Jennifer LaFemina

GNAS and KRAS Mutations Define Separate Progression Pathways in Intraductal Papillary Mucinous Neoplasm-Associated Carcinoma

BACKGROUND Intraductal papillary mucinous neoplasms (IPMN) are being increasingly recognized as important precursors to pancreatic adenocarcinoma. Elucidation of the genetic changes underlying IPMN carcinogenesis may improve the diagnosis and management of IPMN. We sought to determine whether different histologic subtypes of IPMN would exhibit different frequencies of specific genetic mutations. STUDY DESIGN Patients with resected IPMN-associated invasive carcinoma (IPMN-INV) between 1997 and 2012 were reviewed. Areas of carcinoma, high-grade dysplasia, and low-grade dysplasia were micro-dissected from each pathologic specimen. Targeted, massively parallel sequencing was then performed on a panel of 275 genes (including KRAS, GNAS, and RNF43). RESULTS Thirty-eight patients with resected IPMN-INV and sufficient tissue for micro-dissection were identified. Median follow-up was 2.6 years. Mutations in GNAS were more prevalent in colloid-type IPMN-INV than tubular-type IPMN-INV (89% vs 32% respectively; p = 0.0003). Conversely, KRAS mutations were more prevalent in tubular-type than colloid-type IPMN-INV (89% vs 52%, respectively; p = 0.01). For noninvasive IPMN subtypes, GNAS mutations were more prevalent in intestinal (74%) compared with pancreatobiliary (31%) and gastric (50%) subtypes (p = 0.02). The presence of these mutations did not vary according to the degree of dysplasia (GNAS: invasive 61%, high-grade 59%, low-grade 53%; KRAS: invasive 71%, high-grade 62%, low-grade 74%), suggesting that mutations in these genes occur early in IPMN carcinogenesis. CONCLUSIONS Colloid carcinoma associated with IPMN and its intestinal-type preinvasive precursor are associated with high frequencies of GNAS mutations. The mutation profile of tubular carcinoma resembles that of conventional pancreatic adenocarcinoma. Preoperative determination of mutational status may assist with clinical treatment decisions.

Costs and Trends in Pancreatic Cancer Treatment

Pancreatic cancer poses a substantial morbidity and mortality burden in the United States, and predominantly affects older adults. The objective of this study was to estimate the direct medical costs of pancreatic cancer treatment in a population‐based cohort of Medicare beneficiaries, and the contribution of different treatment modalities and health care services to the total cost of care and trends in costs over time.

Adrenocortical carcinoma: Past, present, and future

Adrenocortical carcinoma (ACC) is a rare endocrine malignancy. Due to its rarity, heterogeneity, and a lack of a comprehensive understanding of the pathogenesis, little progress has been made in treatment and outcomes. The current review explores the past, present, and future of the understanding and treatment of this disease process. J. Surg. Oncol. 2012; 106:586–594.

Dysplasia at the surgical margin is associated with recurrence after resection of non-invasive intraductal papillary mucinous neoplasms

BACKGROUND The significance of a positive margin in resected non-invasive pancreatic intraductal papillary mucinous neoplasms (IPMN) remains controversial. The aim of this study was to determine recurrence rates when dysplasia was present at the final surgical margin. METHODS A prospectively maintained database identified 192 patients undergoing resection of non-invasive IPMN. Pathological, peri-operative and recurrence data were analysed. RESULTS Ductal dysplasia was identified at the final surgical margin in 86 patients (45%) and defined as IPMN or Pancreatic Intraepithelial Neoplasia PanIN in 38 (20%) and 54 (28%) patients, respectively. At a median follow-up of 46 months, 40 (21%) patients recurred with 31 developing radiographical evidence of new cysts, 6 re-resected for IPMN and 3 diagnosed with pancreatic cancer within the remnant. Of those with margin dysplasia, 31% developed recurrent disease compared with 13% in those without dysplasia (P = 0.002). On multivariate analysis, margin dysplasia was associated with a three-fold increased risk of recurrence (P = 0.02). No relationship between dysplasia and development of pancreatic cancer was found. DISCUSSION In this study, dysplasia at the margin after a pancreatectomy for non-invasive IPMN was associated with recurrence in the remnant gland, but not at the resection margin. While this finding may warrant closer follow-up, it does not identify a gland at higher risk for the subsequent development of invasive disease.

