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ABSTRACT: Pancreatic adenocarcinoma is an aggressive malignancy. Oncolytic adenoviruses (Ads) are modified genetically to target tumor cells while sparing normal cells. We modified the knob domain of the Ad serotype 5 with a serotype 3 knob domain and incorporated the CXCR4 promoter to regulate Ad E1A gene expression (Ad5/3-CXCR4-E1A). These modifications were made to efficiently infect and lyse pancreatic tumors.
Human pancreatic cancer lines CFPAC-1, PANC-1, AsPC-1, and BxPC-3 were obtained from the American Type Culture Collection. Efficiency of Ad infection in the cells was determined by the use of an Ad construct expressing the green fluorescence protein (GFP) marker in place of the E1A gene (Ad5/3-CXCR4-GFP) and quantified by flow cytometry. Oncolytic activity in the pancreatic cancer cells was determined with the Ad5/3-CXCR4-E1A oncolytic Ad by a crystal violet staining method. To determine the oncolytic effect in vivo, pancreatic cancer cells were implanted on the flanks of 40 SCID mice (4 groups). Tumors were injected intratumorally for 3 days with Ad5/3-CXCR4-E1A, Ad5 wild-type (a positive control), or phosphate-buffered saline (a no virus control). Tumor size, overall survival, and body condition scale score were recorded. Statistical analyses included the Kaplan-Meier survival curve, the log-rank test, and one-way analysis of variance.
The serotype 3 fiber-modified Ad with the CXCR4 promoter (Ad5/3-CXCR4-E1A) was most efficient in infecting and lysing pancreatic cancer cells compared with an Ad containing an unmodified fiber knob (Ad5-CXCR4-E1A). Treatment of pancreatic tumor xenografts in vivo with Ad5/3-CXCR4-E1A group resulted in smaller tumors (P = .001), greater body condition scale score (P = .01), and greater survival time (P = .04) than the other treatment groups.
Ad5/3-CXCR4-E1A treatment significantly prolonged survival in SCID mice pancreatic tumor xenografts. This novel construct represents a potential new therapy against pancreatic cancer.
Surgery 07/2012; 152(3):441-8. · 3.10 Impact Factor
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Journal of Surgical Research 06/2012; · 2.25 Impact Factor
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ABSTRACT: Node-positive breast cancer patients are a high-risk group. However, not all such patients will succumb to the disease. The molecular basis for this biologic heterogeneity is poorly understood. The chemokine receptor CXCR4 is a marker of metastatic disease. Its prognostic role in node-positive patients is unknown. We postulate that high CXCR4 overexpression in node-positive breast cancer specimens predicts a poor outcome.
185 node-positive breast cancer patients were evaluated. All had standardized treatment and surveillance protocols. CXCR4 levels were detected with Western blots. Results were quantified against 1 µg of HeLa cells. CXCR4 expression was defined as high (≥ 7.5-fold) or low (<7.5-fold). Primary endpoints were cancer recurrence and death. Statistical analyses were Kaplan-Meier curves, log-rank test, and Cox proportional hazard model, with a P-value of ≤ 0.05 as significant.
The mean follow-up time was 54 months; 148 patients (80%) had low CXCR4 and 37 patients (20%) had high CXCR4 level. The 5-year overall survival (OS) for the low and high CXCR4 group was 69% and 57%, respectively (P=0.02). The 5-year disease-free survival (DFS) for the low and high CXCR4 group was 62% and 53%, respectively (P=0.08). On multivariate analysis, T stage (P=0.001) and grade (P=0.04) were independent predictors of DFS, while T stage (P=0.005), grade (P=0.024), and CXCR4 level (P=0.01) were independent predictors of OS.
High CXCR4 level in cancer specimens independently predicts a poor outcome for patients with node-positive breast cancer.
Journal of Surgical Oncology 04/2012; 106(4):393-8. · 2.10 Impact Factor
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ABSTRACT: Abstract "Twinning" refers to a constructive partnership between hospitals in developed and developing nations. Such an effort may contribute immensely to capacity building for the developing nation, but one of the reasons given for the lack of sustainability is cost. We share a detailed operating cost analysis of our recent experience with an institution in Vietnam. We were awarded a 1-year $54,000 grant from the Vietnam Education Foundation (VEF) to conduct a live tele-video conferencing course on the "Fundamentals of Clinical Surgery" with Thai Binh Medical University (TBMU). In-country lectures as well as an assessment of the needs at TBMU were performed. Total financial assistance and expenditures were tabulated to assess up-front infrastructure investment and annual cost required to sustain the program. The total amount of direct money ($66,686) and in-kind services ($70,276) was $136,962. The initial infrastructure cost was $41,085, which represented 62% of the direct money received. The annual cost to sustain the program was approximately $11,948. We concluded that the annual cost to maintain a "twinning" program was relatively low, and the efforts to sustain a "twinning" program were financially feasible and worthwhile endeavors. "Twinning" should be a critical part of the surgical humanitarian volunteerism effort.
