bluuebunny/crossref_metadata_2025_split huggingface dataset:
Dendritic Cell Vaccination in Glioblastoma Patients Induces Systemic and Intracranial T-cell Responses Modulated by the Local Central Nervous System Tumor Microenvironment
Authors: Liau Linda M. , Prins Robert M. , Kiertscher Sylvia M. , Odesa Sylvia K. , Kremen Thomas J. , Giovannone Adrian J. , Lin Jia-Wei , Chute Dennis J. , Mischel Paul S. , Cloughesy Timothy F. , Roth Michael D. 
Published: September 2005

AbstractPurpose: We previously reported that autologous dendritic cells pulsed with acid-eluted tumor peptides can stimulate T cell–mediated antitumor immune responses against brain tumors in animal models. As a next step in vaccine development, a phase I clinical trial was established to evaluate this strategy for its feasibility, safety, and induction of systemic and intracranial T-cell responses in patients with glioblastoma multiforme.Experimental Design: Twelve patients were enrolled into a multicohort dose-escalation study and treated with 1, 5, or 10 million autologous dendritic cells pulsed with constant amounts (100 μg per injection) of acid-eluted autologous tumor peptides. All patients had histologically proven glioblastoma multiforme. Three biweekly intradermal vaccinations were given; and patients were monitored for adverse events, survival, and immune responses. The follow-up period for this trial was almost 5 years.Results: Dendritic cell vaccinations were not associated with any evidence of dose-limiting toxicity or serious adverse effects. One patient had an objective clinical response documented by magnetic resonance imaging. Six patients developed measurable systemic antitumor CTL responses. However, the induction of systemic effector cells did not necessarily translate into objective clinical responses or increased survival, particularly for patients with actively progressing tumors and/or those with tumors expressing high levels of transforming growth factor β2 (TGF-β2). Increased intratumoral infiltration by cytotoxic T cells was detected in four of eight patients who underwent reoperation after vaccination. The magnitude of the T-cell infiltration was inversely correlated with TGF-β2 expression within the tumors and positively correlated with clinical survival (P = 0.047).Conclusions: Together, our results suggest that the absence of bulky, actively progressing tumor, coupled with low TGF-β2 expression, may identify a subgroup of glioma patients to target as potential responders in future clinical investigations of dendritic cell–based vaccines.
High Stem Cell Frequency in Acute Myeloid Leukemia at Diagnosis Predicts High Minimal Residual Disease and Poor Survival
Authors: van Rhenen Anna , Feller Nicole , Kelder Angèle , Westra August H. , Rombouts Elwin , Zweegman Sonja , van der Pol Marjolein A. , Waisfisz Quinten , Ossenkoppele Gert J. , Schuurhuis Gerrit Jan 
Published: September 2005

Abstract
Purpose: In CD34-positive acute myeloid leukemia (AML), the leukemia-initiating event originates from the CD34+CD38− stem cell compartment. Survival of these cells after chemotherapy may lead to minimal residual disease (MRD) and subsequently to relapse. Therefore, the prognostic impact of stem cell frequency in CD34-positive AML was investigated.
Experimental Design: First, the leukemogenic potential of unpurified CD34+CD38− cells, present among other cells, was investigated in vivo using nonobese diabetic/severe combined immunodeficient mice transplantation experiments. Second, we analyzed whether the CD34+CD38− compartment at diagnosis correlates with MRD frequency after chemotherapy and clinical outcome in 92 AML patients.
Results: In vivo data showed that engraftment of AML blasts in nonobese diabetic/severe combined immunodeficient mice directly correlated with stem cell frequency of the graft. In patients, a high percentage of CD34+CD38− stem cells at diagnosis significantly correlated with a high MRD frequency, especially after the third course of chemotherapy. Also, it directly correlated with poor survival. In contrast, total CD34+ percentage showed no such correlations.
Conclusions: Both in vivo data, as well as the correlation studies, show that AML stem cell frequency at diagnosis offers a new prognostic factor. From our data, it is tempting to hypothesize that a large CD34+CD38− population at diagnosis reflects a higher percentage of chemotherapy-resistant cells that will lead to the outgrowth of MRD, thereby affecting clinical outcome. Ultimately, future therapies should be directed toward malignant stem cells.
Cyclooxygenase-2 Expression in Postmastectomy Chest Wall Relapse
Authors: Kim Janet H. , Bossuyt Veerle , Ponn Teresa , Lannin Donald , Haffty Bruce G. 
Published: September 2005

