[show abstract][hide abstract] ABSTRACT: Cancer stem cells (CSC) play critical roles in cancer initiation, progression, and therapeutic refractoriness. Although many studies have focused on the genes and pathways involved in stemness, characterization of the factors in the tumor microenvironment that regulate CSCs is lacking. In this study, we investigated the effects of stromal fibroblasts on breast cancer stem cells. We found that compared with normal fibroblasts, primary cancer-associated fibroblasts (CAF) and fibroblasts activated by cocultured breast cancer cells produce higher levels of chemokine (C-C motif) ligand 2 (CCL2), which stimulates the stem cell-specific, sphere-forming phenotype in breast cancer cells and CSC self-renewal. Increased CCL2 expression in activated fibroblasts required STAT3 activation by diverse breast cancer-secreted cytokines, and in turn, induced NOTCH1 expression and the CSC features in breast cancer cells, constituting a cancer-stroma-cancer signaling circuit. In a xenograft model of paired fibroblasts and breast cancer tumor cells, loss of CCL2 significantly inhibited tumorigenesis and NOTCH1 expression. In addition, upregulation of both NOTCH1 and CCL2 was associated with poor differentiation in primary breast cancers, further supporting the observation that NOTCH1 is regulated by CCL2. Our findings therefore suggest that CCL2 represents a potential therapeutic target that can block the cancer-host communication that prompts CSC-mediated disease progression.
Cancer Research 04/2012; 72(11):2768-79. · 8.65 Impact Factor
[show abstract][hide abstract] ABSTRACT: Patients with high-risk locally advanced/inflammatory and oligometastatic (≤3 sites) breast cancer frequently relapse or experience early progression. High-dose chemotherapy combined with peripheral stem cell rescue may prolong progression-free survival/relapse-free survival (PFS/RFS) and overall survival (OS). In this study, patients initiated high-dose chemotherapy with STAMP-V (carboplatin, thiotepa, and cyclophosphamide), ACT (doxorubicin, paclitaxel, and cyclophosphamide), or tandem melphalan and STAMP-V. Eighty-six patients were diagnosed with locally advanced/inflammatory (17 inflammatory) breast cancer, and 12 were diagnosed with oligometastatic breast cancer. Median follow-up was 84 months (range, 6-136 months) for patients with locally advanced cancer and 40 months (range, 24-62 months) for those with metastatic cancer. In the patients with locally advanced cancer, 5-year RFS and OS were 53% (95% CI, 41%-63%) and 71% (95% CI, 60%-80%), respectively, hormone receptors were positive in 74%, and HER2 overexpression was seen in 23%. In multivariate analysis, hormone receptor-positive disease and lower stage were associated with better 5-year RFS (60% for ER [estrogen receptor]/PR [progesterone receptor]-positive versus 30% for ER/PR-negative; P < .01) and OS (83% for ER/PR-positive versus 38% for ER/PR-negative; P < .001). In the patients with metastatic cancer, 3-year PFS and OS were 49% (95% CI, 19%-73%) and 73% (95% CI, 38%-91%), respectively. The favorable long-term RFS/PFS and OS for high-dose chemotherapy with peripheral stem cell rescue in this selected patient population reflect the relative safety of the procedure and warrant validation in defined subgroups through prospective, randomized, multi-institutional trials.
Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 02/2012; 18(8):1273-80. · 3.15 Impact Factor
[show abstract][hide abstract] ABSTRACT: Glucose-regulated protein 78 (GRP78)/BiP is a multifunctional protein which plays a major role in endoplasmic reticulum (ER) protein processing, protein quality control, maintaining ER homeostasis, and controlling cell signaling and viability. Previously, using a transgene-induced mammary tumor model, we showed that Grp78 heterozygosity impeded cancer growth through suppression of tumor cell proliferation and promotion of apoptosis and the Grp78(+/-) mice exhibited dramatic reduction (70%) in the microvessel density (MVD) of the endogenous mammary tumors, while having no effect on the MVD of normal organs. This observation suggests that GRP78 may critically regulate the function of the host vasculature within the tumor microenvironment. In this article, we interrogated the role of GRP78 in the tumor microenvironment. In mouse tumor models in which wild-type (WT), syngeneic mammary tumor cells were injected into the host, we showed that Grp78(+/-) mice suppressed tumor growth and angiogenesis during the early phase but not during the late phase of tumor growth. Growth of metastatic lesions of WT, syngeneic melanoma cells in the Grp78(+/-) mice was potently suppressed. We created conditional heterozygous knockout of GRP78 in the host endothelial cells and showed severe reduction of tumor angiogenesis and metastatic growth, with minimal effect on normal tissue MVD. Furthermore, knockdown of GRP78 expression in immortalized human endothelial cells showed that GRP78 is a critical mediator of angiogenesis by regulating cell proliferation, survival, and migration. Our findings suggest that concomitant use of current chemotherapeutic agents and novel therapies against GRP78 may offer a powerful dual approach to arrest cancer initiation, progression, and metastasis.