International surgery 04/2012; 97(2):155-160. · 0.36 Impact Factor
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ABSTRACT: Node-positive breast cancer patients are at risk for metastatic disease. A routine metastatic workup might or might not be necessary for all patients with N2 or N3 diseases. The National Comprehensive Cancer Network guidelines recommend a metastatic workup for patients with T3N1 disease, yet no definitive recommendations are made for N2/N3 diseases. We hypothesized that for patients with operable pathologic N2/N3 diseases, a metastatic workup should only be considered for patients with T3/T4 lesions.
Two hundred and fifty-six patients with pathologic N2/N3 diseases were identified from a prospective breast cancer database of 1,329 patients with stage 0 to III breast cancer. A metastatic workup included chest x-rays, bone scans, CT scans, and PET scans. Primary end point was incidence of stage IV disease at the time of diagnosis or within 1 month of definitive surgery. Statistical analysis included chi-square test, independent t-test, Kaplan-Meier Survival method, log-rank test, and Cox proportional hazard model. A p value ≤ 0.05 was considered statistically significant.
There were 158 patients with N2 disease (62%) and 98 with N3 disease (38%). Overall, 16% had stage IV disease (N2 = 15%, N3 = 16%). There was no significant difference in age (p = 0.37), tumor size (p = 0.89), tumor grade (p = 0.09), estrogen-receptor status (p = 0.23), or progesterone-receptor status (p = 0.35) between the N2 and N3 groups. Incidences of stage IV disease were T0/T1, 0%; T2, 6%; T3, 22%; and T4, 36%. Multivariate analysis demonstrated that only T stage (p = 0.0006) and grade (p = 0.026) were independent predictors of overall survival.
A metastatic workup is only indicated for N2/N3 patients with T3 or T4 primary lesions.
Journal of the American College of Surgeons 02/2012; 214(4):456-61; discussion 461-2. · 4.55 Impact Factor
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ABSTRACT: Triple-negative breast cancer (TNBC) is an aggressive type of breast cancer that is clinically defined as lacking estrogen and progesterone receptors, as well as being ERBB2 (HER-2) negative. Without specific therapeutic targets, TNBC carries a worse prognosis than other types of breast cancer in the absence of therapy. Research has now further differentiated breast cancer into subtypes based on genetic expression patterns. One of these subtypes, basal-like, frequently overlaps with the clinical picture of TNBC. Additionally, both TNBC and basal-like breast cancer link to BRCA mutations. Recent pharmaceutical advances have created a class of drugs, poly(ADP-ribose) polymerase (PARP) inhibitors, which are showing potential to effectively treat these patients. The aim of this paper is to summarize the basis behind PARP inhibitors and update the current status of their development in clinical trials for the treatment of TNBC.
International journal of breast cancer. 01/2012; 2012:829315.
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ABSTRACT: Introduction. Triple negative breast cancer (TNBC) is biologically aggressive and is associated with a worse prognosis. To understand the impact of race/ethnicity on outcome for patients with TNBC, confounding factors such as socioeconomic status (SES) need to be controlled. We examined the impact of race/ethnicity on a cohort of patients of low SES who have TNBC. Methods. 786 patients with Stage 0-III breast cancer were evaluated. Of these, 202 patients had TNBC (26%). Primary endpoints were cancer recurrence and death. ZIP code-based income tract and institutional financial data were used to assess SES. Data were analyzed using Kaplan-Meier survival analysis, log-rank tests, Cox Proportional hazard regression, chi square test, and t-tests. A P value ≤0.05 was considered statistically significant. Results. Of the 468 African-Americans (60%) in the database, 138 had TNBC; 64 of 318 Caucasians had TNBC. 80% of patients had an annual income of ≤$20,000. The 5-year overall survival was 77% for African-American women versus 72% for Caucasian women (P = 0.95). On multivariate analysis, race/ethnicity had an impact on disease-free survival (P = 0.027) but not on overall survival (P = 0.98). Conclusion. In a predominantly indigent population, race/ethnicity had no impact on overall survival for patients with triple negative breast cancer.