AbstractPurpose: Cyclooxygenase-2 (COX-2) expression has been shown to be associated with radiation resistance, which theoretically could be overcome with the use of COX-2 inhibitors. The purpose of this study was to assess the prognostic significance and clinical correlations of COX-2 expression (COX) in a cohort of patients treated with radiation for postmastectomy chest wall relapse.Experimental Design: Between 1975 and 1999, 113 patients were treated for isolated postmastectomy chest wall relapse. All patients were treated with biopsy and/or excision of the chest wall recurrence followed by radiation therapy. Median follow-up was 10 years. All clinical data, including demographics, pathology, staging, receptor status, HER-2/neu status, and adjuvant therapy, were entered into a computerized database. Paraffin-embedded chest wall recurrence specimens were retrieved from 42 patients, of which 38 were evaluated, created into a tissue microarray, stained by immunohistochemical methods for COX, and graded 0 to 3+. A score of 2 to 3+ was considered positive.Results: Overall survival from original diagnosis for entire cohort was 44% at 10 years. Survival rate after chest wall recurrence was 28% at 10 years. The distant metastasis-free survival rate after chest wall recurrence was 40% at 10 years. Local-regional control of disease was achieved in 79% at 10 years after chest wall recurrence. COX was considered positive in 13 of 38 cases. COX was inversely correlated with estrogen receptor (P = 0.045) and progesterone receptor (P = 0.028), and positively correlated with HER-2/neu (P = 0.003). COX was also associated with a shorter time to postmastectomy chest wall relapse. The distant metastasis-free rate for COX-negative patients was 70% at 10 years, compared with 31% at 10 years for COX-2–positive patients (P = 0.029). COX positive had a poorer local-regional progression-free rate of 19% at 10 years, compared with 81% at 10 years for COX negative. This was of high statistical significance with a P value of 0.003.Conclusions: Outcome following radiation therapy for postmastectomy chest wall relapse is relatively poor. Positive COX correlated with other markers of poor outcome, including a shorter time to local relapse, negative estrogen receptor/progesterone receptor, and positive Her-2/neu status. Positive COX correlated with higher distant metastasis and lower local-regional control of disease. If confirmed with larger studies, these data have implications with respect to the concurrent use of COX-2 inhibitors and radiation for postmastectomy chest wall relapse.
Identification of Two Molecular Groups of Seminomas by Using Expression and Tissue Microarrays
Authors: Hofer Matthias D. , Browne Tara J. , He Le , Skotheim Rolf I. , Lothe Ragnhild A. , Rubin Mark A. 
Published: September 2005

Abstract
Highly effective tailored clinical management of testicular germ cell tumors is based on the identification of two major histologic subtypes: seminomatous and nonseminomatous germ cell tumors. Expression array analysis of these two histologic subtypes using hierarchical clustering reveals two tumor groups, one composed solely of seminomas and the other containing embryonal carcinomas and seminomas. Supervised analysis between these groups identified 55 significantly dysregulated genes (false discovery rate = 2.3). The genes with the highest overexpression in the first group compared with the second included SLC43A1 (POV1), NET-7, IGF2, and JUP; down-regulated genes included GRB7, PFKP, and CDC6. In situ hybridization of SLC43A1 mRNA showed significantly increased signal intensity in the seminomas. At the protein level, expression of the immunohistochemical markers cytokeratins (pan-cytokeratin staining), placental-like alkaline phosphatase, anti-cytokeratin clone 5.2, CD30, anion exchanger 1/3, junction plakoglobulin (JUP), and POU domain, class 5, transcription factor 1 (octomer-binding transcription factor 3/4) was significantly different between seminomas and embryonal tumors. Hierarchical clustering based on a refined protein expression profile identified two groups, the first consisting solely of seminomas the other of seminomas and embryonal carcinomas. No histomorphologic differences were observed between the two seminoma groups such as the presence or absence of lymphocytes or extent of stromal elements. In summary, using independent methodologies and samples, we have identified two groups of seminomas. One group of seminomas has a molecular profile similar to embryonal carcinoma. The findings in the current study may help explain aberrant immunoprofiles seen with some seminomas.
Osteopontin Expression and Prognostic Significance in Non–Small Cell Lung Cancer
Authors: Donati Valentina , Boldrini Laura , Dell'Omodarme Matteo , Prati Maria C. , Faviana Pinuccia , Camacci Tiziano , Lucchi Marco , Mussi Alfredo , Santoro Massimo , Basolo Fulvio , Fontanini Gabriella 
Published: September 2005

