John L. Cameron

Six hundred fifty consecutive pancreaticoduodenectomies in the 1990s: pathology, complications, and outcomes.

OBJECTIVEnThe authors reviewed the pathology, complications, and outcomes in a consecutive group of 650 patients undergoing pancreaticoduodenectomy in the 1990s.nnnSUMMARY BACKGROUND DATAnPancreaticoduodenectomy has been used increasingly in recent years to resect a variety of malignant and benign diseases of the pancreas and periampullary region.nnnMETHODSnBetween January 1990 and July 1996, inclusive, 650 patients underwent pancreaticoduodenal resection at The Johns Hopkins Hospital. Data were recorded prospectively on all patients. All pathology specimens were reviewed and categorized. Statistical analyses were performed using both univariate and multivariate models.nnnRESULTSnThe patients had a mean age of 63 +/- 12.8 years, with 54% male and 91% white. The number of resections per year rose from 60 in 1990 to 161 in 1995. Pathologic examination results showed pancreatic cancer (n = 282; 43%), ampullary cancer (n = 70; 11%), distal common bile duct cancer (n = 65; 10%), duodenal cancer (n = 26; 4%), chronic pancreatitis (n = 71; 11%), neuroendocrine tumor (n = 31; 5%), periampullary adenoma (n = 21; 3%), cystadenocarcinoma (n = 14; 2%), cystadenoma (n = 25; 4%), and other (n = 45; 7%). The surgical procedure involved pylorus preservation in 82%, partial pancreatectomy in 95%, and portal or superior mesenteric venous resection in 4%. Pancreatic-enteric reconstruction, when appropriate, was via pancreaticojejunostomy in 71% and pancreaticogastrostomy in 29%. The median intraoperative blood loss was 625 mL, median units of red cells transfused was zero, and the median operative time was 7 hours. During this period, 190 consecutive pancreaticoduodenectomies were performed without a mortality. Nine deaths occurred in-hospital or within 30 days of operation (1.4% operative mortality). The postoperative complication rate was 41%, with the most common complications being early delayed gastric emptying (19%), pancreatic fistula (14%), and wound infection (10%). Twenty-three patients required reoperation in the immediate postoperative period (3.5%), most commonly for bleeding, abscess, or dehiscence. The median postoperative length of stay was 13 days. A multivariate analysis of the 443 patients with periampullary adenocarcinoma indicated that the most powerful independent predictors favoring long-term survival included a pathologic diagnosis of duodenal adenocarcinoma, tumor diameter <3 cm, negative resection margins, absence of lymph node metastases, well-differentiated histology, and no reoperation.nnnCONCLUSIONSnThis single institution, high-volume experience indicates that pancreaticoduodenectomy can be performed safely for a variety of malignant and benign disorders of the pancreas and periampullary region. Overall survival is determined largely by the pathology within the resection specimen.

Periampullary adenocarcinoma: analysis of 5-year survivors.

OBJECTIVEnThis single-institution experience retrospectively reviews the outcomes in a group of patients treated 5 or more years ago by pancreaticoduodenectomy for periampullary adenocarcinoma.nnnSUMMARY BACKGROUND DATAnControversy exists regarding the benefit of resection for periampullary adenocarcinoma, particularly for pancreatic tumors. Many series report only Kaplan-Meier actuarial 5-year survival rates. There are believed to be discrepancies between the actuarial 5-year survival data and the actual 5-year survival rates.nnnMETHODSnFrom April 1970 through May 1992, 242 patients underwent pancreaticoduodenal resection for periampullary adenocarcinoma at The Johns Hopkins Hospital. Follow-up was complete through May 1997. All pathology specimens were reviewed and categorized. Actual 5-year survival rates were calculated. The demographic, intraoperative, pathologic, and postoperative features of patients surviving > or =5 years were compared with those of patients who survived <5 years.nnnRESULTSnOf the 242 patients with resected periampullary adenocarcinoma, 149 (62%) were pancreatic primaries, 46 (19%) arose in the ampulla, 30 (12%) were distal bile duct cancers, and 17 (7%) were duodenal cancers. There was a 5.3% operative mortality rate during the 22 years of the review, with a 2% operative mortality rate in the last 100 patients. There were 58 5-year survivors, 28 7-year survivors, and 7 10-year survivors. The tumor-specific 5-year actual survival rates were pancreatic 15%, ampullary 39%, distal bile duct 27%, and duodenal 59%. When compared with patients who did not survive 5 years, the 5-year survivors had a significantly higher percentage of well-differentiated tumors (14% vs. 4%; p = 0.02) and higher incidences of negative resection margins (98% vs. 73%, p < 0.0001) and negative nodal status (62% vs. 31%, p < 0.0001). The tumor-specific 10-year actuarial survival rates were pancreatic 5%, ampullary 25%, distal bile duct 21%, and duodenal 59%.nnnCONCLUSIONSnAmong patients with periampullary adenocarcinoma treated by pancreaticoduodenectomy, those with duodenal adenocarcinoma are most likely to survive long term. Five-year survival is less likely for patients with ampullary, distal bile duct, and pancreatic primaries, in declining order. Resection margin status, resected lymph node status, and degree of tumor differentiation also significantly influence long-term outcome. Particularly for patients with pancreatic adenocarcinoma, 5-year survival is not equated with cure, because many patients die of recurrent disease >5 years after resection.

