Showing papers by "Naoto T. Ueno published in 2006"
TL;DR: A thorough and methodological evaluation of the potential prognostic importance of nodal ratios in large multicenter data sets is merited and is currently being undertaken by the International Nodal Ratio Working Group.
Abstract: Purpose The American Joint Committee on Cancer staging system for breast cancer was recently updated to reflect the impact of increasing the absolute number of positive lymph nodes on prognosis. However, numerous studies suggest that nodal ratios (absolute number of involved nodes–number of nodes resected) may have greater prognostic value than absolute numbers of involved nodes. Here we examine the data supporting the use of nodal ratios in breast cancer prognosis and consider the potential advantages and disadvantages of including nodal ratios in breast cancer staging. Methods A systematic review of the literature was conducted using the following search engines: http://www.google.com; Thomson's ISI Web of Science; PubMed. Results In multiple reports from both prospective and retrospectively collected data sets, nodal ratios have been shown to be significant predictors of outcome, including locoregional recurrence and overall survival. These studies span all stages of breast cancer and include various t...
179 citations
TL;DR: It is shown that antisense Bcl-2 efficiently blocks B cl-2 expression, resulting in the apoptosis of breast cancer cells, and that BTG1 is a Bcl3-2-regulated mediator of apoptosis in breast cancers cells, suggesting that its induction contributes to antisense bcl-1-mediated cytotoxic effects.
Abstract: The antiapoptotic protein Bcl-2 is overexpressed in a majority of breast cancers, and is associated with a diminished apoptotic response and resistance to various antitumor agents. Bcl-2 inhibition is currently being explored as a possible strategy for sensitizing breast cancer cells to standard chemotherapeutic agents. Antisense Bcl-2 oligonucleotides represent one method for blocking the antiapoptotic effects of Bcl-2. In this study, we show that antisense Bcl-2 efficiently blocks Bcl-2 expression, resulting in the apoptosis of breast cancer cells. Antisense Bcl-2-mediated cytotoxicity was associated with the induction of the B cell translocation gene 1 (BTG1). Importantly, knockdown of BTG1 reduced antisense Bcl-2-mediated cytotoxicity in breast cancer cells. Furthermore, BTG1 expression seems to be negatively regulated by Bcl-2, and exogenous expression of BTG1 induced apoptosis. These results suggest that BTG1 is a Bcl-2-regulated mediator of apoptosis in breast cancer cells, and that its induction contributes to antisense Bcl-2-mediated cytotoxic effects.
45 citations
TL;DR: It is found that part of the antitumor effect of E1A in ovarian cancer results from cytoplasmic sequestration of the activated form of ERK by PEA15, and that the mechanism responsible for this reduced proliferation is the presence of PEA 15.
Abstract: The adenovirus type 5 gene E1A is known to suppress tumorigenicity by transcriptionally downregulating HER-2/neu (HER2) or by inducing apoptosis. We show here that E1A also suppressed the tumorigenicity of the low-HER2-expressing ovarian cancer cell line OVCAR-3 by decreasing cell proliferation. We further found that the mechanism responsible for this reduced proliferation is the presence of PEA15 (phosphoprotein enriched in astrocytes), which is upregulated by E1A in ovarian cancer; PEA15 promotes translocation of ERK from the nucleus to the cytoplasm, leading to inhibition of ERK-dependent transcription and proliferation. Indeed, siRNA-mediated knockdown of PEA15 expression in OVCAR-3 stable E1A transfectants resulted in a nuclear accumulation of the active form of ERK, followed by an increase in Elk-1 activity, DNA synthesis, and anchorage-independent growth. Finally, PEA15 by itself suppressed colony formation in breast and ovarian cancer cell lines, in which E1A is known to have antitumor activity. We conclude that part of the antitumor effect of E1A in ovarian cancer results from cytoplasmic sequestration of the activated form of ERK by PEA15.
35 citations
TL;DR: Allografting in solid tumors is feasible with limited toxicities and transplant-related mortality; a GVT effect has been documented in many different solid tumors; targeting of the immune response to the tumor by new strategies and identification of the target antigen(s) of the GVTeffect are promising areas of research.
