Survival In Cervical Carcinoma Research Articles

The polymethoxylated flavone hexamethylquercetagetin suppresses NF-κB signaling and inhibits cell survival in cervical carcinoma

Nuclear factor-κB (NF-κB) contributes to the development and progression of cervical carcinoma. To construct a xenograft model, Ca Ski cells were subcutaneously inoculated into BALB/c nude mice. The relative protein expression of NF-κB p65, p-p65, IκBα, and p-IκBα were detected in hexamethylquercetagetin (HTQC) treated cervical carcinoma cells with or without tumor necrosis factor (TNF)α stimulation, or representative tumors tissues in xenograft mice. HTQC could prohibit NF-κB-derived luciferase activity in Ca Ski and C-33 A cells and inhibit the relative NF-κB p-p65 and p-IκBα expression with or without TNFα stimulation. At the same time, HTQC inhibited in vitro cell survival in a concentration-dependent manner and suppressed the tumor volume and weight in xenograft models. In summary, HTQC functions as an NF-κB inhibitor to prohibit the survival and proliferation of cervical carcinoma, which can be considered as an NF-κB target remedy in future clinical practice.

Assessment of Hypoxic Tissue Fraction and Prediction of Survival in Cervical Carcinoma by Dynamic Contrast-Enhanced MRI.

Tumor hypoxia is a major cause of treatment resistance and poor survival in locally-advanced cervical carcinoma (LACC). It has been suggested that K trans and v e maps derived by dynamic contrast-enhanced magnetic resonance imaging can provide information on the oxygen supply and oxygen consumption of tumors, but it is not clear whether and how these maps can be combined to identify tumor hypoxia. The aim of the current study was to find the optimal strategy for calculating hypoxic fraction and predicting survival from K trans and v e maps in cervical carcinoma. K trans and v e maps of 98 tumors of four patient-derived xenograft models of cervical carcinoma as well as 80 patients with LACC were investigated. Hypoxic fraction calculated by using K trans maps correlated strongly (P < 0.0001) to hypoxic fraction assessed with immunohistochemistry using pimonidazole as a hypoxia marker and was associated with disease-free and overall survival in LACC patients. Maps of v e did not provide information on hypoxic fraction and patient outcome, and combinations of K trans and v e were not superior to K trans alone for calculating hypoxic fraction. These observations imply that K trans maps reflect oxygen supply and may be used to identify hypoxia and predict outcome in cervical carcinoma, whereas v e is a poor parameter of oxygen consumption and does not provide information on tumor oxygenation status.

Overexpression of FUBP1 is associated with human cervical carcinoma development and prognosis

AimsFar upstream element-binding protein 1 (FUBP1) has been shown to involve in the tumorigenesis and tumor progression of various cancers. However, the expression and function of FUBP1 in cervical carcinoma remains unknown. Main methodsTranscriptional expression of FUBP1 was initially evaluated using the Oncomine database, followed by evaluation of FUBP1 protein levels using immunohistochemistry in 119 cervical carcinoma patient tissues. In vitro experiments were performed to assess the tumorigenic role of FUBP1. Besides, Gene Set Enrichment Analysis, EnrichmentMap analysis, and protein-protein interaction (PPI) networks were used to evaluate the potential mechanisms of FUBP1 in promoting cervical cancer progression. Key fundingsIn this research, we found both FUBP1 mRNA transcription and protein expression levels increased significantly in cervical carcinoma tissues compared with adjacent normal cervical tissues. Furthermore, elevated FUBP1 expression was positively correlated with age, T classification, N classification, tumor recurrence, Ki67 expression, and poor prognosis in cervical carcinoma patients. Besides, elevated FUBP1 expression acted as an independent unfavorable predictor for overall survival and disease-free survival in cervical carcinoma. Overexpression of FUBP1 significantly promoted cervical carcinoma cell proliferation and inhibits cell apoptosis in vitro, while knockdown of FUBP1 showed the opposite effect. Mechanistically, bioinformatics analysis revealed that FUBP1 promoted the biological function of cervical carcinoma cells via enhancing DNA repair signal pathways. Our results demonstrate for the first time that FUBP1 is a novel prognostic factor and therapeutic target for cervical carcinoma.

