Biomedical subjects

Charles J Yeo

Publications and source records attributed to Charles J Yeo.

At least 19 recordsLinked to original sources

PubMed2007

The case for routine use of adjuvant therapy in pancreatic cancer.

Pancreatic cancer is a devastating disease with a poor prognosis for most patients. Surgical resection remains the cornerstone of treatment, providing the only realistic hope of long-term survival. Even with optimal surgical management, 5-year survival averages 15% to 20% for resectable disease. Progress is being made, however. Currently, the benefits of postoperative therapy for resected pancreatic ductal adenocarcinoma appear clear, and recommendations for such therapy appear to us to be well justified. Additional benefit to patients awaits the development of new agents, molecular targeted drugs, and novel approaches such as immunotherapy.

Adenocarcinoma↗

PubMed2006

Resected periampullary adenocarcinoma: 5-year survivors and their 6- to 10-year follow-up.

BACKGROUND: Many studies have reported 5-year survival data after pancreaticoduodenectomy for periampullary adenocarcinoma. This study evaluates 10-year survival in patients surviving 5 years after initial surgery. METHODS: We reviewed all patients undergoing pancreaticoduodenectomy for periampullary adenocarcinoma from April 1970 to July 1999 at a single institution. All 5-year survivors were identified, and their subsequent 5-year survival was compared with the actuarial survival of the general population starting at 70 years of age. RESULTS: Nine hundred fifteen patients underwent pancreaticoduodenectomy for periampullary adenocarcinoma. Follow-up was complete on 890 patients. There were 201 (23%) 5-year survivors with a median age of 65 years at initial surgery; 51% were male and 92% were Caucasian. For the 5-year survivors, the carcinoma origin was pancreatic in 46%, ampullary in 25%, distal bile duct in 17%, and duodenal in 12%. For all 5-year survivors, the subsequent 5-year actuarial survival rate was 65%, with a median survival after achieving the 5-year landmark of 7.9 additional years. The subsequent 5-year survival by site of tumor origin was 55% for pancreatic, 66% for ampullary, 74% for bile duct, and 85% for duodenal cancer. For the age-matched population, the 5-year survival rate was 87% (P<.001 when compared with those with all periampullary cancers). CONCLUSIONS: While the 5-year survival rate for all patients with resected periampullary adenocarcinoma is only 23%, these data imply that attainment of the 5-year survival landmark carries with it an improved survival for the subsequent 5 years. While the survival rate was less than that of the age-matched population, 65% of 5-year survivors survived 5 more years, bringing them to the 10-year postresection landmark.

Adenocarcinoma↗

PubMed2006

Aberrant methylation of Reprimo correlates with genetic instability and predicts poor prognosis in pancreatic ductal adenocarcinoma.

BACKGROUND: The p53-dependent G2/M checkpoint plays a key role in the maintenance of genomic integrity, thereby protecting cells from neoplastic progression. Reprimo, a gene involved in the p53-induced G2 cell cycle arrest, has been recently identified as a novel target for aberrant methylation in pancreatic and other cancers. The biological and clinical relevance of Reprimo methylation in pancreatic cancer was investigated. METHODS: The methylation status of Reprimo CpG island was analyzed by methylation-specific polymerase chain reaction in a large series of pancreatic cancers and was correlated with p53 mutation status, genetic instability (as measured by the fractional allelic loss), and clinicopathologic features. RESULTS: Aberrant methylation of Reprimo was identified in 60% (75 of 125) of pancreatic cancer xenografts and primary pancreatic adenocarcinomas. Reprimo methylation was also detectable in 30% (19 of 63) of pancreatic intraepithelial neoplasias (PanIN), known precursors to infiltrating carcinoma. Reprimo methylation was unrelated to the p53 mutation status and associated with the increased degree of genetic instability (P = .04). Furthermore, we found that patients with Reprimo methylation in their primary pancreatic cancers have significantly worse prognosis than those without Reprimo methylation (P = .007). In contrast, other methylation targets in pancreatic cancers (SPARC and CXCR4) did not correlate with prognosis. CONCLUSIONS: These results suggest that aberrant methylation of Reprimo is a common event in pancreatic carcinogenesis and is associated with genetic instability and unfavorable outcome after surgical resection.