Cancer Research 04/2011; 71(8):2848-57. · 8.65 Impact Factor
[show abstract][hide abstract] ABSTRACT: Androgens stimulate the expression of vascular endothelial growth factor (VEGF) through activation of hypoxia inducible factor (HIF). These genes play a major role in cancer angiogenesis. This study assesses the relationship among expression levels for the androgen receptor (AR), HIF1a, VEGF-A, and VEGF-C genes in human prostate cancer tissue and their impact on prostate cancer outcomes. It also examines the impact of pre-operative androgen deprivation therapy (ADT) on the expression of these genes.
Radical prostatectomy specimens were obtained from 138 patients with D1 prostate cancer from the University of Southern California prostatectomy database; 30% received pre-operative and 23% received post-operative ADT. Gene expression levels were determined by quantitative real-time PCR. Specimens were stratified into three groups for each gene based on expression levels, and groups were compared for clinical outcomes (PSA and clinical recurrence, overall survival).
There was a significant correlation in expression levels amongst all genes. Patients treated with pre-operative ADT had significantly lower HIF1a expression, mean 2.64 (CI 2.34-2.94) than patients not treated, mean 3.25 (CI 2.97-3.53, P = 0.006), adjusting for age, PSA, Gleason score, and stage. Higher VEGF-A expression was significantly associated with better overall survival (HR 0.49, P = 0.015). The risk of developing clinical recurrence was significantly lower with higher VEGF-C expression (HR 0.4, P = 0.014).
Significant correlation was noted among AR, HIF1a, VEGF-A, and VEGF-C. This study shows that ADT is associated with lower HIF1a gene expression in human prostate cancer tissue and documents prognostic value for VEGF-A and VEGF-C expression levels.
The Prostate 11/2010; 70(15):1692-700. · 3.84 Impact Factor
[show abstract][hide abstract] ABSTRACT: There are few available treatments for hormone refractory prostate cancer. Through the inhibition of integrins, contortrostatin (CN) effects tumor cell growth directly as well as through the inhibition of angiogenesis. The effect of CN in combination with docetaxel on prostate cancer cell lines in vitro and in vivo is evaluated in the present study.
FACS analysis of integrin expression, assessment of CN and docetaxel exposure on viability of plated cancer cells, and scratch test migration analysis were performed on PC-3 prostate cancer cells. CN and docetaxel inhibition of both PC-3 and CWR-22 prostate cancer cell lines were evaluated in a mouse xenograft bone model. Angiogenic activity in tumors were assessed using IHC with antibodies to CD31.
Cell culture experiments indicate that the combination of docetaxel and CN inhibits growth in an additive fashion. FACS analysis of PC-3 cells shows expression of alpha5beta1 and alphavbeta5 integrins, but little expression of the alphavbeta3. CN showed complete inhibition of PC-3 migration in cultures grown on matrigel plates. In mice xenograft bone models, CN with docetaxel showed increased inhibition of both PC-3 and CWR-22 derived tumors. Analysis of treated xenograft tumors showed significantly decreased expression of CD31 indicating suppression of angiogenesis.
The Prostate 09/2010; 70(12):1359-70. · 3.84 Impact Factor
[show abstract][hide abstract] ABSTRACT: Children with relapsed neuroblastoma have poor survival. It is crucial to have a reliable method for evaluating functional response to new therapies. In this study, we compared two functional imaging modalities for neuroblastoma: metaiodobenzylguanidine (MIBG) scan for uptake by the norepinephrine transporter and [(18)F]fluorodeoxyglucose positron emission tomography (FDG-PET) uptake for glucose metabolic activity.
