Decreased Disease Specific Survival Research Articles

10 - Correlating Copy Number Alterations in Dedifferentiated Liposarcoma With Tumor Behavior and Patient Outcome

Dedifferentiated liposarcoma (DDLS), as a most common intermediate- to high-grade lipomatous neoplasm, has metastatic potential and much poorer prognosis than atypical lipomatous neoplasm/well-differentiated liposarcoma (ALN/WDLS). Although tumor location and grade of DDLS have been shown to have prognostic significance, knowledge of genetic alterations for prognosis of DDLS remains limited. Genetic abnormalities underlying the pathogenesis and behavior of DDLS are not well understood. The aim of this study is to evaluate the correlation of specific CNAs with DDLS behavior and patient outcome to identify prognostic markers for risk stratification of liposarcoma patients. FFPE tumor tissues from 47 DDLS with clinical and pathological information were obtained for DNA extraction and cytogenomic microarray analysis (CMA) using a cancer-specific genomic microarray designed by Cancer Genome Consortium (CGC). The results show that copy number alterations including chromosomal gains, amplifications, and losses were very common in DDLS. Amplification of genes (defined as 5 or more copies) within the 12q13-15 region were most common as previously described. CNAs in 12 regions of interest were compared with DDLS FNCLCC grade and clinical disease status. Unlike the findings in previous studies by FISH, Q-PCR, and MLPA in DDLS, our study using CMA showed that higher levels of amplification of MDM2 correlate with an increased risk of adverse event including local recurrence, metastasis, and/or death related to disease in our cohort of DDLS patients. In addition, higher levels of MDM2 amplification were also significantly more likely to be found in retroperitoneal tumors compared to all other sites. Similar to findings in previous studies, we also found that high amplification levels of CDK4 correlated with increased risk of any adverse event related to disease and decreased disease specific survival. Correlations of other copy number alterations with DDLS tumor behavior and prognosis will also be reported and discussed.

MP64-09 DECREASE IN LONG-TERM DISEASE-SPECIFIC SURVIVAL WITH PERIOPERATIVE BLOOD TRANSFUSION FOLLOWING RADICAL CYSTECTOMY

You have accessJournal of UrologyBladder Cancer: Natural History and Pathophysiology1 Apr 2015MP64-09 DECREASE IN LONG-TERM DISEASE-SPECIFIC SURVIVAL WITH PERIOPERATIVE BLOOD TRANSFUSION FOLLOWING RADICAL CYSTECTOMY Bethany K. Burge, Robert H. Blackwell, Evan Carlos, Robert C. Flanigan, Gopal N. Gupta, and Marcus L. Quek Bethany K. BurgeBethany K. Burge More articles by this author , Robert H. BlackwellRobert H. Blackwell More articles by this author , Evan CarlosEvan Carlos More articles by this author , Robert C. FlaniganRobert C. Flanigan More articles by this author , Gopal N. GuptaGopal N. Gupta More articles by this author , and Marcus L. QuekMarcus L. Quek More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2015.02.2320AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Radical cystectomy (RC) is a morbid procedure, which can be associated with substantial blood loss and need for perioperative blood transfusion (PBT). PBT has been associated with a decrease in disease-specific survival for patients undergoing surgery for other malignancies. We hypothesize that receipt of PBT may have an immunosuppressive effect that can impact the natural course of bladder cancer after definitive surgical treatment. We evaluate the effects of blood transfusion on overall (OS), disease-specific (DSS), and recurrence-free survival(RFS)in patients who underwent RC for bladder carcinoma. METHODS A retrospective review was performed of 521 patients who underwent RC at Loyola University Medical Center from 1996 to 2014. Patients were categorized into two cohorts; those who did and did not receive PBT. Student's T-test was used to assess continuous variables, and Pearson's Chi-squared test to assess categorical variables. The effect of PBT on OS, DSS, and RFS were estimated using the Kaplan-Meier method and compared with the log-rank test. RESULTS Blood transfusion data was available for 487 patients (93.5%), with an overall mean follow up of 30 months. Of these patients, 243 (49.8%) received PBT. Cohorts were well-matched with regards to cancer-specific variables, with no differences between pathologic tumor stage, nodal stage, presence of lymphovascular invasion, primary histology, or presence of positive margins. PBT patients were older than control patients (mean age 69.1 vs 66.7, p<0.05). DSS and OS were found to be significantly decreased in PBT patients compared to controls, at median 77.8 months vs. 111.1 months (p=0.002) and 54.5 months vs. 80.3 months (p=0.002), respectively. Figures A and B. RFS approaches significance favoring improved freedom from recurrence in control patients, at median 64.4 months vs. 100.4 months respectively (p=0.059). CONCLUSIONS RC patients who received PBT had a decreased OS and DSS. Coupled with a trend toward a higher rate of cancer recurrence in the PBT group, these results suggest that receipt of blood products may have an immunosuppressive effect that impairs the body's ability to fight microscopic residual disease, contributing to poorer survival in this cohort. © 2015 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 193Issue 4SApril 2015Page: e801 Advertisement Copyright & Permissions© 2015 by American Urological Association Education and Research, Inc.MetricsAuthor Information Bethany K. Burge More articles by this author Robert H. Blackwell More articles by this author Evan Carlos More articles by this author Robert C. Flanigan More articles by this author Gopal N. Gupta More articles by this author Marcus L. Quek More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Current Evidence for the Treatment of Bladder Cancer