Carcinoma, Pancreatic Ductal↗

PubMed2006

Immunohistochemical and genetic evaluation of deoxycytidine kinase in pancreatic cancer: relationship to molecular mechanisms of gemcitabine resistance and survival.

Gemcitabine is considered the standard first-line therapy for patients with advanced pancreatic cancer. More recent strategies have focused on improving the efficacy of gemcitabine by either improving the method of delivery or by combining gemcitabine with other non-cross-resistant chemotherapy agents or with small-molecule drugs. However, the clinical benefits, response rates, and duration of responses have been modest. Deoxycytidine kinase (dCK) is the rate-limiting enzyme involved in the metabolism of gemcitabine. The expression of dCK has been postulated to be correlative of gemcitabine resistance. We determined the relationship of dCK immunohistochemical protein expression and/or genetic status of dCK in a panel of human pancreatic cancer tissues and pancreatic cancer cell lines and determined the relationship of these variables to the clinical outcome of patients treated with gemcitabine. We report that dCK protein expression is expressed in the majority of pancreatic cancers analyzed (40 of 44 cases, 91%) and showed a range of labeling intensities ranging from 1+ (labeling weaker in intensity than normal lymphocytes present in same section) to 3+ (labeling greater in intensity than normal lymphocytes present in same section). When labeling intensity was compared with survival, low dCK expression (1+ labeling) was correlated with both overall survival (P < 0.009) and progression-free survival following gemcitabine treatment (P < 0.04). Low dCK labeling intensity was also significantly correlated with patient age (70.3 +/- 8.1 versus 59.8 +/- 7.4 years; P < 0.0006), suggesting that age-related methylation of the dCK gene may account in part for the observed differences. Sequencing of the entire dCK coding sequence in 17 cell lines and 9 patients' cancer tissues with disease progression while on gemcitabine did not identify any mutations, suggesting that genetic alterations of dCK are not a common mechanism of resistance to gemcitabine for this tumor type. Moreover, dCK labeling showed similar patterns and intensities of labeling among matched pretreatment and post-treatment tissues. In summary, pretreatment levels of dCK protein are most correlated with overall survival following gemcitabine treatment and are stable even after resistance to gemcitabine is clinically documented.

Antimetabolites, Antineoplastic↗

PubMed2006

DNA methylation alterations in the pancreatic juice of patients with suspected pancreatic disease.

Molecular markers of pancreatic neoplasia could aid in the evaluation of visible pancreatic lesions and indicate neoplasia invisible to imaging. We evaluated methylation-specific PCR (MSP) assays that detect aberrantly methylated DNA for their use as markers of pancreatic neoplasia. Methylation analysis was done on pancreatic juice collected endoscopically or surgically from 155 individuals with suspected pancreatic disease: 56 patients had pancreatic ductal adenocarcinoma, 17 had intraductal papillary mucinous neoplasms, 26 had symptomatic chronic pancreatitis, 12 controls lacked evidence of pancreatic disease, and 44 were asymptomatic individuals at increased risk of developing familial pancreatic cancer undergoing screening for pancreatic neoplasia. Pancreatic juice DNA was analyzed for promoter methylation using conventional MSP assays for 17 genes. For six genes, pancreatic juice methylation was quantified using real-time quantitative MSP (QMSP; Cyclin D2, FOXE1, NPTX2, ppENK, p16, and TFPI2). Quantifying pancreatic juice methylation using QMSP with a cutoff of >1% methylated DNA could better predict pancreatic cancer than detecting methylation using conventional MSP. In the endoscopic group, 9 of 11 patients with pancreatic cancer, but none of 64 individuals without neoplasia had > or =1% methylation for two or more of the best five QMSP assays (82% sensitivity and 100% specificity; P < 0.0001). The prevalence of pancreatic juice methylation in patients with chronic pancreatitis was less than in patients with pancreatic cancer but higher than in controls and similar to high-risk individuals. The detection and quantification of aberrantly methylated DNA in pancreatic juice is a promising approach to the diagnosis of pancreatic cancer.

