ABSTRACT
Surface Enhanced Resonance Raman (SERS) is a powerful optical technique, which can help enhance the sensitivity of Raman spectroscopy aided by noble metal nanoparticles (NPs). However, current SERS-NPs are often suboptimal, which can aggregate under physiological conditions with much reduced SERS enhancement. Herein, a robust one-pot method has been developed to synthesize SERS-NPs with more uniform core diameters of 50 nm, which is applicable to both non-resonant and resonant Raman dyes. The resulting SERS-NPs are colloidally stable and bright, enabling NP detection with low-femtomolar sensitivity. An algorithm has been established, which can accurately unmix multiple types of SERS-NPs enabling potential multiplex detection. Furthermore, a new liposome-based approach has been developed to install a targeting carbohydrate ligand, i.e., hyaluronan, onto the SERS-NPs bestowing significantly enhanced binding affinity to its biological receptor CD44 overexpressed on tumor cell surface. The liposomal HA-SERS-NPs enabled visualization of spontaneously developed breast cancer in mice in real time guiding complete surgical removal of the tumor, highlighting the translational potential of these new glyco-SERS-NPs.
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Background and aims: Cancer and atherosclerosis share common risk factors and inflammatory pathways that promote their proliferation via vascular endothelial growth factor (VEGF). Because CCs cause mechanical injury and inflammation in atherosclerosis, we investigated their presence in solid cancers and their activation of IL-1ß, VEGF, CD44, and Ubiquityl-Histone H2B (Ub-H2B), that promote cancer growth. Methods: Tumor specimens from eleven different types of human cancers and atherosclerotic plaques were assessed for CCs, free cholesterol content and IL1-ß by microscopy, immunohistochemistry, and biochemical analysis. Breast and colon cancer cell lines were cultured with and without CCs to select for expression of VEGF, CD44, and Ub-H2B. Western blot and immunofluorescence were performed on cells to assess the effect of CCs on signaling pathways. Results: Cancers displayed higher CC content (+2.29 ± 0.74 vs +1.46 ± 0.84, p < 0.0001), distribution (5.06 ± 3.13 vs 2.86 ± 2.18, p < 0.001) and free cholesterol (3.63 ± 4.02 vs 1.52 ± 0.56 µg/mg, p < 0.01) than cancer free marginal tissues and similarly for atherosclerotic plaques and margins (+2.31 ± 0.51 vs +1.44 ± 0.79, p < 0.02; 14.0 ± 5.74 vs 8.14 ± 5.52, p < 0.03; 0.19 ± 0.14 vs 0.09 ± 0.04 µg/mg, p < 0.02) respectively. Cancers displayed significantly increased expression of IL1-ß compared to marginal tissues. CCs treated cancer cells had increased expression of VEGF, CD44, and Ub-H2B compared to control. By microscopy, CCs were found perforating cancer tumors similar to plaque rupture. Conclusions: These findings suggest that CCs can induce trauma and activate cytokines that enhance cancer growth as in atherosclerosis.
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BACKGROUND: The codon 72 polymorphism in p53 has been implicated in colorectal cancer (CRC) risk, prognosis and CRC health disparities. We examined the functional consequence of this polymorphism in CRC. EXPERIMENTAL DESIGN: Plasmids (pCMV6) that express different phenotypes of p53 [p53 wild type (wt) at codon 72 (R72wt), R72wt with mutation at codon 273 cysteine (R72273Cys), p53 mutation at codon 72 (P72wt) and P72wt with mutation at codon 273 (P72273Cys)] were constructed. The CRC cell line Caco2, which does not express p53 for in vitro studies, was used as host. CRC xenografts were established in severe combined immunodeficient (SCID) mice using established cell lines. CRC surgical specimens, corresponding normal colon, and tumor xenografts were sequenced for codon 72 polymorphism of p53. Proteins signaling mechanisms were evaluated to assess the functional consequence of P72 phenotype of p53. RESULTS: This study demonstrated a significantly increased survival of cells expressing P72wt, mutant phenotype, versus R72wt phenotype. WB analyses revealed that P72wt induced activation of p38 and RAF/MEK/ extracellular signal-regulated kinase (ERK) MAP kinases. Activation of CREB was found to be higher in tumors that exhibit P72 phenotype. Metastatic lesions of CRC expressed more phospho-CREB than non-metastatic lesions. The expression of P72wt promoted CRC metastasis. CONCLUSIONS: P72 contributes to the aggressiveness of CRC. Because P72 is over-expressed in CRC, specifically in African-American patients, this suggests a role for P72 in cancer health disparities. This work was supported by NIH/NCI Workforce Diversity Grant R21-CA171251 & U54CA118948.
