Faculty Bibliography

BACKGROUND:Multiple reports have demonstrated pancreatic cancer patients undergoing surgery have superior outcomes at high-volume hospitals. This study noted trends in access to high-volume centers for pancreatic resection and identified gaps in improving access. STUDY DESIGN/METHODS:We performed a retrospective analysis of the Nationwide Inpatient Sample (NIS 2000 to 2005) linked to the Area Resource File (ARF). Inclusion criteria were patients with primary diagnosis of pancreatic cancer who received pancreatic resection. The primary outcomes variable was treatment at high-volume hospitals (average annual case volume greater than 20). Independent variables included age, gender, race, Charlson Comorbidity Index score, insurance status, calendar year, and region, obtained from the Nationwide Inpatient Sample; community poverty level and density of all physicians, gastroenterologists, surgeons, and radiation oncologists were data obtained from the Area Resource File. RESULTS:A total of 8,370 patients were identified. A minority (38.51%) were referred to high-volume hospitals. A significant increase in overall referral and odds of referral to a high-volume center was observed over time (22.2% in 2000 to 44.4% in 2005). Patients referred to high-volume centers were younger (61.9 versus 63.2 years, p < 0.001) and more likely to be Caucasian (81.7% versus 73.6%, p < 0.001). Patients greater than 85 years old, African Americans, Hispanics, and Asians were less likely to be referred, relative to their younger, Caucasian counterparts (p < 0.01). The overall trend toward improved referral over time was driven by improved referral among Caucasians. In multivariate analysis, access to high-volume centers was associated with calendar year, patient age, and race. In addition, increase in density of gastroenterologists or radiation oncologists in the population was also associated with higher likelihood of referral. CONCLUSIONS:This study demonstrated that less than half of pancreatic cancer patients are being referred to high-volume centers. Unlike referral in Caucasians, improvement in referral for minorities has not occurred.

Brunner's gland hamartomas (BGH) are uncommon benign tumors of the duodenum forming mature Brunner's glands. We report here an unusual case of a giant BGH that was not amenable to endoscopic or surgical local resection thus requiring a pancreaticoduodenectomy for extirpation. The relevant literature is discussed.

BACKGROUND AND PURPOSE/OBJECTIVE:To examine the role of adjuvant chemoradiation (CRT) in patients with resected ampullary adenocarcinoma. MATERIALS AND METHODS/METHODS:The records of patients who underwent curative surgery for ampullary adenocarcinoma at a single institution between 1992 and 2007 were reviewed. Final analysis included 111 patients, 45% of which also received adjuvant CRT. RESULTS:Median overall survival (OS) was 36.2 months for all patients. Adverse prognostic factors for OS included T stage (T3/4 vs. T1/T2, p=0.046), node status (positive vs. negative, p<0.001), and histological grade (grade 3 vs. 1/2, p=0.09). Patients receiving CRT were more likely to have advanced T-stage (p=0.001), node positivity (p<0.001), and poor histologic grade (p=0.015). Patients who received CRT were also significantly younger (p=0.001). On univariate analysis, adjuvant CRT failed to result in a significant difference in survival when compared to surgery alone (median OS: 33.4 vs. 36.2 months, p=0.969). Patients with node-positive resections who underwent CRT had a non-significant improvement in survival (median OS: 21.6 vs. 13.0 months, p=0.092). Thirty-three percent of patients developed distant metastasis. Common sites of distant metastasis included liver (23%) and peritoneum (7%). CONCLUSIONS:Adjuvant chemoradiation following curative resection for ampullary adenocarcinoma did not lead to a statistically significant benefit in overall survival. A significant proportion of patients still developed distant metastatic disease suggesting a need for more effective systemic adjuvant therapy.

OBJECTIVE:To analyze relative perioperative and long-term outcomes of patients undergoing total pancreatectomy versus pancreaticoduodenectomy. BACKGROUND:The role of total pancreatectomy has historically been limited due to concerns over increased morbidity, mortality, and perceived worse long-term outcome. METHODS:Between 1970 and 2007, patients who underwent total pancreatectomy (n = 100) or pancreaticoduodenectomy (n = 1286) for adenocarcinoma were identified. Clinicopathologic, morbidity, and survival data were collected and analyzed. RESULTS:Total pancreatectomy patients had larger median tumor size (4 cm vs. 3 cm; P < 0.001) but similar rates of vascular (50.0% vs. 54.7%) and perineural invasion (90.7% vs. 91.8%) (total pancreatectomy vs. pancreaticoduodenectomy, respectively, both P > 0.05). A similar proportion of total pancreatectomy (74.7%) and pancreaticoduodenectomy (78.3%) patients had N1 disease (P = 0.45). Total pancreatectomy patients had more lymph nodes harvested (27 vs. 16) and were less likely to have positive resection margins (22.2% vs. 43.7%) (total pancreatectomy vs. pancreaticoduodenectomy, respectively, both P < 0.0001). Total pancreatectomy was increasingly used over time (1970-1989, n = 10, 1990-1999, n = 37, 2000-2007, n = 53). Total pancreatectomy was associated with higher 30-day mortality compared with pancreaticoduodenectomy (8.0% vs. 1.5%, respectively; P = 0.0007). However, total pancreatectomy operative mortality decreased over time (1970-1989, 40%; 1990-1999, 8%; 2000-2007, 2%; P = 0.0002). While operative morbidity was higher following total pancreatectomy (69.0% vs. 38.6% for pancreaticoduodenectomy; P < 0.0001), most complications were minor (Clavien Grade 1-2) (59%). Total pancreatectomy and pancreaticoduodenectomy patients had comparable 5-year survival (18.9% vs. 18.5%, respectively, P = 0.32). CONCLUSIONS:Total pancreatectomy perioperative mortality dramatically decreased over time. Long-term survival following total pancreatectomy versus pancreaticoduodenectomy was equivalent. Total pancreatectomy should be performed when oncologically appropriate.