Bladder cancer is the second most common malignancy in urological field. Most new cases are diagnosed as non-muscle invasive bladder cancer (NMIBC), which includes Ta, T1 or carcinoma in situ. Initial management of NMIBC is endoscopic resection, which allows both treatment and pathological staging. Urologist should consider adjuvant intravesical chemotherapy or Bacillus Calmette-Guerin (BCG) immunotherapy, depending on the tumor grade or stage to prevent recurrence and progression. Patients with muscle invasive bladder cancer (MIBC) are best treated with radical cystectomy. However, radical cystectomy should be considered even in patients with NMIBC with high risk of progression and BCG refractory tumors. Delay of radical cystectomy in these patients might lead decreased disease specific survival. Patients treated by radical cystectomy should undergo any form of the urinary diversion. Ileal conduit is still most common method for urinary diversion. Orthotopic neobladder is generally performed by experienced hands in high volume center. Patients undergoing orthotopic neobladder should be educated and manually skillful to manipulate their diversion. Neoadjuvant cisplatin-based chemotherapy is recommended based on level 1 evidence with survival benefit. Recent updated meta-analysis also demonstrated survival benefit in patients with MIBC treated by adju

The arguments for an early cystectomy in patients with urothelial carcinoma.

At the initial diagnosis of bladder cancer, 70% of cases are diagnosed as non–muscle–invasive bladder cancer (NMIBC) and approximately 30% as muscle–invasive bladder cancer (MIBC). Among patients treated with radical cystectomy due to MIBC, 57% had muscle invasion at presentation, while 43% were initially diagnosed with NMIBC which had progressed, despite organ–preserving treatment. Approximately one–third of patients diagnosed with MIBC have undetected metastases at the time of treatment of the primary tumor, while 25% of patients who undergo radical cystectomy present with lymph node involvement at the time of surgery. In cases of MIBC, a cystectomy should not be delayed for >3 months because this delay can increase the risk of progression and cancer–specific mortality (Grade B, EAU Guidelines) [1, 2]. One of the most challenging clinical decisions concerning bladder cancer is the treatment of pT1 high grade tumors. This tumor category is very heterogeneous and requires a special approach. According to the EORTC data, intermediate and high–risk NMIBC should be treated with BCG (Bacillus Calmette Guerin) instillations for at least one year. An individual recurrence and progression risk profile can be assessed using the EORTC–trial, which is composed of over 2500 patients [3]. However, only 7% of the EORTC–collective has been treated with BCG, so the progression risk is overestimated here. The challenge is to find the balance between overtreatment and understaging [4]. The response to BCG–therapy depends on the residual tumor status in TUR and on the presence of CIS. BCG–failure occurs in about 50% of cases and is defined as a relapse or progression to MIBC, a higher tumor grade, or CIS during 3 month and 6 month follow up visits. Patients with BCG failure or recurrence after BCG are unlikely to respond to further BCG therapy; therefore, radical cystectomy is the preferred option. This underlines the need to recommend early radical cystectomy, especially in case of failure of intravesical therapy. According to EAU guidelines, immediate radical cystectomy should be offered to those patients with BCG–failure and NMIBC who are at highest risk of progression [4]: Multiple and/or large (>3 cm) T1, high grade tumors T1, high grade tumors with concurrent CIS Recurrent T1, (HG/G3) tumors T1, G3 and CIS in prostatic urethra Micropapillary variant of urothelial carcinoma Shariat et al. analysed the correlation between clinical (TUR specimen, imaging, bimanual examination) staging before and pathological staging after radical cystectomy. Nearly half (48%) of cT1–patients were upstaged after cystectomy [5]. One of the problems is a low objective reproducibility of the evaluation of TUR pathology. Delay of radical cystectomy may lead to decreased disease–specific survival [6]. A systematic review of over 3000 patients demonstrated the progression of pT1, from high grade to MIBC, in 21% of patients and 14% died as a result of BCa after a median follow–up of 48–123 months. These events occurred relatively early, mainly within 48 months [7]. In another trial 33.4% were upstaged to non–organ–confined stage (≥T3), 16.2% presented lymph node metastases and 35.5% of patients died of metastatic disease during the 2 year follow–up [8]. The overall oncological outcome is good in ≤pT3, pN0 stages and gets dramatically worse with positive lymph nodes and positive surgical margins. We have also learned from studies concerning neoadjuvant chemotherapy, that a delay of cystectomy of over 3 months can lead to worse pathology results and decreased survival [1]. Another argument for an early cystectomy is the functional postoperative result. An early cystectomy for T1–tumor with a possibility of orthotopic urinary diversion is a reasonable oncological treatment option for men and women. The best possible functional result, with high continence and maintained sexual function, can be achieved in these cases due to the preservation of neurovascular bundles in men and of lateral vaginal walls in women [9]. With increasing age there is a higher risk for comorbidities and complications after cystectomy. Poletajew and colleagues present data on the waiting time of patients with urothelial carcinoma of the bladder from establishing the indications for radical cystectomy to surgery in Polish urological centres and analyse the factors that influence it. The waiting time in most cases in Poland did not exceed 90 days, with shortest referral times occurring in provincial hospitals (median waiting time 45 days). However, in the substantial number of cases (22%, 121 patients) radical cystectomy was postponed significantly over 90 days [2]. It would be of great value to compare the disease specific survival of the patients with the waiting time over 90 days vs. those with a time of less than 90 days. Further studies could help to determine the influence of cystectomy delay on functional outcome and patient survival.