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Collagen vascular diseases present a treatment dilemma for patients with breast cancer. Due to the potential for severe, acute, and late complications of radiation therapy, a history of collagen vascular disease (CVD) is a relative contraindication to breast-conserving treatment. We present a case of early stage breast cancer in a patient with severe scleroderma treated with breast-conserving surgery without radiation and a brief review of the published literature regarding the therapeutic approach to the patient with CVD and breast cancer.
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The Nef-M1 peptide competes effectively with the natural ligand of CXC chemokine receptor 4 (CXCR4), stromal cell-derived factor 1-alpha, to induce apoptosis and inhibit growth in colon cancer (CRC) and breast cancer (BC). Its role in tumor angiogenesis, and epithelial-to-mesenchymal transition (EMT) regulation, key steps involved in tumor growth and metastasis, are unknown. We evaluated the angioinhibitory effect of Nef-M1 peptide and examined its role in the inhibition of EMT in these cancers. Colon (HT29) and breast (MDA-MB231) cancer cells expressing CXCR4 were studied in vitro and in xenograft tumors propagated in severe combined immunodeficient mice. The mice were treated intraperitoneally with Nef-M1 or scrambled amino acid sequence of Nef-M1 (sNef-M1) peptide, a negative control, starting at the time of tumor implantation. Sections from tumors were evaluated for tumor angiogenesis, as measured by microvessel density (MVD) based on immunostaining of endothelial markers. In vitro tumor angiogenesis was assessed by treating human umbilical vein endothelial cells with conditioned media from the tumor cell lines. A BC cell line (MDA-MB 468) which does not express CXCR4 was used to study the actions of Nef-M1 peptide. Western blot and immunofluorescence analyses assessed the effect of Nef-M1 on tumor angiogenesis and EMT in both tumors and cancer cells. Metastatic lesions of CRC and BC expressed more CXCR4 than primary lesions. It was also found that tumors from mice treated with sNef-M1 had well established vascularity, while Nef-M1 treated tumors had very poor vascularization. Indeed, the mean MVD was lower in tumors from Nef-M1 treated mice than in sNef-M1 treated tumors. Nef-M1 treated tumor has poor morphology and loss of endothelial integrity. Although conditioned medium from CRC or BC cells supported HUVEC tube formation, the conditioned medium from Nef-M1 treated CRC or BC cells did not support tube formation. Western blot analyses revealed that Nef-M1 effectively suppressed the expression of VEGF-A in CRC and BC cells and tumors. This suggests that Nef-M1 treated CRC and BC cells are more consistent with E-cadherin signature, and thus appears more epithelial in nature. Our data indicate that Nef-M1 peptide inhibits tumor angiogenesis and the oncogenic EMT process. Targeting the chemokine receptor, CXCR4, mediated pathways using Nef-M1 may prove to be a novel therapeutic approach for CRC and BC.
Subject(s)
Breast Neoplasms/pathology , Colonic Neoplasms/pathology , Epithelial-Mesenchymal Transition , Gene Products, nef/chemistry , Neovascularization, Pathologic , Peptide Fragments/chemistry , Peptides/chemistry , Receptors, CXCR4/antagonists & inhibitors , Receptors, CXCR4/metabolism , Animals , Apoptosis , Cell Line, Tumor , Cell Proliferation , Culture Media, Conditioned/metabolism , Disease Progression , Enzyme-Linked Immunosorbent Assay , Human Umbilical Vein Endothelial Cells , Humans , Mice , Mice, SCID , Microcirculation , Neoplasm Metastasis , Neoplasm Transplantation , Platelet Endothelial Cell Adhesion Molecule-1/metabolism , Vascular Endothelial Growth Factor A/metabolismABSTRACT
BACKGROUND: Phyllodes is a rare tumor accounting for less than 1% of all breast neoplasms. Studies defining clinical predictors of malignant phyllodes (MP) are rare and inconsistent. Furthermore, MP occurrence in African American (AA) women has never been analyzed. This study will delineate clinical and pathologic features in AA patients that may reasonably predict the probability of malignancy. METHODS: A retrospective study of clinical records was carried out for 50 AA patients diagnosed with phyllodes tumors (PT) and treated between 1982 and 2012. Patients' charts were analyzed regarding demographics, pathology findings, and treatment. RESULTS: The diagnosis of benign disease was made in 40 (78%), borderline in 3 (6%), and malignancy in 7 (14%) patients; however, 1 patient (2%) had mixed phyllodes with ductal carcinoma in situ. The mean age was significantly different for patients with benign disease (33 years) compared with those with malignancy (54 years; P < .001). The average tumor size was twice as large (11.8 vs 4.1 cm; P = .029) and mitoses were higher with 50% of MPs having greater than 5 per 10 high power fields. Although rare, nodal metastasis, ulceration, and multicentric disease occurred only in MP. CONCLUSIONS: Among AA patients with phyllodes tumors, those with malignant tumors were older and had larger tumors and higher mitotic indices than those with benign disease. AA patients also displayed some of the more rare features of advanced disease and presented with malignancy near the highest reported frequency.
