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.

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.

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.

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.

Laparoscopic Distal Pancreatectomy Following Prior Upper Abdominal Surgery (Pancreatectomy and Prior Surgery).

BACKGROUND AND PURPOSE: Previous abdominal surgery can be a risk factor for perioperative complications in patients undergoing laparoscopic procedures. Today, distal pancreatectomy is increasingly performed laparoscopically. This study investigates the consequences of prior upper abdominal surgery (PUAS) for laparoscopic distal pancreatectomy (LDP). METHODS: Patients who had undergone LDP from April 1997 to January 2020 were included. Based on the history and type of PUAS, these were categorized into three groups: minimally invasive (I), open (II), and no PUAS (III). To reduce possible confounding factors, the groups were matched in 1:2:4 fashion based on age, sex, body mass index (BMI) and American Society of Anesthesiology grade. RESULTS: After matching, 30, 60, and 120 patients were included in the minimally invasive, open and no PUAS groups, respectively. No statistically significant differences were found in terms of intraoperative outcomes. Postoperative morbidity, mortality and length of hospital stay were similar. Open PUAS was associated with higher Comprehensive Complication Index (33.7 vs 20.9 vs 26.2, p = 0.03) and greater proportion of patients with ≥ 2 complications (16.7 vs 0 vs 6.7%, p = 0.02) compared with minimally invasive and no PUAS. Male sex, overweight (BMI 25-29.9 kg/m2), diagnosis of neuroendocrine neoplasia, and open PUAS were risk factors for severe morbidity in the univariable analysis. Only open PUAS was statistically significant in the multivariable model. CONCLUSIONS: PUAS does not impair the feasibility and safety of LDP as its perioperative outcomes are largely comparable to those in patients without PUAS. However, open PUAS increases the burden and severity of postoperative complications.

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.

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.

Long term oncological outcome of laparoscopic techniques in pancreatic cancer.

The laparoscopic technique in distal pancreatic resection (LDP) has been widely accepted, and outcome data support the hypothesis that survival is improved, partly due to improved postoperative safety and recovery, thus optimizing treatment with adjuvant chemotherapy. But laparoscopic pancreaticoduodenectomy (LPD or Whipple-procedures) has spread more slowly, due to the complexity of the procedure. Surgical safety has been a problem in hospitals with low patient volume, resulting in raised postoperative mortality, requiring careful monitoring of outcome during the surgical learning curve. Robotic assistance is expected to improve surgical safety, but data on long term oncological outcome of laparoscopic Whipple procedures with or without robotic assistance is scarce. Future research should still focus surgical safety, but most importantly long term outcome, recorded as recurrence at maximal follow up or - at best - overall long term survival (OS). Available data show median survival above 2.5 years, five year OS more than 30% after LDP even in series with suboptimal adjuvant chemotherapy. Also after LPD, long term survival is reported equal to or longer than open resection. However, surgical safety during the learning curve of LPD is a problem, which hopefully can be facilitated by robotic assistance. Patient reported outcome should also be an endpoint in future trials, including patients with pancreatic ductal adenocarcinoma.

Laparoscopic distal pancreatectomy for pancreatic ductal adenocarcinoma: Long-term oncologic outcomes after standard resection.

