Thomas Schnelldorfer

Long-term survival after pancreatoduodenectomy for pancreatic adenocarcinoma: is cure possible?

Objective:To determine long-term survival after pancreatoduodenectomy for pancreatic ductal adenocarcinoma and to identify clinical factors associated with long-term survival. Summary Background Data:The prognosis for long-term survival even after potentially curative resection for pancreatic adenocarcinoma is thought to be poor. Clinical factors determining short-term survival after pancreatic resection are well studied, but prognostic factors predicting long-term survival with a potential for cure are poorly understood. Methods:A case-control study was conducted of 357 patients who underwent pancreatoduodenectomy for pancreatic ductal adenocarcinoma between 1981 and 2001. Histologic specimens were reanalyzed to confirm diagnosis. Follow-up was at least 5 years or until death. Results:There was an improved survival throughout the observation period (P = 0.004). We found 62 actual 5-year survivors of whom 21 patients survived greater than 10 years, for a 5- and 10-year survival rate of 18% and 13%, respectively. Cohort analysis comparing patients with short-term (<5 years, n = 295) and long-term (≥5 years, n = 62) survival showed that more advanced disease (greatest tumor diameter, lymph node metastasis) and decreased serum albumin concentration were unfavorable for long-term survival (all P < 0.05). In contrast, the extent of resection and more aggressive histologic features did not correlate with long-term survival (all P > 0.05). En-bloc resection (P = 0.005) but not resection margin status (P > 0.05) was associated with long-term survival. Adjuvant chemoradiation therapy did not significantly influence long-term survival. Multivariate analysis identified lymph node status (OR 0.36, 95% CI 0.14–0.89, P = 0.03) as a prognostic factor for long-term survival. Five-year survival was no guarantee of cure because 16% of this subset died of pancreatic cancer up to 7.8 years after operation. Conclusion:Pancreatoduodenectomy for adenocarcinoma in the head of pancreas can provide long-term survival in a subset of patients, particularly in the absence of lymph node metastasis. One of 8 patients can achieve 10-year survival with a potential for cure.

Experience With 208 Resections for Intraductal Papillary Mucinous Neoplasm of the Pancreas

HYPOTHESIS Intraductal papillary mucinous neoplasm (IPMN) is an increasingly recognized disease of the pancreas. We report our experience with pancreatic resection for IPMN. DESIGN Retrospective review from 1992 through 2005 with additional independent histopathologic confirmation. SETTING Mayo Clinic Rochester, a tertiary care center. PATIENTS All patients who underwent primary resection for pancreatic IPMN. MAIN OUTCOME MEASURES Disease-specific operative outcomes, survival, and recurrence patterns. RESULTS Of 208 patients (mean age, 66 years) with IPMN of the pancreas, 168 underwent partial pancreatectomy, and 40 underwent total pancreatectomy; 88 were classified as having adenoma, 38 as having borderline neoplasm, 19 as having carcinoma in situ, and 63 as having invasive carcinoma. The prevalence of a malignant neoplasm was 64% in patients with main duct IPMN compared with 18% in patients with branch duct IPMN. Re-resection of the initial pancreatic margin was necessary in 21% of patients. Final negative margins were achieved in 89% of patients. Five-year survival with noninvasive IPMN was 94%. Patients with invasive IPMN had a similar 5-year survival compared with a matched cohort with ductal adenocarcinoma (31% vs 24%; P = .26). In patients with invasive IPMN, 58% experienced disease recurrence. In patients with noninvasive IPMN, 10% experienced disease recurrence after partial pancreatectomy and 0% experienced disease recurrence after total pancreatectomy. CONCLUSIONS Patients with main duct IPMN or high-risk branch duct IPMN should be considered for targeted pancreatectomy. Invasive IPMN behaves as aggressively as ductal adenocarcinoma, but resection seems to provide the only potential for cure. Even with negative resection margins, the pancreatic remnant harbors a risk of recurrence and, thus, careful long-term surveillance is warranted.

Polycystic liver disease: a critical appraisal of hepatic resection, cyst fenestration, and liver transplantation.