Adenocarcinoma↗

PubMed2006

MKK4 status predicts survival after resection of gastric adenocarcinoma.

HYPOTHESIS: Lack of expression of the tumor-suppressor gene MKK4 is significantly correlated with poor survival after resection of gastric adenocarcinoma. DESIGN: Retrospective review of medical records after construction and immunolabeling of tissue microarrays for clinical correlation. SETTING: The Johns Hopkins Hospital, Baltimore, Md. PATIENTS: Patients operated on because of gastric adenocarcinoma between 1983 and 1995. Main Outcome Measure Long-term survival and MKK4 status. RESULTS: Primary tumors (N = 124) were scored as 0 (no labeling), 1+ (weak labeling), or 2+ (strong labeling) in 9 (7%), 80 (65%), and 35 (28%) patients, and 5-year survival in these patients was 0%, 21%, and 28%, respectively. Given the small size (7%) of the MKK4-negative group (as expected, given the 5%-10% incidence of genetic loss in carcinomas), a Cox proportional hazards analysis was performed, adjusting for age, sex, and tumor stage. This multivariate analysis revealed a 5-fold increased risk of death (P<.001) in patients whose primary tumors were MKK4-negative. Furthermore, the addition of MKK4 status significantly improved the Cox model, changing log likelihood from -1410 to -369, confirming that MKK4 status was truly the effector of the survival difference and not a bystander. CONCLUSIONS: The lack of expression of the tumor-suppressor gene MKK4 in resected gastric adenocarcinoma is robustly associated with poor survival. This finding may provide a useful prognostic tool in patients with gastric adenocarcinoma.

Adenocarcinoma↗

PubMed2006

Diagnostic and treatment modalities for autoimmune pancreatitis.

Since the recognition of autoimmune pancreatitis (AIP) as a clinical entity, many advances have been made in defining clinical, radiologic, histologic, and laboratory parameters to assist in a complete definition of the disease. Despite all these efforts, a preoperative diagnosis still remains a clinical challenge but is of paramount importance, as these cases have been reported to be steroid-responsive; therefore, early treatment may obviate the need for surgical resection. Although the utilization of recently proposed guidelines by the Japanese Pancreas Society and an Italian study group may further assist the clinician and prompt the initiation of steroid treatment, the response to therapy should be observed within 2 to 4 weeks and reflected in progressive resolution of the presenting radiologic and laboratory abnormalities. Should these fail to demonstrate improvement, the diagnosis of AIP should undergo re-evaluation, and consideration for surgical exploration should be made, as the patient may be harboring a malignancy. Surgical resection in the form of pylorus-preserving pancreaticoduodenectomy remains the optimal solution in the attempt to clarify the diagnosis and offer treatment with low complication rates.

Journal Article↗

PubMed2006

Differences in survival for patients with resectable versus unresectable metastases from pancreatic islet cell cancer.

Well-differentiated islet cell tumors can be associated with aggressive biology, resulting in early metastases to the liver. This study was carried out to determine whether survival for patients with malignant islet cell tumors and synchronous liver metastases is affected by complete surgical resection. Thirty-one patients with synchronous liver metastases from islet cell cancer underwent surgical exploration with the intent for complete tumor resection, and all patients underwent resection of the pancreatic primary. The patients were divided into two groups, those with resectable versus unresectable liver metastases. Twenty-six of 31 (84%) patients underwent complete resection of both the primary tumor and all liver metastases, and 5 (16%) patients underwent only complete resection of the pancreatic primary without liver resection. To extirpate the primary tumor, a pancreaticoduodenectomy was performed in 11 of the 26 (42%) completely resected patients and in 4 of the 5 (80%) incompletely resected patients, P = NS. The remainder of the patients underwent distal pancreatectomy. There were no statistical differences in primary tumor size, lymph node metastases, or adjuvant treatments between patients with resected and unresected liver metastases. The median overall survival for the completely resected group was 78 months, longer than the 17 months for the group with unresectable liver metastases (P = 0.06). Complete tumor resection (or the tumor biology that allows such complete resection) affords a survival advantage to patients with metastatic islet cell tumors of the pancreas. Patterns of liver metastases from islet cell tumors, specifically multiple bilobar metastases that are not amenable to resection and/or ablation, predict a poor outcome despite resection of the primary pancreatic tumor.