Subject(s)
Black or African American , Breast Neoplasms/diagnosis , Breast Neoplasms/epidemiology , Phyllodes Tumor/diagnosis , Phyllodes Tumor/epidemiology , Adult , Aged , Female , Humans , Middle Aged , Retrospective StudiesABSTRACT
BACKGROUND: Innovative technologies for drug discovery and development, cancer models, stem cell research, tissue engineering, and drug testing in various cell-based platforms require an application similar to the in vivo system. MATERIALS AND METHODS: We developed for the first time nanomagnetically levitated three-dimensional (3-D) cultures of breast cancer (BC) and colorectal cancer (CRC) cells using carbon-encapsulated cobalt magnetic nanoparticles. BC and CRC xenografts grown in severe combined immunodeficient (SCID) mice were evaluated for N-cadherin and epidermal growth factor receptor expressions. These phenotypes were compared with two-dimensional and 3-D cultures grown in a gel matrix. RESULTS: The BC and CRC cells grown by magnetic levitation formed microtissues. The levitated cultures had high viability and were maintained in culture for long periods of time. It has been observed that N-cadherin and epidermal growth factor receptor activities were highly expressed in the levitated 3-D tumor spheres and xenografts of CRC and BC cells. CONCLUSIONS: Nanomagnetically levitated 3-D cultures tend to form stable microtissues of BC and CRC and maybe more feasible for a range of applications in drug discovery or regenerative medicine.
Subject(s)
Cell Culture Techniques , Magnetic Fields , Metal Nanoparticles , Neoplasms, Experimental , Animals , Cadherins/metabolism , ErbB Receptors/metabolism , Female , HT29 Cells , Heterografts/metabolism , Humans , MCF-7 Cells , Mice, SCID , Neoplasms, Experimental/metabolismSubject(s)
Breast Neoplasms/diagnosis , Carcinoma/diagnosis , Arm , Breast Neoplasms/complications , Breast Neoplasms/pathology , Carcinoma/complications , Carcinoma/pathology , Female , Humans , Middle Aged , Neoplasm Invasiveness , Pleural Effusion, Malignant/etiology , Soft Tissue Neoplasms/complications , Soft Tissue Neoplasms/pathologyABSTRACT
Pseudoangiomatous stromal hyperplasia (PASH) is a benign mesenchymal proliferative lesion of the breast. In 2005, only 109 cases had been reported since its initial description in 1986 by Vuitch et al. Our 24 cases represent one of the largest series to be reported from a single institution. We retrospectively reviewed data from 2004 to 2010 of patients diagnosed with PASH by surgical excision or image-guided biopsy. All pathological specimens were reviewed by a single pathologist. The samples were stained for estrogen and progesterone receptors (ER and PR), CD34, and the lymphatic marker D2-40. All but one of 24 (96%) patients presented with breast masses either on imaging or clinically. Fourteen of the 24 patients (58%) were diagnosed on surgical excision, 10 (42%) diagnosed with core needle biopsy, and five (20%) were diagnosed using both techniques. The tumors ranged in size from 0.3 cm to 7.0 cm. All women except two were premenopausal or perimenopausal at diagnosis. Nineteen samples were available for hormonal receptor staining and of these 18 of 19 (95%) were ER or PR positive. PASH was diagnosed in two men, a transgender male on hormones and the other with gynecomastia. The patients' ages ranged from 18 to 86 years old. In addition to PASH other benign histopathological findings include stromal fibrosis and atypical ductal or lobular hyperplasia. Imaging revealed no distinguishing feature for PASH with benign histology. One patient had synchronous ductal carcinoma in-situ (DCIS). Patients were treated with local excision or observation. This study suggests that PASH is primarily a diagnosis of premenopausal and perimenopausal women. Our series supports a hormonal basis for its development due to the positive staining for hormonal receptors. Management is conservative surgery for larger masses with careful observation being an option in patients not at high risk for breast cancer.
