James F. Griffin

Circulating Tumor Cell Phenotype Predicts Recurrence and Survival in Pancreatic Adenocarcinoma

Objective: We assessed circulating tumor cells (CTCs) with epithelial and mesenchymal phenotypes as a potential prognostic biomarker for patients with pancreatic adenocarcinoma (PDAC). Background: PDAC is the fourth leading cause of cancer death in the United States. There is an urgent need to develop biomarkers that predict patient prognosis and allow for better treatment stratification. Methods: Peripheral and portal blood samples were obtained from 50 patients with PDAC before surgical resection and filtered using the Isolation by Size of Epithelial Tumor cells method. CTCs were identified by immunofluorescence using commercially available antibodies to cytokeratin, vimentin, and CD45. Results: Thirty-nine patients (78%) had epithelial CTCs that expressed cytokeratin but not CD45. Twenty-six (67%) of the 39 patients had CTCs which also expressed vimentin, a mesenchymal marker. No patients had cytokeratin-negative and vimentin-positive CTCs. The presence of cytokeratin-positive CTCs (P < 0.01), but not mesenchymal-like CTCs (P = 0.39), was associated with poorer survival. The presence of cytokeratin-positive CTCs remained a significant independent predictor of survival by multivariable analysis after accounting for other prognostic factors (P < 0.01). The detection of CTCs expressing both vimentin and cytokeratin was predictive of recurrence (P = 0.01). Among patients with cancer recurrence, those with vimentin-positive and cytokeratin-expressing CTCs had decreased median time to recurrence compared with patients without CTCs (P = 0.02). Conclusions: CTCs are an exciting potential strategy for understanding the biology of metastases, and provide prognostic utility for PDAC patients. CTCs exist as heterogeneous populations, and assessment should include phenotypic identification tailored to characterize cells based on epithelial and mesenchymal markers.

Targeted DNA Sequencing Reveals Patterns of Local Progression in the Pancreatic Remnant Following Resection of Intraductal Papillary Mucinous Neoplasm (IPMN) of the Pancreas

Objective: The aim of this study was to characterize patterns of local progression following resection for pancreatic intraductal papillary mucinous neoplasms (IPMN) using targeted next-generation sequencing (NGS). Background: Progression of neoplastic disease in the remnant pancreas following resection of IPMN may include development of a new IPMN or ductal adenocarcinoma (PDAC). However, it is not clear whether this progression represents recurrence of the same neoplasm or an independent second neoplasm. Methods: Targeted-NGS on genes commonly mutated in IPMN and PDAC was performed on tumors from (1) 13 patients who developed disease progression in the remnant pancreas following resection of IPMN; and (2) 10 patients who underwent a resection for PDAC and had a concomitant IPMN. Mutations in the tumors were compared in order to determine the relationship between neoplasms. In parallel, clinical and pathological characteristics of 260 patients who underwent resection of noninvasive IPMN were reviewed to identify risk factors associated with local progression. Results: We identified 3 mechanisms underlying local progression in the remnant pancreas: (1) residual microscopic disease at the resection margin, (2) intraparenchymal spread of neoplastic cells, leading to an anatomically separate but genetically related recurrence, and (3) multifocal disease with genetically distinct lesions. Analysis of the 260 patients with noninvasive IPMNs showed that family history of pancreatic cancer (P = 0.027) and high-grade dysplasia (HGD) (P = 0.003) were independent risk factors for the development of an IPMN with HGD or an invasive carcinoma in the remnant pancreas. Conclusions: Using NGS, we identify distinct mechanisms for development of metachronous or synchronous neoplasms in patients with IPMN. Patients with a primary IPMN with HGD or with positive family history are at an increased risk to develop subsequent high-risk neoplasms in the remnant pancreas.

