Michael G. House

Effect of Hospital Volume, Surgeon Experience, and Surgeon Volume on Patient Outcomes After Pancreaticoduodenectomy: A Single-Institution Experience

OBJECTIVE To determine the importance of hospital volume, surgeon experience, and surgeon volume in performing pancreaticoduodenectomy (PD). DESIGN, SETTING, AND PATIENTS From 1980 through 2007, 1003 patients underwent PD by 19 surgeons at a university hospital. MAIN OUTCOME MEASURES Patient morbidity and mortality, quality of resection, and learning curve were examined according to hospital volume (period 1: 1980-2003 vs period 2: 2004-2007), surgeon experience (total number of PDs), and surgeon volume (number of PDs per year). RESULTS Perioperative morbidity and mortality for all 1003 PDs were 41% and 3%, respectively. Differences existed between period 1 and period 2 in percentage of PDs performed in elderly patients (7% vs 17%), mortality (4% vs 2%), estimated blood loss (1817 mL vs 780 mL), length of stay (18 days vs 12 days), and proportion of International Study Group on Pancreatic Fistula grade C pancreatic fistulae (29% vs 12%). Surgeons with less experience (<50 PDs) performed PD with higher morbidity (53% vs 39%), pancreatic fistula rate (20% vs 10%), estimated blood loss (1918 mL vs 1101 mL), and operative time (458 minutes vs 335 minutes) compared with surgeons with more experience (> or =50 PDs). Experienced surgeons had comparable outcomes irrespective of annual volume. Mortality, margins, and number of lymph nodes resected were not affected by surgeon experience or surgeon volume. Learning curves projected that less experienced surgeons would achieve morbidity and mortality rates equivalent to those of experienced surgeons when they reached 20 and 60 PDs, respectively. CONCLUSIONS Improvement in PD outcomes, including mortality, occurred with increased PD volume at a pancreatic center. Surgeon experience remained an important determinant of overall morbidity. Experienced surgeons, however, had comparable outcomes irrespective of annual volume.

A Randomized Prospective Multicenter Trial of Pancreaticoduodenectomy With and Without Routine Intraperitoneal Drainage

Objective:To test by randomized prospective multicenter trial the hypothesis that pancreaticoduodenectomy (PD) without the use of intraperitoneal drainage does not increase the frequency or severity of complications. Background:Some surgeons have abandoned the use of drains placed during pancreas resection. Methods:We randomized 137 patients to PD with (n = 68, drain group) and without (n = 69, no-drain group) the use of intraperitoneal drainage and compared the safety of this approach and spectrum of complications between the 2 groups. Results:There were no differences between drain and no-drain cohorts in demographics, comorbidities, pathology, pancreatic duct size, pancreas texture, baseline quality of life, or operative technique. PD without intraperitoneal drainage was associated with an increase in the number of complications per patient [1 (0-2) vs 2 (1-4), P = 0.029]; an increase in the number of patients who had at least 1 ≥grade 2 complication [35 (52%) vs 47 (68%), P = 0.047]; and a higher average complication severity [2 (0-2) vs 2 (1-3), P = 0.027]. PD without intraperitoneal drainage was associated with a higher incidence of gastroparesis, intra-abdominal fluid collection, intra-abdominal abscess (10% vs 25%, P = 0.027), severe (≥grade 2) diarrhea, need for a postoperative percutaneous drain, and a prolonged length of stay. The Data Safety Monitoring Board stopped the study early because of an increase in mortality from 3% to 12% in the patients undergoing PD without intraperitoneal drainage. Conclusions:This study provides level 1 data, suggesting that elimination of intraperitoneal drainage in all cases of PD increases the frequency and severity of complications.

Promoter Hypermethylation of Resected Bronchial Margins: A Field Defect of Changes?

