Showing papers by "Karen R. Cleary published in 1996"

Rationale for En Bloc Vein Resection in the Treatment of Pancreatic Adenocarcinoma Adherent to the Superior Mesenteric-Portal Vein Confluence

Abstract: OBJECTIVE: Tumor invasion of the superior mesenteric-portal vein (SMPV) confluence is often considered a contraindication to pancreaticoduodenectomy for patients with malignant tumors of the pancreas or periampullary region. The authors sought to determine whether pancreaticoduodenectomy with en bloc resection of the SMPV confluence could be safely performed and whether tumors involving the SMPV confluence were associated with pathologic parameters suggesting poor prognosis. SUMMARY BACKGROUND DATA: Several centers have reported high rates of retroperitoneal margin positivity after pancreaticoduodenectomy for tumors of the pancreatic head and periampullary region. Positive-margin or incomplete resection is associated with early tumor recurrence and no survival benefit compared with palliative therapy. Tumor adherence to the lateral of posterior wall of the SMPV confluence often represents the only barrier to complete tumor resection at the time of pancreaticoduodenectomy. METHODS: Data on all patients undergoing pancreaticoduodenectomy for adenocarcinoma of the pancreas or periampullary region over a 3.5-year period were entered prospectively in a pancreatic tumor database. To be considered for surgery, patients were required to fulfill the following computed tomography criteria for resectability: 1) the absence of extrapancreatic disease, 2) no tumor encasement of the superior mesenteric artery or celiac axis, and 3) a patent SMPV confluence. Tumor adherence to the superior mesenteric vein or SMPV confluence was assessed intraoperatively, and en bloc venous resection was performed when necessary to achieve complete tumor extirpation. Data on operative characteristics, morbidity, mortality, tumor size, nodal metastases, margin positivity, perineural invasion, and tumor DNA content were compared for patients who did and did not receive venous resection. RESULTS: Fifty-nine patients underwent pancreaticoduodenectomy, 36 without venous resection and 23 with en bloc resection of the SMPV confluence. No differences in median hospital stay, morbidity, mortality, tumor size, margin positivity, nodal positivity, or tumor DNA content were observed between groups. CONCLUSIONS: When necessary, segmental resection of the SMPV confluence may be performed safely during pancreaticoduodenectomy for periampullary malignant tumors. Tumors invading the SMPV confluence are not associated with histologic parameters suggesting a poor prognosis. Our data suggest that venous involvement is a function of tumor location rather than an indicator of aggressive tumor biology.

Platelet-Derived Endothelial Cell Growth Factor in Human Colon Cancer Angiogenesis: Role of Infiltrating Cells

Abstract: Background : Development of new blood vessels is essential for tumor growth and metastasis and depends on the production of angiogenic factors by tumor and/or infiltrating cells. We previously showed that vascular endothelial growth factor (VEGF) expression and vessel count correlate with metastasis in human colon cancer. Although most tumors with high vessel counts express high levels of VEGF, some do not. Recently, platelet-derived endothelial cell growth factor (PD-ECGF), another potent angiogenic factor, has been reported to be expressed in colon cancer. Purpose : In this study, we examined the role of PD-ECGF in colon cancer angiogenesis and whether PD-ECGF is derived from the tumor or infiltrating cells. Methods : Immunostaining for PD-ECGF was performed on 96 colon cancer specimens, some of which were previously stained for VEGF and factor VIII, a marker that is specific for endothelial cells. Double staining was done by using antibodies to PD-ECGF and to CD68 (macrophage specific) or CD3 (lymphocyte specific) to confirm which infiltrating cells produce PD-ECGF. Northern blot analysis for PD-ECGF messenger RNA (mRNA) was performed on four colon cancer specimens and corresponding normal colon mucosae (same patients) and four human colon cancer cell lines (KM12SM, SW620, HT29, and NCI-H508) to determine whether colon cancer epithelium expresses PD-ECGF. Results : Immunohistochemical analysis demonstrated that PD-ECGF was expressed in infiltrating cells in most of the colon cancer specimens (80 [83%] of 96) but rarely in tumor epithelium (five [5%] of 96). Double staining demonstrated that infiltrating cells staining positive for both PD-ECGF and CD68 were more predominant than those staining positive for both PD-ECGF and CD3. The intensity of staining for PD-ECGF in infiltrating cells correlated with vessel counts (Spearman's rank correlation coefficient (R) =.29 ; P =.004), but did not correlate with the intensity of VEGF staining (R =.176, P =.086) or metastasis (Mann-Whitney U test, P =.253). PD-ECGF staining intensity was higher in specimens with a high vessel count (>50 at high magnification) and low VEGF-staining intensity (≤2+) than in specimens with a high vessel count (again, >50) and high VEGF-staining intensity (3+). Northern blot analysis revealed that colon cancer specimens and normal mucosae expressed relatively high levels of PD-ECGF mRNA, whereas PD-ECGF mRNA transcripts were not detectable in colon cancer cell lines. Conclusions and Implications : PD-ECGF expression in human colon cancer specimens is associated with vessel count and may be responsible for tumor vascularity in those tumors with low VEGF expression. Infiltrating cells expressing PD-ECGF may contribute to angiogenesis, thus providing an additional mechanism for tumor neovascularization.

