Andrew L. Warshaw

Hedgehog is an early and late mediator of pancreatic cancer tumorigenesis

Hedgehog signalling—an essential pathway during embryonic pancreatic development, the misregulation of which has been implicated in several forms of cancer—may also be an important mediator in human pancreatic carcinoma. Here we report that sonic hedgehog, a secreted hedgehog ligand, is abnormally expressed in pancreatic adenocarcinoma and its precursor lesions: pancreatic intraepithelial neoplasia (PanIN). Pancreata of Pdx–Shh mice (in which Shh is misexpressed in the pancreatic endoderm) develop abnormal tubular structures, a phenocopy of human PanIN-1 and -2. Moreover, these PanIN-like lesions also contain mutations in K-ras and overexpress HER-2/neu, which are genetic mutations found early in the progression of human pancreatic cancer. Furthermore, hedgehog signalling remains active in cell lines established from primary and metastatic pancreatic adenocarcinomas. Notably, inhibition of hedgehog signalling by cyclopamine induced apoptosis and blocked proliferation in a subset of the pancreatic cancer cell lines both in vitro and in vivo. These data suggest that this pathway may have an early and critical role in the genesis of this cancer, and that maintenance of hedgehog signalling is important for aberrant proliferation and tumorigenesis.

Main-Duct Intraductal Papillary Mucinous Neoplasms of the Pancreas: Clinical Predictors of Malignancy and Long-term Survival Following Resection

Objective:To describe clinical characteristics and outcomes of a large cohort of intraductal papillary mucinous neoplasms (IPMNs) of the pancreas affecting the main pancreatic duct. Summary Background Data:IPMNs are being diagnosed with increasing frequency. Preoperative determination of malignancy remains problematic, and reported results of long-term survival following resection are conflicting. Methods:The combined databases from the Massachusetts General Hospital and the Pancreatic Unit of the University of Verona were analyzed. To avoid confusing overlap with mucinous cystic neoplasms, only patients with tumors of the main pancreatic duct (with or without side branch involvement) were included. A total of 140 tumors consecutively resected between 1990 and 2002 were classified as either benign (adenoma and borderline tumors) or malignant (carcinoma in situ or invasive cancer) to compare their characteristics and survival. Results:Men and women were equally affected (mean age 65 years). Seven patients (12%) had adenomas, 40 (28%) borderline tumors, 25 (18%) carcinoma in situ, and 58 (42%) invasive carcinoma. The median age of patients with benign IPMN was 6.4 years younger than those with malignant tumors (P = 0.04). The principal symptoms were abdominal pain (65%), weight loss (44%), acute pancreatitis (23%), jaundice (17%), and onset or worsening of diabetes (12%); 27% of patients were asymptomatic. Jaundice and diabetes were significantly associated with malignant tumors. Five- and 10-year cancer-specific survival for patients with noninvasive tumors was 100%, and comparable survival of the 58 patients with invasive carcinoma was 60% and 50%. Conclusions:Cancer is found in 60% of patients with main-duct IPMNs. Patients with malignant tumors are 6 years older than their benign counterparts and have a higher likelihood of presenting with jaundice or new onset diabetes. No patients with benign tumors or carcinoma in situ died of their disease following resection, and those with invasive cancer had a markedly better survival (60% at 5 years) than pancreatic ductal adenocarcinoma. These findings support both the concept of progression of benign IPMNs to invasive cancer and an aggressive policy of resection at diagnosis.

