Aggressive Pathological Features Research Articles

Role of fibroblast growth factor in squamous cell carcinoma of the bladder: Prognostic biomarker and potential therapeutic target

BackgroundWe evaluated the association of fibroblast growth factor (FGF2) expression with pathologic features and clinical outcomes of squamous cell carcinoma (SCC) of the urinary bladder. MethodsImmunohistochemistry of FGF2 was performed on radical cystectomy specimens with pure SCC from 1997 to 2003. The relationship between FGF2 and pathologic parameters and oncological outcome was assessed. ResultsThe study included 151 patients with SCC (98 men) with a median age of 52 years (range: 36–74y). Schistosomal infection was found in 81% of patients. Pathologic category was T2 and T3 in 88% of patients and the grade was low in>50%. Lymph node invasion and lymphovascular invasion were found in 30.5% and 16%. Altered FGF2 was associated with tumor grade (P = 0.014), lymph node invasion, and lymphovascular invasion (P = 0.042). Altered FGF2 was associated with both disease recurrence and cancer-specific mortality (P≤0.001) in Kaplan-Meier analyses and was an independent predictor of cancer recurrence (hazard ratio = 2.561, P = 0. 009) and cancer-specific mortality (hazard ratio = 2.679, P = 0. 033) in multivariate Cox regression analyses. Adding FGF2 to a model including standard clinicopathologic prognostics (pathologic T category, lymph node status, and grade) showed a significant improvement (6%) in accuracy of prediction poor oncological outcome. ConclusionsFGF2 overexpression is associated with aggressive pathologic features and worse outcomes after radical cystectomy for SCC, suggesting a good prognostic and possible therapeutic role.

Nicotinamide Phosphoribosyltransferase Promotes Epithelial-to-Mesenchymal Transition as a Soluble Factor Independent of Its Enzymatic Activity

Boosting NAD(+) biosynthesis with NAD(+) intermediates has been proposed as a strategy for preventing and treating age-associated diseases, including cancer. However, concerns in this area were raised by observations that nicotinamide phosphoribosyltransferase (NAMPT), a key enzyme in mammalian NAD(+) biosynthesis, is frequently up-regulated in human malignancies, including breast cancer, suggesting possible protumorigenic effects for this protein. We addressed this issue by studying NAMPT expression and function in human breast cancer in vivo and in vitro. Our data indicate that high NAMPT levels are associated with aggressive pathological and molecular features, such as estrogen receptor negativity as well as HER2-enriched and basal-like PAM50 phenotypes. Consistent with these findings, we found that NAMPT overexpression in mammary epithelial cells induced epithelial-to-mesenchymal transition, a morphological and functional switch that confers cancer cells an increased metastatic potential. However, importantly, NAMPT-induced epithelial-to-mesenchymal transition was found to be independent of NAMPT enzymatic activity and of the NAMPT product nicotinamide mononucleotide. Instead, it was mediated by secreted NAMPT through its ability to activate the TGFβ signaling pathway via increased TGFβ1 production. These findings have implications for the design of therapeutic strategies exploiting NAD(+) biosynthesis via NAMPT in aging and cancer and also suggest the potential of anticancer agents designed to specifically neutralize extracellular NAMPT. Notably, because high levels of circulating NAMPT are found in obese and diabetic patients, our data could also explain the increased predisposition to cancer of these subjects.

Lack of Associations between Body Mass Index and Clinical Outcomes in Patients with Papillary Thyroid Carcinoma.

BackgroundObesity is associated with aggressive pathological features and poor clinical outcomes in breast and prostate cancers. In papillary thyroid carcinoma (PTC), these relationships remain still controversial. This study aimed to evaluate the associations between body mass index (BMI) and the clinical outcomes of patients with PTC.MethodsThis retrospective study included 1,189 patients who underwent total thyroidectomy for PTCs equal to or larger than 1 cm in size. Clinical outcomes were evaluated and compared based on the BMI quartiles.ResultsThere were no significant associations between BMI quartiles and primary tumor size, extrathyroidal invasion, cervical lymph node metastasis, or distant metastasis. However, an increase in mean age was associated with an increased BMI (P for trend <0.001). Multifocality and advanced tumor-node-metastasis (TNM) stage (stage III or IV) were significantly associated with increases of BMI (P for trend 0.02 and <0.001, respectively). However, these associations of multifocality and advanced TNM stage with BMI were not significant in multivariate analyses adjusted for age and gender. Moreover, there were no differences in recurrence-free survivals according to BMI quartiles (P=0.26).ConclusionIn the present study, BMI was not associated with the aggressive clinicopathological features or recurrence-free survivals in patients with PTC.