Abstract: In October 2005, the second international meeting on allogeneic transplantation in solid tumors was convened in Stresa (Italy). The aim of this second meeting was to share clinical experiences of allografting in solid tumors, to discuss preclinical data on the mechanisms of graft-versus-tumor (GVT) effect, and to review methods for more efficacious transplant approaches. On the first day, the most recent results in cancer immunotherapy were reviewed; head-to head comparisons of clinical results achieved by standard therapy and by allografting in renal, breast, and ovarian cancer were presented. On the second day, GVT mechanisms and preclinical models were examined; anecdotal reports of a GVT effect in sarcoma, pancreatic cancer, prostate cancer, colorectal cancer and lung cancer were presented; new strategies for optimizing transplant outcome were discussed, including patient selection, tumor debulking, auto–allo approaches, selective T-cell depletion, targeting with monoclonal antibodies, use of killer cell immunoglobulin-like receptor-ligand mismatched natural killer cells. In conclusion, allografting in solid tumors is feasible with limited toxicities and transplant-related mortality; a GVT effect has been documented in many different solid tumors; targeting of the immune response to the tumor by new strategies and identification of the target antigen(s) of the GVT effect are promising areas of research.
29 citations
TL;DR: The combination of 90Y ibritumomab tiuxetan at 0.4mCI/kg with BEAM is safe and effective in NHL patients undergoing autologous SCT, and further studies are needed to explore its role in NST.
22 citations
TL;DR: A 54-year-old male presented with complex partial seizures, mild eosinophilia, and underwent a matched unrelated donor bone marrow transplant from a 10/10 allele matched donor in July 2005, and died 1 week later of respiratory failure.
Abstract: A 54-year-old male presented with complex partial seizures, mild eosinophilia (10%) and a normal WBC count in April 2000. Over the next 2 years his clinical history was notable for the development of Klebsiella pneumonia 2, 16 episodes of acute bronchitis and persistent eosinophilia. In January 2003, a bone marrow biopsy showed increased eosinophils (10%), magnetic resonance imaging (MRI) of the brain was normal, and multiple stool samples were negative for ova and parasites, including Strongyloides stercoralis. A diagnosis of idiopathic hypereosinophilic syndrome (IHES) was made, based on classic criteria defined as: absolute eosinophil count 41500 for 46 months, no underlying cause for eosinophilia, and signs and symptoms of organ involvement (seizures, bronchitis and pneumonia). No therapy was offered at that point. The diagnosis was confirmed at UT-MDACC in October 2003. The patient had always resided in the Gulf coast area at the Texas–Louisiana border. There was no significant travel history within or outside the US. Owing to persistent eosinophilia and systemic respiratory and neurologic symptoms, the patient was treated with several lines of treatment for IHES. These treatments included imatinib 400mg daily (October–December 2003) without any response; cladribine 12mg/m and cytarabine 1 g/m for one cycle in January 2004, without any response; pegylated interferon-a 0.5mcg/kg/week (May–October 2004) with a transient decrease in eosinophilia; alemtuzumab 10mg i.v. q week for 12 weeks (starting March 2005), with a transient decrease in eosinophilia. In July 2005, the patient underwent a matched unrelated donor bone marrow transplant from a 10/10 allele matched donor. The preparative regimen consisted of fludarabine, melphalan and thymoglobulin. Methotrexate and tacrolimus were used for graft-versus-host disease (GVHD) prophylaxis. His post transplant course was marked by persistent nausea, vomiting, epigastric pain and bloating that started within 3 weeks of transplant. An esophagogastroduodenoscopy (EGD) was unremarkable. Colonoscopy and rectal biopsy showed acute GVHD that was treated with methylprednisolone 2mg/kg but his symptoms persisted. A second EGD was performed due to persistent symptoms. The duodenal biopsy from the second procedure showed helminthic larva, identified as Strongyloides stercoralis (Figure 1). With this new finding, patient was started on treatment for strongyloidiasis with ivermectin (200mcg/kg) 18mg orally for 3 days and thiabendazole 500mg twice-aday orally for 10 days. The patient developed acute respiratory failure requiring endotracheal intubation and mechanical ventilation. Bronchoalveolar lavage cultures only grew Candida glabrata. Aggressive antifungal therapy and stress dose corticosteroids, along with subcutaneous ivermectin and oral thiabendazole were continued. He developed multiorgan failure requiring vasopressors and hemodialysis, and died 1 week later of respiratory failure. Limited autopsy was performed, and showed diffuse alveolar damage with interstitial fibrosis, intra-alveolar hemorrhage and bilateral pleural effusion. No organisms, including Strongyloides stercoralis, were detected by histology or culture. Hypereosinophilic syndromes are a heterogeneous group of uncommon disorders characterized by marked eosinophilia in the peripheral blood and/or tissues often without an identifiable cause. The traditional diagnosis of HES was based on classical critera. Patients generally present with hepatosplenomegaly, anemia, thrombocytopenia, and bone marrow dysplasia or fibrosis, and their clinical course is similar to that of a myeloproliferative disease. The therapeutic objective for patients with HES has been to limit organ damage by controlling the eosinophil count. Common treatments include prednisone, hydroxyurea and interferon-a, the tyrosine kinase inhibitor, imatinib mesylate, and the nucleoside analog, cladribine. Allogeneic hematopoietic stem cell transplantation (HSCT) after reduced intensity preparative regimens has recently been used in HES.