A Better Model of Acute Pancreatitis for Evaluating Therapy

Existing models of acute pancreatitis have limitations to studying novel therapy. Whereas some produce mild self-limited pancreatitis, others result in sudden necrotizing injury. The authors developed an improved model providing homogeneous moderately severe injury by superimposing secretory hyperstimulation on minimal intraductal bile acid exposure. Sprague-Dawley rats (n = 231) received low-pressure intraductal glycodeoxycholic acid (GDOC) at very low (5 or 10 mmol/L) concentrations followed by intravenous cerulein. Cerulein or GDOC alone caused only very mild inflammation. However, GDOC combined with cerulein was uniformly associated with more edema (p less than 0.0005), acinar necrosis (p less than 0.01), inflammation (p less than 0.006), and hemorrhage (p less than 0.01). Pancreatic injury was further increased and death was potentiated by increasing volume and duration of intraductal low-dose GDOC infusion. There was significant morphologic progression between 6 and 24 hours. The authors conclude that (1) combining minimal intraductal bile acid exposure with intravenous hyperstimulation produces homogeneous pancreatitis of intermediate severity that can be modulated at will; (2) the injury is progressive over at least 24 hours with finite mortality rate; (3) the model provides superior opportunity to study innovative therapy.

Cystic Tumors of the Pancreas

Cystic neoplasms of the pancreas are rare but in the last years more frequently detected. Within a 10-year-period we treated 30 patients, including 8 serous cystadenomas, 6 mucinous cystadenomas, 12 mucinous cystadenocarcinomas, 2 cystic neuro-endocrine tumors and 1 papillary cystic tumor respectively acinar cell cyst-adenocarcinoma. 80% of the patients had symptoms, experienced abdominal pain, weight loss, weakness or abdominal mass. In eight patients the tumors had been misdiagnosed as a pancreatic pseudocyst. The correct type of cystic tumor was diagnosed by preoperative investigations only a few cases. All patients with serous or mucinous cystadenomas are well and without evident recurrence after resection of the tumor. However the survival time of malignant cystic tumors varied strongly. The curative resection of these tumors give patients the chance of long-term survival.

Effect of hospital volume on in-hospital mortality with pancreaticoduodenectomy ☆ ☆☆ ★

BACKGROUND Reports of better results at national referral centers than at low-volume community hospitals have prompted calls for regionalizing pancreaticoduodenectomy (the Whipple procedure). We examined the relationship between hospital volume and mortality with this procedure across all US hospitals. METHODS Using information from the Medicare claims database, we performed a national cohort study of 7229 Medicare patients more than 65 years old undergoing pancreaticoduodenectomy between 1992 and 1995. We divided the study population into approximate quartiles according to the hospitals average annual volume of pancreaticoduodenectomies in Medicare patients: very low (< 1/y), low (1-2/y), medium (2-5/y), and high (5+/y). Using multivariate logistic regression to account for potentially confounding patient characteristics, we examined the association between institutional volume and in-hospital mortality, our primary outcome measure. RESULTS More than 50% of Medicare patients a undergoing pancreaticoduodenectomy received care at hospitals performing fewer than 2 such procedures per year. In-hospital mortality rates at these low- and very-low-volume hospitals were 3- to 4-fold higher than at high-volume hospitals (12% and 16%, respectively, vs 4%, P < .001). Within the high-volume quartile, the 10 hospitals with the nations highest volumes had lower mortality rates than the remaining high-volume centers (2.1% vs 6.2%, P < .01). The strong association between institutional volume and mortality could not be attributed to patient case-mix differences or referral bias. CONCLUSIONS Although volume-outcome relationships have been reported for many complex surgical procedures, hospital experience is particularly important with pancreaticoduodenectomy. Patients considering this procedure should be given the option of care at a high-volume referral center.

Resection margins in carcinoma of the head of the pancreas. Implications for radiation therapy.