Bladder cancer in HIV-infected adults: an emerging concern?

IntroductionAs HIV-infected patients get older more non-AIDS-related malignancies are to be seen. Cancer now represents almost one third of all causes of deaths among HIV-infected patients [1]. Albeit bladder cancer is one of the most common malignancy worldwide [2], only 13 cases of bladder cancer in HIV-infected patients have been reported in the literature so far [3].Materials and MethodsWe conducted a monocentric study in our hospital. We selected all patients who were previously admitted (from 1998 to 2013) in our hospital with diagnoses of HIV and bladder cancer. The objective was to assess the prevalence and characteristics of bladder cancers in HIV-infected patients in our hospital. ResultsBased on our administrative HIV database (6353 patients), we found 15 patients (0.2%) with a bladder cancer. Patients’ characteristics are presented in Table 1. Patients were mostly men and heavy smokers. Their median nadir CD4 cell count was below 200 and most had a diagnosis of AIDS. A median time of 14 years was observed in those patients, between the diagnosis of HIV-infection and the occurrence of bladder cancer, although in patients much younger (median age 56) than those developing bladder cancer without HIV infection (71.1 years) [4]. Haematuria was the most frequent diagnosis circumstance in HIV-infected patients who had relatively preserved immune function on highly active antiretroviral therapy (HAART). Histopathology showed relatively advanced cancers at diagnosis with a high percentage of non transitional cell carcinoma (TCC) tumor and of TCC with squamous differentiation, suggesting a potential role for human papilloma virus (HPV) co-infection. Death rate was high in this population.ConclusionsBladder cancers in HIV-infected patients remain rare but occur in relatively young HIV-infected patients with a low CD4 nadir, presenting with haematuria, most of them being smokers, and have aggressive pathological features that are associated with severe outcomes.

Abstract 2867: EGFR expression in T1/T2 oral tongue and floor of the mouth carcinoma

Abstract Epidermal growth factor receptor (EGFR) is a molecular maker that regulates the cell growth and plays an important role in tumor proliferation, invasion and metastasis formation. Objective: In this study we examined the association of immunohistochemical expression of EGFR with clinicopathological parameters, lymph node metastasis, regional recurrence and survival in selected cases of early squamous cell carcinoma (SCC) of the oral tongue and floor of the mouth. Methods: Patients with early stage SCC of oral tongue and floor of the mouth were treated surgically at a single institution from 1980 to 2010. Specimens from 139 patients were analyzed for EGFR expression using monoclonal antibody. Results: This study included 139 patients, 96 men (69%), with ages ranging from 21 to 85 years old (mean, 58 years). The tumor site was the tongue in 105 cases (75.5%) and the floor of the mouth in 34 (24.5%). With regard to pathological T-stage, 69 cases were pT1 (52.7%) and 62 were pT2 (47.3%). EGFR was overexpressed in 18 cases (13%) and was significantly associated with pT (p=0.017), thickness greater than 4mm (p=0.017), muscular invasion (p=0.014), desmoplastic reaction (p=0.021), inflammatory infiltrate (p=0.029), lymphatic embolization (p=0.016), mode of invasion (p=0.027) and perineural invasion (p=0.007). The overexpression of EGFR was also associated with lymph node metastasis (p=0.038) and regional recurrence (p=0.014). The cancer-specific survival in 5 years decreased from 90% in the group without EGFR expression to 75.3% in the EGFR overexpression group (p=0.019). Conclusion: The EGFR overexpression was associated with more aggressive pathological features, lymph node metastasis and regional recurrence in patients with early oral tongue and floor of the mouth squamous cell carcinoma. Citation Format: Natalie Kelner, Clovis Antonio Lopes Pinto, Luiz Paulo Kowalski, Claudia Malheiros Coutinho-Camillo. EGFR expression in T1/T2 oral tongue and floor of the mouth carcinoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2867. doi:10.1158/1538-7445.AM2014-2867