Purpose: Histologically positive bronchial margins after resection for non-small cell lung cancer are associated with shortened patient survival due to local recurrence. We hypothesized that DNA promoter hypermethylation changes at bronchial margins could be detected in patients with no histological evidence of malignancy and that they would reflect epigenetic events in the primary tumor. Experimental Design: Bronchial margins, primary tumor, bronchoalveolar fluid, and paired nonmalignant lung were obtained from 20 non-small cell lung cancer patients who underwent a lobectomy or greater resection. Disease-specific recurrence was the primary end point. The methylation status of p16, MGMT, DAPK, SOCS1, RASSF1A, COX2, and RARβ was examined using methylation-specific polymerase chain reaction. Results: All malignancies had methylation in at least one locus. Concordance of one gene with an identical epigenetic change in the tumor or bronchial margin was observed in 85% of patients. Only one patient had methylation at the bronchial margin for a gene that was not methylated in the corresponding tumor. Median time to recurrence was 37 months (range, 5–71 months). There were two local recurrences and five metastases. There were no significant correlations between DNA methylation in tumor, margins, or bronchoalveolar fluid specimens and either regional recurrence or distant metastases. Conclusions: Histologically negative bronchial margins of resected non-small cell lung cancer exhibit frequent hypermethylation changes in multiple genes. These hyper-methylation abnormalities are also present in the primary tumor and thus may represent a field defect of preneoplastic changes that occurs early in carcinogenesis.

Aberrant Hypermethylation Tumor Suppressor Genes in Pancreatic Endocrine Neoplasms

Objective Because histologic features can be unreliable in determining the malignant potential of pancreatic endocrine neoplasms (PENs), we characterized the methylation patterns of PENs to develop a molecular marker system useful for clinical prognosis. Summary Background Data Aberrant promoter methylation of tumor suppressor genes is associated with a loss of gene function that can afford selective growth advantages to neoplastic cells. Gene hypermethylation, coupled with sporadic genetic mutations, defines the heterogeneous biology of human neoplasms. Methods Forty-eight well-differentiated PENs were subjected to methylation-specific polymerase chain reaction to detect aberrant methylation associated with 11 candidate tumor suppressor genes (INK4a/p16, APC, O6-MGMT, hMLH1, p73, E-cadherin, RAR-&bgr;, p14ARF, GST-&pgr;, TIMP3, and RASSF1A). Methylation differences among PENs, subdivided according to tumor size, lymph node status, or liver metastasis, were analyzed, and the association of gene methylation with tumor recurrence and patient survival was evaluated. Results Aberrant hypermethylation of any of the 11 tumor suppressor genes was detected in 87% of the PENs. In decreasing order of frequency, the 5 most commonly methylated genes were: RASSF1A (75%), INK4a/p16 (40%), O6-MGMT (40%), RAR-&bgr; (25%), and hMLH1 (23%). In general, tumors larger than 5 cm and those associated with lymph node or hepatic metastases exhibited a higher frequency of methylation at each promoter site compared with PENs without malignant histologic features. The methylation of specific tumor suppressor genes was an independent predictor of early PEN recurrence and decreased 5-year survival following surgical resection. The accumulation of methylation of multiple tumor suppressor genes was associated with early tumor recurrence and reduced survival among a subpopulation of patients with lymph node-negative PENs. Conclusions Aberrant methylation of multiple tumor suppressor genes is associated with advanced tumor stage and identifies molecularly distinct PENs with identical histologic characteristics. The methylation status of specific tumor suppressor genes is predictive of PEN behavior.

Met Proto-Oncogene and Insulin-Like Growth Factor Binding Protein 3 Overexpression Correlates with Metastatic Ability in Well-Differentiated Pancreatic Endocrine Neoplasms