Abstract
Purpose: The survival rate of non–small cell lung cancer patients is very low, and knowledge of predictors of outcome is inadequate. To improve the curability of lung cancer, we need to identify new specific molecules involved in tumorigenesis and progression. The purpose of this study was to better define the role of osteopontin in non–small cell lung cancer biology by determining its prognostic significance.
Experimental Design: Osteopontin expression was evaluated by immunohistochemistry, as percentage of neoplastic cells with cytoplasmic immunoreactivity, in a wide series of patients with stage I-IIIA non–small cell lung cancer (207 cases). The median value of this series (20% of positive cells) was used as the cutoff value to distinguish tumors with low (&lt;20%) from tumors with high (≥20%) osteopontin expression.
Results: Taking the series of patients as a whole (207 cases), osteopontin expression was associated with neither overall survival (P = 0.14) nor disease-free survival (P = 0.074). However, among patients with at least 6 years of follow-up (163 cases), 6-year overall survival and disease-free survival were significantly reduced if osteopontin expression was high (P = 0.0085 for overall survival, P = 0.0023 for disease-free survival). Moreover, a statistically significant correlation between high levels of osteopontin and shorter overall survival (P = 0.034) and disease-free survival (P = 0.011) in patients with stage I tumors (136 cases) was shown.
Conclusions: Our results support the hypothesis of an association between high osteopontin expression and poor survival of patients with stage I non–small cell lung cancer, suggesting that osteopontin could be a candidate target for cancer therapy.
Melanoma Therapy via Peptide-Targeted α-Radiation
Authors: Miao Yubin , Hylarides Mark , Fisher Darrell R. , Shelton Tiffani , Moore Herbert , Wester Dennis W. , Fritzberg Alan R. , Winkelmann Christopher T. , Hoffman Timothy , Quinn Thomas P. 
Published: September 2005

Abstract
Purpose: The therapeutic efficacy of a unique melanoma-targeting peptide conjugated with an in vivo generated α-particle-emitting radionuclide was evaluated in the B16/F1 mouse melanoma animal model. α-Radiation is densely ionizing, resulting in high concentrations of destructive radicals and irreparable DNA double-strand breaks. This high linear energy transfer overcomes radiation-resistant tumor cells and oxygen effects resulting in potentially high therapeutic indices in tumors such as melanoma.
Experimental Design: The melanoma targeting peptide, 1,4,7,10-tetraazacyclodecane-1,4,7,10-tetraacetic acid (DOTA)-Re(Arg11)CCMSH, was radiolabeled with 212Pb, the parent of 212Bi, which decays via α and β decay. Biodistribution and therapy studies were done in the B16/F1 melanoma-bearing C57 mouse flank tumor model.
Results: 212Pb[DOTA]-Re(Arg11)CCMSH exhibited rapid tumor uptake and extended retention coupled with rapid whole body disappearance. Radiation dose delivered to the tumor was estimated to be 61 cGy/μCi 212Pb administered. Treatment of melanoma-bearing mice with 50, 100, and 200 μCi of 212Pb[DOTA]-Re(Arg11)CCMSH extended their mean survival to 22, 28, and 49.8 days, respectively, compared with the 14.6-day mean survival of the placebo control group. Forty-five percent of the mice receiving 200 μCi doses survived the study disease-free.
Conclusions: Treatment of B16/F1 murine melanoma–bearing mice with 212Pb[DOTA]-Re(Arg11)CCMSH significantly decreased tumor growth rates resulting in extended mean survival times, and in many cases, complete remission of disease. 212Pb-DOTA-Re(Arg11)CCMSH seems to be a very promising radiopharmaceutical for targeted radionuclide therapy of melanoma.
CpG Immunomer DNA Enhances Antisense Protein Kinase A RIα Inhibition of Multidrug-Resistant Colon Carcinoma Growth in Nude Mice: Molecular Basis for Combinatorial Therapy
Authors: Nesterova Maria V. , Johnson Natalie R. , Stewart Trina , Abrams Scott , Cho-Chung Yoon S. 
Published: September 2005