653P - Gastric Cancer in Young Patients - a Single Portuguese Experience

ABSTRACT Aim: Gastric cancer (GC) is considered to be a disease of older patients (pts), occurring most frequently in the age group of 50-70 years. Only 2-15% of pts are under 45 years. GC in young pts has more aggressive clinical and pathological features. The role of genetic factors may be more prominent in young people than environmental factors. We aim to describe our experience in young GC management. Methods: Retrospective review of young GC pts (≤45 years) treated at a single Portuguese Cancer Center from 2000-2012. Clinical, pathological, management and survival data were analyzed. Results: Of the 105 pts identified (8% of total GC treated), 19 were excluded because they were treated in other centers. 86 pts had complete data and follow-up at our center; 55.8% were male and mean age was 38.5 ± 0.7years (29.1% under 35 years). 34.4% had smoking habits and 16.3% had a first degree relative with gastric cancer. Main complaints were abdominal pain, weight loss and vomiting. Tumor location was: body – 47.7%, antrum – 44.2%, gastroesophageal junction (GEJ) – 12.8%. Histology: diffuse – 67.4%, intestinal – 26.7%, mixed – 3.5%, squamous cell carcinoma – 2.3%. Stages: I – 19.8%, II – 19.8%, III – 22.1%, IV – 38.4% (peritoneal – 57.6%, hepatic – 39.4%). 23.3% had neoadjuvant chemotherapy (CT). Surgery was performed in 68.6% and 15.3% of them had adjuvant CT. 50% of pts needed palliative chemotherapy (mainly ECF, ECX and Docetaxel). One-year survival was 66.3%, 3-year survival 28% and 5-year survival 19.7%. Median overall survival was 18.4 months (IC95%:14.4-22.5). Conclusions: We found a proportion of young patients with GC similar to the described in the literature. Our patients presented with a high proportion of diffuse histology and more aggressive disease at diagnosis, as already described in other young pts case series. In our results, men/female ratio was 1.26:1, in contrast to other studies that report female predominance. Early mortality was high probably due to high metastatic disease rate at diagnosis, but 3-year survival is similar to historical 3-year survival rate in our Center for all ages GC (31% in 2009). Disclosure: All authors have declared no conflicts of interest.

Phosphorylation of activating transcription factor-2 (ATF-2) within the activation domain is a key determinant of sensitivity to tamoxifen in breast cancer.

Activating transcription factor-2 (ATF-2) has been implicated as a tumour suppressor in breast cancer (BC). c-JUN N-terminal kinase (JNK) and p38 MAPK phosphorylate ATF-2 within the activation domain (AD), which is required for its transcriptional activity. To date, the role of ATF-2 in determining response to endocrine therapy has not been explored. Effects of ATF-2 loss in the oestrogen receptor (ER)-positive luminal BC cell line MCF7 were explored, as well as its role in response to tamoxifen treatment. Genome-wide chromatin binding patterns of ATF-2 when phosphorylated within the AD in MCF-7 cells were determined using ChIP-seq. The expression of ATF-2 and phosphorylated ATF-2 (pATF-2-Thr71) was determined in a series of 1,650 BC patients and correlated with clinico-pathological features and clinical outcome. Loss of ATF-2 diminished the growth-inhibitory effects of tamoxifen, while tamoxifen treatment induced ATF-2 phosphorylation within the AD, to regulate the expression of a set of 227 genes for proximal phospho-ATF-2 binding, involved in cell development, assembly and survival. Low expression of both ATF-2 and pATF-2-Thr71 was significantly associated with aggressive pathological features. Furthermore, pATF-2 was associated with both p-p38 and pJNK1/2 (<0.0001). While expression of ATF-2 is not associated with outcome, pATF-2 is associated with longer disease-free (p=0.002) and BC-specific survival in patients exposed to tamoxifen (p=0.01). Furthermore, multivariate analysis confirmed pATF-2-Thr71 as an independent prognostic factor. ATF-2 is important for modulating the effect of tamoxifen and phosphorylation of ATF-2 within the AD at Thr71 predicts for improved outcome for ER-positive BC receiving tamoxifen.

Higher body mass index may be a predictor of extrathyroidal extension in patients with papillary thyroid microcarcinoma.

Recently, higher body mass index (BMI) has been associated with aggressive pathologic features of papillary thyroid carcinoma. The aim of this study was to clarify the relationship between BMI and aggressive pathologic features of papillary thyroid microcarcinoma (PTMC) and to evaluate whether the BMI can be a prognostic factor of PTMC. This retrospective study included 612 PTMC patients who underwent surgical excision at a referral center between April 2006 and December 2007. Patients were grouped according to BMI (<25 or ≥25 kg/m2). Multivariable logistic regression analysis was performed to determine independent predictors of aggressive pathologic features (advanced stage, extrathyroidal extension, and lymph node metastasis), with adjustment for age, gender, tumor size, multifocality, thyroid stimulating hormone (TSH) level, and BMI (value/group). PTMC patients with a BMI≥25 kg/m2 showed significantly higher prevalences of extrathyroidal extension, advanced pathologic TNM stage, and male gender, compared to those of patients with a BMI<25 kg/m2. Lymph node metastasis and mean TSH level were not significantly different between the two BMI subgroups. In multivariable analysis, the BMI≥25 kg/m2 group was positively associated with the presence of extrathyroidal extension (adjusted odds ratio 1.49, P=0.05). Higher BMI was associated with extrathyroidal extension in PTMC patients. This study suggests that the BMI could be considered as a prognostic factor for predicting the presence of extrathyroidal extension and it may help decide the appropriate surgical extent for PTMC patients.