The prognostic role of horizontal and circumferential tumor extent in cervical cancer: Implications for the 2019 FIGO staging system

ObjectiveThe FIGO 2019 update on cervical cancer staging removed horizontal tumor extent (HZTE) as a staging variable. Evidence is needed to substantiate this change. The prognostic significance of HZTE and a related variable, circumferential tumor extent (%CTE), is similarly unknown. We aimed to investigate the association of HZTE and %CTE with survival outcomes in cervical cancer patients. MethodsWe identified patients treated with primary surgery for stage I cervical cancer in a single institution during a 9-year period. HZTE and, when available, %CTE were obtained from pathology records. Cases were staged using 2019 FIGO staging. Correlations between HZTE, %CTE and FIGO stage with recurrence-free (RFS) and disease-specific survival (DSS) were determined using univariable and multivariable analyses. Results285 patients were included with a median follow-up of 48 (range 7–123) months. HZTE was statistically associated with RFS and DSS on univariate and multivariate analysis. None of the 168 stage IA patients in our series had tumor recurrence or death during follow-up, including 42 with HZTE ≥7 mm. None of the patients with a tumor horizontal extent <7 mm experienced recurrence or death. %CTE correlated only with RFS on univariate analysis. 2019 FIGO stage did not independently correlate with RFS or DSS in our sample. ConclusionsHZTE is an independent predictor of survival in cervical carcinoma. In stage IA tumors, however, HZTE does not offer superior prognostic value, supporting the 2019 FIGO recommendations to remove this variable from staging in these cases. HZTE may be useful in larger tumors in which staging depends on maximum tumor size. %CTE is not an independent prognostic variable in cervical cancer, and we advise against its use.

Comprehensive analysis of aberrantly expressed long non‑coding RNAs, microRNAs, and mRNAs associated with the competitive endogenous RNA network in cervical cancer.

Cervical cancer is a common malignant disease that poses a serious health threat to women worldwide. Growing research efforts have focused on protein-coding and non-coding RNAs involved in the tumorigenesis and prognosis of various types of cancer. The potential molecular mechanisms and the interaction among long non-coding RNAs (lncRNAs), microRNAs (miRNAs), and mRNAs require further investigation in cervical cancer. In the present study, lncRNA, miRNA, and mRNA expression profiles of 304 primary tumor tissues from patients with cervical cancer and 3 solid normal tissues from The Cancer Genome Atlas (TCGA) dataset were studied via RNA sequencing (RNA-seq). Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed using R package clusterProfiler to annotate the principal functions of differentially expressed (DE) mRNAs. Kaplan-Meier analysis was also conducted to investigate the effects of DElncRNAs, DEmiRNAs, and DEmRNAs on overall survival. A total of 2,255 mRNAs, 133 miRNAs, and 150 lncRNAs that were differentially expressed were identified with a threshold of P<0.05 and |fold change (FC)|>2. Functional enrichment analysis indicated that DEmRNAs were enriched in cancer-associated KEGG pathways. Furthermore, 255 mRNAs, 15 miRNAs, and 12 lncRNAs that were significantly associated with overall survival in cervical carcinoma were also identified. Importantly, an miRNA-mediated competitive endogenous RNA (ceRNA) network was successfully constructed based on the expression profiles of DElncRNAs and DEmRNAs. More importantly, it was found that the lncRNA EPB41L4A-AS1 may function as a pivotal regulator in carcinoma of the uterine cervix. Taken together, the present study has provided novel insights into investigating the potential mechanisms underlying tumorigenesis, development, and prognosis of cervical cancer, and presented new potential avenues for cancer therapeutics.

MicroRNA-625-5p Sponges lncRNA MALAT1 to Inhibit Cervical Carcinoma Cell Growth by Suppressing NF-κB Signaling.

The exact expression profile and potential involvement of miR-625-5p in the tumor biology of cervical carcinoma are still elusive. In this study, we aimed to analyze the expression status and possible involvements of miR-625-5p in both clinical tissue samples and cell culture of cervical carcinoma. The relative expression levels of miR-625-5p and NF-κB transcript were determined by real-time polymerase chain reaction. Cell proliferation was measured using Cell Counting Kit-8. The protein levels of Cyclin D1, CDK4, NF-κB, and GAPDH were examined by Western blotting. The regulatory effects of miR-625-5p on NF-κB and MALAT1 were interrogated by luciferase reporter assay. We demonstrated that miR-625-5p was downregulated and predicted better survival in cervical carcinoma. Ectopic over-expression of miR-625-5p inhibited cell growth via targeting NF-κB. We further identified MALAT1 as the competitive endogenous long non-coding RNA for miR-625-5p, and over-expression of MALAT1 attenuated the inhibitory effect of miR-625-5p on NF-κB signaling in cervical carcinoma. Our study characterized the suppressive expression of miR-625-5p in cervical carcinoma and unraveled the importance of MALAT1/miR-625-5p/NF-κB signaling in this disease.

