Euan J. Dickson

RE: nab-Paclitaxel Plus Gemcitabine for Metastatic Pancreatic Cancer: Long-Term Survival From a Phase III Trial.

We read with interest the article by Goldstein and colleagues that reports the long-term results of the large phase III randomized trial (IMPACT) of nab-paclitaxel plus gemcitabine or gemcitabine alone in patients with metastatic pancreatic cancer, extending support for the superior efficacy of this combination therapy (1). They reported that the presence of a systemic inflammatory response, as evidenced by an elevated neutrophil lymphocyte ratio (NLR), effectively stratified survival independent of the trial treatment. A pooled treatment analysis demonstrated that patients with an NLR of 5 or less had a statistically significantly prolonged survival compared with patients with an NLR of more than 5 (median = 9.1 vs 5.0 months, P < .001). In the nab-Paclitaxel plus gemcitabine arm there was a statistically significantly longer overall survival vs the gemcitabine arm alone in patients with an NLR of 5 or less (P < .001). Furthermore, when there was evidence of a raised systemic inflammatory response, a trend was evident favoring prolonged survival in the nab-paclitaxel plus gemcitabine arm vs the gemcitabine alone group (P = .079). These results confirm our previous observations in patients with pancreatic adenocarcinoma, that an elevated NLR is an important independent prognostic factor (2). However, there is good evidence that assessment of the systemic inflammatory response using acute phase proteins, in particular C-reactive protein (CRP) and albumin (Glasgow Prognostic Score [GPS]) has superior prognostic value in a variety of common solid tumors (3), including pancreatic cancer both in resectable and nonresectable forms (2). Therefore, it is clear that even in such a poor-prognosis tumor as pancreatic cancer outcomes can be stratified according to the systemic inflammatory response. This new knowledge offers the possibility for simple and effective stratification for patients with this difficult-to-treat cancer. For heterogeneous cancers, in particular pancreatic cancer, a stratified medicine approach offers potential to target an individual’s cancer with the right treatment for the right patient (4). This strategy could improve overall outcomes and quality of life for patients by minimizing unnecessary side effects arising from ineffective therapies. However, as demonstrated in the present study, the concept of stratification should not be limited to tumoror gene-centric aspects but extended to consider patient or host aspects including the burden of the systemic inflammatory response. Moreover, beyond stratification there is also an opportunity for therapeutic targeting of the systemic inflammatory response. Given the role of JAK-STAT signaling in the inflammatory responses of patients with pancreatic cancer (5), it is of interest that a recent randomized phase II trial of the JAK1/JAK2 inhibitor ruxolitinib combined with capecitabine in patients with metastatic pancreatic cancer revealed a statistically significantly prolonged survival for those patients who were administered ruxolitinib with coexisting evidence of an elevated systemic inflammatory response, as measured by CRP and/or the modified GPS (6). It is also of interest that nab-paclitaxel itself has potential to alter the tumor stroma and immune environment (7). In summary, the work of Goldstein and colleagues (1) confirms the prognostic value of the systemic inflammatory response in patients with metastatic pancreatic cancer. Furthermore, it heralds a new era in which the systemic inflammatory response becomes a legitimate target for treatment of these patients.

MicroRNA Molecular Profiles Associated with Diagnosis, Clinicopathologic Criteria, and Overall Survival in Patients with Resectable Pancreatic Ductal Adenocarcinoma

Purpose: MicroRNAs (miRNA) have potential as diagnostic and prognostic biomarkers and as therapeutic targets in cancer. We sought to establish the relationship between miRNA expression and clinicopathologic parameters, including prognosis, in pancreatic ductal adenocarcinoma (PDAC). Experimental Design: Global miRNA microarray expression profiling of prospectively collected fresh-frozen PDAC tissue was done on an initial test cohort of 48 patients, who had undergone pancreaticoduodenectomy between 2003 and 2008 at a single institution. We evaluated association with tumor stage, lymph node status, and site of recurrence, in addition to overall survival, using Cox regression multivariate analysis. Validation of selected potentially prognostic miRNAs was done in a separate cohort of 24 patients. Results: miRNA profiling identified expression signatures associated with PDAC, lymph node involvement, high tumor grade, and 20 miRNAs were associated with overall survival. In the initial cohort of 48 PDAC patients, high expression of miR-21 (HR = 3.22, 95% CI: 1.21–8.58) and reduced expression of miR-34a (HR = 0.15, 95% CI: 0.06–0.37) and miR-30d (HR = 0.30, 95% CI: 0.12–0.79) were associated with poor overall survival following resection independent of clinical covariates. In a further validation set of 24 patients, miR-21 and miR-34a expression again significantly correlated with overall survival (P = 0.031 and P = 0.001). Conclusion: Expression patterns of miRNAs are significantly altered in PDAC. Aberrant expression of a number of miRNAs was independently associated with reduced survival, including overexpression of miR-21 and underexpression of miR-34a. Summary: miRNA expression profiles for resected PDAC were examined to identify potentially prognostic miRNAs. miRNA microarray analysis identified statistically unique profiles, which could discriminate PDAC from paired nonmalignant pancreatic tissues as well as molecular signatures that differ according to pathologic features. miRNA expression profiles correlated with overall survival of PDAC following resection, indicating that miRNAs provide prognostic utility. Clin Cancer Res; 18(2); 534–45. ©2011 AACR.