Patients enrolled onto a phase I study of sequential infusion of iodine-131 ((131)I) MIBG (NANT-2000-01) were eligible for inclusion if they had concomitant FDG-PET and MIBG scans. (131)I-MIBG therapy was administered on days 0 and 14. For each patient, we compared all lesions identified on concomitant FDG-PET and MIBG scans and gave scans a semiquantitative score.
The overall concordance of positive lesions on concomitant MIBG and FDG-PET scans was 39.6% when examining the 139 unique anatomic lesions. MIBG imaging was significantly more sensitive than FDG-PET overall and for the detection of bone lesions (P < .001). There was a trend for increased sensitivity of FDG-PET for detection of soft tissue lesions. Both modalities showed similar improvement in number of lesions identified from day 0 to day 56 scan and in semiquantitative scores that correlated with overall response. FDG-PET scans became completely negative more often than MIBG scans after treatment.
MIBG scan is significantly more sensitive for individual lesion detection in relapsed neuroblastoma than FDG-PET, though FDG-PET can sometimes play a complementary role, particularly in soft tissue lesions. Complete response by FDG-PET metabolic evaluation did not always correlate with complete response by MIBG uptake.
Journal of Clinical Oncology 10/2009; 27(32):5343-9. · 18.04 Impact Factor
[show abstract][hide abstract] ABSTRACT: Currently, tumor grade is the best predictor of outcome at first presentation of noninvasive papillary (Ta) bladder cancer. However, reliable predictors of Ta tumor recurrence and progression for individual patients, which could optimize treatment and follow-up schedules based on specific tumor biology, are yet to be identified.
To identify genes predictive for recurrence and progression in Ta bladder cancer at first presentation using a quantitative, pathway-specific approach.
Retrospective study of patients with Ta G2/3 bladder tumors at initial presentation with three distinct clinical outcomes: absence of recurrence (n=16), recurrence without progression (n=16), and progression to carcinoma in situ or invasive disease (n=16).
Expressions of 24 genes that feature in relevant pathways that are deregulated in bladder cancer were quantified by real-time polymerase chain reaction on tumor biopsies from the patients at initial presentation.
CCND3 (p=0.003) and HRAS (p=0.01) were predictive for recurrence by univariate analysis. In a multivariable model based on CCND3 expression, sensitivity and specificity for recurrence were 97% and 63%, respectively. HRAS (p<0.001), E2F1 (p=0.017), BIRC5/Survivin (p=0.038), and VEGFR2 (p=0.047) were predictive for progression by univariate analysis. Multivariable analysis based on HRAS, VEGFR2, and VEGF identified progression with 81% sensitivity and 94% specificity. Since this is a small retrospective study using medium-throughput profiling, larger confirmatory studies are needed.
Gene expression profiling across relevant cancer pathways appears to be a promising approach for Ta bladder tumor outcome prediction at initial diagnosis. These results could help differentiate between patients who need aggressive versus expectant management.
European urology 09/2009; 57(1):12-20. · 7.67 Impact Factor
[show abstract][hide abstract] ABSTRACT: We determined the glucose metabolism and computed tomographic (CT) density of the normal prostate gland in relation to age and prostate size on [F-18] fluorodeoxyglucose positron emission tomography (PET)-CT.
We determined the CT density (Hounsfield Units, HU) and glucose metabolism (standardized uptake value, SUV) of the normal prostate in 145 men (age range 22-97 years) on PET-CT scans which were performed for indications unrelated to prostate pathology. Correlations among SUV, HU, prostate size, and age were calculated using Pearson's correlation coefficients, scatter plots, and linear regression trend lines. The SUV and HU values were also compared among different primary cancer types using the Kruskal-Wallis test.
The population average and range of the normal prostate size were 4.3 +/- 0.5 cm (mean +/- SD) and 2.9-5.5 cm, respectively. The population average of mean and maximum CT densities was 36.0 +/- 5.1 HU (range 23-57) and 91.7 +/- 20.1 HU (range 62-211), respectively. The population average of mean and maximum SUV was 1.3 +/- 0.4 (range 0.1-2.7) and 1.6 +/- 0.4 (range 1.1-3.7), respectively. Mean SUV tended to decrease as the prostate size increased (r = -0.16, P = 0.058). Higher mean HU was correlated with higher mean SUV (r = 0.18, P = 0.033). The strongest association was observed between age and prostate size. The prostate gets larger as age increases (r = 0.32, P < 0.001). Prostate mean SUV, max SUV, mean HU, and max HU were not significantly different among different types of primary cancers.