Net platelet angiogenic activity (NPAA) correlates with progression and prognosis of non-small cell lung cancer.

Circulating platelets are abundant sources of angiogensis molecules for the tumor vasculature affecting tumor growth and metastasis. The relationship between non-small cell lung cancer (NSCLC) and intra-platelet levels of VEGF, TSP-1 and net platelet angiogenic activity (NPAA) is unclear. The aim of this study was to better understand the role of these factors in the progression of NSCLC cancer and to assess its clinical significance. Platelet VEGF and TSP-1 and NPAA were measured preoperatively in 68 patients with NSCLC by ELISA or Capillary tube formation assay. VEGF, TSP-1 and NPAA distributions in cancer patients and healthy volunteers were compared using the Mann-Whitney U test. The Kaplan-Meier method, univariate and multivariate regression analysis was used to analyze the correlation between these factors and clinicopathological features, overall survival and disease-free survival. Mean intra-platelet TSP-1 level was slightly higher in patients than in healthy subjects (p = 0.092). Intra-platelet TSP-1 levels were significantly higher in patients with involvement greater than T2 or stage III, compared to other patients. Mean intra-platelet VEGF level was 40.8 pg/106 in patients compared to 21.9 ng/106 in healthy subjects (p = 0.041). Median value of NPAA in patients was significantly higher than that in healthy controls (p<0.001). Patients with high NPAA are more likely to exhibit aggressive clinical pathological features. NPAA greater than the median are associated with poor prognosis. The elevated NPAA have better correlation with tumor microvessel density (MVD) than platelet-derived VEGF. The areas under receiver operating curve (AUROC) of NPAA were higher than that of platelet derived VEGF in different groups. A multivariate analysis showed that NPAA are independent prognostic factors. These results indicated that NPAA may be a clinically useful indicator for diagnostic and prognostic evaluation in NSCLC patients.

Clinicopathological analysis of intraductal proliferative lesions of prostate: intraductal carcinoma of prostate, high-grade prostatic intraepithelial neoplasia, and atypical cribriform lesion.

Intraductal carcinoma of the prostate (IDC-P) and high-grade prostatic intraepithelial neoplasia (HGPIN) are two distinct intraductal lesions; the former is usually associated with invasive carcinoma and has an aggressive course while the latter is considered a precancerous lesion. In addition, there are morphologically lesions not well characterized that fall between IDC-P and HGPIN, consequently termed "atypical cribriform lesions (ACLs)." Using whole mount radical prostatectomy specimens, we evaluated the relationship between these intraductal proliferative lesions and clinicopathological parameters. In this study, ACLs were characterized as a loose cribriform intraductal proliferation with greater architectural complexity when compared to HGPIN, but lacking significant nuclear pleomorphism and/or comedonecrosis. Of 901 radical prostatectomies (2006-2012), IDC-P, ACL, and HGPIN were recorded in 155, 22, 436 cases, respectively. Patients with IDC-P showed more aggressive pathologic features when compared to HGPIN. Invasive cancers in patients with ACL had higher Gleason score (P=.00016), larger tumor volume (P=.025), and more advanced pT stage (P=.023) than those with HGPIN. Cases with ACL showed a higher risk of biochemical recurrence than those with HGPIN and a lower risk than those with IDC-P based on log-rank tests (P=.0045 and P=.0069, respectively). In multivariate analysis, the presence of HGPIN was identified as an independent predictor for infrequent biochemical recurrence (P=.0058). We confirmed IDC-P as a marker of adverse pathologic features and clinical aggressiveness. Our results suggest that ACL should be distinguished from HGPIN and these lesions mandate active clinical surveillance.

Fatostatin Displays High Antitumor Activity in Prostate Cancer by Blocking SREBP-Regulated Metabolic Pathways and Androgen Receptor Signaling