Subject(s)
Angiomatosis/pathology , Breast Diseases/pathology , Breast/pathology , Hyperplasia/pathology , Adolescent , Adult , Aged , Aged, 80 and over , Angiomatosis/metabolism , Angiomatosis/surgery , Breast/surgery , Breast Diseases/metabolism , Breast Diseases/surgery , Breast Neoplasms/pathology , Carcinoma, Intraductal, Noninfiltrating/pathology , Female , Follow-Up Studies , Humans , Hyperplasia/metabolism , Hyperplasia/surgery , Male , Mammography , Middle Aged , Perimenopause , Receptors, Estrogen/metabolism , Receptors, Progesterone , Retrospective Studies , Young AdultABSTRACT
Although the prognostic value of p53 abnormalities in Stage III microsatellite stable (MSS) colorectal cancers (CRCs) is known, the gene expression profiles specific to the p53 status in the MSS background are not known. Therefore, the current investigation has focused on identification and validation of the gene expression profiles associated with p53 mutant phenotypes in MSS Stage III CRCs. Genomic DNA extracted from 135 formalin-fixed paraffin-embedded tissues, was analyzed for microsatellite instability (MSI) and p53 mutations. Further, mRNA samples extracted from five p53-mutant and five p53-wild-type MSS-CRC snap-frozen tissues were profiled for differential gene expression by Affymetrix Human Genome U133 Plus 2.0 arrays. Differentially expressed genes were further validated by the high-throughput quantitative nuclease protection assay (qNPA), and confirmed by quantitative real-time polymerase chain reaction (qRT-PCR) and by immunohistochemistry (IHC). Survival rates were estimated by Kaplan-Meier and Cox regression analyses. A higher incidence of p53 mutations was found in MSS (58%) than in MSI (30%) phenotypes. Both univariate (log-rank, Pâ=â0.025) and multivariate (hazard ratio, 2.52; 95% confidence interval, 1.25-5.08) analyses have demonstrated that patients with MSS-p53 mutant phenotypes had poor CRC-specific survival when compared to MSS-p53 wild-type phenotypes. Gene expression analyses identified 84 differentially expressed genes. Of 49 down-regulated genes, LPAR6, PDLIM3, and PLAT, and, of 35 up-regulated genes, TRIM29, FUT3, IQGAP3, and SLC6A8 were confirmed by qNPA, qRT-PCR, and IHC platforms. p53 mutations are associated with poor survival of patients with Stage III MSS CRCs and p53-mutant and wild-type phenotypes have distinct gene expression profiles that might be helpful in identifying aggressive subsets.
Subject(s)
Adenocarcinoma/genetics , Colorectal Neoplasms/genetics , Microsatellite Repeats/genetics , Tumor Suppressor Protein p53/genetics , Adult , Aged , Aged, 80 and over , DNA-Binding Proteins/genetics , Female , Fucosyltransferases/genetics , Gene Expression Regulation, Neoplastic/genetics , Humans , LIM Domain Proteins/genetics , Male , Microfilament Proteins/genetics , Microsatellite Instability , Middle Aged , Mutation , Neoplasm Staging , Nerve Tissue Proteins/genetics , Oligonucleotide Array Sequence Analysis , Plasma Membrane Neurotransmitter Transport Proteins/genetics , Prognosis , Real-Time Polymerase Chain Reaction , Receptors, Lysophosphatidic Acid/genetics , Tissue Plasminogen Activator/genetics , Transcription Factors/geneticsABSTRACT
BACKGROUND: African American (AA) women experience higher breast cancer mortality than white (W) women. These differences persist even among estrogen receptor (ER)-positive breast cancers. The 21-gene recurrence score (RS) predicts recurrence in patients with ER-positive/lymph node-negative breast cancer according to RS score-low risk (RS, 0-18), intermediate risk (RS, 19-31), and high risk (RS, >31). The high-risk group is most likely to benefit from chemotherapy, to achieve minimal benefit from hormonal therapy, and to exhibit lower ER levels (intrinsically luminal B cancers). In the current study, the authors investigated racial differences in RS testing, scores, treatment, and outcome. METHODS: Tumor registry data from 3 Atlanta hospitals identified women who were diagnosed with breast cancers during 2005 through 2009. Medical record abstraction provided information on RS and other tumor/treatment factors. Statistical analyses used chi-square/exact tests and logistic regression. RESULTS: Of 2186 patients, including 1192 AA women and 992 W women, 853 women had stage I or II, ER-positive/lymph node-negative disease and, thus, were eligible for RS testing (AA = 372 [31.2%]; W = 481 [48.5%]; P < .0001); and 272 women (31.8%) received testing (AA = 76 [20.4%]; W = 196 [40.7%]; P < .0001). Tumors were distributed into the following groups according to risk: low risk (n = 133), medium risk (n = 113), and high risk (n = 26). The mean RS did not differ by race, but risk groups did (low-risk group: 46.1% vs 50% for AA women and W women, respectively; high-risk group: 15.8% vs 7.1%, respectively; P = .043). In multivariate analyses, AA race (odds ratio, 3.6) was associated independently with high risk scores. CONCLUSIONS: AA women were half as likely as W women to receive 21-gene RS testing but were 2-fold more likely to be categorized as high risk. The current data suggested that testing guidelines are not applied equivalently, testing bias may attenuate racial differences in RS, and disparate outcomes may be explained in part by differences in RS, although compliance and pharmacogenomics also may play a role.