A retrospective review of the pathology and clinical course of 72 patients undergoing resection of carcinoma of the head of the pancreas was undertaken to identify the frequency of tumor involvement at standard surgical transection margins (stomach, duodenum, pancreas, and bile duct) as well as the peripancreatic soft tissue margin and the potential clinical significance of these findings. Of 72 patients undergoing resection, 37 patients (51%) were found to have tumor extension to the surgical margins. The most commonly involved margin was peripancreatic soft tissue (27 patients) followed by pancreatic transection line (14 patients) and bile duct transection line (4 patients). For 37 patients with tumor present at a resection margin, there were no survivors beyond 41 months. No difference in survival or local control was seen between 14 patients receiving postoperative radiation therapy and 5-fluorouracil (5-FU) compared with 23 patients not receiving additional treatment. In contrast, the 5-year actuarial survival and local control of 35 patients undergoing resection without tumor invasion to a resection margin was 22% and 43%, respectively. The 5-year survival and local control of 16 patients receiving adjuvant radiation therapy and 5-FU was 29% and 42%, respectively, whereas these figures were 18% and 31% for 19 patients not receiving adjuvant therapy (p > 0.10). Because residual local tumor after resection is common, preoperative radiation therapy may be beneficial in this disease. It should minimize the risk of dissemination during operative manipulation and facilitate a curative resection by promoting tumor regression. Because local failure rates approach 60% after resection and adjuvant therapy even in cases having clear resection margins, intraoperative radiation therapy to the tumor bed at the time of resection also might be considered. Protocols evaluating the feasibility and efficacy of preoperative radiation therapy and resection with intraoperative radiation therapy for patients with pancreatic cancer are underway.

Relationship between hospital volume and late survival after pancreaticoduodenectomy.

BACKGROUND Several studies have reported lower perioperative mortality rates with pancreaticoduodenectomy at high-volume hospitals than at low-volume hospitals. We sought to determine whether volume is also related to survival after hospital discharge. METHODS Using information from the Medicare claims database, we performed a retrospective cohort study of all 7229 patients over age 65 undergoing pancreaticoduodenectomy in the United States between 1992 and 1995. We divided the study population into approximate quartiles according to their hospitals average annual volume of pancreaticoduodenectomies in Medicare patients: very low (< 1/y), low (1-2/y, medium (2-5/y), and high (5+/y). To adjust for potentially confounding variables, we used a Cox proportional hazards model to examine relationships between hospital volume and mortality, our primary outcome measure. RESULTS Overall, 3-year survival was higher at high-volume centers (37%) than at medium- (29%), low- (26%), and very low volume hospitals (25%) (log-rank P < .0001). After excluding perioperative deaths and adjusting for case-mix, patients undergoing surgery at high-volume hospitals remained less likely to experience late mortality than patients at very low volume centers (adjusted hazard ratio 0.69, 95% CI 0.62-0.76). Relationships between hospital volume and survival after discharge were not restricted to patients with cancer diagnoses; patients with benign disease had similar improvements in late survival after surgery at high-volume centers. CONCLUSIONS Hospital volume strongly influences both perioperative risk and long-term survival after pancreaticoduodenectomy. Our data suggest that both patient selection and differences in quality of care may underlie better outcomes at high-volume referral centers.

Mucinous cystic neoplasm of the pancreas is not an aggressive entity: lessons from 163 resected patients.

Objective:Mucinous cystic neoplasms (MCNs) of the pancreas have often been confused with intraductal papillary mucinous neoplasms. We evaluated the clinicopathologic characteristics, prevalence of cancer, and prognosis of a large series of well-characterized MCNs in 2 tertiary centers. Methods:Analysis of 163 patients with resected MCNs, defined by the presence of ovarian stroma and lack of communication with the main pancreatic duct. Results:MCNs were seen mostly in women (95%) and in the distal pancreas (97%); 25% were incidentally discovered. Symptomatic patients typically had mild abdominal pain, but 9% presented with acute pancreatitis. One hundred eighteen patients (72%) had adenoma, 17 (10.5%) borderline tumors, 9 (5.5%) in situ carcinoma, and 19 (12%) invasive carcinoma. Patients with invasive carcinoma were significantly older than those with noninvasive neoplasms (55 vs. 44 years, P = 0.01). Findings associated with malignancy were presence of nodules (P = 0.0001) and diameter ≥60 mm (P = 0.0001). All neoplasms with cancer were either ≥40 mm in size or had nodules. There was no operative mortality and postoperative morbidity was 49%. Median follow-up was 57 months (range, 4–233); only patients with invasive carcinoma had recurrence. The 5-year disease-specific survival for noninvasive MCNs was 100%, and for those with invasive cancer, 57%. Conclusions:This series, the largest with MCNs defined by ovarian stroma, shows a prevalence of cancer of only 17.5%. Patients with invasive carcinoma are older, suggesting progression from adenoma to carcinoma. Although resection should be considered for all cases, in low-risk MCNs (≤4 cm/no nodules), nonradical resections are appropriate.