INTRODUCTION/BACKGROUND:Pancreatic leak (PL) remains a major cause of postoperative morbidity in patients undergoing pancreatic resection. We sought to evaluate the incidence of and identify risk factors for the development of PL in patients undergoing distal pancreatectomy (DP) at a single high-volume institution. METHODS:All patients who underwent primary open DP (excluding completion pancreatectomy and debridement) between January 1, 1984 and July 1, 2006 were identified, and their medical records were reviewed. chi and multivariable logistic regression analyses were performed to identify risk factors for PL. RESULTS:In a cohort of 704 patients undergoing primary DP, the indications for DP were benign pancreatic neoplasm (34%), malignant pancreatic neoplasm (31%), other neoplasm (15%), chronic pancreatitis (14%), pseudocyst (3%), and trauma (3%). The pancreatic remnant was sutured alone in 83%, stapled alone in 5%, and both stapled and sutured in 9% of cases. Ligation of the pancreatic duct was performed in 22% of cases. Perioperative mortality was <1%, but overall morbidity was 33%, most commonly PL (12% clinically significant, 21% biochemical). Multivariable logistic regression analysis revealed that neither the method of closure of the pancreatic remnant (P = 0.41) nor ligation of the pancreatic duct (P > 0.05) affected the risk of clinically significant PL. CONCLUSIONS:This largest reported series of DP demonstrates that this procedure can be performed with low mortality but still carries a substantial risk of morbidity, particularly PL. In contrast to some previous studies, this analysis found that surgical management of the pancreatic remnant has no effect on the incidence of clinically significant PL.

PURPOSE/OBJECTIVE:Recently, the majority of protein coding genes were sequenced in a collection of pancreatic cancers, providing an unprecedented opportunity to identify genetic markers of prognosis for patients with adenocarcinoma of the pancreas. EXPERIMENTAL DESIGN/METHODS:We previously sequenced more than 750 million base pairs of DNA from 23,219 transcripts in a series of 24 adenocarcinomas of the pancreas. In addition, 39 genes that were mutated in more than one of these 24 cancers were sequenced in a separate panel of 90 well-characterized adenocarcinomas of the pancreas. Of these 114 patients, 89 underwent pancreaticoduodenectomy, and the somatic mutations in these cancers were correlated with patient outcome. RESULTS:When adjusted for age, lymph node status, margin status, and tumor size, SMAD4 gene inactivation was significantly associated with shorter overall survival (hazard ratio, 1.92; 95% confidence interval, 1.20-3.05; P = 0.006). Patients with SMAD4 gene inactivation survived a median of 11.5 months, compared with 14.2 months for patients without SMAD4 inactivation. By contrast, mutations in CDKN2A or TP53 or the presence of multiple (> or =4) mutations or homozygous deletions among the 39 most frequently mutated genes were not associated with survival. CONCLUSIONS:SMAD4 gene inactivation is associated with poorer prognosis in patients with surgically resected adenocarcinoma of the pancreas.

BACKGROUND:Solid-pseudopapillary neoplasms (SPNs) are rare pancreatic tumors with malignant potential. Clinicopathologic characteristics and outcomes of patients with SPN were reviewed. STUDY DESIGN/METHODS:Longterm outcomes were evaluated in patients with an SPN who were followed from 1970 to 2008. RESULTS:Thirty-seven patients were identified with an SPN. Thirty-three (89%) were women, and median age at diagnosis was 32 years. Most patients were symptomatic; the most common symptom was abdominal pain (81%). Thirty-six patients underwent resection; one patient with distant metastases was not operated on. There were no 30-day mortalities. Median tumor size was 4.5 cm. Thirty-four patients underwent an R0 resection, 1 had an R1 resection, and 1 had an R2 resection. Two patients had lymph node metastases, and one patient had perineural invasion. After resection, 34 (94%) patients remain alive. One patient died of unknown causes 9.4 years after resection, and another died of unrelated causes 25.6 years after operation. The patient with widespread disease who didn't have resection died 11 months after diagnosis. Thirty-five of the 36 patients having resection remained disease free, including those who died of unrelated causes (median followup, 4.8 years). One patient developed a recurrence 7.7 years after complete resection. She was treated with gemcitabine and remains alive 13.6 months after recurrence. CONCLUSIONS:SPNs are rare neoplasms with malignant potential found primarily in young women. Formal surgical resection may be performed safely and is associated with longterm survival.