Subject(s)
Biomarkers, Tumor/genetics , Black or African American/genetics , Breast Neoplasms/ethnology , Gene Expression Profiling , Neoplasm Recurrence, Local/diagnosis , Neoplasm Recurrence, Local/ethnology , Reagent Kits, Diagnostic , White People/genetics , Adult , Aged , Breast Neoplasms/genetics , Breast Neoplasms/therapy , Carcinoma, Ductal, Breast/ethnology , Carcinoma, Ductal, Breast/genetics , Carcinoma, Ductal, Breast/therapy , Carcinoma, Lobular/ethnology , Carcinoma, Lobular/genetics , Carcinoma, Lobular/therapy , Female , Humans , Middle Aged , Neoplasm Grading , Neoplasm Recurrence, Local/therapy , Neoplasm Staging , Receptors, Estrogen/metabolism , Receptors, Progesterone/metabolism , Registries , Treatment OutcomeABSTRACT
BACKGROUND: Although evaluation of at least 12 lymph nodes (LNs) is recommended as the minimum number of nodes required for accurate staging of colon cancer patients, there is disagreement on what constitutes an adequate identification of such LNs. METHODS: To evaluate the minimum number of LNs for adequate staging of Stage II and III colon cancer, 490 patients were categorized into groups based on 1-6, 7-11, 12-19, and ≥ 20 LNs collected. RESULTS: For patients with Stage II or III disease, examination of 12 LNs was not significantly associated with recurrence or mortality. For Stage II (HR = 0.33; 95% CI, 0.12-0.91), but not for Stage III patients (HR = 1.59; 95% CI, 0.54-4.64), examination of ≥20 LNs was associated with a reduced risk of recurrence within 2 years. However, examination of ≥20 LNs had a 55% (Stage II, HR = 0.45; 95% CI, 0.23-0.87) and a 31% (Stage III, HR = 0.69; 95% CI, 0.38-1.26) decreased risk of mortality, respectively. For each six additional LNs examined from Stage III patients, there was a 19% increased probability of finding a positive LN (parameter estimate = 0.18510, p < 0.0001). For Stage II and III colon cancers, there was improved survival and a decreased risk of recurrence with an increased number of LNs examined, regardless of the cutoff-points. Examination of ≥7 or ≥12 LNs had similar outcomes, but there were significant outcome benefits at the ≥20 cutoff-point only for Stage II patients. For Stage III patients, examination of 6 additional LNs detected one additional positive LN. CONCLUSIONS: Thus, the 12 LN cut-off point cannot be supported as requisite in determining adequate staging of colon cancer based on current data. However, a minimum of 6 LNs should be examined for adequate staging of Stage II and III colon cancer patients.
Subject(s)
Colonic Neoplasms/pathology , Lymph Nodes/pathology , Aged , Aged, 80 and over , Female , Humans , Lymphatic Metastasis , Male , Middle Aged , Neoplasm Recurrence, Local/pathology , Neoplasm Staging , Treatment OutcomeABSTRACT
miRNAs serve as micromanagers, negatively regulating gene expression. Since altered miRNA expression is implicated in the pathobiology of various cancers, including colorectal cancers (CRCs), these molecules serve as potential therapeutic targets. Manipulation of miRNAs may offer an alternative therapy for chemo- and radio-resistant CRCs. For CRC patients, miRNA expression patterns can be used for diagnosis, and to predict prognosis and efficacy of therapy. This article describes the methodological approaches for miRNA measurement, their function in the pathobiology of CRCs and their potential clinical utility.