Significance of Vessel Count and Vascular Endothelial Growth Factor and Its Receptor (KDR) in Intestinal-type Gastric Cancer'

Abstract: Angiogenesis is essential for tumor growth and metastasis and depends on the production of angiogenic factors by host and/or tumor cells. The role of angiogenesis and angiogenic factor expression in intestinal- and diffuse-type gastric cancer are undefined. Archival specimens of 51 intestinal-type and 38 diffuse-type human gastric carcinomas were examined for tumor vessel counts, angiogenic factor expression, and the presence or absence of angiogenic factor receptors on tumor endothelium using antibodies against vascular endothelial growth factor (VEGF) and its receptors (KDR and flt-1), basic fibroblast growth factor (bFGF) and its receptors (bek and flg), and factor VIII (endothelial cells). Vessel count and VEGF and bFGF expression were higher in intestinal-type than in diffuse-type gastric cancers (P = 0.01, P < 0.001, and P < 0.001, respectively). Similarly, vessel count and VEGF expression were higher in patients with liver metastasis than in patients with peritoneal dissemination (P = 0.003 and P = 0.01, respectively). Vessel count correlated with VEGF expression and the presence of endothelial KDR in intestinal-type gastric cancer (P = 0.003 and P = 0.02, respectively) but not diffuse-type gastric cancer. Vessel count, VEGF expression, and presence of endothelial KDR increased with increasing stage of disease in intestinal-type gastric cancer but not diffuse-type gastric cancer. The expression of bFGF and its receptors did not correlate with vessel count in either cancer type. These findings suggest that the pattern of metastasis in intestinal-type gastric cancer is angiogenesis dependent. The correlation of VEGF expression and its endothelial receptor with vessel count and stage of disease suggests that VEGF is at least one of the factors responsible for the induction of angiogenesis in intestinal-type gastric cancer.

Preoperative chemoradiation, pancreaticoduodenectomy, and intraoperative radiation therapy for adenocarcinoma of the pancreatic head*