Interobserver Agreement for Detection of Malignant Features of Intraductal Papillary Mucinous Neoplasms of the Pancreas on MDCT

OBJECTIVE The purpose of this retrospective study was to measure interobserver agreement in the assessment of malignant imaging features of intraductal papillary mucinous neoplasms (IPMNs) on MDCT. MATERIALS AND METHODS Pancreatic protocol CT studies were reviewed for 84 patients with resected IPMNs. Maximal diameter of the dominant cyst, presence of a mural nodule, presence of a solid component, and diameters of the main pancreatic duct (MPD) and common bile duct (CBD) were measured by four radiologists independently. In each patient, the IPMN was classified into one of three types: main duct, branch duct, or mixed IPMN. Interobserver agreement of lesion features was examined using the intraclass correlation coefficient (ICC) for continuous features and Fleiss kappa for categorical features. RESULTS The final dataset included 55 branch duct IPMNs, nine main duct IPMNs, and 20 mixed IPMNs. Moderate agreement (ĸ = 0.458; 95% CI, 0.345-0.564) was observed in assigning branch duct, main duct, or mixed IPMN subtypes. Measurement agreement was substantial to excellent for dominant cyst (ICC = 0.852; 95% CI, 0.777-0.907), MPD (0.753, 0.655-0.837), and CBD (0.608, 0.463-0.724) but only fair to moderate for the detection of the presence of mural nodule (ĸ = 0.284, 0.125-0.432) or solid component (ĸ = 0.405, 0211-0.577). CONCLUSION Substantial to excellent interobserver agreement in the measurement of cyst diameter, MPD, and CBD support their use for characterizing malignant features of IPMN on MDCT. However, the subjective interpretation of the presence of solid components and mural nodules by individual radiologists was more variable.

Sonic Hedgehog in pancreatic cancer: From bench to bedside, then back to the bench

Developmental genes are known to regulate cell proliferation, migration, and differentiation; thus, it comes as no surprise that the misregulation of developmental genes plays an important role in the biology of human cancers. One such pathway that has received an increasing amount of attention for its function in carcinogenesis is the Hedgehog (Hh) pathway. Initially the domain of developmental biologists, the Hh pathway and one of its ligands, Sonic Hedgehog (Shh), have been shown to play an important role in body planning and organ development, particularly in the foregut endoderm. Their importance in human disease became known to cancer biologists when germline mutations that resulted in the unregulated activity of the Hh pathway were found to cause basal cell carcinoma and medulloblastoma. Since then, misexpression of the Hh pathway has been shown to play an important role in many other cancers, including those of the pancreas. In many institutions, investigators are targeting misexpression of the Hh pathway in clinical trials, but there is still much fundamental knowledge to be gained about this pathway that can shape its clinical utility. This review will outline the evolution of our understanding of this pathway as it relates to the pancreas, as well as how the Hh pathway came to be a high-priority target for treatment.

Surgical management of proximal bile duct cancers

IntroductionTumors arising from the proximal biliary tree remain particularly challenging with respect to their evaluation and treatment. Complete resection with negative histologic margins is the most effective treatment modality.ResultsHowever, the majority of patients are not candidates for surgery.SummaryOver the last decades, advances have evolved to improve resectability and morbidity after major liver and bile duct resection. However, these disease processes still pose a management challenge. Herein, we provide an overview of proximal bile duct cancers, hilar cholangiocarcinoma (HCCa) and intrahepatic cholangiocarcinoma (ICCa).

Thirty-day outcomes underestimate endocrine and exocrine insufficiency after pancreatic resection.