Is Prophylactic Gastrojejunostomy Indicated for Unresectable Periampullary Cancer?: A Prospective Randomized Trial

OBJECTIVEnThis prospective, randomized, single-institution trial was designed to evaluate the role of prophylactic gastrojejunostomy in patients found at exploratory laparotomy to have unresectable periampullary carcinoma.nnnSUMMARY BACKGROUND DATAnBetween 25% and 75% of patients with periampullary cancer who undergo exploratory surgery with intent to perform a pancreaticoduodenectomy are found to have unresectable disease. Most will undergo a biliary-enteric bypass. Whether or not to perform a prophylactic gastrojejunostomy remains unresolved. Retrospective reviews of surgical series and prospective randomized trials of endoscopic palliation have demonstrated that late gastric outlet obstruction, requiring a gastrojejunostomy, develops in 10% to 20% of patients with unresectable periampullary cancer.nnnMETHODSnBetween May 1994 and October 1998, 194 patients with a periampullary malignancy underwent exploratory surgery with the purpose of performing a pancreaticoduodenectomy and were found to have unresectable disease. On the basis of preoperative symptoms, radiologic studies, or surgical findings, the surgeon determined that gastric outlet obstruction was a significant risk in 107 and performed a gastrojejunostomy. The remaining 87 patients were thought by the surgeon not to be at significant risk for duodenal obstruction and were randomized to receive either a prophylactic retrocolic gastrojejunostomy or no gastrojejunostomy. Short- and long-term outcomes were determined in all patients.nnnRESULTSnOf the 87 patients randomized, 44 patients underwent a retrocolic gastrojejunostomy and 43 did not undergo a gastric bypass. The two groups were similar with respect to age, gender, procedure performed (excluding gastrojejunostomy), and surgical findings. There were no postoperative deaths in either group, and the postoperative morbidity rates were comparable (gastrojejunostomy 32%, no gastrojejunostomy 33%). The postoperative length of stay was 8.5+/-0.5 days for the gastrojejunostomy group and 8.0+/-0.5 days for the no gastrojejunostomy group. Mean survival among those who received a prophylactic gastrojejunostomy was 8.3 months, and during that interval gastric outlet obstruction developed in none of the 44 patients. Mean survival among those who did not have a prophylactic gastrojejunostomy was 8.3 months. In 8 of those 43 patients (19%), late gastric outlet obstruction developed, requiring therapeutic intervention (gastrojejunostomy 7 patients, endoscopic duodenal stent 1 patient; p < 0.01). The median time between initial exploration and therapeutic intervention was 2 months.nnnCONCLUSIONnThe results from this prospective, randomized trial demonstrate that prophylactic gastrojejunostomy significantly decreases the incidence of late gastric outlet obstruction. The performance of a prophylactic retrocolic gastrojejunostomy at the initial surgical procedure does not increase the incidence of postoperative complications or extend the length of stay. A retrocolic gastrojejunostomy should be performed routinely when a patient is undergoing surgical palliation for unresectable periampullary carcinoma.