Although the normal prostate size increases with age, it does not significantly affect the gland's metabolism and CT density, and therefore age-correction of these parameters may be unnecessary.
Annals of Nuclear Medicine 12/2008; 22(9):787-93. · 1.41 Impact Factor
[show abstract][hide abstract] ABSTRACT: Patients with high-risk primary breast cancer remain at high risk for relapse. More precise prognostic and predictive tools are needed to improve treatment of such patients.
Formalin-fixed, paraffin-embedded tumors from 239 high-risk breast cancer patients were examined for expression of human epidermal growth factor receptor 2 (HER2), epidermal growth factor receptor (EGFR), estrogen receptor, progesterone receptor, Ki-67, p16, p21, p27, and p53 by immunohistochemistry. Gene expression of EGFR, HER2, glutathione S-transferase-Pi (GSTP1), excision repair cross complementation1 (ERCC1), p21, beta-tubulin-3, multidurg resistance (MDR1), cyclooxygenase2 (COX2), and cyclin-E was measured by RT-PCR.
Eighty percent of patients presented with locally advanced, or > or =10 axillary nodal metastasis, and 20% with inflammatory breast cancer. The median age was 46 years (26-62 years) and the median number of involved axillary lymph nodes was 12 (0-42). At a median follow-up of 86 months, relapse-free survival (RFS) and overall survival for the entire group were 50% (95% CI 43% to 57%) and 62% (95% CI 56% to 69%). Multivariate Cox stepwise analysis resulted in a simple model for RFS consisting only of p21 expression, EGFR expression assessed by RT-PCR, and number of axillary nodal metastases.
A prognostic model on the basis of the expression of a limited number of proteins and genes may help to guide target-specific therapies in patients with high-risk breast cancer.
Annals of Oncology 11/2008; 19(11):1853-9. · 7.38 Impact Factor
[show abstract][hide abstract] ABSTRACT: To assess subclinical haemostatic activation and clinical variables to predict bleeding during radical retropubic prostatectomy (RP), as haemostatic activation is common in cancer and might be useful for predicting outcomes, but routine coagulation screening does not correlate with bleeding.
Clinical data and blood samples were collected from 153 patients (median age 63 years; prostate-specific antigen, PSA, level 5.92 ng/mL) before RP and lymph node dissection. Plasma was assayed for d-dimer and thrombin-antithrombin complex (TAT). Univariable then multivariable analyses were used to identify associations between plasma markers and clinical variables for bleeding and thrombosis.
Most patients (77%) were stage T1c and most (76.5%) had organ-confined cancer (< or =pT2). Pathological Gleason scores were < or =6 in 68 (44.4%) and > or =8 in 14 (9%) of the patients. The median (range) estimated blood loss (EBL) was 400 (50-3000) mL, the median decrease in haemoglobin level 3.5 (-0.1, 6.6) g/dL, and eight men (5.2%) required a transfusion. In the univariable analysis, a lower TAT before RP (P < 0.001) and d-dimer level (P = 0.023) correlated with a greater decline in haemoglobin level. The platelet count, international normalised ratio, and activated partial thromboplastin time (aPTT) did not predict the EBL nor change in haemoglobin level; the eight transfused patients had lower platelet counts before RP (P = 0.004). Higher surgical volume predicted a lower EBL (P < 0.001) and lower decrease in haemoglobin (P < 0.05). Multivariable linear regression showed that TAT remained significant for the decrease in haemoglobin, and surgical volume for EBL and decrease in haemoglobin.
Haemostatic activation before RP was associated with significantly less bleeding when assessed by objective measures, predicting the decrease in haemoglobin level better than prothrombin time, aPTT or platelet counts. Current surgeon volume might also predict both subjective and objective bleeding variables.
