Biomedical subjects

Richard D Schulick

Publications and source records attributed to Richard D Schulick.

At least 19 recordsLinked to original sources

PubMed2006

A proposed clinical test for monitoring fluoropyrimidine therapy: detection and stability of thymidylate synthase ternary complexes.

5-fluorouracil forms classic (covalent, ternary) complexes consisting of thymidylate synthase, fluoro-deoxyuridine monophosphate, and 5,10-methylene tetrahydrofolate. Despite a high pharmacologic interest in the classic complexes formed in cells treated with fluorouracil anticancer agents, the in vivo stability of the complexes and the possible interference in complex formation by other coadministered compounds have not been adequately described. We visualized classic complexes unaccompanied by unbound thymidylate synthase, inferring complete enzymatic inhibition, in 5-fluorouracil-treated S. cerevisiae and cancer cells in vitro and in murine tumors in vivo treated with 5-fluorouracil. Classic complexes persisted 13 days in cancer cells after a pulse of 5-fluorouracil. Classic complexes were reduced to absent in cancer cells in which the older antifolates methotrexate and aminopterin, or the modern antifolates pemetrexed and tomudex, were coadministered with 5-fluorouracil. Classic complexes were, however, detected when an alternate drug, 5-fluorodeoxyuridine, was administered with methotrexate. We visualized classic complexes at fifteen minutes to seven days after an acute single dose of 5-fluorouracil in mouse tumor models, in tumors and normal tissues. Using the same assay, we detected unbound thymidylate synthase in untreated human tissues, supporting the future use of this assay in evaluating the most appropriate dose of fluoropyrimidine and coadministered agents in clinical settings.

Animals↗

PubMed2006

Resistance of cancers to immunologic cytotoxicity and adoptive immunotherapy via X-linked inhibitor of apoptosis protein expression and coexisting defects in mitochondrial death signaling.

The ability of cancers to evade immune surveillance and resist immunotherapy raises a fundamental question of how tumor cells survive in the presence of a competent immune system. Studies to address this question have primarily focused on mechanisms by which tumor cells avoid recognition by or induce tolerance in the immune system. However, little is known about whether cancer cells also acquire an intrinsic ability to resist killing by immune effectors. We find that cancer cells enhance their ability to withstand an attack by cytotoxic immune effector cells via acquisition of specific genetic alterations that interfere with the shared mitochondrial death signaling pathway entrained by granzyme B, IFN-gamma, and Apo2 ligand/tumor necrosis factor-related apoptosis inducing ligand (Apo2L/TRAIL), three key mediators of immunologic cell-mediated cytotoxicity. We show that the coexistence of specific mitochondrial signaling defects (either deletion of Bax, overexpression of Bcl-x(L), or deletion of Smac) with expression of X-linked inhibitor of apoptosis protein decreases the sensitivity of cancer cells to IFN-gamma/Apo2L/TRAIL- or granzyme B-induced apoptosis, lymphocyte-mediated cytotoxicity in vitro, and adoptive cellular immunotherapy in vivo. Conversely, negating X-linked inhibitor of apoptosis protein expression or function in tumor cells with defective mitochondrial signaling enables direct activation of caspase-3/-7 by granzyme B or Apo2L/TRAIL, and restores their susceptibility to immunologic cytotoxicity. These findings identify an important mechanism by which cancers evade elimination by immune effector cells and suggest that cancer immunotherapy might be improved by concurrent strategies to alleviate or circumvent the intrinsic mitochondrial death signaling defects that help cancer cells resist immunologic cytotoxicity.

Adenocarcinoma↗

PubMed2006

Selective targeting of antitumor immune responses with engineered live-attenuated Listeria monocytogenes.

Improved immunization and ex vivo T-cell culture strategies can generate larger numbers and more potent tumor-specific effector cells than previously possible. Nonetheless, the capacity of these cells to eliminate established tumors is limited by their ability to efficiently enter tumor-bearing organs and mediate their effector function. In the current study, we show that the administration of an engineered organ-homing microbe selectively targets tumor-specific immune responses to metastases within that organ. Specifically, an attenuated Listeria monocytogenes strain, which preferentially infects the liver following systemic administration, dramatically enhances the activity of a cancer vaccine against liver metastases but not metastases in the lung. This enhanced activity results from both local recruitment of innate immune effectors as well as concentration and increased activation of vaccine-induced antitumor T cells within the liver. These findings show a general approach to focus systemic cancer immunotherapies to specific organs bearing tumor metastases by taking advantage of differential tropisms and the proinflammatory nature of microbes.

Animals↗

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

Preoperative positron emission tomography to evaluate potentially resectable hepatic colorectal metastases.

