Human Type 1 Diabetes Is Characterized by an Early, Marked, Sustained, and Islet-Selective Loss of Sympathetic Nerves.

In humans, the glucagon response to moderate-to-marked insulin-induced hypoglycemia (IIH) is largely mediated by the autonomic nervous system. Because this glucagon response is impaired early in type 1 diabetes, we sought to determine if these patients, like animal models of autoimmune diabetes, have an early and severe loss of islet sympathetic nerves. We also tested whether this nerve loss is a permanent feature of type 1 diabetes, is islet-selective, and is not seen in type 2 diabetes. To do so, we quantified pancreatic islet and exocrine sympathetic nerve fiber area from autopsy samples of patients with type 1 or 2 diabetes and control subjects without diabetes. Our central finding is that patients with either very recent onset (<2 weeks) or long duration (>10 years) of type 1 diabetes have a severe loss of islet sympathetic nerves (Δ = -88% and Δ = -79%, respectively). In contrast, patients with type 2 diabetes lose no islet sympathetic nerves. There is no loss of exocrine sympathetic nerves in either type 1 or type 2 diabetes. We conclude that patients with type 1, but not type 2, diabetes have an early, marked, sustained, and islet-selective loss of sympathetic nerves, one that may impair their glucagon response to IIH.

Differential Insulitic Profiles Determine the Extent of ß-Cell Destruction and the Age at Onset of Type 1 Diabetes.

Type 1 diabetes (T1D) results from a T cell-mediated destruction of pancreatic ß-cells following the infiltration of leukocytes (including CD8(+), CD4(+), and CD20(+) cells) into and around pancreatic islets (insulitis). Recently, we reported that two distinct patterns of insulitis occur in patients with recent-onset T1D from the U.K. and that these differ principally in the proportion of infiltrating CD20(+) B cells (designated CD20Hi and CD20Lo, respectively). We have now extended this analysis to include patients from the Network for Pancreatic Organ Donors with Diabetes (U.S.) and Diabetes Virus Detection (DiViD) study (Norway) cohorts and confirm that the two profiles of insulitis occur more widely. Moreover, we show that patients can be directly stratified according to their insulitic profile and that those receiving a diagnosis before the age of 7 years always display the CD20Hi profile. By contrast, individuals who received a diagnosis beyond the age of 13 years are uniformly defined as CD20Lo. This implies that the two forms of insulitis are differentially aggressive and that patients with a CD20Hi profile lose their ß-cells at a more rapid rate. In support of this, we also find that the proportion of residual insulin-containing islets (ICIs) increases in parallel with age at the onset of T1D. Importantly, those receiving a diagnosis in, or beyond, their teenage years retain ∼40% ICIs at diagnosis, implying that a functional deficit rather than an absolute ß-cell loss may be causal for disease onset in these patients. We conclude that appropriate patient stratification will be critical for correct interpretation of the outcomes of intervention therapies targeted to islet-infiltrating immune cells in T1D.

Comparison of Methods to Identify Lymphatic and Blood Vessel Invasion and their Prognostic Value in Patients with Primary Operable Colorectal Cancer.

BACKGROUND/AIM: Lymphatic and blood vessel invasion are important independent prognostic factors in colorectal cancer, but identification of the separate components remains difficult. The aim of the present study was to compare routine hematoxylin and eosin (H&E) and elastica staining with immunohistochemistry using D2-40 and CD31. MATERIALS AND METHODS: A total of 75 surgical specimens of colorectal cancer were examined for blood and lymphatic vessel invasion, by comparing stains. RESULTS: The minimum clinical follow-up of survivors was 5 years. During that time, 45 patients died, 34 from their cancer. Lymphatic invasion by H&E was found in 19% compared to 40% detected with D2-40 (p<0.001). Lymphatic invasion was not associated with T-stage (H&E, p=0.923; D2-40, p=0.724) but was significantly associated with N-stage, (H&E, p=0.001; D2-40, p<0.001). No significant association between lymphatic invasion (H&E or D2-40) and cancer-specific survival was found on univariate analysis. Blood vessel invasion by elastic detection was detected in 53% compared to 32% detected with CD31 (p=0.090). Blood vessel invasion was associated with T-stage, (elastica, p=0.028; CD31, p=0.839) but was not associated with N-stage (elastica, p=0.377; CD31, p=0.519). On univariate analysis of blood vessel invasion was associated with cancer-specific survival (elastica, p=0.009) when detected by elastica, but not when detected by CD31, (p=0.611). Lymphatic invasion (D2-40) was associated with blood vessel invasion (elastic) (p=0.019). On multivariate analysis, blood vessel invasion with elastica had independent prognostic value (hazard ratio=2.55, 95% confidence interval=1.23-5.28; p=0.012). CONCLUSION: The results of the present study indicate that immunohistochemistry using D2-40 improves the identification of lymphatic invasion compared to use of H&E staining only; however, its prognostic value was limited. Elastica staining improves the detection rate of blood vessel invasion (compared to CD31) and venous invasion detected with elastica had independent prognostic value in patients undergoing curative resection for colorectal cancer.