Abstract: Background Local recurrence in the bed of the resected pancreas is the most common site of tumor recurrence following a standard pancreaticoduodenectomy (PD) for adenocarcinoma of the pancreatic head. In an attempt to improve local and regional disease control and thereby enhance the quality and length of survival in patients undergoing potentially curative PD, we have used a protocol of preoperative multimodality therapy. Ptients and methods All patients were treated with external-beam radiation (30.0 or 50.4 Gy) and concomitant 5-fluorouracll (300 mg/m 2 per day) prior to PD. Electron-beam intraoperative radiation therapy was given to the bed of the resected pancreas before reconstruction. Patients were assessed for recurrence by physical examination, chest roentgenography, and computed tomography scan performed at 3-month Intervals following treatment. Results Thirty-nine patients completed all therapy; 1 perioperative death occurred. Thirty-eight tumor recurrences have been documented in 29 patients at a median of 11 months from the date of diagnosis; 23 patients died of disease. The liver was the most frequent site of recurrence, and liver metastases were a component of treatment failure in 53% of patients. Isolated local or peritoneal recurrences were documented in only 4 patients (11%). The only significant clinical or pathologic variable predictive of local-regional recurrence was a previous laparotomy and intraoperative biopsy. The median survival of all 39 patients was 19 months, and the 4-year actuarial survival rate was 19%. Conclusions Preoperative Chemoradiation, PD, and electron-beam intraoperative radiation therapy for adenocarcinoma of the pancreatic head have resulted in improved local-regional tumor control, with distant metastatic disease becoming the predominant site of tumor recurrence. Future treatment stategies should incorporate effective multimodality therapy for local-regional disease as demonstrated in this study. Major improvements in overall survival will likely await the development of systemic or regional therapy for liver metastases.

The need for standardized pathologic staging of pancreaticoduodenectomy specimens

Abstract: A standardized method for pathologic evaluation and staging of pancreaticoduodenectomy (PD) specimens is critical for accurate reporting of the number and location of lymph nodes and margins of resection. We examined the impact of standardized pathologic evaluation (SPE) of PD specimens on the identification of regional lymph nodes and describe our detailed system for the pathologic analysis of the PD specimen. Forty consecutive patients underwent PD for histologically confirmed adenocarcinoma of the pancreatic head between April 1990 and August 1993. Fifteen consecutive specimens were examined before the introduction of the SPE, and 25 consecutive specimens underwent SPE. Resection margins were evaluated by frozen-section analysis, and then the specimen was divided into six regions on an anatomic dissection board for lymph node identification. The 25 specimens examined according to the SPE had a significantly increased number of lymph nodes identified (P = 0.0001) compared with the 15 specimens examined without the SPE. Twelve of the 25 specimens contained positive lymph nodes, 6 of which were confined to the pancreaticoduodenal region. No positive nodes were found in the periaortic region. There were no differences in pathologic variables between patients found to have negative and those with positive regional lymph nodes. SPE of PD specimens provides a method for improved lymph node identification, ensures accurate prospective evaluation of margins of resection, and provides a complete analysis of potentially important pathologic variables. We offer this system as a standardized model for groups engaged in protocol-based clinical research examining innovative multimodality treatment strategies for patients with resectable pancreatic cancer.

Increased apoptosis accompanies neoplastic development in the human colorectum.

Abstract: A disturbance in the balance between cell proliferation and cell loss, or apoptosis, may underlie neoplastic development. Therefore, we determined spontaneous apoptotic and proliferative rates in normal, hyperplastic, adenomatous, and malignant colorectal epithelia. In paired sections, DNA strand breaks were detected using the terminal deoxynucleotidyltransferase-mediated dUTP nick-end labeling assay, and apoptotic cells were also identified in H&E-stained slides by morphological criteria. Cell proliferation, bcl-2, and p53 expression were analyzed using specific monoclonal antibodies. In normal mucosa, luminal epithelial cells demonstrated higher rates of apoptosis compared to cells in the proliferative zone. Neoplastic transformation was associated with a significant increase in rates of apoptosis and proliferation. However, apoptosis, but not proliferation, decreased at the adenoma-to-carcinoma transition coincident with expression of mutant p53. In carcinomas, both mutant p53 and bcl-2 protein levels were associated with attenuated apoptotic rates. In conclusion, apoptosis is an important regulator of growth in normal and neoplastic colorectal epithelia. Increased apoptosis and proliferation accompany neoplastic transformation, suggesting that an alteration in apoptotic rates is an important event in colorectal carcinogenesis. Furthermore, the imbalance in these processes found in carcinomas may facilitate tumor growth and progression.