BACKGROUND: Surgical resection is the only curative option in patients with pancreatic ductal adenocarcinoma. Little is known about the oncologic outcomes of laparoscopic distal pancreatectomy. This bi-institutional study aimed to examine the long-term oncologic results of standard laparoscopic distal pancreatectomy in a large cohort of patients with pancreatic ductal adenocarcinoma. METHODS: From January 2002 to March 2016, 207 patients underwent standard laparoscopic distal pancreatectomy for pancreatic ductal adenocarcinoma at Oslo University Hospital-Rikshospitalet (Oslo, Norway) and Asan Medical Centre (Seoul, Republic of Korea). After the exclusion criteria were applied (distant metastases at operation, conversion to an open operation, loss to follow-up), 186 patients were eligible for the analysis. Perioperative and oncologic variables were analyzed for association with recurrence and survival. RESULTS: Median overall and recurrence-free survivals were 32 and 16 months, while 5-year overall and recurrence-free survival rates were estimated to be 38.2% and 35.9%, respectively. Ninety-six (52%) patients developed recurrence: 56 (30%) extrapancreatic, 27 (15%) locoregional, and 13 (7%) combined locoregional and extrapancreatic. Thirty-seven (19.9%) patients had early recurrence (within 6 months of operation). In the multivariable analysis, tumor size >3 cm and no adjuvant chemotherapy were associated with early recurrence (P = .017 and P = .015, respectively). The Cox regression model showed that tumor size >3 cm and lymphovascular invasion were independent predictors of decreased recurrence-free and overall survival. CONCLUSION: Standard laparoscopic distal pancreatectomy is associated with satisfactory long-term oncologic outcomes in patients with pancreatic ductal adenocarcinoma. Several risk factors, such as tumor size >3 cm, no adjuvant chemotherapy, and lymphovascular invasion, are linked to poor prognosis after standard laparoscopic distal pancreatectomy.

Role of surgery in pancreatic cancer.

Treatment of pancreatic cancer is multimodal and surgery is an essential part, mandatory for curative potential. Also chemotherapy is essential, and serious postoperative complications or rapid disease progression may preclude completion of multimodal treatment. The sequence of treatment interventions has therefore become an important concern, and numerous ongoing randomized controlled trials compare clinical outcome after upfront surgery and neoadjuvant treatment with subsequent resection. In previous years, borderline resectable and locally advanced pancreatic cancer was most often considered unresectable. More effective chemotherapy together with the latest improvements in surgical expertise has resulted in extended operations, pushing the borders of resectability. Multivisceral resections with or without resection of major mesenteric vessels are now performed in numerous patients, resulting in better outcome, recorded as overall survival and/or patient reported outcome. But postoperative morbidity increases concurrently, and clinical benefit must be carefully evaluated against risk of potential harm, associated with new comprehensive multimodal treatment sequences. Even though cost/utility analyses are deficient, extended surgery has resulted in significantly longer and better life for many patients with no other treatment alternative. Improved selection of patients to surgery and/or chemotherapy will in the near future be possible, based on better tumor biology insight. Clinically available biomarkers enabling personalized treatment are forthcoming, but these options are still limited. The importance of surgical resection for each patient's prognosis is presently increasing, justifying sustained expansion of the surgical treatment modality.

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.

A Young, Immunocompetent Woman with Small Bowel and Hepatic Mucormycosis Successfully Treated with Aggressive Surgical Debridements and Antifungal Therapy.

A 24-year-old woman with coeliac disease and transient neutropenia developed mucormycosis with extensive involvement of the liver and small intestine. She was successfully treated with aggressive surgical debridements and long-term antifungal therapy with liposomal amphotericin B and posaconazole.

Perioperative outcomes and survival in elderly patients undergoing laparoscopic distal pancreatectomy.

BACKGROUND: The outcomes following laparoscopic distal pancreatectomy (LDP) in elderly patients have not been widely reported to date. This study aimed to analyze perioperative and oncologic outcomes in patients aged ≥70 years (elderly group) and compare with those <70 years (non-elderly group). METHODS: From April 1997 to September 2015, 402 consecutive patients with lesions in the body and tail of the pancreas underwent LDP at Rikshospitalet, Oslo University Hospital. RESULTS: Of these, 118 (29.4%) were elderly, whereas 284 (70.6%) were non-elderly. Despite higher rate of comorbidities and American Society of Anesthesiologists score (P = 0.001 and 0.001, respectively), elderly patients had lower postoperative morbidity, pancreatic fistula (PF) and readmission rates, compared with non-elderly (P = 0.032, 0.001 and 0.025, respectively). Spleen-preserving LDP (SPLDP) resulted in similar postoperative outcomes in the two groups. Elderly patients with pancreatic ductal adenocarcinoma (PDAC) were comparable to non-elderly in terms of median and 3-year survival (20.2 vs. 19 months (P = 0.94, log-rank) and 26.7% vs. 34.3%, respectively). CONCLUSIONS: Both LDP and SPLDP are safe in patients aged ≥70 years, providing outcomes similar to those in younger group. Elderly patients with PDAC can benefit from LDP, since age itself is not associated with decreased survival after surgery.