Objective:To identify operative morbidity, mortality, and long-term outcome after operative treatment for symptomatic polycystic liver disease (PLD) and develop a treatment algorithm for patients with PLD. Background:PLD represents a challenging clinical problem that can result in massive hepatomegaly and various complications, leading to significant decline in health status and quality of life. The optimal surgical treatment for this disease is still evolving. Methods:All patients who underwent hepatic resection, cyst fenestration, or liver transplantation for PLD from 1985 to 2006 were identified retrospectively. Long-term outcomes were evaluated by patient survey. Mean follow-up was 8 ± 0.5 years. Results:Of 141 patients (122 women; age: 51 ± 1 years) with PLD, 117 had concomitant polycystic kidney disease. All patients suffered from symptomatic hepatomegaly with 85% being functionally impaired (Eastern Cooperative Oncology Group Performance Status: 1–3). Despite significant inferior vena cava or hepatic venous compression in 65%, hepatic function was commonly preserved. A total of 124 patients underwent partial hepatectomy with cyst fenestration, 10 underwent cyst fenestration alone, and 7 underwent liver transplantation for primary treatment of PLD. Overall operative morbidity and mortality was 58% and 4%, respectively, with major complications (Clavien grade: III–V) in 30%. Five- and 10-year survival was 90% and 78%, respectively. Eastern Cooperative Oncology Group Performance Status performance status normalized or improved in 75% of patients and 73% returned to work full-time. At follow-up, health survey scores were similar to the general population despite subsequent recurrence of symptoms in 73% of patients. Conclusion:Selective patients with massive hepatomegaly from PLD benefit from operative intervention. The type of operation performed is mainly dependent on the distribution of the cysts, coincident sectoral vascular patency and parenchymal preservation, and hepatic reserve. Hepatic resection can be performed with acceptable morbidity and mortality, prompt and durable relief of symptoms, and maintenance of liver function. Cyst fenestration and liver transplantation, though effective in selected patients, are less broadly applicable.

Pancreatoduodenectomy for ductal adenocarcinoma: implications of positive margin on survival.

OBJECTIVE To assess the effect of R0 resection margin status and R0 en bloc resection in pancreatoduodenectomy outcomes. DESIGN Retrospective medical record review. SETTING Mayo Clinic, Rochester, Minnesota. PATIENTS Patients who underwent pancreatoduodenectomy for pancreatic adenocarcinoma at our institution between January 1, 1981, and December 31, 2007, were identified and their medical records were reviewed. MAIN OUTCOME MEASURE Median survival times. RESULTS A total of 617 patients underwent pancreatoduodenectomy. Median survival times after R0 en bloc resection (n = 411), R0 non-en bloc resection (n = 57), R1 resection (n = 127), and R2 resection (n = 22) were 19, 18, 15, and 10 months, respectively (P < .001). A positive resection margin was associated with death (P = .01). No difference in survival time was found between patients undergoing R0 en bloc and R0 resections after reexcision of an initial positive margin (hazard ratio, 1.19; 95% confidence interval, 0.87-1.64; P = .28). CONCLUSIONS R0 resection remains an important prognostic factor. Achieving R0 status by initial en bloc resection or reexcision results in similar long-term survival.

Management of Giant Hemangioma of the Liver: Resection versus Observation

BACKGROUND Management of patients with giant hemangiomas of the liver encounters persistent controversy. Although recent case series suggest a low complication rate with nonoperative management, the classic paradigm of preventive operative resection remains. STUDY DESIGN A retrospective cohort study was conducted of 492 patients with giant hepatic hemangioma (>4 cm in size) diagnosed between 1985 and 2005 at Mayo Clinic Rochester. Long-term outcomes were assessed by patient survey, with a follow-up of 11 ± 6.4 years. RESULTS Of 492 patients, 289 responded to the survey. In the nonoperative group (n = 233), 20% had persistent or new onset of hemangioma-associated symptoms, including potentially life-threatening complications in 2%. In the operative group (n = 56), perioperative complications occurred in 14%, including potentially life-threatening complications in 7%. None of the operative patients had persistent or new onset of hemangioma-associated symptoms after resection of the dominant hemangioma. In group comparison, the rate of adverse events was similar (20% versus 14%; p = 0.45) with an overall low risk for potentially life-threatening complications (2% versus 7%; p = 0.07). Size of hemangiomas was not associated with adverse events in either group. Subjective health status and quality of life at follow-up were similar in both groups (p > 0.54). CONCLUSIONS Clinical observation of patients with giant hemangioma of the liver has a similar rate of complications compared with operative management, but might prevent the need for invasive interventions in some patients. Clinical observation is preferred in most patients and operative treatment should be reserved for patients with severe symptoms or disease-associated complications.