Genetic analyses of isolated high-grade pancreatic intraepithelial neoplasia (HG-PanIN) reveal paucity of alterations in TP53 and SMAD4

High‐grade pancreatic intraepithelial neoplasia (HG‐PanIN) is the major precursor of pancreatic ductal adenocarcinoma (PDAC) and is an ideal target for early detection. To characterize pure HG‐PanIN, we analysed 23 isolated HG‐PanIN lesions occurring in the absence of PDAC. Whole‐exome sequencing of five of these HG‐PanIN lesions revealed a median of 33 somatic mutations per lesion, with a total of 318 mutated genes. Targeted next‐generation sequencing of 17 HG‐PanIN lesions identified KRAS mutations in 94% of the lesions. CDKN2A alterations occurred in six HG‐PanIN lesions, and RNF43 alterations in five. Mutations in TP53, GNAS, ARID1A, PIK3CA, and TGFBR2 were limited to one or two HG‐PanINs. No non‐synonymous mutations in SMAD4 were detected. Immunohistochemistry for p53 and SMAD4 proteins in 18 HG‐PanINs confirmed the paucity of alterations in these genes, with aberrant p53 labelling noted only in three lesions, two of which were found to be wild type in sequencing analyses. Sixteen adjacent LG‐PanIN lesions from ten patients were also sequenced using targeted sequencing. LG‐PanIN harboured KRAS mutations in 94% of the lesions; mutations in CDKN2A, TP53, and SMAD4 were not identified. These results suggest that inactivation of TP53 and SMAD4 are late genetic alterations, predominantly occurring in invasive PDAC. Copyright

Neutrophil-to-lymphocyte Ratio is a Predictive Marker for Invasive Malignancy in Intraductal Papillary Mucinous Neoplasms of the Pancreas.

Objective: To evaluate the correlation between neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) values, and the presence of invasive carcinoma in patients with intraductal papillary mucinous neoplasm (IPMN). Background: NLR and (PLR) are inflammatory markers that have been associated with overall survival in patients with invasive malignancies, including pancreatic cancer. Methods: We retrospectively reviewed 272 patients who underwent surgical resection for histologically confirmed IPMN from January 1997 to July 2015. NLR and PLR were calculated and coevaluated with additional demographic, clinical, and imaging data for possible correlation with IPMN-associated carcinoma in the form of a predictive nomogram. Results: NLR and PLR were significantly elevated in patients with IPMN-associated invasive carcinoma (P < 0.001). In the multivariate analysis, NLR value higher than 4 (P < 0.001), IPMN cyst of size more than 3 cm (P < 0.001), presence of enhanced solid component (P = 0.014), main pancreatic duct dilatation of more than 5 mm (P < 0.001), and jaundice (P < 0.001) were statistically significant variables. The developed statistical model has a c-index of 0.895. Implementation of the statistically significant variables in a predictive nomogram provided a reliable point system for estimating the presence of IPMN-associated invasive carcinoma. Conclusions: NLR is an independent predictive marker for the presence of IPMN-associated invasive carcinoma. Further prospective studies are needed to assess the predictive ability of NLR and how it can be applied in the clinical setting.

A Novel Risk Scoring System Reliably Predicts Readmission after Pancreatectomy

BACKGROUND Postoperative readmissions have been proposed by Medicare as a quality metric and can impact provider reimbursement. Because readmission after pancreatectomy is common, we sought to identify factors associated with readmission to establish a predictive risk scoring system. STUDY DESIGN A retrospective analysis of 2,360 pancreatectomies performed at 9 high-volume pancreatic centers between 2005 and 2011 was performed. Forty-five factors strongly associated with readmission were identified. To derive and validate a risk scoring system, the population was randomly divided into 2 cohorts in a 4:1 fashion. A multivariable logistic regression model was constructed and scores were assigned based on the relative odds ratio (OR) of each independent predictor. A composite Readmission after Pancreatectomy (RAP) score was generated and then stratified to create risk groups. RESULTS Overall, 464 (19.7%) patients were readmitted within 90 days. Eight pre- and postoperative factors, including earlier MI (OR = 2.03), American Society of Anesthesiologists class ≥ 3 (OR = 1.34), dementia (OR = 6.22), hemorrhage (OR = 1.81), delayed gastric emptying (OR = 1.78), surgical site infection (OR = 3.31), sepsis (OR = 3.10), and short length of stay (OR = 1.51) were independently predictive of readmission. The 32-point RAP score generated from the derivation cohort was highly predictive of readmission in the validation cohort (area under the receiver operating curve = 0.72). The low-risk (0 to 3), intermediate-risk (4 to 7), and high-risk (>7) groups correlated with 11.7%, 17.5%, and 45.4% observed readmission rates, respectively (p < 0.001). CONCLUSIONS The RAP score is a novel and clinically useful risk scoring system for readmission after pancreatectomy. Identification of patients with increased risk of readmission using the RAP score will allow efficient resource allocation aimed to attenuate readmission rates. It also has potential to serve as a new metric for comparative research and quality assessment.