Pancreatic endocrine neoplasms are neoplastic proliferations of islet cells or islet cell precursors and are capable of secreting a variety of synthetic products, including insulin, glucagon, gastrin, and vasoactive intestinal peptide. The biological behavior of pancreatic endocrine neoplasms is often unpredictable, and there are few reliable histopathologic criteria reliably correlating with metastatic ability. We have used the Affymetrix U133 GeneChip set (HG_U133 A and B; Affymetrix; Santa Clara, CA) representing ∼33,000 characterized transcripts to examine global gene expression profiles from well-differentiated nonmetastatic (n = 5) and metastatic (n = 7) pancreatic endocrine neoplasms to determine molecular markers that predict disease progression. Microarray hybridization data were normalized using the GeneLogic GeneExpress Software System to identify differentially up- and down-regulated genes in metastatic versus nonmetastatic pancreatic endocrine neoplasms. Using a 3-fold change in gene expression as a threshold, we have identified 65 overexpressed and 57 underexpressed genes in metastatic pancreatic endocrine neoplasms as compared with nonmetastatic pancreatic endocrine neoplasms. Several classes of genes, including growth factors and growth factor-related molecules (IGFBP1, IGFBP3, and MET), developmental factors (TBX3 and MEIS2), cytoskeletal factors (β 1 tubulin and ACTN2), cholesterol homeostasis mediators (LRP5, SLC27A2, and RXRG), intracellular signaling pathway mediators (DYRK1A, PKIB, and AK2), methyltransferases (MGMT and GAMT), and DNA repair and regulatory molecules (CHEK1 and ZNF198), were identified as differentially over- or underexpressed via this method. Immunohistochemical validation of microarray data were performed for two overexpressed genes, namely, the met proto-oncogene (MET) and insulin-like growth factor binding protein 3 (IGFBP3) with tissue microarrays of nonmetastatic (n = 24) and metastatic (n = 15) pancreatic endocrine neoplasms. Increased expression of IGFBP3 was confirmed in metastatic versus nonmetastatic pancreatic endocrine neoplasms (12 of 15, 80% versus 10 of 24, 42%), as well as in lymph node (6 of 7, 86%) and liver (9 of 9, 100%) metastases. Similarly, overexpression of MET was confirmed in metastatic versus nonmetastatic pancreatic endocrine neoplasms (5 of 15, 33% versus 4 of 24, 17%), as well as in lymph node metastases (4 of 7, 57%) and liver metastases (5 of 9, 56%). The majority of genes that demonstrated altered expression has not been previously identified as differentially expressed in metastatic pancreatic endocrine neoplasm lesions and may therefore represent newly identified molecules in the progression of these lesions.

Promoter methylation profiles of tumor suppressor genes in intrahepatic and extrahepatic cholangiocarcinoma

Recent studies indicate that tumor suppressor genes can be epigenetically silenced through promoter hypermethylation. To further understand epigenetic alterations in cholangiocarcinoma, we have studied the methylation profiles of 12 candidate tumor suppressor genes (APC, E-cadherin/CDH1, MGMT, RASSF1A, GSTP, RAR-β, p14ARF, p15INK4b, p16INK4a, p73, hMLH1 and DAPK) in 72 cases of cholangiocarcinoma, including equal number cases of intrahepatic cholangiocarcinoma and extrahepatic cholangiocarcinoma. A total of 10 cases of benign biliary epithelia were included as controls. The methylation status of tumor suppressor genes was analyzed using methylation-specific PCR. We found that 85% of all cholangiocarcinomas had methylation of at least one tumor suppressor gene. The frequency of tumor suppressor gene methylation in cholangiocarcinoma was: RASSF1A (65%), p15INK4b (50%), p16INK4a (50%), APC (46%), E-cadherin/CDH1 (43%), p14ARF (38%), p73 (36%), MGMT (33%), hMHL1 (25%), GSTP (14%), RAR-β (14%) and DAPK (3%). Although single tumor suppressor gene methylation can be seen in benign biliary epithelium, methylation of multiple tumor suppressor genes is only seen in cholangiocarcinoma. About 70% (50/72) of the cholangiocarcinomas had three or more tumor suppressor genes methylated and 52% (38/72) of cases had four or more tumor suppressor genes methylated. Concerted methylation of multiple tumor suppressor genes was closely associated with methylation of RASSF1A, p16 and/or hMHL1. Methylation of RASSF1A was more common in extrahepatic cholangiocarcinoma than intrahepatic cholangiocarcinoma (83 vs 47%, P=0.003) while GSTP was more frequently seen in intrahepatic compared to extrahepatic cholangiocarcinoma (31 vs 6%, P=0.012). Our study indicates that methylation of promoter CpG islands of tumor suppressor genes is a common epigenetic event in cholangiocarcinoma. Based on distinct methylation profiles, intrahepatic cholangiocarcinoma and extrahepatic cholangiocarcinoma are two closely related but biologically unique neoplastic processes. Taking advantage of the unique concurrent methylation profile of multiple genes in cholangiocarcinoma may facilitate the distinction of cholangiocarcinoma from benign biliary epithelium in clinical settings.