Current research links aberrant lipogenesis and cholesterogenesis with prostate cancer development and progression. Sterol regulatory element-binding proteins (SREBP; SREBP-1 and SREBP-2) are key transcription factors controlling lipogenesis and cholesterogenesis via the regulation of genes related to fatty acid and cholesterol biosynthesis. Overexpression of SREBPs has been reported to be significantly associated with aggressive pathologic features in human prostate cancer. Our previous results showed that SREBP-1 promoted prostate cancer growth and castration resistance through induction of lipogenesis and androgen receptor (AR) activity. In the present study, we evaluated the anti-prostate tumor activity of a novel SREBP inhibitor, fatostatin. We found that fatostatin suppressed cell proliferation and anchorage-independent colony formation in both androgen-responsive LNCaP and androgen-insensitive C4-2B prostate cancer cells. Fatostatin also reduced in vitro invasion and migration in both the cell lines. Further, fatostatin caused G2-M cell-cycle arrest and induced apoptosis by increasing caspase-3/7 activity and the cleavages of caspase-3 and PARP. The in vivo animal results demonstrated that fatostatin significantly inhibited subcutaneous C4-2B tumor growth and markedly decreased serum prostate-specific antigen (PSA) level compared with the control group. The in vitro and in vivo effects of fatostatin treatment were due to blockade of SREBP-regulated metabolic pathways and the AR signaling network. Our findings identify SREBP inhibition as a potential new therapeutic approach for the treatment of prostate cancer.

MP52-12 COMBINATION OF ANDROGEN RECEPTOR, PTEN AND TMPRSS2-ERG EXPRESSION MAY PREDICT ADVERSE CLINICAL OUTCOMES IN MEN UNDERGOING RADICAL PROSTATECTOMY FOR PROSTATE CANCER

You have accessJournal of UrologyProstate Cancer: Basic Research V1 Apr 2014MP52-12 COMBINATION OF ANDROGEN RECEPTOR, PTEN AND TMPRSS2-ERG EXPRESSION MAY PREDICT ADVERSE CLINICAL OUTCOMES IN MEN UNDERGOING RADICAL PROSTATECTOMY FOR PROSTATE CANCER Claudio Jeldres, Khanh Pham, Xiaoyu Qu, Min Fang, and Christopher R. Porter Claudio JeldresClaudio Jeldres More articles by this author , Khanh PhamKhanh Pham More articles by this author , Xiaoyu QuXiaoyu Qu More articles by this author , Min FangMin Fang More articles by this author , and Christopher R. PorterChristopher R. Porter More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2014.02.1622AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail Introduction and Objectives Several studies have linked genomics abnormality to prostate cancer (PCa), however, to date, a genomic signature to define aggressive disease is sill lacking. The androgen receptor (AR), PTEN and TMPRSS2-ERG expression are well known to be associated with PCa, however, it is unknown how informative they are when used in combination. We hypothesized that a small panel of genomic abnormalities using AR, PTEN and TMPRSS2-ERG expression may help to predict more aggressive disease. Methods We retrospectively reviewed a cohort of 210 patients diagnosed with PCa and treated with radical prostatectomy (RP) at Virginia Mason Medical Center, between 1995 and 2005. Identification of genomic abnormalities was performed for AR, PTEN and TMPRSS2-ERG on RP's specimens using fluorescent in situ hybridization (FISH) technology. AR expression was categorized as: normal vs. AR gain. PTEN expression was categorized as: normal vs. trisomy 10, monosomy 10, homozygous deletion and heterozygous deletion. TMPRSS2-ERG was categorized as: normal vs. single deletion fusion vs. atypical fusion vs. alternative rearrangements vs. rearranged 3'ERG vs. rearranged 5'TMPRSS2 vs. copy number increase without rearrangement. Clinical data such as age at RP, preoperative PSA, pathological Gleason score, pathological stage and biochemical-recurrence (BCR) status was available for all patients. Statistics relied on cross-tabulation and survival analysis. Results Complete clinical and genomic data was available for 151 patients. Median follow-up (n=151) was 5.7 years (range 0.1-16.6 years). The most common genomic features within our cohort were normal AR, PTEN and TMPRSS2-ERG (n=58, 36.5%), and normal AR and PTEN with single deletion fusion (n=33, 21.9%). Aggressive pathological characteristics such as locally advanced disease (pT3/pT4) or high grade Gleason (8-10) score at RP were more commonly seen in patients with normal AR, heterozygous deletion or monosomy 10/PTEN and normal TMPRSS2-ERG. When this group was compared to those with no genomic abnormalities, Gleason 8-10 was seen in 72.7% vs. 8.6% and pT3/T4 in 72.7% vs. 39.7%. Similarly, median BCR-free survival for this group was 1.6 years vs. none reach for the normal group (Log-rank p=0.02). Conclusions Abnormal expression of AR, PTEN and TMPRSS2-ERG are common at radical prostatectomy. Patients with normal AR, normal TMPRSS2-ERG but heterozygous deletion or monosomy 10/PTEN may be at higher risk of harboring adverse pathological features and biochemical recurrence. © 2014FiguresReferencesRelatedDetails Volume 191Issue 4SApril 2014Page: e584 Advertisement Copyright & Permissions© 2014MetricsAuthor Information Claudio Jeldres More articles by this author Khanh Pham More articles by this author Xiaoyu Qu More articles by this author Min Fang More articles by this author Christopher R. Porter More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