Cigarette smoking doubles the risk of pancreatic cancer, and smoking accounts for 20% to 25% of pancreatic cancers. The recent sequencing of the pancreatic cancer genome provides an unprecedented opportunity to identify mutational patterns associated with smoking. We previously sequenced >750 million bp DNA from 23,219 transcripts in 24 adenocarcinomas of the pancreas (discovery screen). In this previous study, the 39 genes that were mutated more than once in the discovery screen were sequenced in an additional 90 adenocarcinomas of the pancreas (validation screen). Here, we compared the somatic mutations in the cancers obtained from individuals who ever smoked cigarettes (n = 64) to the somatic mutations in the cancers obtained from individuals who never smoked cigarettes (n = 50). When adjusted for age and gender, analyses of the discovery screen revealed significantly more nonsynonymous mutations in the carcinomas obtained from ever smokers (mean, 53.1 mutations per tumor; SD, 27.9) than in the carcinomas obtained from never smokers (mean, 38.5; SD, 11.1; P = 0.04). The difference between smokers and nonsmokers was not driven by mutations in known driver genes in pancreatic cancer (KRAS, TP53, CDKN2A/p16, and SMAD4), but instead was predominantly observed in genes mutated at lower frequency. No differences were observed in mutations in carcinomas from the head versus tail of the gland. Pancreatic carcinomas from cigarette smokers harbor more mutations than do carcinomas from never smokers. The types and patterns of these mutations provide insight into the mechanisms by which cigarette smoking causes pancreatic cancer.

BACKGROUND:There are limited data on patterns of recurrence and factors associated with local recurrence following pancreaticoduodenectomy for pancreatic adenocarcinoma and adjuvant 5-flurouracil-based chemoradiation therapy. METHODS AND MATERIALS/METHODS:Between 1995 and 2005, 905 patients underwent pancreaticoduodenectomy for pancreatic adenocarcinoma; 154 patients had complete pattern of recurrence data available. RESULTS:At median follow-up of 20.2 months, 103 (66.9%) patients recurred with median time to recurrence of 16.2 months. Most patients recurred with distant disease only (68.9%), while 21.4% patients recurred with local disease only; ten (9.7%) patients recurred with local and distant disease. Several factors were associated with local recurrence: poor tumor differentiation (hazards ration [HR] 2.39) and presence of metastatic lymph nodes (HR 1.89, both p < 0.05). Among N1 patients, poor tumor differentiation (HR 3.92), >5 metastatic LN (HR 3.75), and lymph node ratio (LNR) >0.4 (HR 2.96) had the highest risk of local recurrence (all p < 0.05). Increasing LNR was associated with an incremental increased risk of local recurrence (LNR <0.2, 21.3% versus LNR >or=0.2 to 0.4, 25.2% versus LNR >0.4, 40.4%; p < 0.05). CONCLUSIONS:Although most patients who receive standard 5-flurouracil-based chemoradiation therapy will ultimately succumb to distant disease, about 30% recur locally. Poor tumor differentiation, a high number of metastatic LN (>5), and LNR >0.4 are associated with the highest risk of local failure. In these patients, radiation dose escalation and/or a combination of radiation with novel chemotherapeutic agents may be necessary to improve outcomes.

Metastasectomy with curative intent has become standard practice for the management of some malignancies. Resection of isolated metastatic colorectal cancer, gastrointestinal stromal tumours, neuroendocrine cancers, renal-cell cancer and sarcoma is associated with longer survival or even cure. The strongest evidence in favour of metastasectomy exists for colorectal cancer, in which resection of limited metastatic disease in some patients is associated with 5-year survival rates of more than 50%.(1-3) High incidence of the disease, predictable tumour biology, and development of successful chemotherapies have encouraged metastasectomy. Furthermore, improved safety of complex surgeries over the past several decades has lowered the threshold for more aggressive surgical intervention. Most literature on metastasectomy pertains to the resection of disease involving the liver, lung, and brain. However, metastasectomy has been described for almost every organ system, including the pancreas. In this Review, we discuss resection of isolated cancer metastases to the pancreas. Pancreatic metastasectomy is most often done through a formal pancreatic resection such as pancreaticoduodenectomy or distal pancreatectomy. Less often, pancreatic metastasectomy is done by enucleation or a pancreas sparing operation such as a central pancreatectomy.