multivariate analysis demonstrated that completion of MMT and tumour grade (G1/G2) were related to mortality rate (p < 0.001). Mortality risk for patients who completed AC was reduced also when adjusting for competing risk (SHR 0.426, p < 0.001). CONCLUSIONS: MMT completion is strongly associated with reduced mortality risk in patients with resectable PDAC undergoing the SF approach. Early disease progression and PMC/poor performance status preclude MMT completion in more than one third of the patients. These reasons for failure to complete MMT underscore the need for strategies to improve patient selection and reduce surgical morbidity in patients with resectable PDAC.

Laparoscopic distal pancreatectomy for pancreatic ductal adenocarcinoma: results of a multicenter cohort study on 196 patients.

BACKGROUND: Laparoscopy is widely accepted as a feasible option for distal pancreatectomy. However, the experience in laparoscopic distal pancreatectomy (LDP) for pancreatic ductal adenocarcinoma (PDAC) is limited to a small number of studies, reported by expert centers. The present study aimed to evaluate perioperative and oncological outcomes after LDP for PDAC in a large, multicenter cohort of patients. METHODS: A retrospective analysis of the data on 196 patients with histologically verified PDAC, operated at Oslo University Hospital-Rikshospitalet (Oslo, Norway), Asan Medical Center (Seoul, Republic of Korea), Institut Mutualiste Montsouris (Paris, France) and University Hospital Southampton (Southampton, UK) between January 2002 and April 2015 was conducted. The patients with standard (SLDP) and extended (i.e., en bloc with adjacent organ, ELDP) resections were compared in terms of perioperative and oncological outcomes. RESULTS: Out of 196 LDP procedures, 191 (97.4 %) were completed through laparoscopy, while five (2.6 %) were converted to open surgery. ELDP was performed in 30 (15.7 %) cases. Sixty-one (31.9 %) patients experienced postoperative complications, including 48 (25.1 %) with pancreatic fistula. The rate of clinically relevant fistula (grade B/C) was 15.7 %. Median postoperative hospital stay was 8 (2-63) days. Median follow-up was 16 months. Median survival was 31.3 months (95 % CI 22.9-39.6). Three- and 5-year actuarial survival rates were 42.4 and 30 %, respectively. SLDP was associated with significantly higher survival compared with ELDP (p = 0.032). CONCLUSIONS: LDP seems to be a feasible and safe procedure, providing satisfactory oncological outcomes in patients with PDAC.

Preoperative cognitive function predicts survival in patients with resectable pancreatic ductal adenocarcinoma.

BACKGROUND: The purpose of this prospective study was to evaluate whether pre-surgery health-related quality of life (HRQoL) and subjectively rated symptom scores are prognostic factors for survival in patients with resectable pancreatic ductal adenocarcinoma (PDAC). METHODS: Patients undergoing pancreatic resection for PDAC completed the Edmonton Symptom Assessment System (ESAS) and the EORTC QLQ-C30 and QLQ-PAN26 questionnaires preoperatively. Patient, tumor and treatment characteristics, recurrence and survival were registered. RESULTS: Sixty-six consecutive patients underwent R0/R1 resection for PDAC. Baseline ESAS and EORTC questionnaire compliance was 44/66 (67%) with no statistically significant differences between compliers (n = 44) and non-compliers (n = 22) when comparing clinicopathological parameters and survival. Univariable analyses showed that three symptoms (nausea, dry mouth, cognitive function) and two clinicopathological factors (CA 19-9 > 400 U/ml, lymph node ratio > 0.1) were significantly associated with shorter survival (p < 0.05). In multivariable analysis, cognitive function was the only independent predictor for survival: hazard ratio = 0.35 (95%CI 0.13-0.93) for high vs low cognitive function. Median survival times for patients with high and low cognitive function were 21 and 10 months, respectively (p < 0.001). CONCLUSION: Presurgery cognitive function is a significant independent predictor of survival in patients with resectable PDAC. Thus, presurgery patient reported outcomes may provide as strong prognostic information as clinicopathological factors.

Serum N-Glycome Characterization in Patients with Resectable Periampullary Adenocarcinoma.

Serum N-glycans are promising biomarkers for systemic disease states. Better understanding of the serum N-glycome of patients with resectable periampullary adenocarcinoma may identify novel prognostic markers for this disease. Serum N-glycans in 70 patients with resectable periampullary adenocarcinoma, 15 patients with benign periampullary tumor, and 129 healthy individuals were quantified using ultra performance liquid chromatography. High-sensitivity C-reactive protein (hsCRP) was analyzed for all samples using an immunoturbidimetric method. The N-glycome was compared to clinical and histopathological data, and to the acute phase response as measured by hsCRP. Whole-genome tumor tissue mRNA expression data were used for correlation and enrichment analysis to investigate underlying biological processes giving rise to changes in the serum N-glycome. Significant changes were found in the serum N-glycome of patients with periampullary adenocarcinoma (n = 70) compared to healthy individuals (n = 129). No significant differences were found between patients with benign (n = 15) and malignant periampullary tumors (n = 70). Many alterations in the N-glycome correlated with systemic acute phase response as measured by hsCRP. Enrichment analysis indicated that immunologic pathways of the cancer microenvironment correlate with specific features of the serum N-glycome. Certain glycans were associated with poor overall and disease free survival in patients with pancreatobiliary type of periampullary adenocarcinoma. Our study supports the hypothesis that certain factors secreted by the tumor affect liver and plasma cells to orchestrate the changes in the serum N-glycome observed. The serum N-glycome could potentially reflect modified phenotypes of the host and/or tumor microenvironment. The prognostic impact of the serum N-glycome should be evaluated in larger, prospective studies.