Islet inflammation in human type 1 diabetes mellitus.

Type 1 diabetes mellitus (T1DM) is caused by the selective deletion of pancreatic ß-cells in response to an assault mounted within the pancreas by infiltrating immune cells. However, this apparently clear and focussed annunciation conceals a stark reality in which the cellular and molecular events leading to ß-cell loss remain poorly understood in humans. This reflects the difficulty of studying these processes in living individuals and the fact that, using pathological specimens, islet inflammation has been analysed in fewer than 200 recent-onset cases of T1DM worldwide, over the past century. Nevertheless, insights have been gained and the composition of the islet infiltrate is being disclosed. This is shown to be primarily lymphocytic in nature, with populations of both CD8+ and CD4+ T cells displaying an autoreactivity against specific islet antigenic peptides. The T cells are often accompanied by influent CD20+ B cells, although new data imply that the proportions of these individual cell types vary and that patients fall into at least two distinct categories having either a hyper-immune (CD20Hi) or a pauci-immune (CD20Lo) phenotype. The overall rate of ß-cell decline appears to correlate with these two phenotypes such that hyper-immune patients lose ß-cells more quickly and tend to develop disease at an earlier age than those with the pauci-immune profile. In this article, we review the evidence which underpins our current understanding of the aetiology of T1DM and highlight both the established features as well as areas of on-going ambiguity and debate.

Blood and islet phenotypes indicate immunological heterogeneity in type 1 diabetes.

Studies in type 1 diabetes indicate potential disease heterogeneity, notably in the rate of ß-cell loss, responsiveness to immunotherapies, and, in limited studies, islet pathology. We sought evidence for different immunological phenotypes using two approaches. First, we defined blood autoimmune response phenotypes by combinatorial, multiparameter analysis of autoantibodies and autoreactive T-cell responses in 33 children/adolescents with newly diagnosed diabetes. Multidimensional cluster analysis showed two equal-sized patient agglomerations characterized by proinflammatory (interferon-γ-positive, multiautoantibody-positive) and partially regulated (interleukin-10-positive, pauci-autoantibody-positive) responses. Multiautoantibody-positive nondiabetic siblings at high risk of disease progression showed similar clustering. Additionally, pancreas samples obtained post mortem from a separate cohort of 21 children/adolescents with recently diagnosed type 1 diabetes were examined immunohistologically. This revealed two distinct types of insulitic lesions distinguishable by the degree of cellular infiltrate and presence of B cells that we termed "hyper-immune CD20Hi" and "pauci-immune CD20Lo." Of note, subjects had only one infiltration phenotype and were partitioned by this into two equal-sized groups that differed significantly by age at diagnosis, with hyper-immune CD20Hi subjects being 5 years younger. These data indicate potentially related islet and blood autoimmune response phenotypes that coincide with and precede disease. We conclude that different immunopathological processes (endotypes) may underlie type 1 diabetes, carrying important implications for treatment and prevention strategies.

Pancreatic pathology in type 1 diabetes mellitus.

Type 1 diabetes is a multifactorial disease resulting from a complex interplay between host genetics, the immune system and the environment, that culminates in the destruction of insulin-producing beta cells. The incidence of type 1 diabetes is increasing at an alarming rate, especially in children under the age of 5 (Gepts in Diabetes 14(10):619-613, 1965; Foulis et al. in Lancet 29(5):267-274, 1986; Gamble, Taylor and Cumming in British Medical Journal 4(5887):260-262 1973). Genetic predisposition, although clearly important, cannot explain this rise, and so, it has been proposed that changes in the 'environment' and/or changes in 'how we respond to our environment' must contribute to this rising incidence. In order to gain an improved understanding of the factors influencing the disease process, it is important, firstly, to focus on the organ at the centre of the illness-the pancreas. This review summarises our knowledge of the pathology of the endocrine pancreas in human type 1 diabetes and, in particular, explores the progression of this understanding over the past 25 years.