The Genomic Landscape of Pancreatic and Periampullary Adenocarcinoma.

Despite advances in diagnostics, less than 5% of patients with periampullary tumors experience an overall survival of five years or more. Periampullary tumors are neoplasms that arise in the vicinity of the ampulla of Vater, an enlargement of liver and pancreas ducts where they join and enter the small intestine. In this study, we analyzed copy number aberrations using Affymetrix SNP 6.0 arrays in 60 periampullary adenocarcinomas from Oslo University Hospital to identify genome-wide copy number aberrations, putative driver genes, deregulated pathways, and potential prognostic markers. Results were validated in a separate cohort derived from The Cancer Genome Atlas Consortium (n = 127). In contrast to many other solid tumors, periampullary adenocarcinomas exhibited more frequent genomic deletions than gains. Genes in the frequently codeleted region 17p13 and 18q21/22 were associated with cell cycle, apoptosis, and p53 and Wnt signaling. By integrating genomics and transcriptomics data from the same patients, we identified CCNE1 and ERBB2 as candidate driver genes. Morphologic subtypes of periampullary adenocarcinomas (i.e., pancreatobiliary or intestinal) harbor many common genomic aberrations. However, gain of 13q and 3q, and deletions of 5q were found specific to the intestinal subtype. Our study also implicated the use of the PAM50 classifier in identifying a subgroup of patients with a high proliferation rate, which had impaired survival. Furthermore, gain of 18p11 (18p11.21-23, 18p11.31-32) and 19q13 (19q13.2, 19q13.31-32) and subsequent overexpression of the genes in these loci were associated with impaired survival. Our work identifies potential prognostic markers for periampullary tumors, the genetic characterization of which has lagged. Cancer Res; 76(17); 5092-102. ©2016 AACR.

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.

Updated therapeutic outcome for patients with periampullary and pancreatic cancer related to recent translational research.

Chemotherapy with improved effect in patients with metastatic pancreatic cancer has recently been established, launching a new era for patients with this very aggressive disease. FOLFIRINOX and gemcitabine plus nab-paclitaxel are different regimens, both capable of stabilizing the disease, thus increasing the number of patients who can reach second line and even third line of treatment. Concurrently, new windows of opportunity open for nutritional support and other therapeutic interventions, improving quality of life. Also pancreatic surgery has changed significantly during the latest years. Extended operations, including vascular/multivisceral resections are frequently performed in specialized centers, pushing borders of resectability. Potentially curative treatment including neoadjuvant and adjuvant chemotherapy is offered new patient groups. Translational research is the basis for the essential understanding of the ongoing development. Even thou biomarkers for clinical management of patients with periampullary tumors have almost been lacking, biomarker driven trials are now in progress. New insight is constantly made available for clinicians; one recent example is selection of patients for gemcitabine treatment based on the expression level of the human equilibrium nucleoside transporter 1. An example of new diagnostic tools is identification of early pancreatic cancer patients by a three-biomarker panel in urine: The proteins lymphatic vessel endothelial hyaluronan receptor 1, regenerating gene 1 alpha and translation elongation factor 1 alpha. Requirement of treatment guideline revisions is intensifying, as combined chemotherapy regimens result in unexpected advantages. The European Study Group for Pancreatic Cancer 4 trial outcome is an illustration: Addition of capecitabine in the adjuvant setting improved overall survival more than expected from the effect in advanced disease. Rapid implementation of new treatment options is mandatory when progress finally extends to patients with this serious disease.