The Impact of Income on Clinical Outcomes in FIGO Stages I to II Endometrioid Adenocarcinoma of the Uterus

To determine the influence of income on clinical outcomes in patients with surgical stages I to II endometrioid adenocarcinoma of the uterus. We retrospectively analyzed the records of 660 women initially treated from 1985 to 2009. On the basis of income data obtained from the 2000 US census, patients were separated into various income groups (halves, tertiles, and quartiles) based on median household income, with most focus on the half income groups. Income groups were similar regarding treatments received and characteristics, with the exception of more African American (AA), unmarried patients, and a predilection for higher grade in the lower half income group (LHIG). Compared with the upper half income group (UHIG), the LHIG had lower disease-specific survival (DSS) (5 y: 93.9% vs. 97.0% and 10 y: 90.1% vs. 95.9%; P=0.023) and a trend toward lower overall survival (OS) (5 y: 83.4% vs. 86.5% and 10 y: 62.6% vs. 68.5%; P=0.067). In patients with higher-risk features, differences in outcomes between LHIG and UHIG were more pronounced; 10-year OS of 43.4% versus 60.2% (P=0.004) and 10-year DSS of 75.0% versus 93.0% (P=0.007), respectively. Regarding race, AA patients in the LHIG had lower OS than AA in the UHIG. On univariate analysis, income group and race were significant predictors for DSS, but on multivariate analysis, they were not statistically significant. Despite similar treatments and characteristics, a small decrease in DSS and a trend toward reduced OS was observed in LHIG patients, but income group was not statistically significant on multivariate analysis of outcome. These differences were more significant in patients with high-risk features.

Dynamin 3: a new candidate tumor suppressor gene in hepatocellular carcinoma detected by triple combination array analysis

BackgroundTo identify genes associated with hepatocellular carcinoma (HCC) pathogenesis, we developed a triple combination array strategy comprising methylation, gene expression, and single nucleotide polymorphism (SNP) array analysis.MethodsSurgical specimens obtained from a 68-year-old female HCC patient were analyzed by triple combination array, and identified Dynamin 3 (DNM3) as a candidate tumor suppressor gene in HCC. Subsequently, samples from 48 HCC patients were evaluated for DNM3 methylation and expression status using methylation specific polymerase chain reaction (PCR; MSP) and semi-quantitative reverse transcriptase (RT)-PCR, respectively. The relationship between clinicopathological factors and DNM3 methylation status was also investigated.ResultsDNM3 was shown to be hypermethylated (methylation value 0.879, range 0–1.0) in cancer tissue compared with adjacent normal tissue (0.213) by methylation array in the 68-year-old female patient. Expression arrays revealed decreased expression of DNM3 in cancerous tissue. SNP arrays revealed that the copy number of chromosome 1q24.3, in which DNM3 resides, was normal. MSP revealed hypermethylation of the DNM3 promoter region in 33 of 48 tumor samples. A trend toward decreased DNM3 expression was observed in patients with DNM3 promoter methylation (P = 0.189). Furthermore, patients with reduced expression of DNM3 in tumor tissues exhibited worse prognosis with decreased disease specific survival compared to patients without decreased expression (P = 0.014).ConclusionThe present study indicates that a triple combination array strategy is an effective method to detect novel genes related to HCC. We propose that DNM3 is a tumor suppressor gene in HCC.

AJCC Cancer Staging Manual 7th Edition Criteria for Colon Cancer: Do the Complex Modifications Improve Prognostic Assessment?

The 7th edition of the AJCC Cancer Staging Manual (AJCC-7) includes substantial changes for colon cancer (CC), which are particularly complex in patients with stage II and III disease. We used a national cancer database to determine if these changes improved prediction of survival. The database of the Surveillance, Epidemiology and End Results Program was queried to identify patients with pathologically confirmed stage I to III CC diagnosed between 1988 and 2008. Colon cancer was staged by the 6(th) edition of the AJCC Cancer Staging Manual (AJCC-6) and then restaged by AJCC-7. Five-year disease-specific survival and overall survival were compared. After all exclusion criteria were applied, AJCC-6 and AJCC-7 staging was possible in 157,588 patients (68.9%). Bowker's test of symmetry showed that the number of patients per substage was different for AJCC-6 and AJCC-7 (p < 0.001). The Akaike information criteria comparison showed superior fit with the AJCC-7 model (p < 0.001). However, although AJCC-7 staging yielded a progressive decrease in disease-specific survival and overall survival of patients with stage IIA (86.3% and 72.4%, respectively), IIB (79.4% and 63.2%, respectively), and IIC (64.9% and 54.6%, respectively) CC, disease-specific survival and overall survival of patients with stage IIIA disease increased (89% and 79%, respectively). Subset analysis of patients with >12 lymph nodes examined did not affect this observation. The AJCC-7 staging of CC does not address all survival discrepancies, regardless of the number of lymph nodes examined. Consideration of other prognostic factors is critical for decisions about therapy, particularly for patients with stage II CC.

Association of BDNF and BMPR1A with clinicopathologic parameters in benign and malignant gallbladder lesions

