tbuckley/cabot-search huggingface dataset:
Effects of 5α reductase inhibition on stromal and epithelial genes associated with the development of high grade prostate cancer
Authors: E. A. Mostaghel, R. Coleman, G. Linda, I. M. Coleman, P. S. Nelson
Journal: Journal of Clinical Oncology (2008)

5054 Background: Whether the increased incidence of high grade prostate cancer (HGPCa) in the Prostate Cancer Prevention Trial (PCPT) is causally related to 5α reductase (SRD5A) inhibition or reflects an improved sensitivity of detection has not been established. We hypothesized that a causal relationship between SRD5A inhibition and development of HGPCa would be reflected in altered expression of epithelial and stromal genes involved in the process of epithelial to mesenchymal transition (EMT) and the development of reactive stroma, mechanisms postulated to underlie the occurrence of invasive tumors. Methods: We evaluated gene expression changes in prostate samples obtained from a clinical trial of men treated with the dual SRD5A inhibitor dutasteride (Dut). Men with localized PCa were randomized to surgery alone (n=25) or 4 months of neoadjuvant Dut (0.5 or 3.5 mg orally daily, n=26 and n=24). Benign epithelial and stromal cells were separately microdissected for RNA isolation, expression profiling and quantitative RT-PCR. Results: No changes were observed in a number of epithelial genes characterizing the EMT phenotype (including E cadherin, vimentin, N cadherin, SNAIL, TWIST, or α smooth muscle actin (αSMA)), nor in stromal genes characteristic of reactive stroma (including vimentin, αSMA, FSP1 and SFRP1), nor in a number of paracrine stromal growth factors (including VEGF, KGF, IGF, EGF or TGFB). However, compared to untreated samples, Dut was significantly associated with lower epithelial expression of CXCL12, higher epithelial expression of ID1, ID3 (genes involved in inhibition of differentiation) and FHL2 (a transcription factor active at the AR), and higher stromal expression of CTGF and HGF (growth factors involved in PCa development; all changes within 2–3 fold). Conclusions: Short term Dut treatment altered the expression of several genes identified as important in the processes of differentiation, EMT and the paracrine involvement of stroma in tumor progression. The effect of these changes on the prostate microenvironment warrants examination in larger studies of longer duration such as the ongoing REDUCE trial of chemoprevention. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration GlaxoSmithKline GlaxoSmithKline
A ligand-independent androgen receptor function protects from inositol hexakisphosphate-induced cell death
Authors: J. Diallo, B. Péant, L. Lessard, N. Delvoye, C. Le Page, A. Mes-Masson, F. Saad
Journal: Journal of Clinical Oncology (2006)

14566 Background: The androgen receptor (AR) is often aberrantly expressed or activated in hormone-refractory (HR) prostate cancer (PCa). Though it is not clear whether this is directly linked to AR expression, various cell survival pathways are over-activated in HR-PCa, which is characterized by its poor clinical outcome and resistance to available therapies. Inositol hexakisphosphate (IP6) is a phytochemical anti-cancer agent, which we have found to be more effective in PCa cell lines that do not express the AR. Our goal was to address the mechanism of IP6-induced cell death and to evaluate if and how the AR may interfere with its activity. Methods: We used LNCaP, DU145, 22Rv1 as well as wild-type PC3 and AR-expressing PC3 (PC3AR) cell lines to assess the metabolic toxicity of IP6 by WST-1 assay in normal, androgen-supplemented, and androgen-depleted cell culture conditions. A siRNA targeting the androgen receptor (AR) was used to control for genuine AR-mediated effects in the PC3/PC3AR cell lines. Apoptosis was quantified using fluorogenic caspase-3 assays as well as quantitative DNA fragmentation assays. Expression of a variety of genes involved in apoptosis and cell survival pathways was evaluated by real time PCR. Results: While the activity of IP6 was not modulated by the presence of androgens for any cell line, PC3AR cells were significantly more resistant to IP6 than wild-type PC3 cells according to WST-1, caspase-3 and DNA fragmentation assays (p &lt; 0.05). Down-regulation of the AR in the PC3AR cell line resulted in increased metabolic toxicity of IP6 on these cells (p &lt; 10 −5 ). Although treatment with IP6 resulted in the up-regulation of the pro-apoptotic genes Puma, Noxa, as well as of IRF-2 and IkB-αλπηα in PC3 cells, this did not occur in PC3AR cells (p &lt; 0.05). Conclusion: We conclude that, at least in PC3/PC3AR, cells IP6 sensitivity is linked to a ligand-independent function of the AR. To our knowledge, this is the first report of a ligand-independent AR function involved in resistance to a cytotoxic compound. Establishing the molecular details of this novel function is a major part of our ongoing research. No significant financial relationships to disclose.