Intraductal papillary mucinous neoplasm of the biliary tract: A real disease?

BACKGROUND Despite increasing numbers of reports, biliary tract intraductal papillary mucinous neoplasm (BT-IPMN) is not yet recognized as a unique neoplasm. The aim of the present study was to define the presence of BT-IPMN in a large series of resected biliary neoplasms. METHODS From May 1994 to December 2006, BT-IPMN cases were identified by reviewing pathology specimens of all resected cholangiocarcinomas and other biliary neoplasms when cystic, papillary or mucinous features were cited in pathology reports. RESULTS BT-IPMN was identified in 23 out of 253 (9%) specimens using the strict histopathological criteria of IPMN. The most common presenting symptom was abdominal discomfort which was present in 15 patients (65%). Only one of the original operative pathology reports used the term IPMN; 16 (70%) used the terms cystic, mucinous and/or papillary. BT-IPMN was isolated to non-hilar extra-hepatic ducts in 12 (52%), intra-hepatic ducts in 6 (26%) and hilar extra-hepatic ducts in 5 patients (22%). Carcinoma was found in association with BT-IPMN in 19 patients (83%); 5-year survival was 38% after resection. CONCLUSION BT-IPMN occurs throughout the intra- and extra-hepatic biliary system and can be identified readily as a unique neoplasm. Broader acceptance of BT-IPMN as a unique neoplasm may lead to a better understanding of the pathogenesis of biliary malignancies.

Epidermal growth factor induces cyclin D1 in human pancreatic carcinoma: evidence for a cyclin D1-dependent cell cycle progression.

Introduction We recently showed that cyclin D1 is overexpressed in human pancreatic carcinoma cells, and that this overexpression correlates significantly with a poor prognosis. Aims To assess the interrelations of epidermal growth factor (EGF), EGF receptor (EGFR), and cyclin D1 in human pancreatic carcinoma. Methodology and Results In pancreatic carcinoma cell lines (BxPC-3, AsPC-1), cell cycle analysis revealed an increase in cells in the S/G1 phase between 18 and 30 hours after stimulation with 50 ng/mL EGF. Cyclin D1 mRNA increased after 2 hours, corresponding to an increase in cyclin D1 protein, with the maximum level between 7.5 and 10 hours after stimulation, as demonstrated by Western blot analysis. We performed immunohistochemical analysis on 61 adenocarcinoma tissues for the expression of EGF, EGFR, and cyclin D1 and demonstrated an overexpression in the tumor cells in 51%, 54%, and 62.3%, respectively, whereas normal human pancreas stained negative for all of the three factors. Interestingly, EGF and EGFR expression correlated significantly with the cyclin D1 expression in human pancreatic tumor cells (p < 0.001 and p < 0.01, respectively). Conclusion These results demonstrate that cyclin D1 overexpression in the tumor cells of pancreatic carcinoma tissue is at least partly dependent on the mitogenic effects of EGF signaling through the EGFR.

Survival after resection for invasive intraductal papillary mucinous neoplasm and for pancreatic adenocarcinoma: a multi-institutional comparison according to American Joint Committee on Cancer Stage.