BackgroundNeurotrophic factors such as brain derived neurotrophic factor (BDNF) are synthesized in a variety of neural and non-neuronal cell types and regulate survival, proliferation and apoptosis. In addition, bone morphogenetic proteins (BMPs) inhibit the proliferation of pulmonary large carcinoma cells bone morphogenetic protein receptor, type IA (BMPR1A). Little is known about the expression of BDNF or BMPR1A in malignant gall bladder lesions. This study was to evaluate BDNF and BMPR1A expression and evaluate the clinicopathological significance in benign and malignant lesions of the gallbladder.MethodsThe BDNF and BMPR1A expression of gallbladder adenocarcinoma, peritumoral tissues, adenoma, polyp and chronic cholecystitis were Immunohistochemically determined.ResultsBDNF expression was significantly higher in gallbladder adenocarcinoma than in peritumoral tissues, adenoma, polyps and chronic cholecystitis samples. However, BMPR1A expression was significantly lower in gallbladder adenocarcinoma than in peritumoral tissues, adenomas, polyps and chronic cholecystitis tissues. The specimens with increased expression of BDNF in the benign lesions exhibited moderate- or severe-dysplasia of gallbladder epithelium. BDNF expression was significantly lower in well-differentiated adenocarcinomas with maximum tumor diameter <2 cm, no metastasis to lymph nodes, and no invasion of regional tissues compared to poorly-differentiated adenocarcinomas with maximal tumor diameter >2 cm, metastasis of lymph node, and invasiveness of regional tissues in gallbladder adenocarcinoma. BMPR1A expression were significantly higher in the well-differentiated adenocarcinoma with maximal tumor diameter <2 cm, no metastasis of lymph node, and no invasion of regional tissues compared to poorly-differentiated adenocarcinomas with maximal tumor diameter >2 cm, metastasis of lymph node, and invasiveness of regional tissues in gallbladder. Univariate Kaplan-Meier analysis indicated increased expression of BDNF or decreased expression of BMPR1A was associated with decreased disease specific survival (DSS) rates. Similarly, multivariate Cox regression analysis showed increased expression of BDNF or decreased expression of BMPR1A are independent predictors of poor DSS rates in gallbladder adenocarcinoma.ConclusionsIn gallbladder malignancies, the increased expression of BDNF and decreased expression of BMPR1A were associated with increased risk of metastasis, regional invasion and mortality. They might serve as novel indicators of gallbladder adenocarcinoma outcomes, which may prove valuable for the development of personalized therapeutic paradigms.

Prognostic Impact of Age in Differentiated Thyroid Cancer

Objective: 1) Determine the impact of age on disease-specific survival in differentiated thyroid cancer. 2) Compare the impact of age on survival between follicular and papillary thyroid cancer subtypes. Method: The SEER Database was searched for patients with differentiated thyroid cancer between 1988-2003. Patient age, gender, tumor type, size, extension, and metastases were collected. Kaplan-Meier analyses were used to estimate disease specific survival based on age ranges. A multivariate analysis was performed to determine hazard ratios of death for various age cutoffs. Results: A total of 42,209 patients were identified. Patients 45 years and older had significantly worse survival than younger patients ( P &lt; .001). A significant decrease in disease specific survival was first seen in patients aged 35 years and older, and survival continued to steadily decrease with each additional decade of age ( P &lt; .001). Patients aged 35 years and older were 14 times more likely to die from differentiated thyroid cancer than patients younger than 35. Age played a stronger prognotic role in death among patients with papillary carcinoma compared to follicular carcinoma. Conclusion: Increasing age is associated with poorer survival in differentiated thyroid cancer. This relationship represents a continuum with an initial decrease in survival starting at age 35 that continues to decline with advancing age.

Reevaluating the Prognostic Significance of Age in Differentiated Thyroid Cancer

To determine the impact of age on disease-specific survival in differentiated thyroid cancer. Retrospective analysis of a large population database. Setting Surveillance, Epidemiology, and End Results (SEER) database/multiple settings. The SEER database was examined to identify patients diagnosed with either papillary or follicular carcinoma of the thyroid between the years 1988 and 2003. Information obtained included patient age, sex, tumor type, size, extension, and nodal or distant metastases. Kaplan-Meier survival analyses were used to estimate disease-specific survival based on patient age range, and the log-rank test was used to assess for statistical differences between survival curves. A multivariate analysis was performed including the variables listed above to determine disease-specific hazard ratios of death for various age cutoffs. A total of 42,209 patients were identified. Patients 45 years and older had significantly worse survival than younger patients (P < .0001). A significant decrease in disease-specific survival was first seen in patients aged 35 years and older, and survival continued to steadily decrease with each additional decade of age (P < .001). Patients aged 35 years and older were 14 times more likely to die from differentiated thyroid cancer than patients younger than 35 years. Increasing age is associated with poorer survival in differentiated thyroid cancer. This relationship represents a continuum with an initial decrease in survival starting at age 35 years that continues to decline with further advancing age.

Abstract LB-325: Androgen receptor phosphorylation is associated with clinical outcome measures in castrate resistant prostate cancer

Abstract Androgen Receptor phosphorylation is associated with clinical outcome measures in castrate resistant prostate cancer. Pamela McCall, Claire Adams, Yinrue Lim, Morag Sewright, Clare Orange and Joanne Edwards. Prostate cancer has high cancer incidence in males and is the second highest cause of male cancer related mortality. Alterations in androgen receptor (AR) phosphorylation may contribute to prostate cancer development and progression. Investigating the phosphorylation status of the AR in clinical samples will further our understanding of the mechanisms underlying the development of castrate resistant prostate cancer (CRPC) and possibly identify innovative therapeutic targets and prognostic markers. We reported expression of AR phosphorylated at serine 213 (ARs213) was associated with poor prognosis in CRPC patients (McCall et al, BJC 2008). We have extended this patient cohort and investigated which other AR phosphorylation sites are related to progression to CRPC. Immunohistochemical analysis was performed to assess expression levels of AR, ARs81, ARs94, ARs213, ARs308, ARs650 and ARs791 in a cohort of 84 prostate cancer patients. In CRPC high expression of AR and ARs213 was associated of presence of metastases at relapse (p=0.018 and p=0.046, respectively) and with decreased time to death from relapse (p=0.038 and p=0.003). ARs213 is also associated with a decreased overall disease specific survival (p=0.008). In contrast low expression of ARs791 was associated with decreased time to death from relapse (p=0.04) and low expression of ARs308 was associated with decreased disease specific survival (p=0.011). Use of paired tumours from each patient allowed changes in protein expression in the transition from hormone naive to castrate resistant disease to be assessed. Total AR, ARs213 and ARs650 increased with the development of CRPC (p&amp;lt;0.001, p&amp;lt;0.001 and p=0.003 respectively) and ARs81 decreased with the development of CRPC (p=0.001). Akt is postulated to phosphorylate serine sites s213 and s791 on AR. As phosphorylation of the AR at these residues appear to be involved in prostate cancer progression inhibition of PI3K by P85 siRNA treatment was analysed. PI3K specific siRNA treatment decreased the expression of Akts473, ARs213 and ARs791, as expected silencing PI3K has no apparent effect on AR or ARs81 expression. Whether targeted inhibition of AR phosphorylation through PI3K siRNA inhibits prostate cancer cell growth and metastasis in vitro remains to be elucidated. In vitro results suggest that phosphorylation at ARs213 sensitises the AR to low levels of androgens and allow prostate cancer growth in low androgen conditions. Therefore ARs213 may serve as a diagnostic tool to predict patient outcome in response to hormone deprivation therapy and inhibition of ARs213 via the PI3K pathway may be an effective therapeutic avenue to investigate for treatment of prostate cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-325. doi:10.1158/1538-7445.AM2011-LB-325