The Impact of the 80-Hour Resident Workweek on Surgical Residents and Attending Surgeons

Objective:To assess the impact of the 80-hour resident workweek restrictions on surgical residents and attending surgeons. Summary Background Data:The ACGME mandated resident duty hour restrictions have required a major workforce restructuring. The impact of these changes needs to be critically evaluated for both the resident and attending surgeons, specifically with regards to the impact on motivation, job satisfaction, the quality of surgeon training, the quality of the surgeons life, and the quality of patient care. Methods:Four prospective studies were performed at a single academic surgical program with data collected both before the necessary workforce restructuring and 1 year after, including: 1) time cards to assess changes in components of daily activity; 2) Web-based surveys using validated instruments to assess burnout and motivation to work; 3) structured, taped, one-on-one interviews with an external PhD investigator; and 4) statistical analyses of objective, quantitative data. Results:After the work-hour changes, surgical residents have decreased “burnout” scores, with significantly less “emotional exhaustion” (Maslach Burnout Inventory: 29.1 “high” vs. 23.1 “medium,” P = 0.02). Residents have better quality of life both in and out of the hospital. They felt they got more sleep, have a lighter workload, and have increased motivation to work (Herzberg Motivation Dimensions). We found no measurable, statistically significant difference in the quality of patient care (NSQIP data). Resident training and education objectively were not statistically diminished (ACGME case logs, ABSITE scores). Attending surgeons perceived that their quality of their life inside and outside of the hospital was “somewhat worse” because of the work-hour changes, as they had anticipated. Many concerns were identified with regards to the professional development of future surgeons, including a change toward a shift-worker mentality that is not patient-focused, less continuity of care with a loss of critical information with each handoff, and a decrease in the patient/doctor relationship. Conclusion:Although the mandated restriction of resident duty hours has had no measurable impact on the quality of patient care and has led to improvements for the current quality of life of residents, there are many concerns with regards to the training of professional, responsible surgeons for the future.

Débridement and closed packing for the treatment of necrotizing pancreatitis.

OBJECTIVE To evaluate the results of débridement and closed packing for necrotizing pancreatitis and to determine the optimal timing of surgical intervention based on patient outcomes. METHODS Between February 1990 and November 1996, 64 consecutive patients with necrotizing pancreatitis were treated with necrosectomy followed by closed packing of the cavity with stuffed Penrose and closed suction drains. The mean APACHE II score immediately before surgery was 9, and 31% of the patients had organ failure. Patients were stratified with an outcome score based on death and major complications; this was correlated with the timing of surgical intervention. The data were then subjected to cut-point analysis by sequential group comparison. RESULTS Patients underwent surgery a median of 31 days after diagnosis. Fifty-six percent had infected necrosis. The mortality rate was 6.2% and was no different in infected or sterile necrosis. Eleven patients required a second surgical procedure and 13 required percutaneous drainage; a single surgical procedure sufficed in 69%. Enteric fistulae occurred in 16% of patients. The mean hospital stay after surgery was 41 days, and the interval until return to regular activities was 147 days. A significant negative correlation between duration of pancreatitis and outcome scores was found, and sequential group comparison demonstrated that the change point at which significantly better outcomes were encountered was day 27. CONCLUSION Débridement of pancreatic necrosis followed by closed packing and drainage is accomplished with a low mortality rate and reduced rates of complications and second surgical procedures. Although intervention is best deferred until the demarcation of necrosis is complete, delay beyond the fourth week confers no additional advantage.