The clinical utility of the combination of T stage and venous invasion to predict survival in patients undergoing surgery for colorectal cancer.

OBJECTIVE: To examine the clinical utility of improved detection of venous invasion (VI) in patients undergoing potentially curative resection of colorectal cancer. BACKGROUND: VI is a feature of colorectal cancer (CRC) progression. Elastica staining can be used to improve detection of VI and correspondingly its prediction of patient survival. METHODS: A single-center, observational study of pathology variables, including detection of VI by staining for elastica, using 631 stage I to III CRC specimens, collected from 1997 to 2009 (176 analyzed retrospectively and 455 analyzed prospectively), was performed. RESULTS: VI was detected in 56% of patients with CRC. Over a median follow-up period of 73 months, 238 patients died (134 from cancer). On multivariate analysis, VI by elastica staining was associated with a shorter survival duration, independent of other pathology features, in all cases [hazard ratio (HR) = 3.94, 95% confidence interval (CI): 2.33-6.65, P < 0.001] and in node-negative cases (HR = 3.55, 95% CI: 1.81-6.97; P < 0.001). In the absence of elastica-detected VI, with the exception of T stage, no other pathology features were associated with survival time. Therefore, the combination of T stage and VI (TVI) on survival was examined. Five-year cancer mortality could be stratified between 100% and 54% for patients with node-negative tumors and between 100% and 33% for patients with node-positive tumors. In all cases, the TVI had similar predictive value as that of T stage and node status (TNM). In node-negative disease, TVI had superior predictive value. CONCLUSIONS: The results of the present study have prompted the development of a novel tumor staging system based on TVI. The TVI has clinical utility, especially in node-negative disease, in predicting outcome following curative resection for CRC.

The clinical utility of the local inflammatory response in colorectal cancer.

BACKGROUND: The host immune response is important in the prevention of tumour progression in solid organ cancers. The aim was to evaluate the clinical utility of the local inflammatory response in patients with colorectal cancer. METHODS: Three hundred and sixty-five patients with primary operable colorectal cancer were included. The local inflammatory response was assessed using three different methods; (1) individual T-cell subtypes (CD3, CD8, CD45R0, FOXP3), (2) an immunohistochemistry-based immune score (Galon Immune Score) and (3) a histopathological assessment (Klintrup-Makinen grade). Relationships with tumour and host characteristics were established and the prognostic value of each method compared. RESULTS: A strong infiltration of tumour infiltrating lymphoctyes (TIL's) was associated with improved cancer-specific survival. When individual T-cell subtypes were considered, CD3-positive cells were the strongest predictor of survival at the invasive margin (CD3(+) IM) while CD8-positive cells were the strongest predictor in the cancer cell nests (CD8(+) CCN). Infiltration of T-cells was related to early tumour stage, expanding growth pattern and lower levels of venous invasion but was not influenced by host characteristics or degree of systemic inflammation. In summary, CD3(+) IM, CD8(+) CCN, The Galon Immune Score and the Klintrup-Makinen grade all exhibited similar survival relationships in both node-positive and node-negative colorectal cancer. CONCLUSION: A coordinated adaptive immune response is an important factor in predicting outcome in patients with primary operable colorectal cancer. By comparing different methodologies we have provided a foundation on which to develop a standardised approach for assessing the local inflammatory response in these patients.

Evaluation of the fidelity of immunolabelling obtained with clone 5D8/1, a monoclonal antibody directed against the enteroviral capsid protein, VP1, in human pancreas.