Hypermethylation of the GATA Genes in Lung Cancer

Purpose: In lung cancer, DNA hypermethylation is known to be a common event. Experimental Design: Gene expression and methylation status of GATA-4, GATA-5, and GATA-6 were analyzed with cell lines and primary human lung cancers. Methylation profiles of primary lung cancers were analyzed and correlated with clinical as well as histopathological data. Results: Complete methylation was detected by methylation-specific PCR for both GATA-4 and GATA-5 in four cell lines (H358, DMS-53, A549, and H1299), all of which had no expression by reverse transcription-PCR analysis. Demethylation with 5-aza-2′deoxycytidine restored expression in each case. GATA-6 was ubiquitously expressed in all of the six cell lines. GATA-4 bisulfite sequencing revealed complete methylation of the GATA-4 promoter in H358 cells, correlating well with its lack of expression at the mRNA level. Only a few CpG sites showed methylation by bisulfite sequencing within the GATA-4 promoter in a cell line that expressed the gene. In 63 cases of primary lung cancers, GATA-4 and GATA-5 promoter methylation was detected in (42 of 63) 67% and (26 of 63) 41%, respectively. GATA-6 remained unmethylated both in cell lines and primary tumors. Six autopsy specimens of normal lung tissue showed no aberrant promoter hypermethylation for the GATA genes. Correlation of concomitant GATA-4 and GATA-5 methylation with clinicopathological parameters only found a statistically significant increase in methylation frequency with increasing patient age (P < 0.001). Conclusions: These epigenetic changes in the GATA genes in lung cancer are tumor-specific, relate to the loss of GATA gene expression, and occur increasingly in the elderly.

Role of EUS for preoperative evaluation of cholangiocarcinoma: a large single-center experience.

BACKGROUND Accurate preoperative diagnosis and staging of cholangiocarcinoma (CCA) remain difficult. OBJECTIVE To evaluate the utility of EUS in the diagnosis and preoperative evaluation of CCA. DESIGN Observational study of prospectively collected data. SETTING Single tertiary referral hospital in Indianapolis, Indiana. PATIENTS Consecutive patients with CCA from January 2003 through October 2009. INTERVENTIONS EUS and EUS-guided FNA (EUS-FNA). MAIN OUTCOME MEASUREMENTS Sensitivity of EUS for the detection of a tumor and prediction of unresectability compared with CT and magnetic resonance imaging (MRI); sensitivity of EUS-FNA to provide tissue diagnosis, by using surgical pathology as a reference standard. RESULTS A total of 228 patients with biliary strictures undergoing EUS were identified. Of these, 81 (mean age 70 years, 45 men) had CCA. Fifty-one patients (63%) had distal and 30 (37%) had proximal CCA. For those with available imaging, tumor detection was superior with EUS compared with triphasic CT (76 of 81 [94%] vs 23 of 75 [30%], respectively; P < .001). MRI identified the tumor in 11 of 26 patients (42%; P = .07 vs EUS). EUS identified CCA in all 51 (100%) distal and 25 (83%) of 30 proximal tumors (P < .01). EUS-FNA (median, 5 passes; range, 1-12 passes) was performed in 74 patients (91%). The overall sensitivity of EUS-FNA for the diagnosis of CCA was 73% (95% confidence interval, 62%-82%) and was significantly higher in distal compared with proximal CCA (81% vs 59%, respectively; P = .04). Fifteen tumors were definitely unresectable. EUS correctly identified unresectability in 8 of 15 and correctly identified the 38 of 39 patients with resectable tumors (53% sensitivity and 97% specificity for unresectability). CT and/or MRI failed to detect unresectability in 6 of these 8 patients. LIMITATION Single-center study. CONCLUSION EUS and EUS-FNA are sensitive for the diagnosis of CCA and very specific in predicting unresectability. The sensitivity of EUS-FNA is significantly higher in distal than in proximal CCA.