BACKGROUND Survival after resection for invasive intraductal papillary mucinous neoplasm (inv-IPMN) is superior to pancreatic ductal adenocarcinoma (PDAC). This difference may be explained by earlier presentation of inv-IPMN. We hypothesized that inv-IPMN has survival comparable with PDAC after resection when matched by stage. STUDY DESIGN From 1999 to 2009, 113 patients underwent resection for inv-IPMN at 2 large academic institutions. These data were compared with 845 patients during the same period undergoing resection for PDAC. Demographics, pathology, and overall survival (OS) were compared according to current American Joint Committee on Cancer stage. RESULTS Mean age with inv-IPMN and PDAC was 68 and 65 years, respectively. Follow-up was 33 and 24 months for inv-IPMN and PDAC, respectively. Median OS was 32 months for inv-IPMN and 17 months in PDAC (p < 0.001). Median OS in lymph node-negative inv-IPMN was 41 months and 24 months in PDAC (p = 0.003), with the greatest absolute difference in stage Ia patients with OS of 80 and 50 months in inv-IPMN and PDAC, respectively (p = 0.03). In node-positive patients, OS was 20 months in inv-IPMN and 15 months in PDAC (p = 0.06). Of inv-IPMN, 24% was colloid versus 75% of tubular subtype; 37(85%) of node-positive inv-IPMN were tubular subtype. Median OS was 23 and 127 months for tubular and colloid subtypes, respectively (p < 0.001). CONCLUSIONS When matched by stage, inv-IPMN has superior survival after resection compared with PDAC. This disparity is greatest in node-negative and least in node-positive disease. These findings suggest the behaviors of inv-IPMN and PDAC, although different, converge with advancing American Joint Committee on Cancer stage because of a greater proportion of tubular subtype.

Combining clinicopathological predictors and molecular biomarkers in the oncogenic K-RAS/Ki67/HIF-1α pathway to predict survival in resectable pancreatic cancer.

Background:The dismal prognosis of patients diagnosed with pancreatic cancer points to our limited arsenal of effective anticancer therapies. Oncogenic K-RAS hyperactivation is virtually universal in pancreatic cancer, that confers drug resistance, drives aggressive tumorigenesis and rapid metastasis. Pancreatic tumours are often marked by hypovascularity, increased hypoxia and ineffective drug delivery. Thus, biomarker discovery and developing innovative means of countervailing oncogenic K-RAS activation are urgently needed.Methods:Tumour specimens from 147 pancreatic cancer patients were analysed by immunohistochemical (IHC) staining and tissue microarray (TMA). Statistical correlations between selected biomarkers and clinicopathological predictors were examined to predict survival.Results:We find that heightened hypoxia response predicts poor clinical outcome in resectable pancreatic cancer. SIAH is a tumour-specific biomarker. The combination of five biomarkers (EGFR, phospho-ERK, SIAH, Ki67 and HIF-1α) and four clinicopathological predictors (tumour size, pathological grade, margin and lymph node status) predict patient survival post surgery in pancreatic cancer.Conclusions:Combining five biomarkers in the K-RAS/Ki67/HIF-1α pathways with four clinicopathological predictors may assist to better predict survival in resectable pancreatic cancer.

Factors Influencing Lymph Node Recovery from the Operative Specimen after Gastrectomy for Gastric Adenocarcinoma

BackgroundRegional lymph node metastases are an important predictor of survival for patients with resectable adenocarcinoma of the stomach. Currently, the number of lymph nodes examined is frequently less than requirements for accurate staging. Clinical factors associated with lymph node recovery are understood poorly.MethodsWe performed a retrospective chart review of 99 consecutive patients who underwent gastrectomy for gastric adenocarcinoma distal to the gastroesophageal junction to determine clinical variables associated lymph node recovery.ResultsNinety-nine patients underwent gastrectomy for gastric adenocarcinoma at our two hospitals. More than 15 lymph nodes were examined in 64% of specimens. Univariate analysis showed an association between the number of lymph nodes recovered and the number of positive nodes, lymphadenectomy extent, hospital, surgeon, and pathology technician (p < 0.001). Multivariate analysis identified the pathology technician as the most important healthcare-related variable contributing to the variation of lymph node recovery, using fixed- (p < 0.001) and random-effects models.ConclusionsThis study suggests that the pathology technician is an important healthcare-related factor influencing lymph node recovery after gastrectomy. In identifying potential areas benefiting from a systems improvements approach, focus on the technical aspects of specimen processing may be of benefit in maximizing the number of lymph nodes recovered.