Southern surgical association articleA Novel Risk Scoring System Reliably Predicts Readmission after Pancreatectomy

BACKGROUND Postoperative readmissions have been proposed by Medicare as a quality metric and can impact provider reimbursement. Because readmission after pancreatectomy is common, we sought to identify factors associated with readmission to establish a predictive risk scoring system. STUDY DESIGN A retrospective analysis of 2,360 pancreatectomies performed at 9 high-volume pancreatic centers between 2005 and 2011 was performed. Forty-five factors strongly associated with readmission were identified. To derive and validate a risk scoring system, the population was randomly divided into 2 cohorts in a 4:1 fashion. A multivariable logistic regression model was constructed and scores were assigned based on the relative odds ratio (OR) of each independent predictor. A composite Readmission after Pancreatectomy (RAP) score was generated and then stratified to create risk groups. RESULTS Overall, 464 (19.7%) patients were readmitted within 90 days. Eight pre- and postoperative factors, including earlier MI (OR = 2.03), American Society of Anesthesiologists class ≥ 3 (OR = 1.34), dementia (OR = 6.22), hemorrhage (OR = 1.81), delayed gastric emptying (OR = 1.78), surgical site infection (OR = 3.31), sepsis (OR = 3.10), and short length of stay (OR = 1.51) were independently predictive of readmission. The 32-point RAP score generated from the derivation cohort was highly predictive of readmission in the validation cohort (area under the receiver operating curve = 0.72). The low-risk (0 to 3), intermediate-risk (4 to 7), and high-risk (>7) groups correlated with 11.7%, 17.5%, and 45.4% observed readmission rates, respectively (p < 0.001). CONCLUSIONS The RAP score is a novel and clinically useful risk scoring system for readmission after pancreatectomy. Identification of patients with increased risk of readmission using the RAP score will allow efficient resource allocation aimed to attenuate readmission rates. It also has potential to serve as a new metric for comparative research and quality assessment.

Pancreatic cancer surgery: past, present, and future

The history of pancreatic cancer surgery, though fraught with failure and setbacks, is punctuated by periods of incremental progress dependent upon the state of the art and the mettle of the surgeons daring enough to attempt it. Surgical anesthesia and the aseptic techniques developed during the latter half of the 19(th) century were instrumental in establishing a viable setting for pancreatic surgery to develop. Together, they allowed for bolder interventions and improved survival through the post-operative period. Surgical management began with palliative procedures to address biliary obstruction in advanced disease. By the turn of the century, surgical pioneers such as Alessandro Codivilla and Walther Kausch were demonstrating the technical feasibility of pancreatic head resections and applying principles learned from palliation to perform complicated anatomical reconstructions. Allen O. Whipple, the namesake of the pancreaticoduodenectomy (PD), was the first to take a systematic approach to refining the procedure. Perhaps his greatest contribution was sparking a renewed interest in the surgical management of periampullary cancers and engendering a community of surgeons who advanced the field through their collective efforts. Though the work of Whipple and his contemporaries legitimized PD as an accepted surgical option, it was the establishment of high-volume centers of excellence and a multidisciplinary approach in the later decades of the 20(th) century that made it a viable surgical option. Today, pancreatic surgeons are experimenting with minimally invasive surgical techniques, expanding indications for resection, and investigating new methods for screening and early detection. In the future, the effective management of pancreatic cancer will depend upon our ability to reliably detect the earliest cancers and precursor lesions to allow for truly curative resections.