Gene expression as a predictive marker of outcome for high-risk transitional-cell carcinoma (TCC) of the bladder in patients (pts) randomized to adjuvant chemotherapy with cisplatin-gemcitabine (PG) or observation (OBS) after radical cystectomy
Authors: C. F. Pollera, G. Pessina, F. Nelli, A. Felici, L. Moscetti, E. Ruggeri, M. Mottolese, M. Gallucci, I. Sperduti, F. Cognetti
Journal: Journal of Clinical Oncology (2007)

15502 Background: A randomized phase III trial comparing PG vs OBS in muscle-invasive TTC of the bladder is currently ongoing. ERCC1 and RRM1 genes are involved in the nucleotide excision repair pathways, and their up-regulation by tumor has been clearly related to resistance of cisplatin and gemcitabine, respectively. Preliminary correlations in patients with bladder cancer randomized to PG were already presented (Proc ASCO 2005, Abstract No: 4589). In the present study, we have examined the predictive value of ERCC1 and RRM1 as markers of tumor progression, as well as their potential correlation with other known prognostic factors also in patients randomized to OBS. Methods: Thirty-nine paraffin-embedded TTC samples of a subset of patients entered the trial were collected. The characteristics were: pT2 23%, pT3 54%, pT4a 23%, pN1–2 46%; G3–4 98%; M/F 10%/90%, median age: 65 years (range 53–74); PG/OBS: 49%/51%. Analysis consisted of real time RT-PCR quantification of mRNA levels of ERCC1 and RRM1. Results: After a median follow-up of 25 months (range 12–51), 17 patients relapsed and 10 deceased. A good correlation was found between mRNA expression levels of both genes. Three-year disease-free survival (DFS) was 74% vs 33% for patients with low and high ERCC1 expression (p=0.03), and 64% vs 22% for those with low and high RRM1 expression (p=0.26), respectively. Comparable result in favour of patients showing lower ERCC1 mRNA levels was found in both groups of patients randomized to PG or obs. Multivariate analysis demonstrated that only the presence of N1–2 and low expression level of ERCC1 were significant prognostic factor for better DFS (HR 4.358, 2.775 and p value = 0.006 and 0.046, respectively). Conclusions: Determination of ERCC1 mRNA expression level in muscle-invasive bladder cancer can make a contribution as an independent predictor of DFS after radical cystectomy. It’s still unclear if quantification of ERCC1 gene expression level could interact with adjuvant chemotherapy. Longer follow-up will help to address this issue (Supported by CNR-MIUR grants 02.00447, 03.00387-ST97). No significant financial relationships to disclose.
