C. Ross Carter

Percutaneous Necrosectomy and Sinus Tract Endoscopy in the Management of Infected Pancreatic Necrosis: An Initial Experience

ObjectiveTo describe the development of a minimally invasive technique aimed at surgical debridement in addition to simple drainage of the abscess cavity. Summary Background DataSurgical intervention for secondary infection of pancreatic necrosis is associated with a death rate of 25% to 40%. Although percutaneous approaches may drain the abscess, they have often failed in the long term as a result of inability to remove the necrotic material adequately. MethodsFourteen consecutive patients with infected necrosis secondary to acute pancreatitis were studied. The initial four patients underwent sinus tract endoscopy along a drainage tract for secondary sepsis after prior open necrosectomy. This technique was then modified to allow primary debridement for proven sepsis to be carried out percutaneously in a further 10 patients. The techniques and initial results are described. ResultsAdditional surgery for sepsis was successfully avoided in the initial four patients managed by sinus tract endoscopy, and none died. Of the following 10 patients managed by percutaneous necrosectomy, 2 died. The median inpatient stay was 42 days. There was one conversion for intraoperative bleeding. Eight patients recovered and were discharged from the hospital after a median of three percutaneous explorations. Only 40% of patients required intensive care management after surgery. ConclusionsThese initial results in an unselected group of patients are encouraging and show that unlike with percutaneous or endoscopic techniques, both resolution of sepsis and adequate necrosectomy can be achieved. The authors’ initial impression of a reduction in postoperative organ dysfunction is particularly interesting; however, the technique requires further evaluation in a larger prospective series.

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.

CXCR2 Inhibition Profoundly Suppresses Metastases and Augments Immunotherapy in Pancreatic Ductal Adenocarcinoma.

Summary CXCR2 has been suggested to have both tumor-promoting and tumor-suppressive properties. Here we show that CXCR2 signaling is upregulated in human pancreatic cancer, predominantly in neutrophil/myeloid-derived suppressor cells, but rarely in tumor cells. Genetic ablation or inhibition of CXCR2 abrogated metastasis, but only inhibition slowed tumorigenesis. Depletion of neutrophils/myeloid-derived suppressor cells also suppressed metastasis suggesting a key role for CXCR2 in establishing and maintaining the metastatic niche. Importantly, loss or inhibition of CXCR2 improved T cell entry, and combined inhibition of CXCR2 and PD1 in mice with established disease significantly extended survival. We show that CXCR2 signaling in the myeloid compartment can promote pancreatic tumorigenesis and is required for pancreatic cancer metastasis, making it an excellent therapeutic target.

Tissue Biomarkers for Prognosis in Pancreatic Ductal Adenocarcinoma: A Systematic Review and Meta-analysis

Purpose: The management of pancreatic ductal adenocarcinoma (PDAC) continues to present a great challenge particularly with regard to prediction of outcome following pancreaticoduodenectomy. Molecular markers have been extensively investigated by numerous groups with the aim of enhancing prognostication; however, despite hundreds of studies that have sought to assess the potential prognostic value of molecular markers in predicting the clinical course following resection of PDAC, at this time, no molecular marker assay forms part of recommended clinical practice. Experimental Design: We conducted a systematic review and meta-analysis of the published literature for immunohistochemistry-based biomarkers of PDAC outcome. A dual search strategy was applied to the PubMed database on January 6, 2010, to identify cohort studies that reported associations between immunohistochemical biomarker expression and survival outcomes in PDAC, and conformed to the REMARK (REporting recommendations for tumor MARKer prognostic studies) criteria. Results: A total of 103 distinct proteins met all inclusion criteria. Promising markers that emerged for the prediction of overall survival included BAX (HR = 0.31, 95% CI: 0.71–0.56), Bcl-2 (HR = 0.41, 95% CI: 0.27–0.63), survivin (HR = 0.46, 95% CI: 0.29–0.73), Ki-67: (HR = 2.42, 95% CI: 1.87–3.14), COX-2 (HR = 1.39, 95% CI: 1.13–1.71), E-cadherin (HR = 1.80, 95% CI: 1.33–2.42), and S100 calcium-binding proteins, in particular S100A2 (HR = 3.23, 95% CI: 1.58–6.62). Conclusions: We noted that that there was incomplete adherence to the REMARK guidelines with inadequate methodology reporting as well as failure to perform multivariate analysis. Addressing the persistent incomplete adoption of these criteria may eventually result in the incorporation of molecular marker assessment within PDAC management algorithms. Clin Cancer Res; 17(10); 3316–31. ©2011 AACR.