Abstract LB-44: Effect of modulation of I kappa B kinases (IKKs) in prostate cancer cell growth and apoptosis

Abstract Prostate cancer is the most common cancer in men. Although a wide variety of treatments such as surgery, radiation and hormone therapy exist, patients diagnosed with locally advanced or metastatic disease eventually progress to a castrate resistant state [1]. Understanding the mechanism by which castrate resistant prostate cancer (CRPC) develops remains a major issue. Elevated nuclear factor kappa B (NFkB) activity has been observed in many tumors including prostate cancer [2]. In this study, we employed patient samples in combination with in vitro methods to examine the role of NFkB and IKKs in prostate cancer growth and apoptosis. Tissue microarray technology was employed to assess NFkB p65 protein expression in 255 prostate cancer specimens obtained at diagnosis. Immunohistochemistry was performed using an antibody to p65 and expression assessed using the weighted histoscore method. IKKα and/or IKKβ were down regulated in PC3 cells by electroporation with specific siRNA. The effects of IKKα and/or IKKβ silencing on cell growth, cell cycle markers and apoptosis were examined. Full clinical follow-up was available for the patient cohort, mean follow-up was 8.05 years, 129 patients died of their disease and 56 patients had metastases at diagnosis. Gleason sum (p=0.001), presence of metastasis (p=0.001), stage (p=0.016) and androgen receptor status (p=0.002) significantly correlated with decreased disease specific survival. NFkB p65 expression was observed in both the tumor cell cytoplasm and nucleus (location when activated). Cytoplasmic p65 expression was not associated with any known clinical parameters, however high (supra medium) nuclear p65 expression was associated with decrease in disease specific survival (p=0.005) and this was independent when combined with Gleason sum, presence of metastasis stage and androgen receptor status on multivariate analysis (p=0.004, hazard ratio 4.5 (1.6-12.8)). We further designed a series of experiments to assess the effect of inhibiting NFkB activation on prostate cancer cells via knocking down IKKα and/or IKKβ expression. When IKKα and IKKβ alone or combined were silenced, p65 expression in PC3 cells was observed only in the cell cytoplasm and not in the nucleus, suggesting NFkB activation had been inhibited. However, no significant effect on cell proliferation (as measured by WST-1) or apoptosis (Annexin V/ ViaProbe) was observed. Furthermore, no significant change was observed in protein levels of cyclin D1, A, B1 or E as measured by western blotting, however an inhibition of Wee 1, a known G2 checkpoint regulator, was observed following IKKβ silencing revealing a novel cell cycle target for IKKs. In conclusion, NFkB p65 nuclear expression is a negative prognostic marker for prostate cancer at diagnosis and modification of IKKα and IKKβ alone or combined may offer a potential therapeutic target by modifying the functions of cell cycle regulators.

Abstract 3368: Characterization of stem cell like cells in kidney cancer

Abstract Contemporary tumor biology challenges the previous belief that all cancer cells are capable of sustaining tumor growth. Instead, data is accumulating in favor of a concept where a small percentage of the total tumor cell number, are believed to have the capacity to drive cancerous growth. These cells are called tumor initiating cells or cancer stem cells (CSCs). The presence of CSCs in the tumor may increase malignancy potential, mediate resistance to conventional therapy and lead to poor survival outcomes. To achieve effective prognostic and therapeutic strategies it is important to identify markers for and CSC-unique properties. Our study aims at identifying cells with stem cell like properties in renal cell carcinoma (RCC) and specify their role in tumorigenesis. ALDH activity has been used to isolate hematopoetic and breast stem cells and high expression of ALDH has been identified in breast cancer with poor prognosis. We have used the ALDEFLUOR assay to isolate stem cell like cells from both primary and established RCC cultures. We found that the ALDH positive cells have a greater colony forming capacity and ability to grow under low attachment conditions, as compared to cells with low ALDH activity. We also found that CD133, another known stem cell marker, was expressed at higher levels in the ALDH positive cells. The ALDH positive cells were characterized using global gene expression analysis, producing a framework for further characterization. The clinical validity of this population was assessed using gene expression from a data set of 176 primary RCCs and these analysis indicate that the stem cell expression profile is associated with decreased disease specific survival. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3368.