BJU International 07/2008; 102(9):1086-91. · 3.05 Impact Factor
[show abstract][hide abstract] ABSTRACT: In an initial epigenetic characterization of diffuse large B-cell lymphoma (DLBCL), we evaluated the DNA methylation levels of over 500 CpG islands. Twelve CpG islands (AR, CDKN1C, DLC1, DRD2, GATA4, GDNF, GRIN2B, MTHFR, MYOD1, NEUROD1, ONECUT2 and TFAP2A) showed significant methylation in over 85% of tumors. Interestingly, the methylation levels of a CpG island proximal to FLJ21062 differed between the activated B-cell-like (ABC-DLBCL) and germinal center B-cell-like (GCB-DLBCL) subtypes. In addition, we compared the methylation and expression status of 67 genes proximal (within 500 bp) to the methylation assays. We frequently observed that hypermethylated CpG islands are proximal to genes that are expressed at low or undetectable levels in tumors. However, many of these same genes were also poorly expressed in DLBCL tumors where their cognate CpG islands were hypomethylated. Nevertheless, the proportional reductions in BNIP3, MGMT, RBP1, GATA4, IGSF4, CRABP1 and FLJ21062 expression with increasing methylation suggest that epigenetic processes strongly influence these genes. Lastly, the moderate expression of several genes proximal to hypermethylated CpG tracts suggests that DNA methylation assays are not always accurate predictors of gene silencing. Overall, further investigation of the highlighted CpG islands as potential clinical biomarkers is warranted.
Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 06/2008; 22(5):1035-43. · 8.30 Impact Factor
[show abstract][hide abstract] ABSTRACT: The unfolded protein response (UPR) is an evolutionarily conserved mechanism that activates both proapoptotic and survival pathways to allow eukaryotic cells to adapt to endoplasmic reticulum (ER) stress. Although the UPR has been implicated in tumorigenesis, its precise role in endogenous cancer remains unclear. A major UPR protective response is the induction of the ER chaperone GRP78/BiP, which is expressed at high levels in a variety of tumors and confers drug resistance in both proliferating and dormant cancer cells. To determine the physiologic role of GRP78 in in situ-generated tumor and the consequence of its suppression on normal organs, we used a genetic model of breast cancer in the Grp78 heterozygous mice where GRP78 expression level was reduced by about half, mimicking anti-GRP78 agents that achieve partial suppression of GRP78 expression. Here, we report that Grp78 heterozygosity has no effect on organ development or antibody production but prolongs the latency period and significantly impedes tumor growth. Our results reveal three major mechanisms mediated by GRP78 for cancer progression: enhancement of tumor cell proliferation, protection against apoptosis, and promotion of tumor angiogenesis. Importantly, although partial reduction of GRP78 in the Grp78 heterozygous mice substantially reduces the tumor microvessel density, it has no effect on vasculature of normal organs. Our findings establish that a key UPR target GRP78 is preferably required for pathophysiologic conditions, such as tumor proliferation, survival, and angiogenesis, underscoring its potential value as a novel therapeutic target for dual antitumor and antiangiogenesis activity.
Cancer Research 02/2008; 68(2):498-505. · 8.65 Impact Factor
[show abstract][hide abstract] ABSTRACT: Patients with malignant mesothelioma (MM), an aggressive cancer associated with asbestos exposure, usually present clinically with advanced disease and this greatly reduces the likelihood of curative treatment. MM is difficult to diagnose without invasive techniques; the development of non-invasively detectable molecular markers would therefore be highly beneficial. DNA methylation changes in cancer cells provide powerful markers that are potentially detectable non-invasively in DNA shed into bodily fluids. Here we examined the methylation status of 28 loci in 52 MM tumors to investigate their potential as molecular markers for MM. To exclude candidate MM markers that might be positive in biopsies/pleural fluid due to contaminating surrounding non-tumor lung tissue/DNA, we also examined the methylation of these markers in lung samples (age- or environmentally induced hypermethylation is frequently observed in non-cancerous lung). Statistically significantly increased methylation in MM versus non-tumor lung samples was found for estrogen receptor 1 (ESR1; p = 0.0002), solute carrier family 6 member 20 (SLC6A20; p = 0.0022) and spleen tyrosine kinase (SYK; p=0.0003). Examination of associations between methylation levels of the 28 loci and clinical parameters suggest associations of the methylation status of metallothionein genes with gender, histology, asbestos exposure, and lymph node involvement, and the methylation status of leucine zipper tumor suppressor 1 (LZTS1) and SLC6A20 with survival.