Multicomponent Analysis of the Pancreatic Adenocarcinoma Progression Model Using a Pancreatic Intraepithelial Neoplasia Tissue Microarray

A multistep model for pancreatic adenocarcinoma has been proposed recently. In this model, well-defined, noninvasive ductal lesions are recognized as precursors of invasive cancer and have been classified under the nomenclature of pancreatic intraepithelial neoplasia, or PanIN. Increasing evidence suggests that PanINs represent true neoplasms of the pancreatic ductal epithelium, accumulating histologic and genetic abnormalities in their progression toward invasive cancer. We have constructed a tissue microarray containing 55 PanIN lesions of all histologic grades in order to perform a multicomponent analysis of the pancreatic adenocarcinoma progression model. The protein products of 14 genes encompassing a variety of functional classes, such as tumor suppressor genes (p53, Smad4/Dpc4), oncogenes (β-catenin), cell cycle antigens (p16, cyclin D1), proliferation antigens (Ki-67, topoisomerase II alpha), and epithelial apomucins (MUC1, MUC2, MUC5), as well as “novel” genes described as differentially up-regulated in invasive pancreas cancer by global microarray expression analysis (mesothelin, prostate stem cell antigen, fascin, and 14-3-3σ), were analyzed by immunohistochemistry on the PanIN tissue microarray. Comparison of the results from the current study with previously published data performed on routine histologic sections of PanINs demonstrates that tissue microarrays are a valid platform for molecular analysis not only of invasive cancers but of precursor lesions as well. In addition, this study demonstrates that molecular abnormalities in PanINs are not random but can usually be stratified into “early” changes (e.g., expression of MUC5 and prostate stem antigen, or loss of p16), “intermediate” changes (e.g., expression of cyclin D1), and “late” changes (e.g., expression of p53, proliferation antigens, MUC1, mesothelin, and 14-3-3σ, or loss of Smad4/Dpc4). Understanding the molecular pathogenesis of precursor lesions of invasive pancreatic adenocarcinomas using a high-throughput tissue microarray–based approach is a valuable adjunct to designing rational strategies for early detection of this lethal neoplasm.

Pancreaticoduodenectomy with or without extended retroperitoneal lymphadenectomy for periampullary adenocarcinoma: Comparison of morbidity and mortality and short-term outcome

OBJECTIVEnThis prospective, randomized, single-institution trial was designed to evaluate the end points of mortality, morbidity, and survival in patients undergoing standard versus radical (extended) pancreaticoduodenectomy (including distal gastrectomy and retroperitoneal lymphadenectomy).nnnSUMMARY BACKGROUND DATAnNumerous retrospective reports and one prospective randomized trial have suggested that the performance of an extended lymphadenectomy in association with a pancreaticoduodenal resection may improve long-term survival for some patients with pancreatic and other periampullary adenocarcinomas. Many of these previously published studies can be criticized for their retrospective and nonrandomized designs, for the inclusion of nonconcurrent control groups, and for their small numbers.nnnMETHODSnBetween April 1996 and December 1997, 114 patients with periampullary adenocarcinoma were enrolled in an ongoing, prospective, randomized trial at The Johns Hopkins Hospital. After intraoperative verification of completely resected periampullary adenocarcinoma, the patients were randomized to receive either a standard pancreaticoduodenectomy (removing only the peripancreatic lymph nodes en bloc with the specimen) or a radical pancreaticoduodenectomy (standard resection plus distal gastrectomy and retroperitoneal lymphadenectomy). All pathology specimens were reviewed and categorized. The postoperative morbidity, mortality, and short-term outcomes were examined.nnnRESULTSnOf the 114 patients randomized, 56 underwent a standard pancreaticoduodenectomy and 58 a radical pancreaticoduodenectomy. The two groups were statistically similar with regard to age and gender, but there was a higher percentage of white patients in the radical group. All the patients in the radical group underwent distal gastric resection, whereas 86% of the patients in the standard group underwent pylorus preservation. The mean operative time in the radical group was 6.8 hours, compared with 6.2 hours in the standard group. There were no significant differences between the two groups with respect to the intraoperative blood loss, transfusion requirements, location of primary tumor, mean tumor size, positive lymph node status, or positive margin status. There were three deaths in the standard group and two in the radical group. The complication rates were 34% for the standard group and 40% for the radical group. Patients undergoing radical resection had a higher incidence of early delayed gastric emptying but had similar rates of other complications, such as pancreatic fistula, wound infection, intraabdominal abscess, and need for reoperation. The mean total number of lymph nodes resected was higher in the radical group. Of the 58 patients in the radical group, only 10% had metastatic carcinoma in the resected retroperitoneal lymph nodes, and none of those patients had the retroperitoneal nodes as the only site of lymph node involvement. The 1-year actuarial survival rate for patients surviving the immediate postoperative periods was 77% for the standard resection group and 83% for the radical resection group.nnnCONCLUSIONSnThese data demonstrate that radical pancreaticoduodenectomy (with the addition of a distal gastrectomy and extended retroperitoneal lymphadenectomy to a standard pancreaticoduodenectomy) can be performed with similar morbidity and mortality to standard pancreaticoduodenectomy. However, the survival data are not sufficiently mature and the numbers of patients enrolled are not adequate to allow firm conclusions to be drawn regarding survival benefit.