HYPOTHESIS: Positron emission tomography (PET) influences clinical management in the preoperative evaluation of patients with hepatic metastases from colorectal cancer. DESIGN: Prospective cohort study. SETTING: Academic tertiary care center. PATIENTS: From January 1, 2000, through December 31, 2002, 71 consecutive patients referred with potentially resectable hepatic metastases based on conventional imaging findings underwent PET or PET with computed tomography in the subsequent preoperative evaluation. INTERVENTION: Performance of hepatic resection was based on the results of the overall preoperative evaluation. MAIN OUTCOME MEASURES: Concordance with conventional imaging findings, identification of additional findings, and change in clinical management were analyzed. RESULTS: The PET findings confirmed the lesions identified by conventional imaging techniques in 64 (90%) of the patients. Additional lesions were identified on PET in 23 patients (32%). The information obtained by PET resulted in a change in clinical management in 17 cases (24%). False-positive PET findings occurred in 6 patients (8%), whereas false understaging occurred in 11 (15%). In no cases did PET findings have an adverse impact on patient outcome. CONCLUSIONS: Positron emission tomography provides useful information in the selection of patients with hepatic metastases from colorectal cancer being considered for surgical therapy. Such improved selection may serve to reduce the number of unnecessary surgical explorations and result in improved long-term survival in patients undergoing resection. Positron emission tomography should be integrated into the routine preoperative evaluation of patients being considered for hepatic resection of colorectal metastases.

Adult↗

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

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

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

Endocrine tumors of the pancreas.

PURPOSE OF REVIEW: Neoplasms of the endocrine pancreas, commonly referenced as pancreatic islet cell tumors, are rare, often well differentiated endocrine neoplasms, whose biology remains poorly characterized. This article reviews the current clinical management of pancreatic islet cell tumors and describes the molecular events that have been studied to guide future therapies of these peculiar neoplasms. RECENT FINDINGS: While some islet cell tumors arise in association with the MEN-1 syndrome, the majority of these neoplasms are sporadic lesions whose underlying genetic and molecular events remain largely unknown. Recent work has identified changes in gene expression occurring in metastatic and non-metastatic islet cell tumors, which appear to correlate with the occurrence of lymph node and liver metastases. Epigenetic alterations of select tumor suppressor genes may influence patient survival, and the presence of gene promoter methylation may be used as a prognostic marker system. In addition, multiple molecular alterations, including changes in expression of cellular proteins with migratory, cell cycle or angiogenic functions, have been demonstrated to influence islet cell tumor growth, invasion and metastatic spread. SUMMARY: Understanding the molecular events underlying the biology of pancreatic islet cell tumors will aid the development of accurate prognostic markers and will guide improved therapeutic modalities in the future.

Adenoma, Islet Cell↗

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

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↗

PubMed2005

Combined PET/CT for detecting recurrent ovarian cancer limited to retroperitoneal lymph nodes.

OBJECTIVE: To evaluate the utility of combined positron emission tomography/computed tomography (PET/CT) for detecting recurrent epithelial ovarian cancer limited to retroperitoneal adenopathy. METHODS: Fourteen patients (median age = 53 years) with rising serum CA125 levels, and negative or equivocal conventional CT imaging > or = 6 months after primary therapy were retrospectively identified as having recurrent disease limited to retroperitoneal lymph nodes by combined PET/CT and underwent surgical reassessment of targeted nodal basins. Fisher's Exact Test was used to measure the ability of PET/CT to predict isolated retroperitoneal nodal disease. RESULTS: The median increase in serum CA125 from baseline nadir was 14 U/ml (range = 2-76 U/ml). There were 29 target nodes in 15 nodal basins identified with increased metabolic uptake on combined PET/CT. Eleven patients (78.6%) had recurrent ovarian cancer in retroperitoneal lymph nodes targeted by PET/CT. Of 143 nodes retrieved, 59 contained recurrent ovarian cancer (median nodal diameter = 2.5 cm, range = 0.8-5.2 cm). For all target nodal basins, the sensitivity, specificity, positive and negative predictive values, and accuracy for recurrent ovarian cancer in dissected lymph nodes were: 40.7% (24/59), 94.0% (79/84), 82.8% (24/29), 69.3% (79/114), and 72.0% (103/143) (P < 0.001). PET/CT failed to identify microscopic disease in 59.3% of pathologically positive nodes. CONCLUSION: Combined PET/CT demonstrates high positive predictive value in identifying recurrent ovarian cancer in retroperitoneal lymph nodes when conventional CT findings are negative or equivocal. The high incidence of occult disease within the target nodal basins suggests that regional lymphadenectomy may be necessary for complete secondary cytoreduction of recurrent disease.