Lung Cancer 12/2007; 58(2):220-30. · 3.39 Impact Factor
[show abstract][hide abstract] ABSTRACT: Metastasis to the bone is seen in 56% of patients with neuroblastoma and contributes to morbidity and mortality. Using a murine model of bone invasion, we have reported previously that neuroblastoma cells invade the bone by activating osteoclasts. Here, we investigated the antitumoral and antiosteolytic activities of zoledronic acid, a bisphosphonate inhibitor of osteoclasts, in combination with cytotoxic chemotherapy in our model. We first show that zoledronic acid given at the same time (early prevention) or 2 weeks after tumor cell injection (late prevention) significantly prevented the formation of severe osteolytic lesions. It also prevented formation of these lesions when given 4 weeks after tumor cell injection (intervention) when combined with chemotherapy including cyclophosphamide and topotecan. The combination of zoledronic acid + cyclophosphamide/topotecan also significantly improved survival (P < 0.001). In mice treated with zoledronic acid, we observed a marked inhibition of osteoclasts inside the bone associated with a decrease in tumor cell proliferation and increase in tumor cell apoptosis. In vitro, zoledronic acid inhibited neuroblastoma cell proliferation and induced apoptosis, and these effects were significantly enhanced by the addition of 4-hydroxyperoxycyclophosphamide (4-HC). The proapoptotic effect of zoledronic acid and zoledronic acid in combination with 4-HC on tumor cells was associated with an increase in caspase-3 activity and a decrease in phosphorylated Bcl-2, Bcl-2, and Bcl-X(L) expression. Zoledronic acid inhibited the association of Ras with the plasma membrane and activation of c-Raf, Akt, and extracellular signal-regulated kinase 1/2. The data indicate that zoledronic acid, in addition to inhibiting osteoclasts, is active against tumor cells and suggest that zoledronic acid in combination with cytotoxic chemotherapy may be effective in children with neuroblastoma that has metastasized to the bone.
Cancer Research 11/2007; 67(19):9346-55. · 8.65 Impact Factor
[show abstract][hide abstract] ABSTRACT: To use a clinical model of androgen-deprivation therapy (ADT) followed by radical prostatectomy (RP) to test the hypothesis that prostatic intraepithelial neoplasia (PIN, a premalignant lesion of the prostate causally linked to prostate cancer) is heterogeneous for hormone responsiveness, which might explain aspects of the heterogeneity of the natural history of prostate cancer, for although ADT has been used to reduce prostate cancer, there are controversial data on the effect of ADT on PIN.
We assessed retrospectively patients with biopsy-confirmed prostate cancer who had RP; some patients had received >or=3 months of ADT at the discretion of their surgeons, and patients from the same cohort who did not have ADT were used as controls. Patients were sequentially selected from the database and their pathology slides were reviewed by a pathologist unaware of the initial presence of PIN (assessed by an independent observer). Fisher's exact test was used to compare the proportions of patients who had residual PIN in the study and control groups. Exact logistic regression was used to evaluate the duration of ADT on PIN regression.
Eighteen patients initially diagnosed with PIN who had no ADT were identified, and 28 with PIN who had ADT were also assessed. All patients who had had no ADT had residual PIN, whereas seven of 28 receiving ADT had no residual PIN (P=0.043). The evaluation of ADT between responders and nonresponders showed a statistically significant association between PIN regression and the duration of ADT (P<0.001). However, the response of PIN to ADT was not uniform, as 16% of patients on ADT for >6 months had residual PIN, suggesting variable sensitivity of PIN to ADT.
These results show that ADT causes PIN to regress, and that there is heterogeneity in this effect with the duration of ADT. We propose future prospective, multicentre, randomized trials in which the effect of ADT on PIN is characterized further.
BJU International 06/2007; 99(5):1024-7. · 3.05 Impact Factor
[show abstract][hide abstract] ABSTRACT: To determine if the quantity of lymph vascular space invasion (LVSI) correlates with time to recurrence in women with early-stage squamous carcinoma of the cervix.
101 consecutive women with Stages IA2, IB, and IIA squamous carcinoma of the cervix who had undergone radical hysterectomy between 1991 and 1997, with previously reported histopathologic quantification of LVSI by four methods, were prospectively followed. The outcome measure was time to recurrence. Univariate and stratified log-rank test analysis was performed to test the association of time to recurrence with prognostic factors. Further analysis was focused on recurrence in those patients who had negative surgical margins and whose tumors contained LVSI, incorporating the four quantification measures.