A retrospective analysis of the effect of planning tumour volume on survival in cervical carcinoma

Introduction: Locally advanced stages of invasive cervical cancer (ICC) are associated with poor outcomes; factors influencing survival include increased tumour volume. In resource-constrained sett...

Correlations between immune response and vascularization qRT-PCR gene expression clusters in squamous cervical cancer

BackgroundThe tumour microenvironment comprises a network of immune response and vascularization factors. From this network, we identified immunological and vascularization gene expression clusters and the correlations between the clusters. We subsequently determined which factors were correlated with patient survival in cervical carcinoma.MethodsThe expression of 42 genes was investigated in 52 fresh frozen squamous cervical cancer samples by qRT-PCR. Weighted gene co-expression network analysis and mixed-model analyses were performed to identify gene expression clusters. Correlations and survival analyses were further studied at expression cluster and single gene level.ResultsWe identified four immune response clusters: ‘T cells’ (CD3E/CD8A/TBX21/IFNG/FOXP3/IDO1), ‘Macrophages’ (CD4/CD14/CD163), ‘Th2’ (IL4/IL5/IL13/IL12) and ‘Inflammation’ (IL6/IL1B/IL8/IL23/IL10/ARG1) and two vascularization clusters: ‘Angiogenesis’ (VEGFA/FLT1/ANGPT2/ PGF/ICAM1) and ‘Vessel maturation’ (PECAM1/VCAM1/ANGPT1/SELE/KDR/LGALS9). The ‘T cells’ module was correlated with all modules except for ‘Inflammation’, while ‘Inflammation’ was most significantly correlated with ‘Angiogenesis’ (p < 0.001). High expression of the ‘T cells’ cluster was correlated with earlier TNM stage (p = 0.007). High CD3E expression was correlated with improved disease-specific survival (p = 0.022), while high VEGFA expression was correlated with poor disease-specific survival (p = 0.032). Independent predictors of poor disease-specific survival were IL6 (hazard ratio = 2.3, p = 0.011) and a high IL6/IL17 ratio combined with low IL5 expression (hazard ratio = 4.2, p = 0.010).Conclusions‘Inflammation’ marker IL6, especially in combination with low levels of IL5 and IL17, was correlated with poor survival. This suggests that IL6 promotes tumour growth, which may be suppressed by a Th17 and Th2 response. Measuring IL6, IL5 and IL17 expression may improve the accuracy of predicting prognosis in cervical cancer.

Expression of the p53 target Wig-1 is associated with HPV status and patient survival in cervical carcinoma.

The p53 target gene WIG-1 (ZMAT3) is located in chromosomal region 3q26, that is frequently amplified in human tumors, including cervical cancer. We have examined the status of WIG-1 and the encoded Wig-1 protein in cervical carcinoma cell lines and tumor tissue samples. Our analysis of eight cervical cancer lines (Ca Ski, ME-180, MS751, SiHa, SW756, C-4I, C-33A, and HT-3) by spectral karyotype, comparative genomic hybridization and Southern blotting revealed WIG-1 is not the primary target for chromosome 3 gains. However, WIG-1/Wig-1 were readily expressed and WIG-1 mRNA expression was higher in the two HPV-negative cervical cell lines (C33-A, HT-3) than in HPV-positive lines. We then assessed Wig-1 expression by immunohistochemistry in 38 cervical tumor samples. We found higher nuclear Wig-1 expression levels in HPV-negative compared to HPV positive cases (p = 0.002) and in adenocarcinomas as compared to squamous cell lesions (p<0.0001). Cases with moderate nuclear Wig-1 staining and positive cytoplasmic Wig-1 staining showed longer survival than patients with strong nuclear and negative cytoplasmic staining (p = 0.042). Nuclear Wig-1 expression levels were positively associated with age at diagnosis (p = 0.023) and histologic grade (p = 0.034). These results are consistent with a growth-promoting and/or anti-cell death function of nuclear Wig-1 and suggest that Wig-1 expression can serve as a prognostic marker in cervical carcinoma.

