Host systemic inflammatory response influences outcome in pancreatic cancer.

This review of the influence of host systemic inflammatory response(SIR) on the outcome of pancreatic ductal adenocarcinoma (PDAC)was the kernel of the 2014 George E Palade Memorial Prize Lecture at the Combined IAP-EPC Meeting held June 25-8 in Southampton,UK. The ability of the modified Glasgow Prognostic Score(mGPS) to stratify cancer outcomes has been demonstrated in >50 studies including >25000 patients from many countries. Other markers of SIR such as Prognostic Index and neutrophil/lymphocyte ratio(NLR) may also be used emphasising the non homogeneity of the PDAC patients. The mGPS score 0 is associated with better outcome,while scores of 1 & 2 are linked to poor performance status, greater weight loss, comorbidity and earlier death. Two papers show in resectable PDAC that longer life (27-37 months) occurs with mGPS 0, and < 18 months for mGPS 1 and 2, such that alternative therapy employing RFA may well be better than resection in those patients. In the greater number of PDAC patients unsuitable for resection the JAK-STAT inhibitor, ruxolitinib, has been found only to favourably modify PDAC in those with mGPS 1 or 2. Likewise the possible benefits of older anti inflammatory agents may be confined to these patients. An urgent reappraisal of the prognostic and therapeutic implications is now required in PDAC. Local inflammatory responses(LIR) are beneficial in PDAC and other cancers. Four grade stratification systems using Klintrup histology, T cell subtype analysis and Galon immune scores are accurate prognosticators.

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 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.

Positive mobilization margins alone do not influence survival following pancreatico-duodenectomy for pancreatic ductal adenocarcinoma.

OBJECTIVE: To determine the prognostic influence of residual tumor at or within 1 mm of the mobilization margins (R1Mobilization) compared with transection margins (R1Transection) following pancreaticoduodenectomy for pancreatic ductal adenocarcinoma (PDAC). BACKGROUND: The prognostic strength of R1 status increases with frequency of margin positivity and is enhanced by protocol driven pathology reporting. Currently, margins are treated uniformly with tumor at or close to any margin considered of equal prognostic significance. The resection involves a mobilization phase freeing the posterior margin and anterior surface then a transection phase requiring lympho-vascular division forming the medial resection and pancreatic transection margin. The comparative assessment of the relative importance of tumor involvement of these different margins has not previously been investigated. METHODS: Retrospective analysis of 148 consecutive resections for PDAC from 1996-2007 was performed. The individual (pancreatic transection, medial, posterior, and anterior surface) margins were separately identified and analyzed by a senior pathologist. An R1 resection was defined as microscopic evidence of tumor < or = 1 mm from a resection margin. R1Mobilization tumor extension included both R1Anterior and R1Posterior cases; while R1Transection included pancreatic neck/body transection, R1Medial and adjacent transection margins. RESULTS: R1 status was confirmed in 109 patients (74%). The medial (46%) and posterior (44%) margins were most commonly involved. R1 status was found to an independent predictor of poor outcome (P < 0.001). R1Mobilization involvement only (n = 48) was associated with a significantly longer median survival of 18.9 months (95% CI, 13.7-24.8) versus 11.1 months (95% CI, 7.1-15.0) for those with R1Transection tumor involvement (n = 61) (P < 0.001). There was no significant difference in the survival of the R1Mobilization compared with R0 group (P = 0.52). CONCLUSIONS: Following pancreaticoduodenectomy for PDAC, involvement of the transection margins in contrast to mobilization margins defines a group whose outcome is significantly worse. This may impact upon the allocation of adjuvant therapy within the setting of randomized controlled trials.

'Do not put off the writing ... unpublished work effectively does not exist!'. An Interview with Clem W. Imrie, Emeritus Professor of Surgery, West of Scotland Pancreatic Unit, Royal Infirmary, Glasgow, UK. [Interviewed by Martín E Fernández-Zapico].

In this interview, Professor Clem W. Imrie shares with Pancreatology his life experience as a surgeon and scientist in pancreatic research. He is a world-recognized pancreatologist for his contribution to the understanding of pancreatic diseases; his work on the characterization of pathogenesis as well as the treatment of pancreatitis has been seminal. and IAP.

Extended pancreatectomy in pancreatic ductal adenocarcinoma: definition and consensus of the International Study Group for Pancreatic Surgery (ISGPS).

BACKGROUND: Complete macroscopic tumor resection is one of the most relevant predictors of long-term survival in pancreatic ductal adenocarcinoma. Because locally advanced pancreatic tumors can involve adjacent organs, "extended" pancreatectomy that includes the resection of additional organs may be needed to achieve this goal. Our aim was to develop a common consistent terminology to be used in centers reporting results of pancreatic resections for cancer. METHODS: An international panel of pancreatic surgeons working in well-known, high-volume centers reviewed the literature on extended pancreatectomies and worked together to establish a consensus on the definition and the role of extended pancreatectomy in pancreatic cancer. RESULTS: Macroscopic (R1) and microscopic (R0) complete tumor resection can be achieved in patients with locally advanced disease by extended pancreatectomy. Operative time, blood loss, need for blood transfusions, duration of stay in the intensive care unit, and hospital morbidity, and possibly also perioperative mortality are increased with extended resections. Long-term survival is similar compared with standard resections but appears to be better compared with bypass surgery or nonsurgical palliative chemotherapy or chemoradiotherapy. It was not possible to identify any clear prognostic criteria based on the specific additional organ resected. CONCLUSION: Despite increased perioperative morbidity, extended pancreatectomy is warranted in locally advanced disease to achieve long-term survival in pancreatic ductal adenocarcinoma if macroscopic clearance can be achieved. Definitions of extended pancreatectomies for locally advanced disease (and not distant metastatic disease) are established that are crucial for comparison of results of future trials across different practices and countries, in particular for those using neoadjuvant therapy.

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.

Evaluation of an inflammation-based prognostic score in patients with inoperable pancreatic cancer.

BACKGROUND/AIMS: Patients with pancreatic cancer have one of the poorest survival rates and selection of patients for active treatment remains problematical. The present study assesses the value of an inflammation-based score (Glasgow Prognostic Score, GPS) in patients with inoperable pancreatic cancer. METHODS: The GPS was constructed as follows: patients with both an elevated C-reactive protein (>10 mg/l) and hypoalbuminaemia (<35 g/l) were allocated a score of 2. Patients in whom only 1 or none of these biochemical abnormalities was present were allocated a score of 1 or 0, respectively. RESULTS: One hundred and eighty-seven patients were studied and 49 (26%) underwent an operative palliative bypass procedure. At the end of follow-up, 181 (97%) patients died, 17% of patients were alive at 12 months. On univariate analysis, age (p < 0.01), TNM stage (p < 0.001) and the GPS (p < 0.001) were significant predictors of survival. On multivariate survival analysis, stratified for bypass procedure, age (hazard ratio 1.53, 95%CI 1.12-2.10, p = 0.008), TNM stage (hazard ratio 1.70, 95%CI 1.33-2.18, p < 0.001) and the GPS (hazard ratio 1.72, 95%CI 1.40-2.11, p < 0.001) remained independent significant predictors of survival. CONCLUSION: At diagnosis, the presence of a systemic inflammatory response (as measured by the GPS) appears to be a useful indicator of poor outcome, independent of TNM stage, in patients with inoperable pancreatic cancer.