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.

Targeting mTOR dependency in pancreatic cancer

Objective Pancreatic cancer is a leading cause of cancer-related death in the Western world. Current chemotherapy regimens have modest survival benefit. Thus, novel, effective therapies are required for treatment of this disease. Design Activating KRAS mutation almost always drives pancreatic tumour initiation, however, deregulation of other potentially druggable pathways promotes tumour progression. PTEN loss leads to acceleration of KrasG12D-driven pancreatic ductal adenocarcinoma (PDAC) in mice and these tumours have high levels of mammalian target of rapamycin (mTOR) signalling. To test whether these KRAS PTEN pancreatic tumours show mTOR dependence, we compared response to mTOR inhibition in this model, to the response in another established model of pancreatic cancer, KRAS P53. We also assessed whether there was a subset of pancreatic cancer patients who may respond to mTOR inhibition. Results We found that tumours in KRAS PTEN mice exhibit a remarkable dependence on mTOR signalling. In these tumours, mTOR inhibition leads to proliferative arrest and even tumour regression. Further, we could measure response using clinically applicable positron emission tomography imaging. Importantly, pancreatic tumours driven by activated KRAS and mutant p53 did not respond to treatment. In human tumours, approximately 20% of cases demonstrated low PTEN expression and a gene expression signature that overlaps with murine KRAS PTEN tumours. Conclusions KRAS PTEN tumours are uniquely responsive to mTOR inhibition. Targeted anti-mTOR therapies may offer clinical benefit in subsets of human PDAC selected based on genotype, that are dependent on mTOR signalling. Thus, the genetic signatures of human tumours could be used to direct pancreatic cancer treatment in the future.

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.

Fascin Is Regulated by Slug, Promotes Progression of Pancreatic Cancer in Mice, and Is Associated With Patient Outcomes

Background & Aims Pancreatic ductal adenocarcinoma (PDAC) is often lethal because it is highly invasive and metastasizes rapidly. The actin-bundling protein fascin has been identified as a biomarker of invasive and advanced PDAC and regulates cell migration and invasion in vitro. We investigated fascin expression and its role in PDAC progression in mice. Methods We used KRasG12D p53R172H Pdx1-Cre (KPC) mice to investigate the effects of fascin deficiency on development of pancreatic intraepithelial neoplasia (PanIn), PDAC, and metastasis. We measured levels of fascin in PDAC cell lines and 122 human resected PDAC samples, along with normal ductal and acinar tissues; we associated levels with patient outcomes. Results Pancreatic ducts and acini from control mice and early-stage PanINs from KPC mice were negative for fascin, but approximately 6% of PanIN3 and 100% of PDAC expressed fascin. Fascin-deficient KRasG12D p53R172H Pdx1-Cre mice had longer survival times, delayed onset of PDAC, and a lower PDAC tumor burdens than KPC mice; loss of fascin did not affect invasion of PDAC into bowel or peritoneum in mice. Levels of slug and fascin correlated in PDAC cells; slug was found to regulate transcription of Fascin along with the epithelial−mesenchymal transition. In PDAC cell lines and cells from mice, fascin concentrated in filopodia and was required for their assembly and turnover. Fascin promoted intercalation of filopodia into mesothelial cell layers and cell invasion. Nearly all human PDAC samples expressed fascin, and higher fascin histoscores correlated with poor outcomes, vascular invasion, and time to recurrence. Conclusions The actin-bundling protein fascin is regulated by slug and involved in late-stage PanIN and PDAC formation in mice. Fascin appears to promote formation of filopodia and invasive activities of PDAC cells. Its levels in human PDAC correlate with outcomes and time to recurrence, indicating it might be a marker or therapeutic target for pancreatic cancer.

Infected pancreatic necrosis: minimizing the cut

The challenge for the pancreatologist managing patients with infected pancreatic necrosis is to devise a treatment algorithm that enables recovery but at the same time limits the morbidity and mortality. The current gold standard remains open necrosectomy. Recent literature contains scattered reports of endoscopic, radiologic, laparoscopic, percutaneous and lumbotomy approaches to managing patients with this condition. This literature review addresses the role of techniques that aim to minimize the physiological insult to the patient with infected pancreatic necrosis.