Survival factors in 186 patients younger than 40 years old with colorectal adenocarcinoma

Abstract: BACKGROUND We sought to determine the clinical factors and tumor characteristics associated with the reported poor prognosis in young patients with carcinoma of the colon and rectum. STUDY DESIGN A retrospective review was performed of 186 patients younger than 40 years of age who were treated for primary colorectal adenocarcinoma. The median age was 34.3 years, and the median follow-up period was 9.4 years. Clinical and tumor histopathologic parameters were analyzed. RESULTS Regional lymph node metastases, distant metastases, or both, were seen at first examination in 65.6 percent of young patients. Histopathologic indicators of more aggressive tumor biology were present at a significantly higher frequency in young patients compared with patients older than 40 years (p < 0.001). Poorly differentiated tumor grade was present in 41.0 percent, signet-ring cell tumors were found in 11.1 percent, and infiltrating tumor leading edges were present in 69.0 percent of young patients. Among young patients with stage II disease, vascular invasion was a significant negative prognostic variable (p < 0.05). CONCLUSIONS We have demonstrated an increased incidence of three biological indicators of aggressive and potentially metastatic tumor biology in 186 young patients with carcinoma of the colon and rectum: signet-ring cell carcinoma, infiltrating tumor edges, and aggressive histologic grade in the primary adenocarcinoma. The increased incidence of these three histologic measures of more aggressive carcinoma of the colon and rectum in part accounts for the higher rate of advanced disease at presentation in patients younger than 40.

Multiparametric in situ mRNA hybridization analysis to predict disease recurrence in patients with colon carcinoma.

Abstract: We examined the expression level of several genes that regulate different steps of metastasis in formalin-fixed, paraffin-embedded archival specimens of primary human colon carcinomas from patients with at least 5 years of follow-up. The expression of epidermal growth factor receptor, basic fibroblast growth factor, type IV collagenase, E-cadherin, and multidrug resistance (mdr-1) was examined by a colorimetric in situ mRNA hybridization technique concentrating on reactivity at the periphery of the neoplasms. The in situ hybridization technique revealed inter- and intratumor heterogeneity for expression of the metastasis-related genes. The expression of basic fibroblast growth factor, collagenase type IV, epidermal growth factor receptor, and mdr-1 mRNA was higher in Dukes's stage D than in Dukes' stage B tumors. Among the 22 Dukes' stage B neoplasms, 5 specimens exhibited a high expression level of epidermal growth factor receptor, basic fibroblast growth factor, and collagenase type IV. Clinical outcome data (5-year follow-up) revealed that all 5 patients with Dukes' stage B tumors developed distant metastasis (recurrent disease), whereas the other 17 patients with Dukes' stage B tumors expressing low levels of the metastasis-related genes were disease-free. Multivariate analysis identified high levels of expression of collagenase type IV and low levels of expression of E-cadherin as independent factors significantly associated with metastasis or recurrent disease. More specifically, metastatic or recurrent disease was associated with a high ratio (> 1.35) of expression of collagenase type IV to E-cadherin (specificity of 95%). Collectively, the data show that multiparametric in situ hybridization analysis for several metastasis-related genes may predict the metastatic potential, and hence the clinical outcome, of individual lymph-node-negative human colon cancers.

bcl-2 and p53 expression in resectable pancreatic adenocarcinomas: Association with clinical outcome

Abstract: The bcl-2 proto-oncogene and the p53 tumor suppressor gene are important determinants of tumor cell susceptibility to apoptosis. bcl-2 and mutant p53 proteins inhibit apoptosis in vitro and can provide prognostic information in certain tumor types. We analyzed bcl-2 and p53 expression in archival pancreatic (n = 35) and ampullary (n = 6) adenocarcinomas, resected for cure, and their relationship to overall survival. Patients were treated with 5-fluorouracil and irradiation either pre- (n = 21) or postoperatively (n = 15); 5 patients received surgery alone. Using specific monoclonal antibodies, cytoplasmic bcl-2 and nuclear p53 proteins were detected in 22 of 40 (55%) and 20 of 37 (54%) tumors, respectively. No relationship was found between bcl-2 and p53 expression. Neither bcl-2 nor p53 correlated with histological response to preoperative chemoradiation. Lymph node involvement predicted poor overall survival (P = 0.02). A trend toward improved survival was seen in well-differentiated (P = 0.08) tumors and in those with increased bcl-2 expression (P = 0.06). p53 expression was not related to clinical outcome. In a multivariate analysis, nodal status was the single most important predictor of overall survival. Of note, the combined variable of bcl-2 expression and histological grade was a stronger prognostic variable than nodal status alone. Unlike nodal status, these features can potentially be evaluated in preoperative biopsy specimens.