15 citations
TL;DR: Both OS and PFS were better in patients whose disease became operable after chemotherapy than in those whose disease remained inoperable.
Abstract: The role of high-dose chemotherapy (HDCT) in patients with refractory breast cancer is not well established. Forty-two female patients (median age of 46 years) with breast cancer refractory to neoadjuvant chemotherapy received HDCT (cyclophosphamide, carmustine and thiotepa) supported by an autologous peripheral blood stem cells transplant. Their disease had been refractory (defined as less than partial response) to one (18 patients) or two (24 patients) regimens of neoadjuvant chemotherapy. Twenty-nine patients had surgery before HDCT. The best response after surgery, HDCT, and radiation therapy was assessed 60 days after transplantation. Thirty patients had complete remission, eight had a PR, one had a minor response, and three had progressive disease. In seven of 13 patients whose disease was inoperable before HDCT, it became operable. After a median follow-up of 42 months, 21 patients were alive, and 15 remained disease free. Five-year overall survival (OS) was 57% (CI, 50-64%), and the estimated 5-year progression-free survival was 40% (CI, 32-48%). Both OS and PFS were better in patients whose disease became operable after chemotherapy than in those whose disease remained inoperable. A randomized study is warranted in this patient population.
6 citations
TL;DR: Results indicate that irradiation of normal cells rapidly upregulates the expression of wt p53, which binds to the p53 binding sequence of the PG13-Bcl-2 plasmid and increases the transcriptional activity of B cl-2, which may allow such cells to be protected from radiation-induced toxicity.
Abstract: Radiation-induced apoptosis is thought to underlie the toxicity of radiation to normal tissues as well as to cancer cells. We hypothesized that specific ectopic overexpression of the antiapoptotic molecule Bcl-2 in normal cells would inhibit radiation-induced apoptosis and thereby reduce radiation-induced toxicity in normal cells. To express Bcl-2 specifically in normal cells (which have wild-type (wt) p53) but not in cancer cells (which often have mutated p53), we constructed a Bcl-2 expression plasmid (PG13-Bcl-2) with a minimal promoter regulated by multiple wt p53 DNA-binding sites and found that the presence of wt p53 protein strongly upregulated Bcl-2 expression through this plasmid. Transfection of NIH 3T3 fibroblasts, which express wt p53, with PG13-Bcl-2 increased cell survival and reduced apoptosis; however, transfection of MDA-MB-231 breast cancer cells, which have mutated p53, did not affect survival and apoptosis of those cells. These results indicate that irradiation of normal cells rapidly upregulates the expression of wt p53, which binds to the p53 binding sequence of the PG13-Bcl-2 plasmid and increases the transcriptional activity of Bcl-2. Ectopic expression of Bcl-2 reduced radiation-induced apoptosis only in normal cells (not in cancer cells). Bcl-2 expression was detected in the lung from mice injected via a tail vein with LPD-PG13-Bcl-2 or LPD-CMV-Bcl-2, but did not in the lung from mice treated with DOTAP or LPD-PG13-mock. This novel approach to inhibiting radiation-induced apoptosis in normal cells may allow such cells to be protected from radiation-induced toxicity. Further preclinical in vivo studies are needed.
4 citations