BACKGROUND Long-term incidence of endocrine and exocrine insufficiency after pancreatectomy is poorly described. We analyze the long-term risks of pancreatic insufficiency after pancreatectomy. METHODS Subjects who underwent pancreatectomy from 2002 to 2012 were identified from a prospective database (n = 227). Subjects who underwent total pancreatectomy or pancreatitis surgery were excluded. New post-operative endocrine and exocrine insufficiency was defined as the need for new pharmacologic intervention within 1000 days from resection. RESULTS 28 (16%) of 178 subjects without pre-existing endocrine insufficiency developed post-operative endocrine insufficiency: 7 (25%) did so within 30 days, 8 (29%) between 30 and 90 days, and 13 (46%) after 90 days. 94 (43%) of 214 subjects without pre-operative exocrine insufficiency developed exocrine insufficiency: 20 (21%) did so within 30 days, 29 (31%) between 30 and 90 days, and 45 (48%) after 90 days. Adjuvant radiation was associated with new endocrine insufficiency. On multivariate regression, pancreaticoduodenectomy and chemotherapy were associated with a greater risk of exocrine insufficiency. CONCLUSION Reporting 30-day functional outcomes for pancreatic resection is insufficient, as nearly 45% of subjects who develop disease do so after 90 days. Reporting of at least 90-day outcomes may more reliably assess risk for post-operative endocrine and exocrine insufficiency.

Transgastric Pancreaticogastric Anastomosis An Alternative Operative Approach for Middle Pancreatectomy

OBJECTIVE To determine short-term outcomes following middle pancreatectomy with transgastric pancreaticogastric anastomosis. DESIGN, SETTING, AND PATIENTS A retrospective analysis of 23 patients who underwent middle pancreatectomy with transgastric pancreaticogastric anastomosis at the Massachusetts General Hospital, Boston, from June 22, 2005, through April 29, 2009. MAIN OUTCOME MEASURES Indications for procedure, operative time, length of stay, morbidity, mortality, and need for readmission, antibiotics, reoperation, additional procedures, or transfusion. RESULTS The mean age of 15 women and 8 men who underwent middle pancreatectomy with transgastric pancreaticogastric anastomosis was 55.0 years. The median follow-up time was 12.9 months. The most commonly resected tumors were intraductal papillary mucinous neoplasms (n = 9), serous cystadenomas (n = 5), and neuroendocrine tumors (n = 4). The mean (SD) operative time was 191 (39) minutes. No patients required intraoperative transfusion. The median hospital stay was 5 days. The most common complications were pancreatic fistula (n = 6), intra-abdominal abscess (n = 4), and superficial skin infection (n = 4). Three patients had splenic artery pseudoaneurysms. Seven patients required readmission; 2 required reoperation. No patients developed postoperative new or worsening endocrine or exocrine insufficiency. There were no deaths. CONCLUSIONS Middle pancreatectomy with transgastric pancreaticogastric anastomosis offers a safe alternative to the traditional Roux-en-Y pancreaticojejunostomy and may be technically simpler.

Novel xenograft and cell line derived from an invasive intraductal papillary mucinous neoplasm of the pancreas give new insights into molecular mechanisms.

Objectives: Intraductal papillary mucinous neoplasms (IPMNs) of the pancreas are a unique entity with malignant potential. Histologically, pancreatic ductal adenocarcinoma (PDAC) arising in IPMN (intraductal papillary mucinous carcinoma [IPMC]) appears similar to sporadic PDAC; biologically, however, IPMC seems to have a less aggressive clinical course. Little is known about the genetic signature of IPMC. In this study, we describe a novel xenograft model and cell culture created to biologically and genetically characterize these tumors. Methods: Xenograft mice and cell lines were created from IPMC. Global genomic changes were evaluated by cytogenetic analysis and array comparative genomic hybridization. Specific mutations and sonic hedgehog (Shh) pathway activity were examined and xenografts evaluated for sensitivity to anti-Shh therapy. Results: Cytogenetic analysis showed a tetraploid karyotype with multiple aberrations. KRAS and p53 mutations and overexpression of the Shh pathway were identified. Array comparative genomic hybridization revealed multiple chromosomal aberrations comparable with previously published data in IPMNs. Murine xenograft tumors were sensitive to anti-Shh treatment. Conclusions: Characterization of IPMC cell lines and xenografts reveals similarities to previously published data on IPMN. In comparison to PDAC, moreover, these data reveal shared aberrations and distinct genomic changes. Thus, these xenograft model and cell lines may be useful for future preclinical investigations.