Allogeneic transplantation for advanced leukemia: improved short-term outcome with blood stem cell grafts and tacrolimus.

Abstract: We have evaluated the use of blood stem cell grafts for rapid hematopoietic recovery and tacrolimus (FK506) as GVHD prophylaxis to reduce early mortality after allogeneic transplantation. Eighty-five adults with advanced leukemia received high-dose thiotepa, busulfan, and cyclophosphamide as a preparative regimen in a prospective Phase II study. All donors were HLA-matched and related. Marrow (BMT) was used for 44 patients and filgrastim-mobilized blood stem cells (SCT) for 41 patients. GVHD prophylaxis consisted of cyclosporine (CsA) or FK506 with methotrexate (MIX) or methylprednisolone (MP). The median time to neutrophil recovery was earlier after SCT than after BMT (day 10 vs. 17, P<0.001), but this was due to the selective use of MIX only in the BMT patients. The risk of grades 2-4 GVHD was lower with FK506 than with CsA (16% vs. 45%, P=0.02) and was the same for SCT recipients as for BMT recipients (33% vs. 34%). Regimen-related toxicity was significantly lower after SCT than after BMT but did not differ between the FK506 and CsA patients. In comparison with those receiving the standard transplant (BMT with CsA and MTX), only the SCT recipients using FK506 and MP had a significantly higher survival at day 180 posttransplant (84% vs. 73%, P=0.014). In multivariate analyses, use of FK506 was associated with a lower risk of treatment-related mortality and a higher survival at day 180, while the diagnosis of acute lymphoblastic leukemia was associated with a higher risk of treatment-related mortality. These data suggest that the use of blood stem cell grafts and FK506 can reduce the early mortality after allogeneic transplantation for advanced leukemia.

Pancreatic adenocarcinoma cell line, MDAPanc-28, with features of both acinar and ductal cells.

Abstract: Conclusion We established a new human pancreatic adenocarcinoma cell line, MDAPanc-28. Studies on this new line indicate that it expresses both acinar and ductal gene products suggesting that the patterns of gene expression in the pancreatic adenocarcinoma from which this cell line arose have features similar to those of the protodifferentiated cells hypothesized by Rutter and his colleagues for the developing pancreas (1,2).

Orofacial granulomatosis and Crohn's disease.

Abstract: Orofacial granulomatosis is a clinical entity of either unknown or specific causation. Specific causes include sarcoidosis, chronic infective granulomas, and Crohn's disease. The remainder of cases are idiopathic, but the clinical presentations of orofacial swellings and intraoral mucosal lesions are similar. So, too, are the histopathologic findings of noncaseating granulomas, edema, and chronic lymphoproliferative infiltrate. Crohn's disease is not responsible for all forms of orofacial granulomatosis, but the orofacial manifestations of the disease may herald its diagnosis.

Extramedullary plasmacytoma mimicking primary colonic carcinoma in a patient with Crohn's disease. Case report and literature review.

Abstract: . We present the case of a 45-year-old man who underwent segmental resection for what was considered clinically to be a primary colonic carcinoma. Histopathologic evaluation revealed the tumor to be a malignant plasmacytoma of the colon. Additionally, the entire segment of distal ileum and colon was involved by an inflammatory process with the features of Crohn's disease, accompanied by focal glandular dyplasia of the colonic mucosa. This case reemphasizes that plasmacytoma of the colon can closely mimic carcinoma of the colon in its presentation. The association between plasmacytoma of the colon and Crohn's disease has not, to our knowledge, been described previously.