AIMS/HYPOTHESIS: Enteroviral infection has been implicated in the development of islet autoimmunity in type 1 diabetes and enteroviral antigen expression has been detected by immunohistochemistry in the pancreatic beta cells of patients with recent-onset type 1 diabetes. However, the immunohistochemical evidence relies heavily on the use of a monoclonal antibody, clone 5D8/1, raised against an enteroviral capsid protein, VP1. Recent data suggest that the clone 5D8/1 may also recognise non-viral antigens; in particular, a component of the mitochondrial ATP synthase (ATP5B) and an isoform of creatine kinase (CKB). Therefore, we evaluated the fidelity of immunolabelling by clone 5D8/1 in the islets of patients with type 1 diabetes. METHODS: Enteroviral VP1, CKB and ATP5B expression were analysed by western blotting, RT-PCR and immunocytochemistry in a range of cultured cell lines, isolated human islets and human tissue. RESULTS: Clone 5D8/1 labelled CKB, but not ATP5B, on western blots performed under denaturing conditions. In cultured human cell lines, isolated human islets and pancreas sections from patients with type 1 diabetes, the immunolabelling of ATP5B, CKB and VP1 by 5D8/1 was readily distinguishable. Moreover, in a human tissue microarray displaying more than 80 different cells and tissues, only two (stomach and colon; both of which are potential sites of enterovirus infection) were immunopositive when stained with clone 5D8/1. CONCLUSIONS/INTERPRETATION: When used under carefully optimised conditions, the immunolabelling pattern detected in sections of human pancreas with clone 5D8/1 did not reflect cross-reactivity with either ATP5B or CKB. Rather, 5D8/1 is likely to be representative of enteroviral antigen expression.

Histomolecular phenotypes and outcome in adenocarcinoma of the ampulla of vater.

PURPOSE: Individuals with adenocarcinoma of the ampulla of Vater demonstrate a broad range of outcomes, presumably because these cancers may arise from any one of the three epithelia that converge at that location. This variability poses challenges for clinical decision making and the development of novel therapeutic strategies. PATIENTS AND METHODS: We assessed the potential clinical utility of histomolecular phenotypes defined using a combination of histopathology and protein expression (CDX2 and MUC1) in 208 patients from three independent cohorts who underwent surgical resection for adenocarcinoma of the ampulla of Vater. RESULTS: Histologic subtype and CDX2 and MUC1 expression were significant prognostic variables. Patients with a histomolecular pancreaticobiliary phenotype (CDX2 negative, MUC1 positive) segregated into a poor prognostic group in the training (hazard ratio [HR], 3.34; 95% CI, 1.69 to 6.62; P < .001) and both validation cohorts (HR, 5.65; 95% CI, 2.77 to 11.5; P < .001 and HR, 2.78; 95% CI, 1.25 to 7.17; P = .0119) compared with histomolecular nonpancreaticobiliary carcinomas. Further stratification by lymph node (LN) status defined three clinically relevant subgroups: one, patients with histomolecular nonpancreaticobiliary (intestinal) carcinoma without LN metastases who had an excellent prognosis; two, those with histomolecular pancreaticobiliary carcinoma with LN metastases who had a poor outcome; and three, the remainder of patients (nonpancreaticobiliary, LN positive or pancreaticobiliary, LN negative) who had an intermediate outcome. CONCLUSION: Histopathologic and molecular criteria combine to define clinically relevant histomolecular phenotypes of adenocarcinoma of the ampulla of Vater and potentially represent distinct diseases with significant implications for current therapeutic strategies, the ability to interpret past clinical trials, and future trial design.

The prognostic influence of resection margin clearance following pancreaticoduodenectomy for pancreatic ductal adenocarcinoma.

INTRODUCTION: The poor overall survival associated with pancreatic ductal adenocarcinoma (PDAC) despite complete resection suggests that occult metastatic disease is present in most at the time of surgery. Resection margin involvement (R1) following resection is an established poor prognostic factor. However, the definition of an R1 resection varies and the impact of margin clearance on outcome has not been examined in detail. METHODS: In a cohort of 217 consecutive patients who underwent pancreaticoduodenectomy for PDAC with curative intent at a single institution between 1996 and 2011, the prognostic significance of the proximity of margin clearance was investigated. Microscopic margin clearance was stratified by 0.5 mm increments from tumor present at the margin to >2.0 mm. Groups were dichotomized into clear and involved groups according to the different R1 definitions. Multivariate survival analysis was used to establish independent prognostic factors. RESULTS: For the 38 patients (17.5 %) where the tumor was >1.5 mm from the closest involved margin, there was a significantly prolonged overall median survival (63.1 months; 95 % confidence interval, 32.5-93.8) compared to R1 resections (16.9 months; 95 % confidence interval, 14.5-19.4; P < 0.0001, log-rank test). This cutoff represented the optimum distance for predicting long-term survival. As margin clearance increased, R1 status became a more powerful independent predictor of outcome; however, margin clearance did not relate to site of tumor recurrence. CONCLUSION: These data demonstrate that margin clearance by at least 1.5 mm identifies a subgroup of patients which may potentially achieve long-term survival. This study further confirms the need to achieve standardization across pancreatic specimen reporting. Stratification of patients into future clinical trials based upon the degree of margin clearance may identify those patients likely to benefit from adjuvant therapy.