The study of the coexistence of Hashimoto’s thyroiditis with papillary thyroid carcinoma

Hashimoto's thyroiditis (HT) is the most common type of autoimmune thyroid disease, and the incidence is rising in recent years. The aim of this study was to evaluate the pathological characteristics, treatment and prognosis of HT with papillary thyroid carcinoma (PTC). From July 2004 to December 2011, 8,524 patients underwent thyroid surgery in our hospital and 1,735 patients were diagnosed with PTC. The data from these patients were statistically analyzed using SAS software. There were 839 patients with a final diagnosis of HT in this study. A greater incidence of PTC was found in those with HT (29.4 %) than those without HT (19.4 %; p < 0.05). Male HT patients had a significantly higher rate of PTC (27/61, 44.3 %) when compared to female patients (220/778, 28.3 %; p < 0.05). The HT patients with co-occurring PTC were more likely to be younger (43.1 vs. 46.6, p < 0.01) and had smaller nodules (1.10 vs. 1.34 cm, p < 0.05), less external invasion (0.4 vs. 2.5 %, p < 0.05), less lymph node metastasis in lateral neck area (17.2 vs. 26.9 %, p < 0.05) and less advanced TNM stages than PTC patients without HT. Hashimoto's thyroiditis is associated with a significantly higher risk of PTC, and the incidence of PTC is much higher in male HT patients. More attention should be paid to HT patients, especially male HT patients, for signs of PTC. Based on the less aggressive pathological features in HT-PTC group, we should not blindly expand the indication and extent of surgery.

Detection of Live Circulating Tumor Cells by a Class of Near-Infrared Heptamethine Carbocyanine Dyes in Patients with Localized and Metastatic Prostate Cancer

Tumor cells are inherently heterogeneous and often exhibit diminished adhesion, resulting in the shedding of tumor cells into the circulation to form circulating tumor cells (CTCs). A fraction of these are live CTCs with potential of metastatic colonization whereas others are at various stages of apoptosis making them likely to be less relevant to understanding the disease. Isolation and characterization of live CTCs may augment information yielded by standard enumeration to help physicians to more accurately establish diagnosis, choose therapy, monitor response, and provide prognosis. We previously reported on a group of near-infrared (NIR) heptamethine carbocyanine dyes that are specifically and actively transported into live cancer cells. In this study, this viable tumor cell-specific behavior was utilized to detect live CTCs in prostate cancer patients. Peripheral blood mononuclear cells (PBMCs) from 40 patients with localized prostate cancer together with 5 patients with metastatic disease were stained with IR-783, the prototype heptamethine cyanine dye. Stained cells were subjected to flow cytometric analysis to identify live (NIR+) CTCs from the pool of total CTCs, which were identified by EpCAM staining. In patients with localized tumor, live CTC counts corresponded with total CTC numbers. Higher live CTC counts were seen in patients with larger tumors and those with more aggressive pathologic features including positive margins and/or lymph node invasion. Even higher CTC numbers (live and total) were detected in patients with metastatic disease. Live CTC counts declined when patients were receiving effective treatments, and conversely the counts tended to rise at the time of disease progression. Our study demonstrates the feasibility of applying of this staining technique to identify live CTCs, creating an opportunity for further molecular interrogation of a more biologically relevant CTC population.

Does adjuvant treatment affect survival in patients with positive lymph nodes at radical prostatectomy?