Adult↗

PubMed2006

Fibromatosis of the remnant pancreas after pylorus-preserving pancreaticoduodenectomy.

Intra-abdominal fibromatosis or desmoid tumors are rare forms of connective tissue cellular dysplasia characterized by proliferation of fibroblasts and abundant collagen. Most often these tumors associated with familial adenomatous polyposis or Gardner's syndrome. Those tumors not associated with polyposis are termed sporadic desmoids and tend to be locally aggressive in nature. Sporadic intra-abdominal desmoids involving the pancreas are quite rare, as only six previously reported cases exist. In this report we present a seventh case of a sporadic intraabdominal desmoid involving the pancreas. The patient, a 63-year-old white man, developed the desmoid tumor following a pylorus-preserving pancreaticoduodenectomy for an insulinoma. The patient was managed via further pancreatectomy, consisting of a distal pancreatectomy with en bloc splenectomy, sparing a 6-cm portion of pancreatic neck and proximal body. Finally, we present a complete review of the six previous cases of sporadic pancreatic fibromatosis.

Fibroma↗

PubMed2006

Pancreaticoduodenectomy in the very elderly.

It is estimated that by 2050, there will be a 300% increase in the elderly population (> or =65 years) and a corresponding increase in elderly patients presenting for surgical evaluation. Surgical decision-making in this population can be difficult because outcomes in the elderly are poorly defined. We reviewed 2698 consecutive pancreaticoduodenectomies (PDs) at our institution over a 35-year period (April 1970 through March 2005), with the last 1000 resections being done in the last 4 years. Data collected included surgical indication, mortality (defined as 30-day or in-hospital mortality), complications, and survival. Patients were divided by age into three groups (<80, 80-89, and > or =90 years) and evaluated using multiple logistic regression. Two hundred seven patients > or =80 years old underwent a PD (7.7% of 2698). Patients 80-89 years of age had a mortality rate of 4.1% (8 of 197) and a complication rate of 52.8% (99 of 197), whereas patients < or =79 years of age had a mortality of 1.7% and a complication rate of 41.6% (P < 0.05). There were no perioperative deaths among the 10 patients > or =90 years of age, and their complication rate was 50% (5 of 10). One-year survival for patients 80-89 years of age was 59.1%, and that for patients > or =90 years was 60%. Age was not an independent risk factor for perioperative mortality and morbidity following PD after adjusting for preoperative comorbidities. We demonstrate that PD can be safely performed in patients over 80 years of age and conclude that age alone should not be a contraindication to pancreatic resection. The advent of improved surgical outcomes and an aging population will likely result in a significant increase in the number of PDs performed in the next few decades.

Age Factors↗

PubMed2006

Does pancreatic duct stenting decrease the rate of pancreatic fistula following pancreaticoduodenectomy? Results of a prospective randomized trial.