Induction of apoptosis of myeloid leukemia with CSC17.1, a unique monoclonal antibody targeting CD45RA
Authors: R. J. Tesi, H. Tran, J. Christensen, J. Morales, M. Karimi, M. Sagy, V. Palath
Journal: Journal of Clinical Oncology (2007)

3030 Background: Blast crisis from myeloid leukemia is may be responsive to chemotherapy, but a majority of patients die from their disease. Relapse may be due to persistence of cancer stem cells (CSC). A monoclonal antibody (mAb) that targets myeloid blast cells including the CSC without targeting the hematopoietic stem cell (HSC: CD34+90+) may be of value. CSC phenotype of CML-BC (CD34+38+123+45RA+) and AML (CD34+38–90-) have been defined. Method: We developed a biologically based mAb platform with 2 important steps after generating the mAb library: i) mAb must not bind the HSC (SS; safety screen); and ii) must bind the target cells (RxS; therapeutic screen). HSC for the SS were from G-CSF mobilized blood; cells for RxS was patient specimens of CML-BC and AML. After screens, the target was indentified, in vitro and in vivo functional assays are performed. Results: 5 of 400 mAb passed the SS and RxS. CSC17.1, an IgG2b isotype binding a unique, linear, 12 amino acid sequence of CD45RA has been selected. CML (Kasumi4), AML (Kasumi3 and KG1a), ALL (MOLT3) and NHL (Pfeiffer) cel lines express high levels of CD45RA. Five of 5 CML-BC and 3 of 3 AML patient specimens express CD45RA in high levels. Kausmi4 and Pfeiffer cell lines and patient specimens of CML-BC and AML undergo apoptosis in a dose and time dependent manner after exposure to CSC17.1 (&gt;80% apoptosis at 1ug/ml@8h). KG1a is refractory to apoptosis despite high levels of target on the cell surface (15% apoptosis at 1ug/ml@8h). Normal T,B and NK cells express high levels of CD45RA, but do not undergo apoptosis or activation when exposed to CSC17.1. CSC17.1 causes capping and patching, but not internalization of CD45RA in cell lines and CD8+ normal cells. Commercially available antibodies to CD45RA do not inhibit binding of CSC17.1 to CD45RA, do not cause apoptosis, do not cause patching and capping, but do undergo internalization. In vivo murine models with cell lines and patient specimens of CML-BC and AML are underway. Conclusions: 1) CSC17.1 binds a previously undefined epitope of CD45RA that causes apoptosis of selected hematopoietic tumor cell lines and patient specimens of CML-BC and AML; 2) apoptosis, is a unique function of CSC17.1 compared to other mAb against CD45RA; 3) CML-BC and AML CSC include the CD45RA antigen suggesting CSC17.1 will target these cells. No significant financial relationships to disclose.
Adverse events (AE) following diagnosis (Dx) in older metastatic colorectal cancer (mCRC) patients (Pts).
Authors: Veena Shankaran, David G Mummy, David K Blough, Lisel Koepl, Yeun Mi Yim, Elaine Yu, Scott David Ramsey
Journal: Journal of Clinical Oncology (2012)

e14068 Background: The relative safety of newer drugs in older pts with mCRC is understudied. The objective of this analysis is to determine factors associated with AEs in a population-based sample of older mCRC pts treated in real-world clinical settings. Methods: Pts ≥ age 65 Dx with mCRC in 2004-2007 were identified from SEER-Medicare, and excluded if they were enrolled in a Medicare HMO or lacked Medicare parts A and B. Pts who received 1 st line (1L) chemotherapy (CTx) within 3 mo of Dx were dichotomized as 1L CTx alone and 1L CTx + bevacizumab (BV). Preexisting conditions (PCs) identified from claims in the 12 mo prior to start of 1L CTx were grouped into 5 categories (cardiovascular (CV), cerebrovascular (CNS), gastrointestinal (GI), tissue integrity (TI), and pulmonary (Pulm)). Claims for any of these same conditions between start of 1L CTx and end of follow-up were identified as