Subject(s)
Biomarkers, Tumor/metabolism , Colorectal Neoplasms/diagnosis , Colorectal Neoplasms/therapy , MicroRNAs/metabolism , Biomarkers, Tumor/genetics , Chromosomal Instability , Colorectal Neoplasms/genetics , Early Detection of Cancer , Epigenesis, Genetic , Humans , MicroRNAs/analysis , Microsatellite Instability , PrognosisABSTRACT
A variety of genetic and molecular alterations underlie the development and progression of colorectal neoplasia (CRN). Most of these cancers arise sporadically due to multiple somatic mutations and genetic instability. Genetic instability includes chromosomal instability (CIN) and microsatellite instability (MSI), which is observed in most hereditary non-polyposis colon cancers (HNPCCs) and accounts for a small proportion of sporadic CRN. Although many biomarkers have been used in the diagnosis and prediction of the clinical outcomes of CRNs, no single marker has established value. New markers and genes associated with the development and progression of CRNs are being discovered at an accelerated rate. CRN is a heterogeneous disease, especially with respect to the anatomic location of the tumor, race/ethnicity differences, and genetic and dietary interactions that influence its development and progression and act as confounders. Hence, efforts related to biomarker discovery should focus on identification of individual differences based on tumor stage, tumor anatomic location, and race/ethnicity; on the discovery of molecules (genes, mRNA transcripts, and proteins) relevant to these differences; and on development of therapeutic approaches to target these molecules in developing personalized medicine. Such strategies have the potential of reducing the personal and socio-economic burden of CRNs. Here, we systematically review molecular and other pathologic features as they relate to the development, early detection, diagnosis, prognosis, progression, and prevention of CRNs, especially colorectal cancers (CRCs).
Subject(s)
Colorectal Neoplasms/genetics , Colorectal Neoplasms/metabolism , Animals , Biomarkers, Tumor/genetics , Biomarkers, Tumor/metabolism , Carcinoma in Situ/genetics , Carcinoma in Situ/metabolism , Colorectal Neoplasms/diagnosis , Colorectal Neoplasms/mortality , Disease Progression , Gene Expression Regulation, Neoplastic , Humans , Prognosis , Risk FactorsABSTRACT
OBJECTIVE: Since the anti-tumor activity of 5-fluorouracil (5-FU) is due to induction of apoptosis, we assessed the value of expression of key apoptotic molecules (Bax, Bcl-2 and p53) in predicting the efficacy of 5-FU therapy for colorectal adenocarcinomas (CRCs). METHODS: Archival tissues of CRCs from 56 patients who received a complete regimen of 5-FU-based chemotherapy after surgery, and 56 patients matched for age, gender, ethnicity, tumor stage, tumor location, and tumor differentiation who had undergone only surgery (without any pre- or post-surgery therapy), were evaluated for immunophenotypic expression of Bax, Bcl-2, and p53. Also, these CRCs were evaluated for Bax mutations. The predictive capacity or prognostic value of these markers was assessed by estimating overall survival. RESULTS: The majority of low Bax expressing CRCs have exhibited mutations at the G (8) tract. There was no significant difference in overall survival rates between the categories of surgery alone and 5-FU-treated patients. However, a better survival was observed for patients who received chemotherapy when their CRCs had low Bax/Bcl2 ratio (HR, 1.55; 95% CI: 1.46-31.00). Patients who received surgery alone and whose CRCs lacked Bax expression had 5.33 times higher mortality than those with high Bax expression (95% CI: 1.78-15.94), when controlled for tumor stage and other confounders. Bcl-2 and nuclear p53 accumulation had no predictive value in either patient group. CONCLUSION: These findings are the first to demonstrate that high Bax expression is a good prognosticator for patients who underwent surgery alone, and that patient with low Bax/Bcl-2 expression ratio benefit from 5-FU-based adjuvant therapies.