Peritumoral interstitial fluid flow velocity predicts survival in cervical carcinoma

Background and purposeHigh tumor interstitial fluid pressure (IFP) is associated with poor outcome in locally advanced carcinoma of the uterine cervix. We have recently developed a noninvasive assay of the IFP of tumors, and in this assay, the outward interstitial fluid flow velocity at the tumor surface (v0) is measured by Gd-DTPA-based DCE-MRI and used as a parameter for IFP. Here, we investigated the independent prognostic significance of v0 in cervical cancer patients given cisplatin-based concurrent chemoradiotherapy with curative intent. PatientsThe study involved 62 evaluable patients from a cohort of 74 consecutive patients (Stage IB through IIIB) with a median follow-up of 5.5years. ResultsThe actuarial disease-free survival (DFS) and overall survival (OS) at 5years were 67% and 76%, respectively. Significant associations were found between v0 dichotomized about the median value and DFS and OS, both in the total patient cohort and a subcohort of 40 Stage IIB patients. Multivariate analysis involving stage, tumor volume, lymph node status, and v0 revealed that only v0 provided independent prognostic information about DFS and OS. ConclusionThis investigation demonstrates a strong, independent prognostic impact of the pretreatment peritumoral fluid flow velocity in cervical cancer.

Aldehyde dehydrogenase 1 (ALDH1) positivity correlates with poor prognosis in cervical cancer.

To analyse the associations between aldehyde dehydrogenase 1 (ALDH1) tumour immunopositivity and disease-free survival in cervical carcinoma. ALDH1 immunohistochemistry was performed on formalin-fixed, paraffin wax-embedded cervical tumour tissue samples obtained from hospital archives. Data regarding disease-free survival were obtained. Kaplan-Meier survival analyses and Cox proportional hazards regression models were performed. Patients with ALDH1-positive tumours (n = 31) had significantly shorter disease-free survival than those with ALDH1-negative tumours (n = 167; 41.99 ± 0.90 vs 53.64 ± 2.67 months). ALDH1 positivity was associated with poor prognosis (relative risk 2.727; 95% confidence intervals 1.253, 5.914). ALDH1 positivity is associated with poor prognosis of cervical carcinoma, and may be an independent predictor of prognosis.

EP-1827: Radio-induced apoptosis of peripheral blood CD8+ T-lymphocytes predict the survival of cervical carcinoma

EP-1827: Radio-induced apoptosis of peripheral blood CD8+ T-lymphocytes predict the survival of cervical carcinoma

Overexpression of cystic fibrosis transmembrane conductance regulator (CFTR) is associated with human cervical cancer malignancy, progression and prognosis

ObjectiveTo investigate the correlation of cystic fibrosis transmembrane conductance regulator (CFTR) to cervical cancer progression and prognosis by examining CFTR expression levels in different cervical tissues and cell lines. MethodsParaffin-embedded cervical tissue samples (n=192) were collected for immunohistochemistry (IHC), while fresh cervical tissue samples (n=165) and human cervical cell lines were collected for protein and mRNA detection by quantitative real-time PCR and western blot, respectively. Correlations between CFTR expression levels to cancer clinicopathologic features and prognosis were statistically analyzed. ResultsBoth CFTR mRNA and protein expression gradually increased from normal to precancerous (LSIL, HSIL) and cervical cancer tissues (p<0.05). Furthermore, CFTR expression level was well-correlated to tumor stage (p<0.001), histological grades (p<0.001), lymphatic metastasis (p<0.001), vascular invasion (p<0.05), interstitial invasive depth (p<0.05), tumor size (p<0.05) and HPV infection (p<0.05). In vitro, CFTR mRNA and protein were expressed strongly both in SiHa and HeLa, but little was seen in Caski and H8 (p<0.05). More importantly, overexpression of CFTR conferred significantly poorer survival in cervical carcinoma (Log rank p=0.028), although it was not an independent predictor for prognosis according to multivariate analysis (p>0.05). ConclusionsThese results suggest that higher CFTR expression is closely associated with cervical cancer progression, aggressive behaviors and poorer prognosis, indicating that CFTR may function as a novel tumor marker, a prospective prognostic indicator and a potential therapeutic target for cervical cancer.