Predicting resectability of periampullary cancer with three-dimensional computed tomography.

The radiographic assessment of extent of tumor burden and local vascular invasion appears to be enhanced with three-dimensional computed tomography (3D-CT). The purpose of this study was to evaluate the impact of preoperative 3D-CT in determining the resectability of patients with periampullary tumors. Intraoperative findings from exploratory laparotomy were gathered prospectively from 140 patients who were thought to have periampullary tumors and were deemed resectable after undergoing preoperative 3D-CT imaging. CT findings were compared to intraoperative findings, and the accuracy of 3D-CT in predicting tumor resectability and, ultimately, the likelihood of obtaining a margin-negative resection were assessed. Of the 140 patients who were thought to have resectable periampullary tumors after preoperative 3D-CT, 115 (82%) were subsequently determined to have periampullary cancer. The remaining 25 patients had benign disease. Among the patients with periampullary cancer, the extent of local tumor burden involving the pancreas and peripancreatic tissues was accurately depicted by 3D-CT in 93 % of the patients. 3D-CT was 95% accurate in determining cancer invasion of the superior mesenteric vessels. Preoperative 3D-CT accurately predicted periampullary cancer resectability and a margin-negative resection in 98% and 86% of patients, respectively. For patients with pancreatic adenocarcinoma (n=85), preoperative 3D-CT resulted in a resectability rate and a margin-negative resection rate of 79% and 73%, respectively. The ability of 3 D-CT to predict a margin-negative resection for periampullary cancer, including pancreatic adenocarcinoma, relies on its enhanced assessment of the extent of local tumor burden and involvement of the mesenteric vascular anatomy.

Incidence and Outcome of Biliary Strictures After Pancreaticoduodenectomy

Objective:This single-institution review examined the incidence of biliary stricture formation after pancreaticoduodenectomy (PD) for benign and malignant periampullary disease. Background:The incidence and course of stricture of the hepaticojejunostomy have not been documented after PD. Methods:Between January 1995 and April 2003, 1595 patients underwent PD for periampullary disease (392 benign, 1203 malignant). A retrospective analysis of a prospectively collected database was performed to determine the incidence of biliary stricture after PD. Results:Forty-two of the 1595 patients (2.6%) who underwent PD developed postoperative jaundice secondary to a stricture of the biliary-enteric anastomosis. There was no difference in the incidence of biliary strictures after resection for benign (n = 10, 2.6%) or malignant disease (n = 32, 2.6%). The median time to stricture formation resulting in jaundice was 13 months (range, 1–106 months) and was similar for patients with benign and malignant disease. Preoperative jaundice did not protect against biliary stricture formation. By univariate analysis, biliary strictures were associated with preoperative percutaneous biliary drainage (odds ratio [OR] = 2.11, P = 0.02) and postoperative biliary stenting (OR = 2.11, P = 0.013). Postoperative chemoradiotherapy in patients with malignant disease was not associated with stricture formation. All strictures were initially managed with percutaneous biliary balloon dilatation and stenting, and only 2 patients required redo hepaticojejunostomy. Recurrent neoplastic disease was discovered in only 3 of the 32 patients (9%) with malignant disease. All 3 of these patients had cholangiocarcinoma as their initial diagnosis. Conclusions:Biliary stricture formation is an infrequent complication after PD and can be managed successfully with percutaneous biliary dilatation and short-term stenting in most patients. The only significant univariate predictors for biliary stricture formation were preoperative and postoperative percutaneous biliary drainage. The development of a biliary stricture in patients who have undergone PD for malignant disease is usually benign and should not be automatically attributed to anastomotic tumor recurrence.