International journal of breast cancer. 01/2012; 2012:764570.
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Journal of Surgical Research 11/2011; · 2.25 Impact Factor
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Bulletin of the American College of Surgeons 11/2011; 96(11):12-8.
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ABSTRACT: Chemokine receptor CXCR4 is a marker of metastatic disease. We found initially that CXCR4 level is a predictive marker for patients with locally advanced breast cancer (LABC). We now confirm our initial observations.
We evaluated 77 LABC patients who had neoadjuvant therapy. Specimens were taken at the time of definitive operation. CXCR4 levels were detected with Western blots. CXCR4 expression >6.6-fold over known concentration of HeLa cells was defined as high. Primary endpoints were cancer recurrence and death. Statistical analyses were Kaplan-Meier curves, log-rank test, and Cox proportional hazard model.
Median follow-up time was 42 months; 55 patients (71%) had low CXCR4 level. The 5-year overall survival for the low and high CXCR4 group was 78% and 50%, respectively (P = .015). The 5-year disease-free survival (DFS) for the low and high CXCR4 group was 67% and 41%, respectively (P = .024). On multivariate analysis, CXCR4 overexpression (P = .003) and nodal status (P = .044) were independent predictors of overall survival; CXCR4 overexpression (P = .003) and nodal status (P = .026) were also independent predictors of DFS.
We confirmed that high CXCR4 levels in cancer specimens after neoadjuvant therapy independently predict a poor outcome for patients with LABC.
Surgery 09/2011; 150(3):459-65. · 3.10 Impact Factor
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ABSTRACT: CXCR4 is a G-protein coupled receptor that has been linked with metastasis in several cancers, including breast cancer. We recently demonstrated that high CXCR4 levels in primary tumors of patients with breast cancer had a prognostic significance. We hypothesize that patients whose tumors had a low CXCR4 overexpression level following neoadjuvant chemotherapy will have a lower recurrence rate than those whose tumors remained high.
Seventeen locally advanced breast cancer (LABC) patients were accrued, and tumor specimens were obtained before and after neoadjuvant therapy. CXCR4 levels were quantified by Western blots against 1 μg of protein from HeLa cells. The primary end-point was cancer recurrence. Statistical tests utilized include Kaplan-Meier survival analysis and log-rank test. A P value ≤ 0.05 was considered significant.
We previously defined low CXCR4 overexpression as ≤6-fold elevation and high overexpression as >6-fold elevation over HeLa cells. Of 17 LABC tumors evaluated, 10 (59%) remained in the low group, 5 (29%) reduced from high to low overexpression, and 2 (12%) maintained a high overexpression after neoadjuvant therapy. With a median follow-up of 28 mo, patients whose tumors maintained a high CXCR4 overexpression level after neoadjuvant therapy had a significantly higher rate of cancer recurrence (P = 0.0068).
CXCR4 was a predictive molecular marker of response to neoadjuvant chemotherapy for patients with LABC. Patients whose tumors had a persistently high CXCR4 overexpression level after neoadjuvant therapy are at a significant risk for recurrence, and therefore, should be targeted for more intensive and/or novel therapy.
Journal of Surgical Research 03/2011; 166(1):14-8. · 2.25 Impact Factor
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ABSTRACT: Reflecting the resected portion of the proximal jejunum behind the mesenteric vessels during a pancreaticoduodenectomy (Whipple) procedure can be a challenging maneuver.
We describe a simple technique employing a penrose drain that is sutured to the resected "specimen" portion of the jejunum and then pulling it behind the mesenteric vessels.
Seven patients underwent this procedure over a 2-month period without difficulties.
This simple technique helps simplify one of the key maneuvers in performing a Whipple procedure.
Journal of Gastrointestinal Surgery 02/2011; 15(9):1630-2. · 2.83 Impact Factor
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ABSTRACT: The expected outcome for hormone receptor-positive, node-negative patients should be favorable. However, some patients do develop metastatic disease and the mechanism for this observation is poorly understood. CXCR4 is a chemokine receptor that has been implicated to play a pivotal role in breast cancer growth and metastasis. Its predictive role has not been fully evaluated. We determined to see whether CXCR4 can predict outcome in this subset of patients.
We accrued and analyzed data from 101 patients with hormone receptor-positive, node-negative breast cancers. The CXCR4 level was detected using Western blots and its level was defined as either low (<6.6-fold) or high (≥6.6-fold). Primary end points were systemic cancer recurrence and death. Statistical analysis performed included Spearman's correlation, Kaplan-Meier survival analysis, and Cox proportional hazard model.