Overexpression of Phosphorylated 4E-BP1 Predicts for Tumor Recurrence and Reduced Survival in Cervical Carcinoma Treated With Postoperative Radiotherapy

To examine the prognostic value of the 4E-BP1 activation state and related upstream/downstream signaling proteins on the clinical outcome of patients with intermediate- or high-risk early-stage cervical carcinoma treated with postoperative radiotherapy and to determine the optimal treatment of early-stage cervical carcinoma. Immunohistochemical staining was performed on 64 formalin-fixed, paraffin-embedded cervical carcinoma surgical specimens for each protein of the panel (p4E-BP1, phosphorylated mitogen-activated protein kinase, pAkt, vascular endothelial growth factor, KDR, Bcl-2, TP53, receptor for activated C-kinase 1). The expression patterns were related to the clinical data. All patients received postoperative radiotherapy. Concurrent chemotherapy was added if high-risk features were present. The median follow-up was 40 months. Of the 64 patients, 13 received concomitant chemotherapy. p4E-BP1 overexpression in moderate/high-risk early-stage cervical carcinoma correlated significantly with disease-free survival (hazard ratio, 4.39; p = .009) and overall survival (hazard ratio, 4.88; p = .005). Vascular endothelial growth factor, and its receptor KDR, had positive immunoreactivity in all tumor samples. No correlation with clinical outcome was found for the remaining proteins evaluated. In this study, moderate/high-risk early-stage cervical carcinoma with low p4E-BP1 expression was highly curable with the current postoperative treatments. For tumors with p4E-BP1 overexpression, new investigational strategies are needed.

Association of Posttherapy Positron Emission Tomography With Tumor Response and Survival in Cervical Carcinoma

Retrospective studies have demonstrated that the use of positron emission tomography (PET) with F-18 fluorodeoxyglucose (FDG) in the posttherapy evaluation of patients with cervical carcinoma is predictive of survival outcome. To validate the association between the metabolic response on the 3-month posttherapy FDG-PET and long-term survival outcome. A prospective cohort study designed to validate our previous finding that the results of a 3-month posttherapy FDG-PET are predictive of long-term clinical outcome. A total of 92 women were treated with external irradiation, brachytherapy, and concurrent chemotherapy from January 2003 through September 2006. Posttherapy whole-body FDG-PET was performed 2 to 4 months (mean, 3 months) after completion of therapy. The primary outcome end points were metabolic response, progression-free survival, and cause-specific survival. Posttherapy FDG-PET showed a complete metabolic response in 65 patients (70%), a partial metabolic response in 15 (16%), and progressive disease in 12 (13%). Their 3-year progression-free survival rates were 78%, 33%, and 0%, respectively (P < .001). Multivariate analysis demonstrated that the hazard ratio (HR) for risk of recurrence based on the posttherapy metabolic response showing progressive disease was 32.57 (95% confidence interval [CI], 10.22-103.82). A partial metabolic response had an HR of 6.30 (95% CI, 2.73-14.56). These were more predictive of survival outcome than the pretreatment lymph node status (HR, 3.54; 95% CI, 1.54-8.09). In this single-site study population of women with cervical cancer, 3-month posttherapy FDG uptake, as detected by whole-body PET, was predictive of survival.

Does a Fall in Lymphocyte or Neutrophil Count During Chemoradiotherapy Predict Survival in Cervical Carcinoma?

Does a Fall in Lymphocyte or Neutrophil Count During Chemoradiotherapy Predict Survival in Cervical Carcinoma?

Human papillomavirus-31-related types predict better survival in cervical carcinoma.