Abstract 4711: The role ERK1/2 and Androgen Receptor phosphorylation at serine 81 in the progression from hormone naive to castrate resistant prostate cancer

Abstract Prostate cancer incidence in the UK is approximately 35,500 cases per year and the second most common cause of male cancer-specific death. The high mortality rate associated with prostate cancer is attributed to the development of castrate resistance prostate cancer (CRPC). Following the development of CRPC there are few therapeutic options with the mean survival period being only 18-24 months. Cell line studies implement ERK1/2 activation in the transition from hormone naïve prostate cancer (HNPC) to CRPC. Recent evidence suggests that ERK kinase activation induces phosphorylation of AR at Serine 81 (AR81) to stimulate prostate cancer cell growth and induce PSA expression (Shigemura K et al Prostate 2009, 69(9) 949-955). This data suggests that the ERK kinase pathway may provide a novel therapeutic target for treatment of CRPC The aim of the current study was to investigate if the relationship between the AR and ERK1/2 is upheld in clinical prostate cancer specimens. A cohort of 55 patients with matched HNPC and CRPC tissue was established with full clinical follow-up. Immunohistochemistry was employed to assess expression of AR, AR81, ERK1/2 and phosphorylated ERK1/2 (pERK). All 55 patients in the cohort were diagnosed with HNPC and subsequently progressed to CRPC. The median age at diagnosis was 70(66-73), median Gleason sum at diagnosis was 8(6-9) and median time to biochemical relapse was 2.3 years. Mean follow-up was 7.5 (4.3-11.7) years, 4 patients were alive at last follow-up, 35 patients died of their disease and 16 patients died of other causes. In the transition of HNPC to CRPC 8% of patients exhibited an increase in AR81 expression and 20% exhibited an increase in ERK1/2 expression. PSA at diagnosis (p=0.034) and high pERK expression in HNPC (p=0.03) were associated with shorter time to biochemical relapse. A negative correlation between AR and ERK1/2 expression was observed in HNPC (R2=-0.383, p=0.004), but no association with AR81 and ERK1/2 or pERK was observed in this stage of disease. Gleason sum (p=0.009), presence of metastasis at diagnosis (p=0.0002), presence of metastasis at relapse (p=0.003) and high ERK1/2 expression in CRPC (p=0.003) were associated with shorter disease specific survival. In CRPC no correlations were observed between AR or AR81 and ERK1/2 or pERK. AR81 expression did however positively correlate with proliferation index as assessed by Ki67 expression (R2=0.339, p=0.025). Combined expression of AR81 and ERK1/2 resulted in a significantly shorter disease specific survival. Whereas, expression of these protein alone (4.2 years vs. 5.4 years) or not at all (7.2 years) resulted in a longer disease specific survival p=0.0006. In conclusion, although no correlations with AR81 and ERK1/2 or pERK were observed in the current study, high expression of AR81 and ERK1/2 combined had a synergistic effect of decreased disease specific survival. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4711.

Src Kinase Family Members Expression in Human Breast Tissue and Their Association to Clinical Outcome of Breast Cancer Patients.

Abstract Background: There is a paucity in the literature about expression levels of Src kinase family members (SKFMs) in human breast tissue. The aim of this study was to assess m-RNA SKFM expression levels in human breast specimens and to assess protein expression of the most significant SKFMs in invasive breast cancer to establish their association to clinical outcome.Material and Methods: m-RNA expression of eight SKFMs (Src, Lck, Lyn, Fgr, Fyn, Hck, Blk, Yes) was assessed by quantitative real time PCR. IHC was performed using antibodies to c-Src, Y419Src, Lck and Lyn. Expression was assessed using the weighted histoscore method.Results: Cohort one consisted of 52 invasive breast cancers (M), 36 non-malignant (NM) and 10 normal (N) breast tissue samples. Median age of the patients was 60 years. Median size of breast cancer was 25mm (IQR 20-40mm). ER status was not significantly different between tissue types (p=0.50). Every SKFM expression was quantified in all tissue samples. Fyn was the most expressed SKFM in normal tissue and Lyn in the NM breast tissue. Blk was the least expressed SKFM in all breast tissues. In malignant breast tissue Src and Lyn were most expressed. Higher expression levels of Lck were observed in invasive breast cancers compared to NM and N (p=&amp;lt;0.001). SKFMs Lck and Lyn were higher expressed in ER negative compared to ER positive tumours. c-Src (p=0.01) and Fyn (p=0.03) were expressed at higher levels in lobular compared to ductal carcinomas. There were no correlations observed between c-Src and SKFMs in N breast tissue. However in NM and M tissue, all seven SKFMs correlated with c-Src expression; strongest correlation observed was with Lyn (p&amp;lt;0.001, c.c 0.805) and least with Yes (p=0.003, c.c.=0.489). No association was noticed between SKFM expression, tumour grade, size and LN positivity.Cohort two consisted of 320 patients with median follow-up of 6.3 years. Median age was 58 years (IQR 24-90). Median tumour size was 20mm (IQR 15-30mm). In both cohorts majority of the cancer specimens were pathologically graded as G2 and G3. 49% of the patients were axillary lymph node positive. High cytoplasmic Src and membrane Y419Src kinase expression levels were significantly associated with decreased disease specific survival (p=0.028, p=0.023). Lyn was not associated with survival at any cellular location. High membrane Lck expression was significantly associated with improved survival (p=0.039).Patient Cohort 2 Patient NumbersP valueAge&amp;lt;50 yrs810.351 &amp;gt;50 yrs239 Tumour typeDuctal2980.714 Lobular18 Others6 Grade1220.014 2152 3146 Size&amp;lt;20mm126&amp;lt;0.001 20-50mm173 &amp;gt;50mm21 ER statusPositive212&amp;lt;0.001 Negative108 PR statusPositive1520.006 Negative168 HER2 statusPositive550.010 Negative265 c-Src cytoplasmPositive1410.023 Negative179 Y419Src membranePositive1540.028 Negative166 Lck membranePositive140.039 Negative266 Discussion: All eight SKFMs are expressed in different breast tissues. In invasive breast cancer Src kinase is highest expressed and seems to have a negative impact on disease specific survival. Whereas, high membrane expression of Lck provides better clinical outcome in those breast cancer patients. Further investigations are required to determine underlying mechanisms for this observation. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 6130.