Pancreatic duct stenting remains an attractive strategy to reduce the incidence of pancreatic fistulas following pancreaticoduodenectomy (PD) with encouraging results in both retrospective and prospective studies. We performed a prospective randomized trial to test the hypothesis that internal pancreatic duct stenting reduces the development of pancreatic fistulas following PD. Two hundred thirty-eight patients were randomized to either receive a pancreatic stent (S) or no stent (NS), and stratified according to the texture of the pancreatic remnant (soft/normal versus hard). Four patients were excluded from the study; in three instances due to a pancreatic duct that was too small to cannulate and in the other instance because a total pancreatectomy was performed. Patients who randomized to the S group had a 6-cm-long segment of a plastic pediatric feeding tube used to stent the pancreaticojejunostomy anastomosis. In patients with a soft pancreas, 57 randomized to the S group and 56 randomized to the NS group. In patients with a hard pancreas, 58 randomized to the S group and 63 randomized to the NS group. The S and NS groups for the entire study population, as well as for the subgroup of high-risk patients with soft pancreata, were similar as regard to demographics, past medical history, preoperative symptoms, preoperative procedures, and intraoperative data. The pancreatic fistula rate for the entire study population was 9.4%. The fistula rates in the S and NS subgroups with hard pancreata were similar, at 1.7% and 4.8% (P = 0.4), respectively. The fistula rates in the S and NS subgroups with soft pancreata were also similar, at 21.1% and 10.7% (P = 0.1), respectively. A nonstatistically significant increase in the pancreatic fistula rate in the S group persisted after adjusting for the operating surgeon and technical details of the operation (e.g., anastomotic technique, anastomotic orientation, pancreatic duct size, and number of intra-abdominal drains placed). In patients with soft pancreata, 63% percent of the pancreatic fistulas in stented patients required adjustment to the clinical pathway (including two deaths), compared to 47% of the pancreatic fistulas in patients in the NS group (P = 0.3). Internal pancreatic duct stenting does not decrease the frequency or the severity of postoperative pancreatic fistulas.

Adult↗

PubMed2006

Hospital readmission after pancreaticoduodenectomy.

Data exist on the morbidity and mortality of patients undergoing pancreaticoduodenectomy (PD), but there are few reports about hospital readmissions after this procedure. Our aim was to evaluate the number of and reasons for readmission after PD and the factors influencing readmission. We reviewed the initial hospitalization and readmissions for 1643 patients undergoing PD compared patients requiring readmission to patients that did not require readmission. Twenty-six percent of patients were readmitted a total of 678 times after PD. Patients readmitted were younger than those not readmitted (61.8 versus 64.6 years, P < 0.0001). Vessel resection, abscess formation, wound infection, postoperative percutaneous biliary stents, estimated blood loss >1000 ml, and age < or =65 years were independently associated with readmission. The length of stay for all patients decreased over time, from 10.5 days in 1996 to 7 days in 2003. The percentage of patients being readmitted also decreased from 33% in 1996 to 20% (P = 0.004) in 2003. The readmission rate after PD was 26%. Younger age, blood loss, postoperative complications, and vessel resection were independent risk factors for readmission. The early hospital readmission rate has not increased in association with a decreased LOS, supporting the idea that reduction in LOS did not lead to increased readmission rates.

Aged↗

PubMed2006

1423 pancreaticoduodenectomies for pancreatic cancer: A single-institution experience.

Pancreaticoduodenectomy (PD) with the possible addition of neoadjuvant or adjuvant therapy is the standard of care in the United States for adenocarcinoma originating in the pancreatic head, neck, and uncinate process. We reviewed 1423 patients who underwent a PD for a malignancy originating in the pancreas at our institution between 1970 and 2006. We examined 1175 PDs for ductal adenocarcinomas in greater detail. Eighteen different histological types of pancreatic cancer were identified; the most common diagnoses included ductal adenocarcinoma, neuroendocrine carcinoma, and IPMN with invasive cancer. Patients with ductal adenocarcinoma were analyzed in detail. The median age was 66 years, with patients in the present decade significantly older (68 years), on average, than patients in the three prior decades (e.g., 60 years in 1970, P = 0.02). The median tumor diameter was 3 cm; 42% of the resections had positive margins and 78% had positive lymph nodes. The perioperative morbidity was 38%. The median postoperative stay declined over time, from 16 days in the 1980s to 8 days in the 2000s (P < 0.001). The perioperative mortality declined from 30% in the 1970s to 1% in the 2000s (P < 0.001). The median survival for all patients with ductal adenocarcinoma was 18 months (1-year survival = 65 %, 2-year survival = 37%, 5-year survival = 18%). In a Cox proportional hazards model, pathological factors having a significant impact on survival included tumor diameter, resection margin status, lymph node status, and histologic grade. This is the largest single-institution experience with PD for pancreatic cancer. Patients who have cancers with favorable pathological features have a statistically significant improved long-term survival.