Obstructive Sleep Apnea and Pathological Characteristics of Resected Pancreatic Ductal Adenocarcinoma

Background Prospective studies have identified obstructive sleep apnea (OSA) as a risk factor for increased overall cancer incidence and mortality. The potential role of OSA in the risk or progression of specific cancers is not well known. We hypothesized that pathological differences in pancreatic cancers from OSA cases compared to non-OSA cases would implicate OSA in pancreatic cancer progression. Methods We reviewed the medical records of 1031 patients who underwent surgical resection without neoadjuvant therapy for pancreatic ductal adenocarcinoma (PDAC) at Johns Hopkins Hospital between 2003 and 2014 and compared the TNM classification of their cancer and their overall survival by patient OSA status. Results OSA cases were significantly more likely than non-OSA cases to have lymph node-negative tumors (37.7% vs. 21.8%, p = 0.004). Differences in the prevalence of nodal involvement of OSA vs. non-OSA cases were not associated with differences in other pathological characteristics such as tumor size, tumor location, resection margin status, vascular or perineural invasion, or other comorbidities more common to OSA cases (BMI, smoking, diabetes). A logistic regression model found that a diagnosis of OSA was an independent predictor of lymph node status (hazard ratio, 0.051, p = 0.038). Patients with OSA had similar overall survival compared to those without OSA (HR, 0.89, (0.65–1.24), p = 0.41). Conclusion The observed pathological differences between OSA-associated and non-OSA-associated pancreatic cancers supports the hypothesis that OSA can influence the pathologic features of pancreatic ductal adenocarcinoma.

Is It Time to Expand the Role of Total Pancreatectomy for IPMN

Intraductal papillary mucinous neoplasms (IPMN) are cystic precursors to pancreatic cancer believed to arise within a widespread neoplastic field defect. The tendency for some patients to present with multifocal disease and/or develop additional lesions over time argues in favor of a field defect and complicates surgical management decisions. Surgery usually consists of partial pancreatic resection, which leaves behind a pancreatic remnant at risk for recurrent disease and progression to cancer. As an alternative, total pancreatectomy (TP) provides the most complete oncologic resection, but postoperative morbidity and quality of life (QoL) issues have generally limited its use to only the highest risk patients. Significant progress has been made in the management of the post-TP apancreatic state and studies now show less morbidity with acceptable QoL comparable to type 1 diabetic and post-pancreaticoduodenectomy patients. These improvements do not yet justify the routine use of TP, but they have opened the door for expansion to additional subsets of non-invasive IPMN. Here, we have identified several groups of patients that we believe would benefit from TP over partial resection based on the most current literature.

Pancreatic and Periampullary Cancer

Abstract Pancreatic and periampullary tumors include a diverse group of malignant neoplasms that arise in the pancreas or at or near the ampulla of Vater. These neoplasms commonly include adenocarcinomas of the pancreas (pancreatic ductal adenocarcinomas [PDAC]), duodenum, distant common bile duct, or ampulla of Vater in addition to pancreatic neuroendocrine tumors (PNET). Other neoplasms located in this region include intraductal papillary mucinous neoplasms (IPMN), acinar cell cancer, mucinous cystic neoplasms (MCN), and solid pseudopapillary neoplasms (SPN). Presentation of these tumors is often similar given their common location of origin with symptoms including abdominal discomfort, obstructive jaundice and pruritus for lesions located in the head of the pancreas or periampullary region, and pain or abdominal discomfort for pancreatic tail lesions. The surgical management of these neoplasms is often similar given their shared location, but differences in underlying biology can dictate subtle differences in care requiring the need for accurate diagnosis and differentiation of these neoplasms.