The significance of the ratio of metastatic to examined lymph nodes in endometrioid uterine cancer

15043 Background: To determine the impact benign to positive lymph node ratio (LNR) on the disease-specific survival of women with advanced endometrioid corpus cancer. Methods: Demographic and clinico-pathologic information were obtained from the Surveillance, Epidemiology and End Results Program from 1988–2001 and analyzed using Kaplan-Meier methods and Cox proportional hazards regression. Results: Of the 1,222 women diagnosed with stage IIIC-IV endometrioid uterine cancer with nodal disease, the median age was 64 (range: 28–93). 1,025 (83.9%) were White, 75 (6.1%) Black, 91 (7.5%) were Asian and 31 (2.5%) were Other. All patients underwent surgical staging including a lymph node assessment and were found to have nodal metastases. 639 (52.3%) had stage IIIC, 24 (2.0%) IVA, and 559 (45.7%) IVB disease. Furthermore, 123 (10.1%), 466 (38.1%), and 581 (47.6%) women had grade 1, 2, and 3 disease, respectively. Grade information was unavailable for 51 (4.2%) patients. The benign to positive lymph node ratios (LNR) were divided in four subgroups: ≤5%, &gt;5% to ≤10%, &gt;10% to ≤20%, and &gt;20% to determine impact of LNR on disease-specific survival. Increasing LNR (≤5%, &gt;5% to ≤10%, &gt;10% to ≤20%, and &gt;20%) was associated with a decrease in disease-specific survival at 83.8%, 73.2%, 62.4%, and 50.8%, respectively (p &lt; 0.0001). More specifically, LNR was an important factor only in patients with 11–20 and &gt;20 lymph nodes removed but not for those with less than 10 nodes resected. Women with higher (LNR) received significantly more adjuvant radiotherapy at 72.0%, 69.7%, 61.1%, and 52.6%, respectively. On multivariate analysis, age, stage, grade, and lymph node ratio were significant independent prognostic factors for survival. Adjuvant radiation was not an important independent prognostic factor in multivariate analysis. Conclusion: The ratio of metastatic to examined lymph nodes in endometrioid uterine cancer is an important prognostic factor. Clinical trials on adjuvant therapy should be designed with consideration of this significant prognosticator. No significant financial relationships to disclose.

Management of T3N1 Glottic Carcinoma: Therapeutic Outcomes

The aim of the current study was to determine the best total laryngectomy (TL) approach to the treatment of T3N1 glottic cancer, to study the impact of early nodal disease on stage III glottic cancers, and to describe the preliminary results in a group of patients recently treated for laryngeal preservation (LP). A retrospective study of Tumor Research Project data were performed on previously untreated patients with T3N1 glottic squamous cell carcinoma who were treated with curative intent by TL and neck dissection (ND) with or without adjuvant radiation therapy (TL +/- RT) from April 1, 1955 to October 8, 1999 at Washington University School of Medicine/Barnes Jewish Hospital. A preliminary analysis of a similar group of patients more recently treated for LP (1-1-2000 to 1-1-2005) is reported. Forty-two patients with T3N1 glottic carcinoma were treated with TL and ND (TL/ND-16) and TL with ND and TL (TL/ND/RT-26). The 5 year observed survival (OS) and disease-specific survival (DSS) for TL/ND were similar at 62.5%. The 5 year OS and DSS for TL/ND/RT were 53.8% and 58.3%, respectively. There was no survival difference between the two methods. The overall local-regional control rate was 73.9% (11/42 recurrences). The overall recurrence rate was 38%, with 7.1% recurrence at both the primary site and neck. Recurrence was not related to treatment method. The overall salvage rate (5 year DSS after retreatment) was 20% with 50% salvage for patients with neck recurrence. No patients with local recurrence were survivors. The incidence of second primary cancers was 6.8%. More recently, 26 similar patients were treated with LP techniques. Preliminary results showed a 3 year OS of 63.5% and DSS of 76.8%. Local-regional control was 85.4%. LP was 88.5%. The two TL modalities had statistically similar results in terms of survival, recurrence, and complications. Decreased DSS was seen in older patients (>65 years) and in patients with involved resection margins, recurrent disease, and distant metastasis. Patients with T3N1 glottic cancer had an 8% decrease in DSS compared to patients with T3N0 disease. Previously patients with T3N1 disease have been treated with TL resulting in loss of natural voice in all patients. Preliminary results on 26 patients with T3N1 disease, treated between 2000 and 2005 with voice preservation intent, indicate that the OS, DSS, and local-regional control rates were similar to the TL group, whereas 88.5% of patients maintained natural voice and natural breathing. Use of LP techniques should be the initial therapeutic approach for patients with T3N1 glottic cancer.

The Impact of Radiotherapy for Post-operative Patients with Stage II or Stage III Non-Small Cell Lung Cancer Utilizing the Surveillance, Epidemiology, and End Results Database