Adult↗

PubMed2005

In vivo costimulatory role of B7-DC in tuning T helper cell 1 and cytotoxic T lymphocyte responses.

B7-DC, one of the recently described B7 family members, has the capacity to inhibit T cell responses via engagement of the immunoreceptor tyrosine-based inhibitory motif-containing inhibitory PD-1 receptor as well as enhance responses via an as yet unidentified costimulatory receptor. B7-DC is highly homologous to a coinhibitory B7 family member, B7-H1, which also binds PD-1. It is currently unclear which B7-DC function-costimulation or inhibition-predominates in vivo. To study in vivo functions of B7-DC, we evaluated immune responses in B7-DC knockout (KO) mice. Although not eliminated, interferon-gamma (IFN-gamma) production by CD4 T cells and IFN-gamma-dependent humoral responses were reduced in B7-DC KO mice relative to wild type mice. Antigen-specific CD8 T cell responses and cytotoxic T lymphocyte (CTL) activity were also diminished in B7-DC KO mice. Hepatic tumors grew more quickly in B7-DC KO mice, associated with a decrease in intrahepatic tumor-specific CD8 T cells. These results highlight the contrasting in vivo roles of B7-DC and B7-H1 and indicate that B7-DC functions as a tuning molecule, selectively augmenting T helper 1 and CTL responses.

Animals↗

PubMed2004

Elimination of hepatic metastases of colon cancer cells via p53-independent cross-talk between irinotecan and Apo2 ligand/TRAIL.

The majority of colorectal cancers have lost/inactivated the p53 tumor suppressor gene. Using isogenic human colon cancer cells that differ only in their p53 status, we demonstrate that loss of p53 renders tumor cells relatively resistant to the topoisomerase I inhibitor, irinotecan. Whereas irinotecan-induced up-regulation of the proapoptotic proteins PUMA and Noxa requires p53, we find that irinotecan inhibits Janus kinase 2 (JAK2)-signal transducer and activator of transcription 3 and 5 (STAT3/5) signaling in both p53-proficient and p53-deficient tumor cells. We show that irinotecan inhibits JAK2-STAT3/5-dependent expression of survival proteins (Bcl-x(L) and XIAP) and cooperates with Apo2 ligand/tumor necrosis factor-related apoptosis-inducing ligand (Apo2L/TRAIL) to facilitate p53-independent apoptosis of colon cancer cells. Whereas xenografts of p53-deficient colon cancer cells are relatively resistant to irinotecan compared with their p53-proficient counterparts, combined treatment with irinotecan and Apo2L/TRAIL eliminates hepatic metastases of both p53-proficient and p53-deficient cancer cells in vivo and significantly improves the survival of animals relative to treatment with either agent alone. Although the synergy between chemotherapy and Apo2L/TRAIL has been ascribed to p53, our data demonstrate that irinotecan enhances Apo2L/TRAIL-induced apoptosis of tumor cells via a distinct p53-independent mechanism involving inhibition of JAK2-STAT3/5 signaling. These findings identify a novel p53-independent channel of cross-talk between topoisomerase I inhibitors and Apo2L/TRAIL and suggest that the addition of Apo2L/TRAIL can improve the therapeutic index of irinotecan against both p53-proficient and p53-deficient colorectal cancers, including those that have metastasized to the liver.

Adenocarcinoma↗

PubMed2004

Analysis of novel tumor markers in pancreatic and biliary carcinomas using tissue microarrays.

Using global gene expression analyses, multiple novel tumor markers overexpressed in infiltrating ductal adenocarcinomas of the pancreas have recently been identified. However, the expression of these markers in morphologically similar adenocarcinomas of the biliary tree has not been investigated. The purpose of the present study was 3-fold. First, we used 8 markers that have been shown to be overexpressed in whole tissue sections of pancreatic adenocarcinomas to validate tissue microarrays (TMAs) created from a series of pancreatic adenocarcinomas (n=68). The labeling patterns of 6 epithelial markers (fascin, mucin 4, 14-3-3sigma, prostate stem cell antigen, topoisomerase IIalpha, and cdc2/p34) were concordant with previously published studies on whole tissue sections, yet required far fewer slides and reagents. Mesothelin, an epithelial marker, and heat shock protein 47, a marker of peritumoral desmoplasia, showed lower levels of expression in the TMAs when compared with whole tissue sections. Second, we examined the previously unknown expression of the same 8 novel tumor proteins in cancers of the biliary tree by using TMAs created from a series of intrahepatic cholangiocarcinomas, gallbladder adenocarcinomas, and adenocarcinomas of the distal common bile duct (n=38). Each of the 8 markers was overexpressed in the biliary cancers, ranging from 14% demonstrating at least focal labeling with prostate stem cell antigen to 100% labeling with cdc2/p34. Most of the markers showed lower frequencies of expression in the biliary tract carcinomas in comparison to the pancreatic adenocarcinomas. In addition, expression patterns varied with location in the biliary system (intrahepatic versus gallbladder versus distal common bile duct). These differences were statistically significant (P<0.05) for mesothelin, mucin 4, and heat shock protein 47. Finally, the expression of selected markers in neoplastic progression of gallbladder cancer was examined. Two markers, fascin and mesothelin, showed up-regulation of expression with transition from carcinoma in situ to invasive adenocarcinoma, implicating a role for these markers in neoplastic progression. The results of this study indicate that TMA technology provides valid and cost-effective means to screen large numbers of novel tumor markers, even in tumors such as pancreatic and biliary adenocarcinomas that characteristically have abundant desmoplastic stroma. In addition, novel tumor markers of pancreatic adenocarcinomas show similar, yet not identical, expression patterns in biliary carcinomas. Therefore, these markers are potentially useful in developing diagnostic tests and treatment paradigms for tumors involving the biliary system.