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 ≤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.

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.

Hypermutation In Pancreatic Cancer

Pancreatic cancer is molecularly diverse, with few effective therapies. Increased mutation burden and defective DNA repair are associated with response to immune checkpoint inhibitors in several other cancer types. We interrogated 385 pancreatic cancer genomes to define hypermutation and its causes. Mutational signatures inferring defects in DNA repair were enriched in those with the highest mutation burdens. Mismatch repair deficiency was identified in 1% of tumors harboring different mechanisms of somatic inactivation of MLH1 and MSH2. Defining mutation load in individual pancreatic cancers and the optimal assay for patient selection may inform clinical trial design for immunotherapy in pancreatic cancer.

Incorporation of Procedure-specific Risk Into the ACS-NSQIP Surgical Risk Calculator Improves the Prediction of Morbidity and Mortality After Pancreatoduodenectomy.

Objective: This multicenter study sought to evaluate the accuracy of the American College of Surgeons National Surgical Quality Improvement Programs (ACS-NSQIP) surgical risk calculator for predicting outcomes after pancreatoduodenectomy (PD) and to determine whether incorporating other factors improves its predictive capacity. Background: The ACS-NSQIP surgical risk calculator has been proposed as a decision-support tool to predict complication risk after various operations. Although it considers 21 preoperative factors, it does not include procedure-specific variables, which have demonstrated a strong predictive capacity for the most common and morbid complication after PD – clinically relevant pancreatic fistula (CR-POPF). The validated Fistula Risk Score (FRS) intraoperatively predicts the occurrence of CR-POPF and serious complications after PD. Methods: This study of 1480 PDs involved 47 surgeons at 17 high-volume institutions. Patient complication risk was calculated using both the universal calculator and a procedure-specific model that incorporated the FRS and surgeon/institutional factors. The performance of each model was compared using the c-statistic and Brier score. Results: The FRS was significantly associated with 30-day mortality, 90-day mortality, serious complications, and reoperation (all P < 0.0001). The procedure-specific model outperformed the universal calculator for 30-day mortality (c-statistic: 0.79 vs 0.68; Brier score: 0.020 vs 0.021), 90-day mortality, serious complications, and reoperation. Neither surgeon experience nor institutional volume significantly predicted mortality; however, surgeons with a career PD volume >450 were less likely to have serious complications (P < 0.001) or perform reoperations (P < 0.001). Conclusions: Procedure-specific complication risk influences outcomes after pancreatoduodenectomy; therefore, risk adjustment for performance assessment and comparative research should consider these preoperative and intraoperative factors along with conventional ACS-NSQIP preoperative variables.

Genetics of Response to Proton Pump Inhibitor Therapy

Proton pump inhibitors (PPIs) are highly effective agents for the treatment of gastric acid-related disorders. They are metabolized by the cytochrome P450 (CYP) system, mainly via the enzyme CYP2C19. A genetically determined defect in this pathway results in impaired metabolism of PPIs, giving rise to three distinct phenotypes: rapid extensive (fast), extensive (medium), and poor (slow) metabolizers. These genetic mutations are more common in certain races, and there is, therefore, considerable inter-individual and -ethnic variation in the capacity to metabolize PPIs.The incidence of mutant alleles in a population treated for acid-related disorders may influence the efficacy of the treatment, with clinical implications for the prescribers of PPIs. Therapeutic failure, such as lack of symptom relief, or ineffective Helicobacter pylori eradication, can occur in rapid metabolizers who will have less available drug at a given dose. Conversely, poor metabolizers may be at risk of over-treatment, with increased incidence of adverse effects and unnecessary financial burden.Approaches to this problem include phenotyping or, preferably, genotyping patients prior to treatment with PPIs. This will allow tailoring dose regimens to the individual’s metabolic capacity. An alternative strategy is the development of drugs that are either metabolized by genotype-independent pathways or are less susceptible to inter-individual genetic variation. Non-racemic PPIs fall into the latter category, and the first such agent, esomeprazole, is now commercially available.