Although benign breast tissues had an undetectable level of CXCR4, all 101 cancer specimens had overexpressed CXCR4 (mean 6.4 ± 3.4-fold). There were 79 patients in the low CXCR4 group and 22 patients in the high CXCR4 group. High CXCR4 overexpression was predictive of both cancer recurrence (P = .002) and overall survival (P = .0012).
High CXCR4 overexpression in primary tumors was predictive of worse outcomes in hormone receptor-positive, node-negative breast cancer patients.
Surgery 02/2011; 149(2):193-9. · 3.10 Impact Factor
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ABSTRACT: The molecular basis of sarcoma remains poorly understood. However, recent studies have begun to uncover some of the molecular pathways involved in sarcomagenesis. The chemokine receptor CXCR4 has been implicated in sarcoma development and has been found to be a prognostic marker for poor clinical outcome. There is growing evidence that overexpression of CXCR4 plays a significant role in development of metastatic disease, especially in directing tumor cells towards the preferential sites of metastases in sarcoma, lung and bone. Although further investigation is necessary to validate these pathways, there is potential for clinical application, particularly in the use of pharmacologic inhibitors of CXCR4 as means of preventing sarcoma metastasis.
Sarcoma 01/2011; 2011:593708.
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ABSTRACT: Inflammatory breast cancer (IBC) is a rare and most aggressive form of breast cancer. The onset and progression of disease are rapid; diagnosis must be made expediently to initiate treatment quickly. In this review, the clinical presentation, trimodal therapy, surgical principles and a brief summary of the Louisiana State University at Shreveport experience with IBC are presented. With this aggressive approach, 5-year survival of better than 40-50% can be expected. This represents a substantive improvement in clinical outcome for IBC patients compared with 30 years ago.
Oncology 11/2010; 79(1-2):3-12. · 2.27 Impact Factor
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ABSTRACT: Due to advances in viral design, oncolytic adenoviruses have emerged as a promising approach for treatment of breast cancer. Tumor tissue slices offer a stringent model system for preclinical evaluation of adenovirus therapies, since the slices retain a morphology and phenotype that more closely resembles the in vivo setting than cell line cultures, and this system has been shown to have utility in the evaluation of viral infectivity and replication. In this study, we evaluated the efficacy of viral infection and replication using a tropism-modified oncolytic adenovirus.
Breast tumor tissue slices were infected with a tropism-modified oncolytic adenovirus, and a wild-type adenovirus for comparison. Efficiency of infection was evaluated using fluorescent microscopy, as the viruses used have been modified to express red fluorescent protein. Replication of the viruses was evaluated with quantitative real-time polymerase chain reaction (PCR) to assay viral E4 genome copy number, a surrogate indicator for the number of virions. The breast tumor tissue slices were evaluated for the expression of CD46 expression by immunohistochemistry.
Infection and replication of our tropism modified oncolytic virus has been observed in the breast cancer tissue slice model system and is comparative to wild-type virus. A qualitative increase in the number of cells showing red fluorescent protein (RFP) expression was observed correlating with increasing multiplicity of infection. Higher relative infectivity of the virus was observed in tumor tissue compared with normal breast tissue. Replication of the virus was demonstrated through increases in E4 copy number at 48 and 72 h after infection in human breast tumor slices.
We have shown that a tropism modified oncolytic adenovirus can infect and replicate in breast cancer tissue slices, which may be an important preclinical indicator for its therapeutic utility.
Journal of Surgical Research 10/2010; 163(2):270-5. · 2.25 Impact Factor
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ABSTRACT: Triple-receptor negative breast cancers (TNBC) are aggressive neoplasms that lack estrogen-receptor, progesterone-receptor, and HER-2 expressions. Comparative analysis of breast conservation therapy (BCT) versus mastectomy for TNBC is reported sparsely. We hypothesized that, despite its aggressive behavior, TNBC can be managed with BCT.
Outcomes for 202 patients with TNBC who were treated with BCT or mastectomy were analyzed. Primary endpoints were cancer recurrence and death. Statistical analysis performed included Kaplan-Meier survival analysis, log-rank, independent samples t test, Cox proportional hazard model, and Chi-square.