157 Background: Men who are found to have positive LN at the time of RP are at risk for worse prognosis and outcomes. Our purpose is to determine whether RT after RP has a greater survival benefit than ADT alone or surgery alone in these men. Methods: This study cohort consisted of men who had RP at the University of California, San Francisco. Men with positive pelvic LN were stratified by type of adjuvant therapy: ADT, RT with or without ADT, or RP only. T-test and chi-square were used to compare clinical and pathologic characteristics. Biochemical recurrence-free, metastatic recurrence-free, and disease-specific survival were assessed with the Kaplan-Meier method, log-rank test, and Cox proportional hazards regression. Biochemical recurrence was defined as two consecutive prostate-specific antigen values &gt;=0.2ng/mL. Results: Of the 1,600 men had pelvic LN dissection at time of RP, 105 had positive LN. Mean age was 61 (SD 7). Median number of LN dissected was 14 (IQR 10-21) for pN1 patients versus nine (5 to 15) for pN0, p&lt;0.01. Median percentage of positive LN was 11% (IQR 7-17). Men with positive LN had higher clinical risk and worse pathologic grade, positive margin rates, and T-stage compared to men without positive LN, all p&lt;0.01. Recurrence-free survival was 55% for pN1 versus 81% for pN1 at 5 years, log-rank p&lt;0.01. Following positive LN dissection at RP, 29 men received ADT monotherapy, 43 men received RT (+/- ADT), and 33 had not yet undergone treatment after RP during a median follow up of 28 months (IQR 6 to 70). Rates of seminal vesicle invasion by treatment group were 52% for ADT, 65% for RT (+/- ADT), and 35% for RP only, p=0.03. Men who underwent ADT alone, RT (+/- ADT), and RP only had few outcome events to date and similar rates of MFS (97% versus 93% versus 92%, p=0.76) and DSS (96% vs. 100% vs. 100%, p=0.32) at 3 years. Cox regression adjusted for surgical CAPRA score also showed that MFS and DSS did not differ between ADT alone, RT (+/- ADT), and RP only groups. Conclusions: Men with positive LN at the time of RP have aggressive clinical and pathologic features. Nevertheless, metastatic recurrence-free and prostate cancer-specific survival rates 3 years after surgery remain good. Although no additional survival benefit to post-RP RT was seen in this cohort of men with limited follow up, further follow up is ongoing.

Overall survival with preoperative biliary drainage in patients with resectable pancreatic cancer.

314 Background: Resectable pancreatic cancer patients often present with obstructive jaundice necessitating the placement of biliary stents or percutaneouse drainage catheters. We sought to evaluate whether preoperative biliary drainage affects recurrence and survival. Methods: An IRB-approved study was conducted on our institutional tumor registry to identify pancreatic cancer patients who were treated with upfront surgery between 2000 and 2012. Patients were then stratified by preoperative use of endoscopically placed stents (ERCP), percutaneous catheters (PTC), or no biliary drainage (NBD). The primary endpoint was overall survival (OS). Survival curves were calculated using the Kaplan-Meier method and the log-rank test. Multivariate analysis (MVA) was performed with a Cox regression model. Results: We identified 202 patients for the study (21 PTC; 89 ERCP; 92 NBD). Key differences between the 3 groups were mean pathologic tumor size (p=0.005), pathologic T3/4 (p =0.01), and pathologic N1 (p=0.007) status, with more aggressive pathologic features in PTC patients. PTC patients had a non-significant increase in rate of hepatic recurrences compared with ERCP and NBD patients (47.4% vs. 26.6% vs. 28.7%, respectively; p=0.20). PTC patients also had worse median and 3 year survival (21 months and 16%) compared to ERCP (23.3 months and 39%) and NBD patients (29 months and 45%, p=0.02). MVA revealed that PTC was an independent predictor of worse overall survival (HR 2.3[95% CI 1.3-4.0], p=0.005), along with pathologic tumor size (HR 1.1[1.0-1.3], p=0.008), nodes positive (HR 1.1[1.1-1.2], p=0.001), and post-operative CA19-9 &gt;90 (HR 2.6[1.5-4.4], p=0.001). Conclusions: Patients with resectable pancreatic cancer who require a pre-operative PTC drain had a non-significant increase in hepatic recurrence rate and worse overall survival than patients who either had an ERCP stent placed or no biliary decompression prior to surgery. Given their worse prognosis, patients who require PTC placement might also benefit from neoadjuvant treatment with restaging prior to surgery.

BRAF mutation may predict higher necessity of postoperative radioactive iodine ablation in papillary thyroid cancer.

PurposeThe primary aim of the present study was to analyze the association between high-risk clinicopathologic characteristics and the BRAFV600E mutation.MethodsFrom March 2010 to September 2012, we performed analysis of the BRAF mutation (assessing V600E point mutation of BRAF gene, exon 15, on chromosome 7q34 by real-time polymerase chain reaction kit) from 499 papillary thyroid carcinoma (PTC) patients who underwent thyroidectomy. We analyzed the relation between the mutation and known clinicopathologic risk factors of PTC.ResultsBRAF mutations were found in 353 of 499 patients (70.7%). On univariate analysis, BRAF mutations were more frequently detected in patients with central lymph node metastasis (78.5% vs. 66.7%, P = 0.007) and classic PTC type (71.3% vs. 16.7%, P = 0.011). Patients with one or more aggressive pathologic feature such as lymph node metastasis, multifocality, and extrathyroidal extension showed higher BRAF mutation rate (73.5% vs. 62.3%, P = 0.022). BRAF mutation group showed more aggressive pathologic features, which is considered as higher necessity of radioactive iodine ablation (relative risk, 1.617; P = 0.035).ConclusionThis study found that BRAF mutation is associated with classic PTC and central lymph node metastasis and higher necessity of radioactive iodine ablation.