Serum amylase on the night of surgery predicts clinically significant pancreatic fistula after pancreaticoduodenectomy

OBJECTIVES Drainage after pancreaticoduodenectomy (PD) remains controversial because the risk for uncontrolled postoperative pancreatic fistula (POPF) must be balanced against the potential morbidity associated with prolonged and possibly unnecessary drainage. This study investigated the utility of the level of serum amylase on the night of surgery [postoperative day (PoD) 0 serum amylase] to predict POPF. METHODS A total of 185 patients who underwent PD were studied. Occurrences of POPF were graded using the International Study Group on Pancreatic Fistula (ISGPF) classification. Receiver operating characteristic (ROC) analysis identified a threshold value of PoD 0 serum amylase associated with clinically significant POPF (ISGPF Grades B and C) in a test cohort (n = 45). The accuracy of this threshold value was then tested in a validation cohort (n = 140). RESULTS Overall, 43 (23.2%) patients developed clinically significant POPF. The threshold value of PoD 0 serum amylase for the identification of clinically significant POPF was ≥ 130 IU/l (P = 0.003). Serum amylase of <130 IU/l had a negative predictive value of 88.8% for clinically significant POPF (P < 0.001). Serum amylase of ≥ 130 IU/l on PoD 0 and a soft pancreatic parenchyma were independent risk factors for clinically significant POPF. CONCLUSIONS Postoperative day 0 serum amylase of <130 IU/l allows for the early and accurate categorization of patients at least risk for clinically significant POPF and may identify patients suitable for early drain removal.

Pre‐operative cardiopulmonary exercise testing predicts adverse post‐operative events and non‐progression to adjuvant therapy after major pancreatic surgery

BACKGROUND Surgery followed by chemotherapy is the primary modality of cure for patients with resectable pancreatic cancer but is associated with significant morbidity. The aim of the present study was to evaluate the role of cardiopulmonary exercise testing (CPET) in predicting post-operative adverse events and fitness for chemotherapy after major pancreatic surgery. METHODS Patients who underwent a pancreaticoduodenectomy or total pancreatectomy for pancreatic head lesions and had undergone pre-operative CPET were included in this retrospective study. Data on patient demographics, comorbidity and results of pre-operative evaluation were collected. Post-operative adverse events, hospital stay and receipt of adjuvant therapy were outcome measures. RESULTS One hundred patients were included. Patients with an anaerobic threshold less than 10 ml/kg/min had a significantly greater incidence of a post-operative pancreatic fistula [International Study Group for Pancreatic Surgery (ISGPS) Grades A-C, 35.4% versus 16%, P = 0.028] and major intra-abdominal abscesses [Clavien-Dindo (CD) Grades III-V, 22.4% versus 7.8%, P = 0.042] and were less likely to receive adjuvant therapy [hazard ratio (HR) 6.30, 95% confidence interval (CI) 1.25-31.75, P = 0.026]. A low anaerobic threshold was also associated with a prolonged hospital stay (median 20 versus 14 days, P = 0.005) but not with other adverse events. DISCUSSION CPET predicts a post-operative pancreatic fistula, major intra-abdominal abscesses as well as length of hospital stay after major pancreatic surgery. Patients with a low anaerobic threshold are less likely to receive adjuvant therapy.

‘Step‐port’ laparoscopic cystgastrostomy for the management of organized solid predominant post‐acute fluid collections after severe acute pancreatitis

BACKGROUND Post-acute pancreatic collections (PAPCs) may require intervention when persistent, large or symptomatic. An open cystgastrostomy is an effective treatment option particularly for larger, solid predominant collections. A laparoscopic cystgastrostomy (LCG) as initially described, could be technically challenging. This report describes the evolution of the operative technique and the results from LCG in a tertiary referral centre. METHODS Retrospective analysis of the units prospectively populated database was conducted. All patients who underwent a surgical cystgastrostomy (SCG) were identified. Patient demographics, outcome and complications were collected and analysed. RESULTS Forty-four patients underwent SCG: 8 open and 36 laparoscopic. Of the 36 LCG, 6 required open conversion, although with evolution of the technique all of the last 17 cases were completed laparoscopically. The median interquartile range (IQR) length of stay in patients completed laparoscopically was 6 (2-10) compared with 15.5 days (8-19) in those patients who were converted (P = 0.0351). The only peri-operative complication after a LCG was a self-limiting upper gastrointestinal bleed. With a median (IQR) follow-up of 891 days (527-1495) one patient required re-intervention for a residual collection with no recurrent collections identified. CONCLUSION LCG is a safe and effective procedure in patients with large, solid predominant PAPCs. With increased experience and technical expertise conversion rates can be lowered and outcome optimized.