AbstractPurpose: CpG DNAs induce cytokines, activate natural killer cells, and elicit vigorous T-cell response leading to antitumor effects. Antisense oligodeoxynucleotides targeted against the RIα subunit of protein kinase A (antisense PKA RIα) induce growth arrest, apoptosis, and differentiation in a variety of cancer cell lines in vitro and in vivo. This study investigated the use of a combinatorial therapy consisting of the RNA-DNA second-generation antisense PKA RIα and the CpG immunomer (CpG DNA linked through 3′-3′ linkage containing two accessible 5′ ends).Experimental Design: HCT-15 multidrug-resistant colon carcinoma growth in nude mice was used as an experimental model. The inhibitory effect on tumor growth and apoptotic activity of antisense RIα and CpG immunomer, singly and in combination, were measured by tumor growth, levels of RIα subunit, and antiapoptotic and proapoptotic proteins. Effect on host-immune system was measured by mouse spleen size, interleukin-6 (IL-6) levels in mouse blood, and nuclear factor-κB (NF-κB) transcription activity in mouse spleen cells.Results: In combination, CpG immunomer and antisense PKA RIα induced additive/supra-additive effect on the inhibition of tumor growth. Antisense RIα but not CpG immunomer increased Bax and Bak proapoptotic protein levels and decreased Bcl-2 and RIα protein levels in tumor cells. CpG immunomer but not antisense RIα induced an enlargement of mouse spleen, increased IL-6 levels in mouse blood, and increased NF-κB transcription activity in mouse spleen cells.Conclusions: These results show that type I PKA down-regulation and induction of apoptosis in tumor cells by antisense PKA RIα, and host-immune stimulation by CpG immunomer are responsible at the molecular level for the supra-additive effects of tumor growth inhibition. Thus, antisense PKA RIα and CpG immunomer in combination work cooperatively and as tumor-targeted therapeutics to treat human cancer.
Gene Promoter Methylation in Plasma and Sputum Increases with Lung Cancer Risk
Authors: Belinsky Steven A. , Klinge Donna M. , Dekker Joseph D. , Smith Mitzi W. , Bocklage Theresa J. , Gilliland Frank D. , Crowell Richard E. , Karp Daniel D. , Stidley Christine A. , Picchi Maria A. 
Published: September 2005

AbstractPurpose: Lung cancer is the leading cause of cancer mortality in the United States, due in part to the lack of a validated and effective screening approach for early detection. The prevalence for methylation of seven and three genes was examined in DNA from sputum and plasma, respectively, from women at different risk for lung cancer.Experimental Design: Lung cancer survivors (n = 56), clinically cancer-free smokers (n = 121), and never smokers (n = 74) comprised the study population. Plasma was collected from all three groups, whereas sputum was collected from lung cancer survivors and smokers.Results: Methylation was detected in plasma DNA from 10 of 74 women who never smoked. Prevalence for methylation of the p16 gene in plasma was highest in lung cancer survivors. Lung cancer survivors showed a significant increase in the odds of having at least one or more genes methylated in plasma (odds ratio, 3.6; 95% confidence interval, 1.9-9.1) than never smokers. The prevalence for methylation of the O6-methylguanine-DNA methyltransferase, ras effector homologue 1, death associated protein kinase, and PAX5α genes in sputum was significantly higher in lung cancer survivors compared with smokers. Lung cancer survivors had 6.2-fold greater odds (95% confidence interval, 2.1-18.5) for methylation of three or more genes in sputum compared with smokers. Methylation was more commonly detected in sputum than plasma for O6-methylguanine-DNA methyltransferase and ras effector homologue 1, but not p16, in lung cancer survivors.Conclusion: Concomitant methylation of multiple gene promoters in sputum is strongly associated with lung cancer risk.
Messenger RNA Expression Ratios among Four Genes Predict Subtypes of Renal Cell Carcinoma and Distinguish Oncocytoma from Carcinoma
Authors: Chen Yao-Tseng , Tu Jiangling J. , Kao Jean , Zhou Xi K. , Mazumdar Madhu 
Published: September 2005