Adult↗

PubMed2006

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.

Cholestasis↗

PubMed2006

Periampullary and pancreatic incidentaloma: a single institution's experience with an increasingly common diagnosis.

BACKGROUND: While incidental masses in certain organs have received particular attention, periampullary and pancreatic incidentalomas (PIs) remain poorly characterized. METHODS: We reviewed 1944 consecutive pancreaticoduodenectomies (PD) over an 8-year period (April 1997 to October 2005). A total of 118 patients (6% of all PDs) presented with an incidental finding of a periampullary or pancreatic mass. The PI patients were analyzed and compared with the rest of the cohort (NI, nonincidentaloma group, n = 1826). RESULTS: Thirty-one percent of the PI patients (n = 37) had malignant disease (versus 76% of the NI patients, P < 0.001), 47% (n = 55) had premalignant disease, and the remaining 22% (n = 26) had little or no risk for malignant progression. The 3 most common diagnoses in the PI group were IPMN without invasive cancer (30%), cystadenoma (17%), and pancreatic ductal adenocarcinoma (10%). The PI group had a higher overall complication rate (55% versus 43%, P = 0.02), due in part to a significantly increased rate of pancreatic fistulas (18.4% PI versus 8.5% NI, P < 0.001). Patients in the PI group with malignant disease had a superior long-term survival (median, 30 months, P = 0.01) compared with patients in the NI group with malignant disease (median, 21 months). CONCLUSIONS: Incidentally discovered periampullary and pancreatic masses comprise a substantial proportion of patients undergoing PD. Roughly three fourths of these lesions are malignant or premalignant, and amenable to curative resection. Resected malignant PIs have favorable pathologic features as compared with resected malignant NIs, and resection of these early lesions in asymptomatic individuals is associated with improved survival, compared with patients with symptomatic disease.

Adolescent↗

PubMed2006

Assessment of complications after pancreatic surgery: A novel grading system applied to 633 patients undergoing pancreaticoduodenectomy.

OBJECTIVE: To define a simple and reproducible classification of complications following pancreaticoduodenectomy (PD) based on a therapy-oriented severity grading system. BACKGROUND: While mortality is rare after PD, morbidity rates remain high. The lack of standardization in evaluating morbidity after PD has severely hampered meaningful comparisons over time and among centers. We adapted a novel classification of complication to stratify morbidity by severity after PD, to test whether the incidence of pancreatic fistula has changed over time, and to identify risk factors in a single North American center. METHODS: The classification was applied to a consecutive series of 633 patients undergoing PD between February 2003 and August 2005. Another series of 141 patients treated between 1987 and 1990 was also analyzed to identify changes in the incidence and severity of fistula. Univariate and multivariate analyses were performed to link respective complications with preoperative and intraoperative parameters, length of hospital stay, and long-term survival. RESULTS: A total of 263 (41.5%) patients did not develop any complication, while 370 (58.5%) had at least one complication; 62 (10.0%) patients had only grade I complications (no need for specific intervention), 192 patients (30.0%) had grade II (need for drug therapy such as antibiotics), 85 patients (13.5%) had grade III (need for invasive therapy), and 19 patients (3.0%) had grade IV complications (organ dysfunction with ICU stay). Grade V (death) occurred in 12 patients (2.0%). A total of 57 patients (9.0%) developed pancreatic fistula, of which 33 (58.0%) were classified as grade II, 17 (30.0%) as grade III, 5 (9.0%) as grade IV, and 2 (3.5%) as grade V. Delayed gastric emptying was documented in 80 patients (12.7%); half of them were scored as grade II and the other half as grade III. A significant decrease in the incidence of fistula was observed between the 2 periods analyzed (14.0% vs. 9.0%, P < 0.001), mostly due to a decrease in grade II fistula. Cardiovascular disease was a risk factor for overall morbidity and complication severity, while texture of the gland and cardiovascular disease were risk factors for pancreatic fistula. CONCLUSION: This study demonstrates the applicability and utility of a new classification in grading complications following pancreatic surgery. This novel approach may provide a standardized, objective, and reproducible assessment of pancreas surgery enabling meaningful comparison among centers and over time.