The relationship between tumor inflammatory cell infiltrate and outcome in patients with pancreatic ductal adenocarcinoma.

BACKGROUND: The tumor-associated inflammatory cell infiltrate is recognized to have prognostic value in various common solid tumors. However, the prognostic value of the tumor inflammatory cell infiltrate has not been established in pancreatic ductal adenocarcinoma (PDAC) nor has its relationship with the systemic inflammatory response. METHODS: Retrospective study was made of 173 patients who underwent surgery between 1997 and 2009. Routine pathology specimens were scored according to density of the tumor inflammatory cell infiltrate, and biochemical data were collected preoperatively. RESULTS: Low-grade tumor inflammatory cell infiltrate was associated with earlier tumor recurrence (P < 0.001) and particularly in the liver (P = 0.027). It was also associated with T3 tumors (P < 0.05), lymph node involvement (P < 0.05), and resection margin involvement (P < 0.05). On univariate survival analysis, age <65 years (P < 0.05), mGPS (P < 0.001), increased tumor stage (P < 0.01), nodal involvement (P < 0.01), size (P < 0.05), grade (P < 0.05), perineural invasion (P < 0.05), venous invasion (P < 0.01), resection margin involvement (P ≤ 0.001), vascular reconstruction (P < 0.05), and no adjuvant chemotherapy (P < 0.05) were associated with poor survival. In contrast, high-grade tumor inflammatory cell infiltrate was associated with better survival (P < 0.001). On multivariate survival analysis, mGPS [hazard ratio (HR): 1.77, 95% confidence interval (95% CI): 1.19-2.62, P = 0.005], tumor stage (HR: 2.21, 95% CI: 1.16-4.23, P = 0.016), resection margin involvement (HR: 2.19, 95% CI: 1.41-3.44, P = 0.001), venous invasion (HR: 1.79, 95% CI: 1.22-2.63, P = 0.003), tumor inflammatory cell infiltrate (HR: 0.37, 95% CI: 0.25-0.55, P = 0.0001), and adjuvant chemotherapy (P = 0.04) were independently prognostic. CONCLUSIONS: The results of the study show, for the first time, that the presence of a high-grade tumor inflammatory cell infiltrate is an independent predictor of prolonged overall survival following resection for PDAC. Furthermore, measures of the local and the systemic inflammatory response were inversely associated.

A comparison of inflammation-based prognostic scores in patients with cancer. A Glasgow Inflammation Outcome Study.

INTRODUCTION: Components of the systemic inflammatory response, combined to form inflammation-based prognostic scores (modified Glasgow Prognostic Score (mGPS), Neutrophil Lymphocyte Ratio (NLR), Platelet Lymphocyte Ratio (PLR), Prognostic Index (PI), Prognostic Nutritional Index (PNI)) have been associated with cancer specific survival. The aim of the present study was to compare the prognostic value of these scores. METHODS: Patients (n=27,031) who had an incidental blood sample taken between 2000 and 2007 for C-reactive protein, albumin, white cell, neutrophil, lymphocyte and platelet counts, as well as a diagnosis of cancer (Scottish Cancer Registry) were identified. Of this group 8759 patients who had been sampled within two years following their cancer diagnosis were studied. RESULTS: On follow up, there were 5163 deaths of which 4417 (86%) were cancer deaths. The median time from blood sampling to diagnosis was 1.7 months. An elevated mGPS, NLR, PLR, PI and PNI were predictive of a reduced cancer specific survival independent of age, sex and deprivation and tumour site (all p<0.001). The area under the receiver operator curves was greatest for mGPS and PI. Specifically, in colorectal cancer, an elevated mGPS and PI were predictive of a reduced cancer specific survival independent of age, sex, deprivation and tumour stage (both p<0.001). CONCLUSION: The results of the present study show that systemic inflammation-based scores, in particular the mGPS and PI, have prognostic value in cancer independent of tumour site. Based on the present results and the existing validation literature, the mGPS should be included in the routine assessment of all patients with cancer.

A prospective comparison of the prognostic value of tumor- and patient-related factors in patients undergoing potentially curative surgery for pancreatic ductal adenocarcinoma.