BCT was performed in 30% of patients. Isolated local recurrence rate for BCT and mastectomy was 0% and 10.6%, respectively (P = .02). Isolated regional recurrence rate for BCT and mastectomy was 1.6% and 1.4%, respectively (P = .61). Neither concomitant locoregional and distant recurrence rate (P = .73) nor isolated distant recurrence rate (P = .71) was significantly different between the BCT and mastectomy groups. The 5-year overall survival (OS) was better for the BCT group than the mastectomy group (89% vs 69%; P = .018); however, this was likely due to the mastectomy group having a larger neoplasm size (T3/T4: 4% BCT vs 27% mastectomy; P = .0002), advanced N-disease (N2/3: 8% BCT vs 25% mastectomy; P = .0003), and advanced stage of disease (stage 3: 8% BCT vs 35% mastectomy; P < .0001). On multivariate analysis, surgical approach had no effect on either disease-free survival (P = .60) or OS (P = .19); only t-stage was an independent predictor of disease-free survival (P = .02), while N-stage was an independent predictor for OS (P = .03).
Despite TNBC's aggressive behavior, breast conservation therapy is a viable option for selected patients with TNBC.
Surgery 08/2010; 148(2):386-91. · 3.10 Impact Factor
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ABSTRACT: African American women have a higher breast cancer mortality rate than Caucasian women. Estrogen receptor (ER)-negative tumors, which are more aggressive than ER-positive tumors, occur more frequently in African American women than in Caucasian women and may contribute to apparent disparities in outcomes. However, outcome results need to be controlled for socioeconomic status (SES). We evaluated the effect of race and ethnicity on outcomes of patients with ER-negative tumors by determining outcomes in African American and Caucasian women with low SES but similar access to care.
From a prospective database of 786 patients with stage 0 to III breast cancer, all 375 patients with ER-negative tumors were evaluated. Patients received standard definitive operations and adjuvant treatment. Compliance with treatment was more than 90%. Primary endpoints were cancer recurrence and overall survival (OS). Statistical analysis performed included Kaplan-Meier survival analysis, log-rank test, Cox proportional hazard model, Student's t-test, and chi-squared test. A p value < or = 0.05 was considered statistically significant.
Fifty-four percent of African American patients had ER-negative tumors versus 39% in Caucasian patients. In both groups, 69% of patients received free care or Medicaid, with a median income of $16,577 (range $15,367 to $36,788). Comparing the 2 racial and ethnic groups, mean tumor size (p = 0.19), tumor grade distribution (p = 0.32), nodal distribution (p = 0.50), stage distribution (p = 0.30), rate of mastectomy (p = 0.47), receipt of adjuvant chemotherapy (p = 0.07), and financial class distribution (p = 0.67) were not significantly different. The 5-year OS was 77% for both groups (p = 0.59). On multivariate analysis, race and ethnicity were not independent predictors of OS (p = 0.73).
In a predominantly indigent population, race and ethnicity had no impact on outcomes for ER-negative breast cancer.
Journal of the American College of Surgeons 05/2010; 210(5):585-92, 592-4. · 4.55 Impact Factor
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Journal of Clinical Oncology 12/2009; 28(4):e56; author reply e57. · 18.37 Impact Factor
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ABSTRACT: African American women have a higher breast cancer mortality rate than Caucasian women. To understand this difference, socioeconomic status (SES) needs to be controlled, which can be achieved by evaluating outcome within a population that is underinsured or low SES. We elected to examine the effect of race/ethnicity on outcome of patients with operable breast cancer by evaluating outcome in a population with low SES and similar access to care.
From a prospective breast cancer database created in 1998, we examined outcome for 786 patients with stage 0 to III breast cancer treated up to September 2008. Patients were treated at Louisiana State University Health Sciences Center in Shreveport and E.A. Conway Hospital and the majority received standard definitive surgery as well as appropriate adjuvant treatment. Primary endpoints were cancer recurrence and death. Statistical analysis performed included Kaplan-Meier survival analysis, log-rank test, Cox proportional hazards model, independent-samples t test, and chi(2) test. P <or= 0.05 was considered statistically significant.
Sixty percent of patients were African American and over two thirds of patients were classified as either free care or Medicaid. The 5-year overall survival (OS) for African American and Caucasian patients was similar (81% and 84%, respectively; P = 0.23). On multivariate analysis, race/ethnicity was not an independent predictor of OS (P = 0.5); OS for the entire cohort was comparable with what was reported in the National Cancer Data Base.
In a predominantly indigent population, race/ethnicity had no effect on breast cancer outcome.
Cancer Epidemiology Biomarkers & Prevention 09/2009; 18(8):2157-61. · 4.12 Impact Factor