AEs. Crude AE incidence rates were determined. Logistic regression was used to examine factors associated with BV use. Factors associated with time to 1 st AE were identified in a Cox model. Results: 4,514 pts (median age 77) met inclusion, of whom 1,139 (25%) received 1L CTx only and 669 (15%) received 1L CTx + BV. BV use was less likely among pts age ≥ 75 (OR 0.35, p&lt;0.001), non-whites (OR 0.75, p=0.002), and women (OR 0.8, p=0.001). Bev use was as likely in pts with CV, Pulm, or CNS PCs, and more likely in pts with GI (OR 1.67, p &lt;0.001) and TI (OR 2.75, p=0.001) PCs. In a Cox model of time to 1 st AE with death as a competing risk, increased risk of AE was associated with age ≥ 75 (HR 1.13, p=0.02), CNS PC (HR 1.35, p=0.02), and CV PC (HR 1.13, p=0.05). Relative to 1L CTx alone, pts receiving 1L CTx + BV did not have a higher AE risk (HR 0.89, 95% CI 0.80-0.99). AE incidence was higher in pts receiving 1L CTx alone (without subsequent biologic) (185 events / 100,000 person-days (P-D) compared with pts receiving 1L CTx + BV (139 events / 100,000 P-D). Conclusions: In this cohort, pts who received 1L CTx + BV had neither increased AE incidence nor increased risk of 1 st AE compared to pts who received 1L CTx alone. PCs were not associated with decreased BV use. These data suggests BV utilization may not increase AE risk among elderly mCRC pts tx in the community.
Nuclear factor-kB (NF-kB), p53, survivin, Ki-67, and Bcl-2 as prognostic factors in locally advanced rectal cancer patients receiving radiochemotherapy
Authors: R. Berardi, A. Mandolesi, A. Onofri, E. Maccaroni, G. Mantello, I. Bearzi, M. Scartozzi, C. Pierantoni, C. Marmorale, S. Cascinu
Journal: Journal of Clinical Oncology (2009)

e22062 Background: NF-kB, p53, Survivin, Ki-67 and Bcl-2 expressions have been demonstrated to be prognostic factors in solid tumors. The aim of our analysis was to investigate the importance of their expression, as prognostic factors in patients with locally advanced rectal cancer patients receiving receiving neoadjuvant radiochemotherapy Methods: We analyzed the expression of NF-kB, p53, Survivin, Ki-67 and Bcl-2 in patients with locally advanced rectal cancer who underwent neoadjuvant treatment (radiotherapy ± chemotherapy) at our Department Results: Seventy-four patients were eligible for our analysis. Median age at diagnosis was 66 years (range 36–85). Male/female ratio was 47/37; 37 patients (90%) were diagnosed with adenocarcinoma, whilst 4/41 (10%) with mucinous adenocarcinoma. All the patients received radiotherapy ± 5-fuorouracil/capecitabile-based chemotherapy. Median follow up was 28 months (range 6,7–56,6 months). At univariate and multivariate analysis of the above mentioned parameters, NF-kB, Ki67 and bcl-2 showed an impact on outcome.In particular, in NF-kB-strongly positive patients time to progression (TTP) and overall survival were significantly shorter (p=0,011 and p=0,018 respectively). Moreover a high expression of Ki-67 and a low expression of bcl-2 were associated with a better TTP Conclusions: Our results suggest that NF-kB, bcl-2 and Ki-67 could represent important parameters able to predict the outcome in patients receiving neoadjuvant treatment for rectal cancer. Further prospective studies are warranted in order to confirm the prognostic role of the above mentioned factors in this setting. This could be useful in order to select patients to receive adjuvant chemotherapy after neoadjuvant treatment and surgery for locally advanced rectal cancer, intensifying the adjuvant therapy in some groups of patients and obviating the use of the some drugs (i.e. those involving NF-kB in their mechanism of action) in selected patients No significant financial relationships to disclose.
Breast cancer and vitamin D in postmenopausal minorities.