BACKGROUND: Outcome prediction after resection with curative intent for pancreatic ductal adenocarcinoma remains a challenge. There is increasing evidence that the presence of an ongoing systemic inflammatory response is associated with poor outcome in patients undergoing resection for a variety of common solid tumors. Our aim was to prospectively evaluate the prognostic value of tumor- and patient-related factors including the systemic inflammatory response in patients undergoing potentially curative surgery for pancreatic ductal adenocarcinoma of the head of pancreas. METHODS: The prognostic impact of tumor factors such as stage and host factors, including the systemic inflammatory response (modified Glasgow Prognostic Score [mGPS]), were evaluated in a prospective study of 135 patients who underwent elective pancreaticoduodenectomy for pancreatic ductal adenocarcinoma from January 2002 to April 2009. RESULTS: In addition to the established tumor-related pathological factors (in particular margin involvement; hazard ratio [HR] 2.82, 95% confidence interval [CI] 1.65-4.84, P < 0.001), an elevated mGPS (HR 2.26, 95% CI 1.43-3.57, P < 0.001) was independently associated with lower overall survival after pancreaticoduodenectomy. Additionally, in an adjuvant therapy subgroup of 74 patients, both margin involvement and an elevated mGPS remained independently associated with reduced overall survival. CONCLUSIONS: We have prospectively validated the influence of tumor-related and patient-related factors. Margin involvement and the preoperative mGPS were the most important determinants of overall survival in patients undergoing potentially curative pancreaticoduodenectomy. Furthermore, both had independent prognostic value in those patients receiving adjuvant chemotherapy. In the future, this may be considered a stratification factor for entry onto therapeutic trials.

Immunopathology of the human pancreas in type-I diabetes.

Type 1 diabetes is a chronic autoimmune disease characterised by the selective destruction of pancreatic beta (ß) cells. The understanding of the aetiology of this disease has increased dramatically in recent years by the study of tissue recovered from patients, from analysis of the responses of isolated islet and ß-cells in tissue culture and via the use of animal models. However, knowledge of the immunopathology of type 1 diabetes in humans is still relatively deficient due largely to the difficulty of accessing appropriate samples. Here we review the state of current knowledge in relation to the histopathological features of the disease in humans. We focus specifically on recent-onset type 1 diabetes cases since in such patients, evidence of the ongoing disease process is still present. We chart the progression of the disease by describing the characteristic features of the pancreas, consider the sequence of immune cell infiltration and discuss the abnormalities of MHC antigen expression. The possibility that these changes might derive from a persistent enteroviral infection of the islet beta cells is examined.

Peripancreatic fat invasion is an independent predictor of poor outcome following pancreaticoduodenectomy for pancreatic ductal adenocarcinoma.

BACKGROUND: Following pancreaticoduodenectomy for pancreatic ductal adenocarcinoma (PDAC), identification of peripancreatic fat tumor invasion promotes a tumor to stage T3. We sought to understand better the impact of histological peripancreatic fat invasion on prognosis and site of recurrence in a cohort of patients with PDAC. METHODS: We analyzed the patient demographics, outcome, and recurrence data that had been prospectively collected in 189 consecutive PDAC undergoing potentially curative pancreaticoduodenectomy between 1996 and 2009. Pathological features were reassessed for all patients. Survival outcome was compared using Kaplan-Meier/Cox proportional hazards analysis. The primary site of recurrence was defined as either locoregional or distant metastases. RESULTS: The median survival of this PDAC cohort was 18.9 months (95% confidence interval (CI) 15.7-22.2). Histological peripancreatic fat invasion was evident in 51 (27%) patients and was associated with lymph node metastases (p = 0.004) and larger tumor size (p = 0.015). The presence of peripancreatic fat invasion was associated with reduced overall survival following resection (12.4 months [95% CI 9.9-15.0]) when compared to those patients with no evidence of fat invasion (22.6 months [95% CI 18.5-26.7]; p < 0.0001). By multivariate survival analysis, independent predictors of overall survival included tumor grade (p = 0.002), lymph node involvement (p = 0.025), resection margin status (p = 0.003), venous invasion (p = 0.045), and peripancreatic fat invasion (p = 0.007). Invasion into the pancreatic fat was significantly associated with the primary site of recurrence being locoregional failure (p = 0.002). CONCLUSIONS: Peripancreatic fat invasion was identified as being an independent predictor of poor outcome following pancreaticoduodenectomy for PDAC. Additionally, the presence of peripancreatic fat invasion was associated with locoregional disease as the primary site of recurrence. This may have implications for the staging of PDAC and potentially require incorporation into future staging systems to improve outcome stratification.