Purpose/Objective: We investigated the impact of post-operative radiotherapy (PORT) on overall survival (OS) and disease specific survival (DSS) for patients with Stage II or III Non-Small Cell Lung Cancer (NSCLC) who had undergone a definitive surgical procedure utilizing the Surveillance, Epidemiology, and End Results Database (SEER). Materials/Methods: We selected (within SEER) adult patients diagnosed between and including 1988 and 2001 with Stage II or III NSCLC who underwent a lobectomy or pneumonectomy. Patients were excluded from analysis if they received radiotherapy other then PORT or if they had N3 nodal disease. Patients were also excluded if complete information was not available for extent of disease, course of therapy, and cause of death, if applicable. To account for peri-operative mortality, patients were excluded if survival was 3 months or less. Categorical variables included T-stage (T1/T2 vs. T3/T4), size of tumor (< 3cm vs. > 3 cm), N-stage (N0, N1, and N2), number of positive lymph nodes (less then 3 vs. 3 or more), histology (brochioalveolar carcinoma vs. other), and the use of PORT. OS and DSS were the study endpoints. Results: A total of 6953 patients with a median age of 66 years met our selection criteria, or which 3390 (48.76%) received PORT. The median follow-up for patients still alive was 3.25 years. On univariate analysis, size greater then 3 cm (p<0.0001), T3/T4 T-stage (p<0.0001), non N0 N-stage (p<0.0001), 3 or more positive lymph nodes (p<0.0001), non-brochioalveolar histology (p=0.0075), and the use of PORT (p=0.0003) were associated with worse survival. When a multivariate model was constructed utilizing all categorical variables, only non-bronchioalveolar histology (p=0.0901) and use of PORT (p=0.5548) failed to maintain significance. When DSS was examined, patients who received PORT were more likely to die of lung cancer in both univariate (p<0.0001) and multivariate analysis (p=0.0419). Subgroup analysis was performed for patients with N2 nodal disease with univariate analysis showing that patients who received PORT had increased OS (p=0.0029) and DSS (p=0.0336). The 5 year OS for patients with N2 nodal disease who received PORT was 26.9 ± 1.4%, while for other patients it was 18.7 ± 2.0%. The 5 year DSS for patients with N2 nodal disease who receive PORT was 35.0 ± 1.6%, while for other patients it was 25.8 ± 2.4%. When subgroup multivariate analysis for patients with N2 nodal disease was performed with the other categorical variables, the use of PORT maintained prognostic significance for both improved OS (HR=0.826; CI:0.736-0.926; p=0.0011) and improved DSS (HR=0.854; CI:0.751-0.970; p=0.0150). Conclusions: In our large retrospective series of almost 7000 patients with stage II and III NSCLC, PORT does not appear to impact on OS and has a significant decrease in DSS. This decrease in DSS may likely be a reflection of standard clinical practice to offer PORT to patients with early stage disease with factors associated poorer prognosis. Importantly, PORT was associated with improved outcomes for both OS and DSS in patients with N2 disease.

998: Lymphov Ascular Invasion Independently Predicts Decreased Disease Specific Survival in Patients with Transitional Cell Carcinoma of the Upper Urinary Tract

You have accessJournal of UrologyDiscussed Poster, Tuesday, May 24, 2005, 8:00 am - 12:00 pm1 Apr 2005998: Lymphov Ascular Invasion Independently Predicts Decreased Disease Specific Survival in Patients with Transitional Cell Carcinoma of the Upper Urinary Tract Eiji Kikuchi, Yutaka Horiguchi, Naoki Hatakeyama, Mayuko Matsumoto, Toru Nishiyama, Akira Miyajima, Jun Nakashima, and Masaru Murai Eiji KikuchiEiji Kikuchi More articles by this author , Yutaka HoriguchiYutaka Horiguchi More articles by this author , Naoki HatakeyamaNaoki Hatakeyama More articles by this author , Mayuko MatsumotoMayuko Matsumoto More articles by this author , Toru NishiyamaToru Nishiyama More articles by this author , Akira MiyajimaAkira Miyajima More articles by this author , Jun NakashimaJun Nakashima More articles by this author , and Masaru MuraiMasaru Murai More articles by this author View All Author Informationhttps://doi.org/10.1016/S0022-5347(18)35154-1AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail "998: Lymphov Ascular Invasion Independently Predicts Decreased Disease Specific Survival in Patients with Transitional Cell Carcinoma of the Upper Urinary Tract." The Journal of Urology, 173(4S), p. 270 © 2016 by American Urological AssociationFiguresReferencesRelatedDetails Volume 173Issue 4SApril 2005Page: 270 Advertisement Copyright & Permissions© 2016 by American Urological AssociationMetricsAuthor Information Eiji Kikuchi More articles by this author Yutaka Horiguchi More articles by this author Naoki Hatakeyama More articles by this author Mayuko Matsumoto More articles by this author Toru Nishiyama More articles by this author Akira Miyajima More articles by this author Jun Nakashima More articles by this author Masaru Murai More articles by this author Expand All Advertisement Loading ...

Association of cyclooxygenase-2 and matrix metalloproteinase-2 expression in human breast cancer

Expression of cyclooxygenase-2 (COX-2) and matrix metalloproteinase-2 (MMP-2) associates with reduced survival in human breast cancer. COX-2 may be directly involved with mammary carcinogenesis, since expression of COX-2 is sufficient for formation of breast tumors in transgenic mice, and COX-2 selective inhibitors can suppress tumorigenesis in rodent models of breast cancer. MMP-2 is an extracellular matrix degrading proteolytic enzyme that bas been linked to invasion and metastasis. A direct link between COX-2 and MMP-2 may exist, since inhibition of COX-2 activity can result in reduction of MMP-2 expression and activity. In this study we analyzed protein expression of COX-2 and MMP-2 in tissue array specimens of 278 invasive breast cancers by immunohistochemistry. Immunopositivity of these two markers was correlated with each other and with various clinicopathological parameters including survival. We found high COX-2 expression in 30% and high MMP-2 expression in 83% of the breast cancer specimens, and there was a positive association between the expression of these two factors (p = 0.003). It was especially evident that whenever COX-2 expression was high, MMP-2 expression was almost invariably high (95%). Furthermore, high expression of either COX-2 or MMP-2 associated with decreased disease specific survival when compared with the COX-2 or MPP-2 low group (p = 0.026 and p = 0.021, respectively). Taken together, our results indicate that expression of COX-2 protein is associated with expression of MMP-2 protein in human breast cancer and that both COX-2 and MMP-2 are markers of poor prognosis in breast cancer.