Authors: Demet Gokalp Yasar, Pam Khosla
Journal: Journal of Clinical Oncology (2012)

17 Background: Bone health is a particular concern for breast cancer survivors, because these women have 15% higher fracture risk than women without a history of breast cancer. Many studies have suggested that vitamin D deficiency may be involved in breast cancer initiation, progression, and prognosis. This study examines the prevalence of vitamin D deficiency among postmenopausal breast cancer patients in minority population. Methods: This retrospective study reviewed the electronic records of 200 postmenopausal breast cancer patients from ethnic groups of blacks, Hispanics and Asians. Results: Of the 200 patients, 84 (42%) had their 25-OHD levels checked at least once. Of patients, 42.7% found body mass index (BMI)&gt;30kg/m 2 . There was significant difference between race and BMI (p&lt;0.05). Black Vitamin D deficiency (level&lt; 20ng/mL) found in 35 (41.7%), vitamin D insufficiency (level range 20-30ng/mL) found in 30 (35.7%) of the patients. The median serum 25-OHD level was 21 (range 4-65ng/ml). The serum 25-OHD levels did not have significant difference among blacks and Hispanics. Tumor stages found negatively correlated with 25-OHD levels r=-0.227 and p=0.04. Conclusions: This study revealed that vitamin D deficiency has a high prevalence among postmenopausal breast cancer minority population. Data from Third National Health and Nutrition Examination survey showed that mean serum 25-OHD levels among white, Hispanic and black women were 76ng/ml, 56.7ng/ml and 45.3ng/ml, respectively. Also, prevalence rate of vitamin D deficiency is reported in the studies among breast cancer patients are approximately 30%. Our data compared with this general population’s numbers is low; our median 25-OHD level was 21ng/ml. Our study found negative correlation with Vitamin D levels and stages of the breast cancer. Information is lacking on direct prognostic effect of vitamin D in breast cancer but this findings including our study support the hypothesis that vitamin D has a role in the pathogenesis of breast cancer. In the setting of breast cancer diagnosis either for bone health, or for breast cancer prognosis in postmenopausal women, we advocate routine 25-OHD levels screening for the vitamin D deficiency especially in minority populations would be beneficial.
Abstract 15745: Antibody-Mediated Rejection is Associated with Microvasculopathy after Heart Transplantation
Authors: Nicola E Hiemann, Ernst Wellnhofer, Sophie Kretschmer, Claudia Christan, Roland Hetzer, Rudolf Meyer
Journal: Circulation (2012)

Purpose. Antibody-mediated rejection (AMR) and microvasculopathy are associated with poor survival after heart transplantation (HTx). Following the new guidelines of the ISHLT we tested the effect ...
Phase I-II Study of Paclitaxel, Cisplatin, and Gemcitabine in Advanced Transitional-Cell Carcinoma of the Urothelium
Authors: J. Bellmunt, V. Guillem, L. Paz-Ares, J.L. González-Larriba, J. Carles, E. Batiste-Alentorn, A. Sáenz, M. López-Brea, A. Font, M. Nogué, R. Bastús, M.A. Climent, J.J. de la Cruz, J. Albanell, J.M. Banús, E. Gallardo, E. Diaz-Rubio, H. Cortés-Funes, J. Baselga
Journal: Journal of Clinical Oncology (2000)

PURPOSE: To determine the maximum-tolerated dose and the antitumor activity of a combination of paclitaxel, cisplatin, and gemcitabine in advanced transitional-cell carcinoma (TCC) of the urothelium. PATIENTS AND METHODS: Patients with measurable, previously untreated, locally advanced or metastatic TCC and with Eastern Cooperative Oncology Group performance status ≤ 2 and creatinine clearance ≥ 55 mL/min were eligible. Cisplatin was given on day 1 at a fixed dose of 70 mg/m 2 . Paclitaxel and gemcitabine were given on days 1 and 8 at increasing dose levels. Cycles were repeated every 21 days to a maximum of six cycles. RESULTS: Sixty-one patients were registered. In phase I, 15 patients were entered