Nineteen (19%) women had cancer recurrence. The presence of LVSI (P = 0.05), cervical stromal invasion (P = 0.01), parametrial involvement (P < 0.001), and positive margins (P < 0.0001) were significantly related to time to recurrence on univariate analysis. In patients whose tumors had negative surgical margins and contained LVSI (65%), percentage of all sections with LVSI >29% and total number of foci with LVSI >5 were significantly related to time to recurrence (P = 0.006). When stratifying for cervical stromal invasion, lymph node status, and parametrial involvement in this group, percentage of all sections with LVSI >29% and total number of foci with LVSI >5 were significantly related to time to recurrence (P = 0.05).
The quantity of LVSI, as defined by the percentage of all sections with LVSI and total number of foci with LVSI, is an independent prognostic factor for time to recurrence in women with early-stage squamous carcinoma of the cervix.
[show abstract][hide abstract] ABSTRACT: Species-specific urokinase receptor (uPAR) ligands with improved pharmacokinetics were generated by site-specific mutagenesis and amino-terminal pegylation. These molecules were used to probe the role of uPAR in brain tumor progression and angiogenesis. The ligands blocked endothelial cell tube formation in Matrigel in a species-specific manner and reduced both baseline and uPA amino-terminal fragment-stimulated cell migration on vitronectin gradients. Treatment of U87MG gliomas implanted orthotopically in mice with single species-specific or combination uPAR ligands resulted in significant decreases in tumor size, which translated to increases in survival time, and which were most significant when the murine-specific ligand was included. Further analysis of tumors showed that the reduced sizes were correlated with a decrease in tumor cell proliferation and mean vessel density and an increase in tumor cell apoptosis. In addition, a large increase in collagen deposition was observed in the treated groups. Statistical analysis showed that the combination therapy demonstrated a clear synergy as compared to the individual agent treatments. These results suggest that the major role of the uPAR system in brain tumor progression is in the stromal compartment and particularly in neovascularization, a hallmark of invasive brain tumors.
[show abstract][hide abstract] ABSTRACT: Despite histologically negative lymph nodes, approximately 15% of patients with early-stage cervical cancer will develop recurrence. Micrometastases have been shown to be important in staging and treatment of breast cancers and melanoma and have been identified by polymerase chain reaction analysis in cervical cancers. This study sought to estimate the frequency of micrometastases identified by immunohistochemistry in histologically negative lymph nodes and compare this to other known risk factors for recurrence of cervical cancer.
Early-stage (stages IA2, IB1, and IB2) cervical cancer patients of all histologic subtypes were identified from the surgical logs of the Los Angeles County-University of Southern California Medical Center for the period 1994-2000. One hundred thirty-two patients had histologically negative lymph nodes. Immunohistochemical assay was performed on 3,106 lymph nodes by using antibodies against cytokeratins AE-1 and CAM 5.2 in combination according to standard protocols. The stained nodes were then evaluated for the presence of micrometastases and compared against the respective clinicopathologic information in each case.
Micrometastases were detected in 19 of 132 (15%, 95% confidence interval [CI] 9%, 22%) patients, found in 29 of the 3,106 (0.9%) lymph nodes evaluated. Vascular space invasion was seen in 50 of 132 cases (38%, 95% CI 30%, 47%) and in 8 of 19 (42%, 95% CI 21%, 66%) cases with micrometastases. Surgical margins of the resected specimen were negative in 120 of 132 cases (91%, 95% CI 84%, 95%) and in 16 of 19 (84%, 95%CI 60%, 96%) of those cases with micrometastases. Micrometastases were seen most frequently in pelvic lymph nodes (25 of 29, 86%). Patients with more than 20 lymph nodes removed were more likely to demonstrate metastasis (P <.001). There was no statistically significant association between micrometastasis and vascular space invasion or tumor volume.
Micrometastases are identifiable in histologically negative lymph nodes in 15% (95% CI 9%, 22%) of early-stage cancer patients, a frequency which approximates the recurrence rate for patients with negative nodes. In this series, patients with greater numbers of lymph nodes analyzed were more likely to have lymph node micrometastasis identified. There appears to be no relationship between tumor volume and the identification of micrometastases. Although micrometastases can be identified in histologically negative lymph nodes, their presence is not strongly associated with other known factors of cervical cancer recurrence. Further research is needed to determine whether the presence of lymph node micrometastases is associated with an unfavorable prognosis.
Obstetrics and Gynecology 06/2004; 103(6):1204-10. · 4.80 Impact Factor