ABSTRACT
PURPOSE: Although, for patients with cancer, comorbidity can affect the timing of cancer detection, treatment, and prognosis, there is little information relating to the question of whether the choice of comorbidity index affects the results of studies. Therefore, to compare the association of comorbidity with mortality after surgery for colon cancer, this study evaluated the Adult Comorbidity Evaluation-27 (ACE-27), the National Institute on Aging (NIA) and National Cancer Institute (NCI) Comorbidity Index, and the Charlson Comorbidity Index (CCI). PATIENTS AND METHODS: The study population consisted of colon cancer patients (N = 496) who underwent surgery at the University of Alabama at Birmingham Hospital from 1981 to 2002. Hazard ratios (HRs) with 95% CIs were obtained using the method of Cox proportional hazards for the three comorbidity indices in predicting overall and colon cancer-specific mortality. The point estimates obtained for comorbidity and other risk factors across the three models were compared. RESULTS: For each index, the highest comorbidity burden was significantly associated with poorer overall survival (ACE-27: HR = 1.63; 95% CI, 1.24 to 2.15; NIA/NCI: HR = 1.83; 95% CI, 1.29 to 2.61; CCI: HR = 1.46; 95% CI, 1.14 to 1.88) as well as colon cancer-specific survival. For the other risk factors, there was little variation in the point estimates across the three models. CONCLUSION: The results obtained from these three indices were strikingly similar. For patients with severe comorbidity, all three indices were statistically significant in predicting shorter survival after surgery for colon cancer.
Subject(s)
Colonic Neoplasms/mortality , Colonic Neoplasms/surgery , Aged , Alabama/epidemiology , Cause of Death , Colonic Neoplasms/epidemiology , Comorbidity , Female , Humans , Male , Middle Aged , Outcome Assessment, Health Care/methods , Outcome Assessment, Health Care/statistics & numerical data , Prognosis , Proportional Hazards Models , Risk Factors , Survival Analysis , Survival RateABSTRACT
CXC chemokine receptor 4 (CXCR4) has been implicated in prostate cancer metastasis and this receptor also acts as a coreceptor for HIV-1 120-kDa glycoprotein variant IIIB (gp120-IIIB). The interaction between CXCR4 and gp120-IIIB has been shown to mediate apoptosis of both immune and endothelial cells. In this study, we have examined the effects of gp120-IIIB on hormone-refractory prostate cancer cells (PC3 and DU145) in vitro and tumor growth in vivo. Normal prostatic epithelial (PrEC) and prostate cancer cell lines were treated with gp120-IIIB with or without anti-CXCR4 antibody. Caspase expression was evaluated by real-time PCR and active caspase assays. Apoptosis was determined by flow cytometry. gp120-IIIB treatment correlated with active caspase-3 and -9 expression and apoptosis of prostate cancer cells but not PrEC cells. This effect was significantly inhibited after CXCR4 blockade. PC3 and DU145 tumor-bearing mice received intraperitoneal injections of gp120-IIIB and controls received bovine serum albumin in PBS. PC3 and DU145 tumor sizes were measured over time and excised tumors were evaluated for CD44, CD34, lymphatic endothelial cell marker LYVE-1, active caspase-3, and active caspase-9 expression by immunohistochemistry. The tumor size in mice receiving gp120-IIIB was significantly smaller than compared with tumors in control mice. This regression was associated with significant decreases in CD44, CD34, and LYVE-1 and increases in active caspase-3 and -9 expression. These results suggest that gp120-IIIB induced apoptosis in prostate cancer cells and reduced tumor-associated lymphoendothelial cells.