at four different dose levels. Dose-limiting toxicity consisted of early onset (after the first cycle) grade 2 asthenia (two of six patients) and grade 3 asthenia (one of six patients) at dose level 4. A paclitaxel dose of 80 mg/m 2 and gemcitabine 1,000 mg/m 2 was recommended for phase II, and 46 additional patients were entered at this level for a total of 49 patients. Main nonhematologic toxicity was grade 2 asthenia in 18 patients, with early onset in five patients, and grade 3 in four patients. Grade 3/4 neutropenia and thrombocytopenia occurred in 27 (55%) and 11 (22%) patients, respectively. Overall, febrile neutropenia was seen in 11 patients, and one toxic death occurred because of neutropenic sepsis. The combination was active at all dose levels. In total, 58 of 61 eligible patients were assessable for response; 16 complete responses (27.6%) and 29 partial responses (50%) were observed for an overall response rate of 77.6% (95% confidence interval, 60% to 98%). The median survival time (MST) available for the phase I part of the study is 24.0 months. MST has not been reached for the whole group with the current follow-up. CONCLUSION: This combination of paclitaxel, cisplatin, and gemcitabine is feasible and highly active in patients with advanced TCC of the urothelium. Further evaluation of this regimen in patients with TCC is warranted.
Phase II trial report of the new neoadjuvant chemotherapy with S-1 and docetaxel for advanced breast cancer
Authors: K. Okazaki, M. Kira, H. Yamai, Y. Nakagawa, T. Nagao, K. Kenzaki, Y. Bando, T. Morimoto, K. Kondo, A. Tangoku
Journal: Journal of Clinical Oncology (2009)

1121 Background: Primary chemotherapy with anthracycline and taxanes is a gold standard regimen which realize pathologically complete response in 20% of patients with advanced breast cancer. However, sequential administration of anthracycline and taxanes induces serious side effects. This regimen is therefore difficult to use for higj-risk patients. S-1 is a new oral anti-tumor drug, which is composed of 5-fluoro-1-(tetrahydro -2- furanyl)-2, 4(1H, 3H)-pyrimidinedione (Tegafur, FT), 5-chloro-2, 4- dihydroxypyridine (Gimeracil, CDHP) and potassium 1, 2, 3, 4-tetrahydro-2, 4-dioxo-1, 3, 5-triazine-6-carboxylate (potassium Oteracil, Oxo). Combined treatment with docetaxel and S-1 yielded significant response in patients with gastric cancer with minimal side effects due to biochemical modulation of both CDHP and Oxo. The purpose of this study was to evaluate the efficacy and toxicity of docetaxel in combination with S-1 for advanced breast cancer. Methods: Patients with advanced breast cancer (Stage IIA to IV) were treated with i.v. docetaxel (40mg/m 2 ) on day 1 and oral S-1(80mg as FT/m 2 /day) on days 1 to 14 every 3 weeks for 8 courses. The clinical response was evaluated every 3 months with MMG, MRI, ultrasonography and CT scan based on RECIST criteria. The patients underwent surgery after completion of chemotherapy. Pathologic examination was performed with thin-sliced specimens. The specimens were also reserved for genetic analysis. Written informed consent was obtained from all patients or family members after the Ethics Committee of Tokushima University Hospital approved the study protocol. Results: Twenty-two patients completed the therapy and underwent surgery. Four cases (18.2%) of pathologic complete response (pCR) were recognized on pathologic examination. The response rate was 90.9% and 95.5% of the patients could preserved their breast. Bone marrow suppression was substantial, and low-grade anorexia, nausea, and peripheral neuropathy were observed. Conclusions: The new regimen of S-1 combined with docetaxel is expected to exhibit satisfactory efficacy in treating advanced breast cancer as primary chemotherapy. Genetic analysis will be performed to examine and to find biomarkers for measurement of the efficacy of this therapy. No significant financial relationships to disclose.