Single Positive Core Prostate Cancer Has Less Aggressive Pathologic Features than Multiple Positive Core Prostate Cancer but Should It Still Be Considered an Indolent Tumor?

Introduction: A single positive core (SPC) in a prostate biopsy is usually associated with indolent prostate cancer (PCa), and is considered one active surveillance criteria. To determine if a SPC should qualify a patient for surveillance, we compared the pathological findings for SPC and multiple positive core in a matched population who underwent radical prostatectomy (RP). Material and Methods: We evaluated 373 SPC patients who underwent RP (Group 1) and 375 consecutive cases with multiple positive core (Group 2) who were matched according to age, prostate weight, PSA level and clinical stage. In addition to preoperative data and epidemiological characteristics, we compared the rates of positive surgical margins (PSMs), extraprostatic extension (EPE) and seminal vesicle invasion (SVI) according to the Gleason scores (GSs) of the biopsies. Results: Both groups were similar according age, PSA level, prostate weight and clinical stage. Group 1 had a lower PSM rate (20.9% vs 37.6%, p

Risk factors and natural history of breast cancer in younger Chinese women.

To investigate the age differences in the risk factors, clinicopathological characteristics and patterns of treatment of female breast cancer patients. Seven thousand one hundred and fifty-two women with primary breast cancer from the Hong Kong Breast Cancer Registry were recruited after receiving patients' consent, they were asked to complete standardized questionnaires which captured their sociodemographic characteristics and risk factors associated with breast cancer development. Among them, clinicopathological data and patterns of treatment were further collected from medical records of 5523 patients with invasive breast cancers. Patients were divided into two groups according to the age at diagnosis: younger (< 40 years old) vs older patients (≥ 40 years old) for subsequent analyses. Analysis on the sociodemographic characteristics and exposure to risk factors were performed on 7152 women with primary breast cancer and the results revealed that younger patients were more likely to have unhealthy lifestyles; these include a lack of exercise (85.4% vs 73.2%, P < 0.001), having high stress in life (46.1% vs 35.5%, P < 0.001), having dairy/meat-rich diets (20.2% vs 12.9%, P < 0.001), having alcohol drinking habit (7.7% vs 5.2%, P = 0.002). Younger patients were also more likely to have hormone-related risk factors including nulliparity (43.3% vs 17.8%, P < 0.001) and an early age at menarche (20.7% vs 13.2%, P < 0.001). Analyses on clinicopathological characteristics and patterns of treatment were performed on 5523 women diagnosed with invasive breast cancer. The invasive tumours in younger patients showed more aggressive pathological features such as having a higher percentage of grade 3 histology (45.7% vs 36.5%, P < 0.001), having a higher proportion of tumours with lymphovascular invasion (39.6% vs 33.2%, P = 0.003), and having multifocal disease (15.7% vs 10.3%, P < 0.001); they received different patterns of treatment than their older counterparts. Younger patients in Hong Kong are more likely to encounter risk factors associated with breast cancer development and have more aggressive tumours than their older counterparts.

Clinicopathological features of rare BRAF mutations in Korean thyroid cancer patients.

The most common BRAF mutation in thyroid cancer is c.1799T>A (p.Val600Glu), and other BRAF mutations are rarely reported. We investigated the clinicopathological features of thyroid cancer with rare BRAF mutations. A total of 2,763 patients with thyroid cancer underwent molecular testing by direct DNA sequencing for mutations in BRAF exon 15. Among them, 2,110 (76.4%) had BRAF mutations. The c.1799T>A mutation was found in 2,093 (76.9%) of 2,722 papillary carcinomas and in one of 7 medullary carcinomas. Sixteen cases (0.76%) harbored rare mutation types. Five cases had single-nucleotide substitutions, 5 cases had small in-frame deletion or insertion, and one harbored a two-nucleotide substitution. Of these mutations, 2 were novel (c.1797_1798insGAGACTACA, c.[1799T>A; 1801_1812del]). The c.1801A>C mutation was identified in 4 follicular variant papillary carcinomas and one follicular carcinoma. None of the patients with the c.1801A>C mutation showed extrathyroidal extension or lymph node metastasis. The prevalence of rare BRAF mutations was 0.76% of all BRAF-positive thyroid cancers, and the rare mutations were associated with less aggressive pathologic features. Although BRAF mutations are detected exclusively in papillary carcinoma, they are also found in medullary carcinoma and follicular carcinoma.Graphical