MUC4 Expression Increases Progressively in Pancreatic Intraepithelial Neoplasia

Pancreatic adenocarcinoma is believed to develop from histologically identifiable intraductal lesions known as pancreatic intraepithelial neoplasias (PanINs) that undergo a series of architectural, cytologic, and genetic changes, a progression model similar to the adenoma-carcinoma sequence in the colon. The apomucin MUC4 has been implicated in invasive pancreatic adenocarcinoma. MUC4 expression is not detectable at the RNA level in normal pancreas but is detectable at high levels in invasive pancreatic adenocarcinoma. We documented the pattern of expression of MUC4 in PanINs by studying a series of 71 PanIN lesions immunohistochemically using a new monoclonal antibody to MUC4. Five (17%) of 30 PanIN-1 lesions, 10 (36%) of 28 PanIN-2 lesions, 11 (85%) of 13 PanIN-3 lesions, and 25 (89%) of 28 invasive adenocarcinomas labeled with the MUC4 antibody used in the study. In addition, afew nonneoplastic lesions labeled with the MUC4 antibody, including reactive ducts in chronic pancreatitis, atrophic ducts filled with inspissated secretions, and ducts showing squamous metaplasia. Our data help establish the patterns of MUC4 expression in neoplastic precursors in the pancreas and add further support to the progression model for pancreatic adenocarcinoma.

Patient Readmission and Mortality after Colorectal Surgery for Colon Cancer: Impact of Length of Stay Relative to Other Clinical Factors

BACKGROUNDnData on readmission as well as the potential impact of length of stay (LOS) after colectomy for colon cancer remain poorly defined. The objective of the current study was to evaluate risk factors associated with readmission among a nationwide cohort of patients after colorectal surgery.nnnSTUDY DESIGNnWe identified 149,622 unique individuals from the Surveillance, Epidemiology, and End Results-Medicare dataset with a diagnosis of primary colorectal cancer who underwent colectomy between 1986 and 2005. In-hospital morbidity, mortality, LOS, and 30-day readmission were examined using univariate and multivariate logistic regression models.nnnRESULTSnPrimary surgical treatment consisted of right (37.4%), transverse (4.9%), left (10.5%), sigmoid (22.8%), abdominoperineal resection (7.3%), low anterior resection (5.6%), total colectomy (1.2%), or other/unspecified (10.3%). Mean patient age was 76.5 years and more patients were female (52.9%). The number of patients with multiple preoperative comorbidities increased over time (Charlson comorbidity score ≥3: 1986 to 1990, 52.5% vs 2001 to 2005, 63.1%; p < 0.001). Mean LOS was 11.7 days and morbidity and mortality were 36.5% and 4.2%, respectively. LOS decreased over time (1986 to 1990, 14.0 days; 1991 to 1995, 12.0 days; 1996 to 2000, 10.4 days; 2001 to 2005, 10.6 days; p < 0.001). In contrast, 30-day readmission rates increased (1986 to 1990, 10.2%; 1991 to 1995, 10.9%; 1996 to 2000, 12.4%; 2001 to 2005, 13.7%; p < 0.001). Factors associated with increased risk of readmission included LOS (odds ratio = 1.02), Charlson comorbidities ≥3 (odds ratio = 1.27), and postoperative complications (odds ratio = 1.17) (all p < 0.01).nnnCONCLUSIONSnReadmission rates after colectomies have increased during the past 2 decades and mean LOS after this operation has declined. More research is needed to understand the balance and possible trade off between these hospital performance measures for all surgical procedures.