Adenocarcinoma↗

PubMed2004

Expression of neuropilin-1 in high-grade dysplasia, invasive cancer, and metastases of the human gastrointestinal tract.

Neuropilin-1 (NRP-1) functions as an axonal guidance molecule in the developing nervous system, and recent work has identified NRP-1 up-regulation in several cancers, including neuroblastomas and breast carcinoma. We examined for the first time NRP-1 expression in a large variety of gastrointestinal carcinomas and precursor lesions to determine whether NRP-1 up-regulation correlated with invasive growth in this system. Protein expression and localization of NRP-1 were studied by immunolabeling and semiquantification in >300 dysplastic, invasive, and metastatic lesions of the gastrointestinal tract, and confirmation of NRP-1 protein expression was performed by Western blot analysis on pancreatic cancer cell lines. NRP-1 expression was limited within normal tissues of the gastrointestinal tract, with prominent labeling present only in endothelial cells, pancreatic islet cells, and the most apical colonic epithelium. Invasive cancer of the esophagus, gallbladder, ampulla of Vater, pancreas (endocrine and exocrine), and colon, however, all demonstrated striking NRP-1 expression. NRP-1 was also identified in precursor lesions of gastrointestinal adenocarcinomas, such as Barrett esophagus and colorectal adenomas. Within the spectrum of precursor lesions, a progressive increase in both intensity and area of expression was evident during histologic progression from low-grade to high-grade dysplasia. Notably, the most intense up-regulation of NRP-1 was apparent at or around the point of invasion, with focal expression of NRP-1 at levels equivalent to the invasive cancer (2- to 3-fold increase). Prominent labeling for NRP-1 was apparent in primary invasive cancers, liver metastases, and a subset of lymph node metastases, with a 2- to 3-fold increase of NRP-1 over dysplastic lesions. We conclude that increased expression of NRP-1 occurs in gastrointestinal adenocarcinomas and in a subset of high-grade precursor lesions. This up-regulation appears to parallel invasive behavior and may therefore be used as a potential marker for cancer aggressiveness in this system.

Adenocarcinoma↗

PubMed2003

Prognostic value of hMLH1 methylation and microsatellite instability in pancreatic endocrine neoplasms.

BACKGROUND: The aberrant promoter methylation of the mismatch repair gene, hMLH1, is associated with microsatellite instability (MSI) in cancer cells and often is associated with a favorable prognosis. METHODS: Pancreatic endocrine neoplasms (PENs) were obtained from 48 patients who underwent surgical resection. Methylation-specific polymerase chain reaction was used to detect methylation in the hMLH1 promoter. Tumor MSI at loci BAT26, BAT25, D2S123, D5S346, and D17S250 was determined with microsatellite polymerase chain reaction. RESULTS: Hypermethylation of the hMLH1 promoter was present in 11 of 48 PENs (23%). Five of the 11 hMLH1-methylated PENs were found to be microsatellite unstable, and MSI was restricted to PENs with hMLH1 hypermethylation. Tumor recurrence at 2 years after surgical resection was significantly less common among the hMLH1-methylated PENs (11%), compared with the unmethylated PENs (35%; P=.038). Patients with hMLH1-methylated PENs experienced improved 5-year survival (100%) compared with patients with unmethylated tumors (56%; P=.010). Likewise, MSI-positive PENs were associated with improved survival compared with MSI-negative tumors (100% vs 59%; P=.017) at 5 years. CONCLUSION: As in hereditary nonpolyposis colorectal cancer in which MSI is associated with improved survival, methylation of hMLH1 leads to MSI in PENs and affords a favorable prognosis.

Adaptor Proteins, Signal Transducing↗