Abstract
Purpose: Morphologic distinction among clear cell, papillary, and chromophobe types of renal cell carcinoma (RCC) can be difficult, as is the differential diagnosis between oncocytoma and RCC. Whether these renal tumors can be distinguished by their mRNA expression profile of a few selected genes was examined.
Experimental Design: The expression of four genes in renal tumor was evaluated by quantitative reverse transcription-PCR: carbonic anhydrase IX (CA9), methylacyl-CoA racemase (AMACR), parvalbumin (PVALB), and chloride channel kb (CLCNKB). Thirty-one fresh-frozen and 63 formalin-fixed, paraffin-embedded tumor specimens were analyzed.
Results: CA9 expression was highest in clear cell carcinoma and lowest in chromophobe RCC and in oncocytoma. AMACR expression was highest in papillary RCC, and CLCNKB was highest in chromophobe RCC/oncocytoma. PVALB was highest in chromophobe RCC, variable in oncocytoma, and low in clear cell and papillary types. Similar findings were observed in fresh-frozen and formalin-fixed specimens. The mRNA expression ratios among these genes (i.e., CA9/AMACR and AMACR/CLCNKB ratios) further accentuate the gene expression differences among these tumors, and a molecular diagnostic algorithm was established. This algorithm accurately classified the 31 fresh-frozen tumors into 14 clear cell, 5 papillary, 6 chromophobe, and 6 oncocytomas. In the formalin-fixed group, the molecular criteria accurately classified the cases into 15 clear cell, 16 papillary, and 32 in the chromophobe/oncocytoma group but could only separate some, but not all, oncocytomas from chromophobe RCC.
Conclusions: RNA expression ratios based on the four-gene panel can accurately classify subtypes of RCC as well as help distinguish some oncocytomas from chromophobe RCC.
Phase 1 Study of ABT-751, a Novel Microtubule Inhibitor, in Patients with Refractory Hematologic Malignancies
Authors: Yee Karen W.L. , Hagey Anne , Verstovsek Srdan , Cortes Jorge , Garcia-Manero Guillermo , O'Brien Susan M. , Faderl Stefan , Thomas Deborah , Wierda William , Kornblau Steven , Ferrajoli Alessandra , Albitar Maher , McKeegan Evelyn , Grimm David R. , Mueller Toby , Holley-Shanks Rhonda R. , Sahelijo Leonardo , Gordon Gary B. , Kantarjian Hagop M. , Giles Francis J. 
Published: September 2005

AbstractPurpose: ABT-751 is an oral antimitotic agent that binds to the colchicine site on β-tubulin. A phase 1 study was conducted to determine the maximum tolerated dose and toxicities of ABT-751 in patients with advanced myelodysplastic syndrome and relapsed or refractory acute leukemias.Study Design: Thirty-two patients were treated: nine with 100 (n = 3), 125 (n = 3), or 150 mg/m2 (n = 3) of ABT-751 given orally once daily for 7 days every 3 weeks and 23 with 75 (n = 3), 100 (n = 3), 125 (n = 5), 150 (n = 5), 175 (n = 3), or 200 mg/m2 (n = 4) of ABT-751 given orally once daily for 21 days every 4 weeks. Consenting patients had pharmacogenetic sampling and enumeration of circulating endothelial cells (CEC).Results: Dose-limiting toxicity consisted of ileus in one patient at 200 mg/m2, with a subsequent patient developing grade 2 constipation at the same dose level. One patient with relapsed acute myelogenous leukemia achieved a complete remission that was sustained for 2 months. Four other patients had transient hematologic improvements, consisting of a decrease in peripheral blood blasts and improvements in platelet counts. CEC number was reduced in three patients with a concomitant reduction in peripheral blasts. A previously undescribed nonsynonymous single nucleotide polymorphism, encoding Ala185Thr, was identified in exon 4 of the β-tubulin gene, TUBB, in three other patients. The recommended phase 2 dose in hematologic malignancies is 175 mg/m2 daily orally for 21 days every 4 weeks.Conclusion: Further assessment of ABT-751, especially in combination with other agents, in patients with acute leukemias is warranted.
Induction of Higher-Avidity Human CTLs by Vector-Mediated Enhanced Costimulation of Antigen-Presenting Cells
Authors: Yang Sixun , Tsang Kwong-Yok , Schlom Jeffrey 
Published: September 2005

AbstractThe efficacy of antigen-specific CD8+ CTLs depends not only on the quantity of CTLs generated but also perhaps, more importantly, on the avidity of the CTLs. To date, however, no strategy has been shown to preferentially induce higher-avidity human CTLs. In the present study, antigen-presenting cells (APC) generated from human peripheral blood mononuclear cells were infected with a recombinant avipox vector (rF-) containing the transgenes for a triad of costimulatory molecules (human B7.1, intercellular adhesion molecule-1, and LFA-3, designated as rF-TRICOM) and then used to elicit peptide-specific CTLs from autologous T cells. Compared with peptide-pulsed noninfected APCs or peptide-pulsed APCs infected with wild-type vector, peptide-pulsed APCs infected with rF-TRICOM induced not only more CTLs but also higher-avidity CTLs; this was shown by tetramer staining, tetramer dissociation, IFN-γ production, and cytolytic assays. Peptide-pulsed rF-TRICOM-infected dendritic cells were also shown to induce CTLs with a &gt;10-fold higher avidity than CTLs induced using CD40L-matured dendritic cells; the use of peptide-pulsed CD40L-matured dendritic cells infected with rF-TRICOM as APCs induced CTLs of even greater avidity. To our knowledge, these studies are the first to show a methodology to induce higher-avidity human CTLs and have implications for the development of more efficient vaccines for a range of human cancers.