Trends in Survival after Surgery for Cholangiocarcinoma: A 30-Year Population-Based SEER Database Analysis

The prognosis of patients with cholangiocarcinoma historically has been poor, even after surgical resection. Although data from some single-institution series indicate improvement over historical results, survival after surgical therapy for cholangiocarcinoma has not been investigated in a population-based study. We used the Surveillance, Epidemiology, and End Results database to identify patients who underwent surgery for cholangiocarcinoma from 1973 through 2002. Multivariate modeling of survival after surgery for intrahepatic cholangiocarcinoma showed an improvement in survival only within the last decade studied, resulting in a cumulative 34.4% improvement in survival from 1992 through 2002. In contrast, multivariate modeling of survival after surgery for extrahepatic cholangiocarcinoma revealed a 23.3% increase in adjusted survival per each decade studied, resulting in a cumulative 53.7% improvement from 1973 through 2002. We conclude that survival after surgery for extrahepatic cholangiocarcinoma has dramatically improved since 1973. Patients with intrahepatic cholangiocarcinoma, however, have achieved an improvement in survival largely confined to more recent years. We suggest that these trends are largely caused by developments in imaging technology, improvements in patient selection, and advances in surgical techniques.

Surgical palliation of unresectable periampullary adenocarcinoma in the 1990s

BACKGROUNDnAdvances in the nonoperative staging and palliation of periampullary carcinoma have dramatically changed the management of this disease. Currently, surgical palliation is used primarily for patients found to be unresectable at the time of laparotomy performed for the purpose of determining resectability.nnnSTUDY DESIGNnA review of all patients undergoing operative management for periampullary adenocarcinoma at a single, high-volume institution was performed. The review focused on patients found to be unresectable who, therefore, underwent surgical palliation.nnnRESULTSnBetween December 1991 and December 1997, 256 patients with unresectable periampullary adenocarcinoma were operatively palliated. During the same time period, 512 patients underwent pancreaticoduodenectomy (PD) for periampullary carcinoma. Sixty-eight percent of patients were unresectable secondary to liver metastases or peritoneal metastases, and 32% were deemed unresectable because of local vascular invasion. Of the 256 patients, 51% underwent double bypass (hepaticojejunostomy [HJ] and gastrojejunostomy [GJ]), 11% underwent HJ alone, 19% underwent GJ alone, and 19% did not undergo any form of bypass. Celiac block was performed in 75% of patients. Palliated patients were significantly younger, with a mean age of 64.0 years compared with 65.8 years in the resected group (p = 0.04). Gender and race distributions were similar in the 2 groups, with 57% of palliated patients and 55% of resected patients being men (p = NS) and 91% of patients in each group being Caucasian (p = NS). Palliative procedures were performed with a mortality rate of 3.1%, compared to 1.9% in those successfully resected (p = NS). Those undergoing operative palliation had a significantly lower incidence of postoperative complications when compared with those undergoing pancreaticoduodenectomy (22% versus 35%, p<0.0001) and had significantly shorter lengths of stay (10.3 days versus 14.8 days, p<0.0001). As expected, palliated patients had a significantly poorer prognosis, with 1-, 2- and 4-year survivals of 25%, 9%, and 6% (median 6.5 months), respectively, compared with 75%, 47%, and 24% in their resectable counterparts (median 21 months, p<0.0001).nnnCONCLUSIONSnSurgical palliation continues to play an important role in the management of periampullary carcinoma. In this high-volume center, 33% of patients undergoing operative management of this disease were unresectable. Surgical palliation can be accomplished with acceptable perioperative mortality (3.1%) and morbidity (22%), with excellent longterm results.

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.