The aim of the current study was to explore the clinical implications and prognostic value of human papillomavirus (HPV) genotype in cervical carcinomas. A total of 152 patients diagnosed with International Federation of Gynecology and Obstetrics Stage I-IV cervical carcinoma were studied between 1992-1999. HPV DNA status was assessed from paraffin-embedded, formaldehyde-fixed cervical carcinoma specimens by polymerase chain reaction-based methods using E7 type-specific and L1 modified general primers (MY11/GP6+ and GP5+/GP6+). The authors divided the patients into four groups: HPV-16-related, HPV-18-related, HPV-31-related, and HPV-58-related types. The relations with clinicopathologic data and overall survival were evaluated. HPV DNA was detected in 98% of the tumor specimens and 28.9% of the tumor specimens contained multiple HPV types. The HPV-16-related types were detected more often in squamous cell carcinomas, whereas the HPV-18-related types were more prevalent in adenocarcinomas and adenosquamous carcinomas. In addition, Stage I-II diseases were found more frequently in the HPV-16-related group than in the other groups (P = 0.001). Otherwise, no significant correlation between the HPV genotype and other clinicopathologic parameters was found. After a median follow-up of 64.5 months, the 5-year survival rate was 92% in the HPV-31-related group compared with 70% in the HPV-16-related group, 69% in the HPV-18-related group, and 36% in the HPV-58-related group. The survival rates statistically differed among the four groups by log-rank test (P = 0.02). However, the presence of multiple HPV types was not associated with prognosis. After stratifying for clinical stage, multivariate analysis demonstrated that HPV genotype was an independent prognostic factor. Compared with the HPV-16-related group, the long-term mortality rate was 73 % lower in the HPV-31-related group (relative risk, 0.27; 95% confidence interval, 0.09-0.76; P = 0.013). The presence of HPV-31-related types was an independent predictor of better survival in patients with cervical carcinoma. Therefore, HPV genotyping of cervical carcinomas may have profound implications for future patient management.

Expression of Ku70 correlates with survival in carcinoma of the cervix

Cervical carcinoma affects around 3400 women in the UK each year and advanced disease is routinely treated with radiation. As part of a programme to establish rapid and convenient methods of predicting tumour and patient responses to radiotherapy, we have examined the relationship between the pre-treatment expression of the Ku components of the DNA damage recognition complex DNA-PK and patient survival in cervical carcinoma. Using immunohistochemistry of formalin-fixed sections of tumour biopsies, antibodies to Ku70 and Ku80 stained identical regions of tumour and there was a high degree of correlation between the mean number of cells stained positive for the two components in 77 tumours (r = 0.82, P< 0.001). In 53 tumours there was a borderline significant correlation between measurements of tumour radiosensitivity (surviving fraction at 2 gray: SF2) and Ku70 expression (r = 0.26, P = 0.057) and no correlation for Ku80 (r = 0.18, P = 0.19). However, all tumours with a low number of Ku70 or Ku80 positive cells were radiosensitive. Furthermore, using log-rank analysis there was significantly higher survival in the patients whose tumours had a low Ku70 expression (P = 0.046). This difference was also reflected with Ku80, but did not reach statistical significance (P = 0.087). The study suggests that lack of Ku protein leads to radiosensitivity in some tumours and that other factors are responsible for radiosensitive tumours with high Ku expression. It is likely that the most accurate prediction of treatment outcome will lie in assessing the expression of several proteins involved in the recognition and repair of DNA damage, one of which will be Ku. © 2000 Cancer Research Campaign http://www.bjcancer.com

Blood transfusion and disease free survival in cervical carcinoma

Summary The case notes of 201 patients who had had radical hysterectomy and pelvic node dissection, with or without postoperative radiotherapy, for stages 1 b or 2a cervical carcinoma, were analysed to determine if those who had not been transfused had a longer disease free survival time. When patients were divided into those who had received a blood transfusion and those who had not, no differences were found in patients’ ages, tumour types or length of follow up. Separate analysis of patients treated with or without radiotherapy found no survival advantage for patients not transfused. Similar analysis of the different histopathological tumour types also found no difference in disease free survival for patients not transfused. These results are in contrast to previously published reports that have shown an improvement in disease free survival in patients not transfused.

The impact of lymph node status on survival in cervical carcinoma

Four hundred and sixty three patients with Stage IB through IIIB primary squamous cell carcinoma of the cervix were treated at the M.D. Anderson Hospital and Tumor Institute between 1968 and 1971. Lymphangiography was performed in 215 patients with tumors in Stages III to IIIB. Data on these 215 patients were reviewed and survival was correlated with lymphangiogram (LAG) status, tumor volume (stage) and selected patient characteristics. Three risk categories were identified using clinical staging and LAG criteria. These risk categories differed in median survival as follows: good risk (Stage IIA and B, LAG negative - 92+ months); intermediate risk (Stage 1111, LAG positive, Stage IIIA and B, LAG negative - 31 months) and poor risk (Stage IIIA and B, LAG positive - 11 months). Frequency of persistent disease and two year failure rates were both positively correlated with stage among LAG negative and LAG positive patients.