Subject(s)
Apoptosis , Caspase 3/metabolism , Caspase 9/metabolism , HIV Envelope Protein gp120/metabolism , Prostatic Neoplasms/metabolism , Prostatic Neoplasms/pathology , Receptors, CXCR4/metabolism , Animals , Antigens, CD34/metabolism , Cell Line, Tumor , Glycoproteins/metabolism , HIV Envelope Protein gp120/genetics , Hyaluronan Receptors/metabolism , Male , Membrane Transport Proteins , Mice , Mice, SCID , Prostatic Neoplasms/genetics , Receptors, CXCR4/genetics , Xenograft Model Antitumor AssaysABSTRACT
BACKGROUND: Compared with white women, African-American (AA) women who are diagnosed with breast cancer experience an excess in mortality. To improve outcomes, the authors implemented community education and outreach initiatives in their cancer center, at affiliated primary care sites, and in the surrounding communities. They then assessed the effectiveness of these outreach initiatives and internal patient navigation on stage of diagnosis. METHODS: This cross-sectional study was an analysis of all women with breast cancer who were diagnosed and/or treated in the years from 2001 through 2004. The outreach initiatives were implemented in 2001; 125 trained Community Health Advocates (CHAs) provided educational programs to the community, and Patient Navigators communicated directly with patients to encourage screening, diagnostic procedures, and treatment. RESULTS: In total, 487 patients were diagnosed/treated from 2001 through 2004. Since 2001, there were 1148 community interventions by CHAs with an estimated program attendance of >10,000 participants. In the interval from 2001 through 2004, the proportion of stage 0 (in situ) breast cancers increased from 12.4% (n = 14) to 25.8% (n = 33; P < .005), and there was a decline in stage IV invasive breast cancers from 16.8% (n = 19) to 9.4% (n = 12; P < .05). CONCLUSIONS: The outreach initiatives and internal patient navigation appear to have improved stage at diagnosis. To determine whether specific patients presented earlier as a result of specific community outreach initiatives, prospective work is underway to measure the effects of these interventions on potential stage migration. Similarly, prospective data are being collected to determine whether Patient Navigators influence treatment and appointment adherence as well as the underlying reasons for barriers to specific interventions in this underserved minority population.
Subject(s)
Black or African American/education , Breast Neoplasms/diagnosis , Health Education/methods , Mass Screening , Black or African American/statistics & numerical data , Breast Neoplasms/pathology , Community Networks , Cross-Sectional Studies , Female , Follow-Up Studies , Health Services Accessibility , Hospitals, Urban , Humans , Medical Oncology , Neoplasm Staging , Socioeconomic Factors , White People/statistics & numerical dataABSTRACT
BACKGROUND: A disparate proportion of breast cancer deaths occur among young women, those of African-American (AA) ancestry, and particularly young AA women. Estrogen receptors (ER), progesterone receptors (PR), and human epidermal growth factor receptor-2 (HER-2) are key clinically informative biomarkers. The triple-negative (ER-/PR-/HER-2-) tumor subgroup is intrinsically resistant to treatment and portends a poor prognosis. Age, race, and socioeconomic status have been associated with triple-negative tumors (TNT). In the current study, the authors investigated breast cancer subgroups among patients in an urban cancer center serving a multiracial, low socioeconomic population. METHODS: This case series analyzed female invasive breast cancers diagnosed and/or treated between 2003 and 2004 in the AVON Comprehensive Breast Center at Grady Hospital in Atlanta, Georgia. Data were obtained from the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) program, and augmented by the hospital registry and pathology reports. Statistical analyses utilized frequency distributions and logistic regression. RESULTS: Of 190 breast cancers; 167 (88%) were diagnosed among AA and 23 (12%) were diagnosed among non-AA women. The median age at diagnosis in the 2 groups was 58 years and 57 years, respectively. TNT prevalence was found to differ by race (29.3% among AA women and 13.0% among non-AA women; P = .010). Differences persisted after adjustment for age and stage (odds ratio [OR] of 3.1; 95%confidence interval [95% CI], 0.8-11.6). The majority of recurrences (40.0%) occurred among women with TNT, who were also most likely to experience a fatal event (OR of 3.7; 95%CI, 1.1-13.0). CONCLUSIONS: Despite a similarity in their age at diagnosis, AA women in our urban cancer center presented with a higher prevalence of TNT and TNT was found to predict the poorest outcomes. Institutional interactive breast conferences and intervention/navigation programs could help to dispel breast cancer disparities and improve outcomes.
Subject(s)
Breast Neoplasms/epidemiology , Breast Neoplasms/metabolism , Receptor, ErbB-2/metabolism , Receptors, Estrogen/metabolism , Receptors, Progesterone/metabolism , Adult , Black or African American/statistics & numerical data , Aged , Aged, 80 and over , Breast Neoplasms/pathology , Female , Hospitals, Urban , Humans , Medical Oncology , Middle Aged , Neoplasm Invasiveness , Prevalence , Social ClassABSTRACT
Catheter-based techniques have become commonplace in the diagnosis and treatment of cardiovascular disease. Despite the significant improvements in materials and techniques, catheter separation or fracture may occur and result in catheter embolization or intravascular retention. We present such an occurrence during antegrade access to the common femoral artery. Although the sheared catheter was visualized fluoroscopically, attempts at percutaneous recovery were futile. Our findings at exploration confirmed total intravascular retention and impaction of the catheter. Practitioners should recognize this problem and avoid the dangers associated with percutaneous recovery.