Adult↗

PubMed2006

Claudin-4, mitogen-activated protein kinase kinase 4, and stratifin are markers of gastric adenocarcinoma precursor lesions.

Approximately 23,000 new gastric cancer cases and 12,000 associated deaths occur annually in the United States. Intestinal metaplasia and gastric epithelial dysplasia are precursor lesions to gastric adenocarcinoma, but are not readily detectable clinically, radiographically, or endoscopically. A noninvasive method of precursor detection would require the ability to distinguish precursor lesions from adjacent normal mucosa. In search of such markers, tissue microarrays were prepared for 133 patients of resected gastric adenocarcinoma. Tissue microarrays contained primary cancer, normal stomach, intestinal metaplasia, and gastric epithelial dysplasia and were probed with antibodies against nine potential markers that were either identified in a database of genes overexpressed in gastric adenocarcinoma or were already of interest to our laboratory: claudin-4, mitogen-activated protein kinase kinase 4 (MKK4), 14-3-3sigma (stratifin), S100A4, mesothelin, fascin, topoisomerase IIalpha, HER-2/neu, and epithelial growth factor receptor. Three markers discriminated gastric adenocarcinoma precursor lesions from normal gastric mucosa. Claudin-4 expression was present in 36 intestinal metaplasia lesions (100%) and 14 gastric epithelial dysplasia lesions (100%), but in only 16 normal stomach samples (15%). MKK4 expression was present in 24 intestinal metaplasia lesions (89%) and 12 gastric epithelial dysplasia lesions (100%), but in only 6 normal stomach samples (8%). Stratifin expression was present in 29 intestinal metaplasia lesions (97%) and 8 gastric epithelial dysplasia lesions (100%), but in only 2 normal stomach samples (3%). Sensitivity and specificity for detection of the precursor lesion intestinal metaplasia were 100% and 85%, respectively, for claudin-4; 89% and 92%, respectively, for MKK4; and 97% and 97%, respectively, for stratifin. In primary cancers, 123 of 125 (98.4%) were positive for claudin-4, 116 of 126 (94%) for MKK4, and 111 of 120 (92%) for stratifin. In conclusion, claudin-4, MKK4, and stratifin immunolabeling detects precursor lesions of gastric adenocarcinoma that are otherwise clinically, radiographically, and endoscopically inapparent. These findings may prove useful in the diagnosis and therapeutic targeting of gastric adenocarcinoma precursor lesions.

14-3-3 Proteins↗

PubMed2006

Assessment of celecoxib pharmacodynamics in pancreatic cancer.

Cyclooxygenase-2 (COX-2) inhibitors are being developed as chemopreventive and anticancer agents. This study aimed to determine the biological effect of the COX-2 inhibitor celecoxib in pancreatic cancer as an early step to the further development of the agent in this disease. Eight patients scheduled for resection of an infiltrating adenocarcinoma of the pancreas were randomized to receive celecoxib at a dose of 400 mg twice daily or placebo for 5 to 15 days before the surgery. In addition, carcinomas from nine additional patients were xenografted in nude mice, expanded, and treated with vehicle or celecoxib for 28 days. Celecoxib markedly decreased the intra-tumor levels of prostaglandin E2 in patient carcinomas and in the heterotransplanted xenografts. However, this effect did not result in inhibition of cell proliferation or microvessel density (as assessed by Ki67 and CD31 staining). In addition, a panel of markers, including bcl-2, COX-1, COX-2, and VEGF, did not change with treatment in a significant manner. Furthermore, there was no evidence of antitumor effects in the xenografted carcinomas. In summary, celecoxib efficiently inhibited the synthesis of prostaglandin E2 both in pancreatic cancer surgical specimens and in xenografted carcinomas but did not exert evident antitumor, antiproliferative, or antiangiogenic effect as a single agent. The direct pancreatic cancer xenograft model proved to be a valuable tool for drug evaluation and biological studies and showed similar results to those observed in resected pancreatic cancer specimens.

Animals↗