Improved survival and quality of life in patients undergoing R1 pancreatic resection compared to patients with locally advanced unresectable pancreatic adenocarcinoma.

OBJECTIVE: To prospectively record the clinical consequences of R1 resection of pancreatic adenocarcinoma compared to patients with locally advanced tumours not undergoing surgery. BACKGROUND: Surgery is the only potentially curative treatment of pancreatic cancer, and postoperative safety is increasing. The rate of R1 resections might also increase unintentionally as surgical procedures with curative goal become more comprehensive, and the clinical outcome requires further prospective evaluation. MATERIAL AND METHODS: Prospective observational cohort study from October 2008 to December 2010. Outcome after R1 resection (group 1, surgery, n = 32) and conservative palliative chemoradiation/endoscopy (group 2, no surgery, n = 56) is compared with survival and longitudinal patient-reported quality of life (QoL) as endpoints. QoL was assessed by the Edmonton Symptom Assessment System (ESAS). RESULTS: Demographic characteristics and tumour diameters were similar in both groups: 38.0 (31.3, 49.8) mm in group 1 versus 44.0 (39.6, 49.1) mm in group 2 (p = 0.18). Perioperative morbidity was 25% with no mortality. Disease-specific survival was 18.0 (14.5, 23.8) months in group 1 versus 8.1 (4.8, 10.1) months in group 2 (p < 0.0001). Overall survival was 11 (7.8, 14.4) months. Reduction in fatigue was significantly improved in the surgery group 6, 12, and 19 weeks after baseline, whereas reduction in global health was significantly better in group 2. CONCLUSION: Radical removal (R0 resection) is the primary aim of surgery, but also R1 resection seems to improve survival and QoL, compared to outcome in patients with locally advanced tumours not undergoing surgery.

Opportunities of improvement in the management of pancreatic and periampullary tumors.

Abstract Objective. The first objective of the present study was to identify opportunities of improvement for clinical practice, assessed by local quality indicators, then to analyze possible reasons why we did not reach defined treatment quality measures. The second objective was to characterize patients, considered unresectable according to present criteria, for future arrangement of interventional studies with improved patient selection. Material and methods. Prospective observational cohort study from October 2008 to December 2010 of patients referred to the authors' institution with suspected pancreatic or periampullary neoplasm. Results. Of 330 patients, 135 underwent surgery, 195 did not, 129 due to unresectable malignancies. The rest had benign lesions. Perioperative morbidity rate was 32.6%, mortality 0.7%. Radical resection (R0) was obtained in 23 (41.8%) of 55 patients operated for pancreatic adenocarcinoma and 6.3% underwent reconstructive vascular surgery. Diagnostic failure/delay resulted in unresectable carcinoma, primarily misconceived as serous cystic adenoma in two patients. One resected lesion turned out to be focal autoimmune pancreatitis. One case with misdiagnosed cancer was revised to be a pseudoaneurysm. Palliative treatment was offered to 144 patients with malignant tumors, 62 due to locally advanced disease and all pancreatic adenocarcinomas. Conclusions. Quality improvement opportunities were identified for patient selection and surgical technique: Too few patients underwent reconstructive vascular surgery. The most important quality indicators are those securing resectional, radical (R0) surgery. Altogether 143 patients (57.9%) of those with malignant tumors were found unresectable, most of these patients are eligible for inclusion in future interventional studies with curative and/or palliative intention.

Development and preliminary validation of the pancreatic cancer disease impact score.

OBJECTIVE: Patient-reported outcomes are important for clinical practice and research, and should reflect what patients perceive as important. The objective of this study was to develop and preliminarily validate a brief, patient-derived, disease-specific tool, the pancreatic cancer disease impact (PACADI) score. METHODS: The development was performed in two phases. Forty-one patients with confirmed pancreatic cancer (PC) selected dimensions of health related to the impact of the disease. A weighting of the eight most frequently reported dimensions was performed in a second sample of 80 PC patients who also rated the impact on eight numeric rating scales (NRS, range 0 to 10). The relative weights and the scores from the NRS were used to compute the PACADI score (range 0 to 10). The patients also completed Edmonton Symptom Assessment System (ESAS) and EQ-5D. RESULTS: Dimensions reported by more than 20% of the patients were included in the PACADI score (relative weights in parenthesis): pain/discomfort (0.16), fatigue (0.16), anxiety (0.15), bowel/digestive problems (0.14), loss of appetite (0.13), dry mouth (0.11), itchiness (0.08), and nausea (0.07). The PACADI score in the 80 PC patients had a mean (SD) value of 3.26 (2.06) (95% CI 2.80, 3.71), was moderately to strongly correlated to ESAS sense of well-being (r = 0.69) and EQ-5D (r = -0.52), and discriminated significantly between patients with and without PC. CONCLUSION: The PACADI score is a new eight-item, patient-derived, disease-specific measure. Preliminary validation regarding construct validity and discrimination encourages further validation in independent patient samples.

Endometriosis of the pancreas.

Endometrial cyst of the pancreas was first described in 1984. The condition is extremely rare, and only a few case reports have been described. Herein we present a case report of a peripancreatic endometriosis cyst in a perimenopausal woman. Computed tomography, magnetic resonance imaging, and regression of the cyst during an observation period of a few months made the diagnosis most likely before laparoscopic surgery. Awareness of the condition, optimal preoperative imaging, and clinical features are discussed.