bluuebunny/crossref_metadata_2025_split huggingface dataset:
Concurrent Chemoradiotherapy for Unresectable Stage III Non–Small Cell Lung Cancer
Authors: Vokes Everett E. , Crawford Jeffrey , Bogart Jeffrey , Socinski Mark A. , Clamon Gerald , Green Mark R. 
Published: September 2005

Abstract
Over the last two decades, several approaches to multimodality therapy have been investigated in patients with advanced unresectable non–small cell lung cancer. These include induction chemotherapy and concurrent chemoradiotherapy. Both approaches have been shown to be superior to radiation therapy alone. However, in several randomized trials, concomitant chemoradiotherapy was shown to be superior to the induction chemotherapy approach. It has been hypothesized that the addition of systemic dose sequential chemotherapy to concurrent chemoradiotherapy, either as induction or as consolidation chemotherapy, might further improve survival rates. Recently, the Cancer and Leukemia Group B reported on a randomized phase III trial directly evaluating the addition of two cycles of carboplatin and paclitaxel to concurrent chemoradiotherapy. In this study, induction chemotherapy failed to further improve survival rates of concurrent chemoradiotherapy. A previously conducted randomized phase II study also suggested no benefit from the addition of induction chemotherapy to concomitant chemoradiotherapy. Favorable phase II data have been published supporting the use of consolidation chemotherapy. However, to date, no large randomized study evaluating a possible benefit from consolidation chemotherapy has been completed. In addition to evaluating optimal sequencing strategies of combined modality therapy, current investigations are also focusing on the integration of novel agents, including chemotherapeutic and targeted therapies. Currently ongoing trials involving novel approaches are reviewed here.
Prognostic Factors in Patients with Advanced Renal Cell Carcinoma
Authors: Bukowski Ronald M. , Negrier Sylvie , Elson Paul 
Published: September 2005

Abstract
The identification of prognostic factors in patients with metastatic renal cell carcinoma represents an area of increasing interest. Multiple publications identifying pertinent clinical and laboratory variables have appeared since 1986. The current study of 353 patients with advanced disease treated at The Cleveland Clinic from 1987 to 2002 was conducted to additionally assess and validate a model proposed recently by investigators from Memorial Sloan-Kettering Cancer Center. The data presented are similar to those reported previously, which demonstrated that patients with metastatic renal cell carcinoma can be categorized into good-, intermediate-, and poor-risk groups, using readily available clinical factors. Additionally, comparability of patients in this database to a group treated recently in France was assessed. These two groups appear similar in their distribution of various clinical factors and survival. Finally, a group of international investigators has been developed to provide a comprehensive database of &gt;4,000 patients with metastatic renal cell carcinoma to provide and validate a single model that can be used to predict survival. This project is now under way.
The Hepatocyte Growth Factor Regulatory Factors in Human Breast Cancer
Authors: Parr Christian , Watkins Gareth , Mansel Robert E. , Jiang Wen G. 
Published: September 2005

Abstract
Purpose: Hepatocyte growth factor (HGF) stimulates tumor cell-cell interactions, matrix adhesion, migration, invasion, and angiogenesis. This factor is produced as an inactive precursor called pro-HGF, which requires proteolytic conversion, by HGF activator (HGFA) and matriptase, to evoke a biological response. Two new HGFA inhibitors, HAI-1 and HAI-2, inhibit the generation of biologically active HGF, through their interaction with HGFA. This study determined the expression of this HGF regulatory system in breast cancer. We examined HGF, the HGF receptor (c-Met), HGFA, matriptase, and the activation inhibitors (HAI-1 and HAI-2), tissues from patients with breast cancer.
Experimental Design: Breast cancer tissue (n = 100) and normal background tissue (n = 20) was obtained immediately after surgery. The median follow-up for the patients was 72 months. HGF, c-Met, HGFA, matriptase-1, HAI-1, and HAI-2 expression was quantified using real-time quantitative PCR. The distribution of these factors in mammary tissues was also examined through immunohistochemistry.
Results: The breast cancer specimens expressed a significantly higher level of HGF, c-Met, HGFA, HAI-1, and HAI-2, but not matriptase, compared with the normal background tissues. Tumor tissues from node-positive patients expressed a higher level of HGFA than from the patients without nodal involvement. Interestingly, HAI-2 was expressed to a lower degree in positive nodes than that of the node-negative breast cancer tissues. HAI-1 and HAI-2 were both significantly reduced in grade 3 tumors compared with the well-differentiated tumors. In addition, on comparison of Tumor-Node-Metastasis (TNM) classification groups, HAI-2 was also found to be statistically lower in the TNM 3 breast cancer group when compared with TNM groups 1 and 2, thus associated with a poor prognosis.
Conclusions: This study shows that there are aberrant levels of HGF, c-Met, HGFA, HAI-1, and HAI-2 expressed in breast cancer tissues compared with background breast tissue. HAI-1 and HAI-2 are expressed to a significantly lower level in poorly differentiated breast tumors, and HAI-2 is also inversely correlated with nodal involvement and tumor spread. Overall a low level of HAI-2 in the breast cancer tissues was associated with an overall poor outlook. Therefore, the HGF regulatory system may have an important role in the progression of breast cancer.
Vaccination of Cancer Patients Against Telomerase Induces Functional Antitumor CD8+ T Lymphocytes
Authors: Vonderheide Robert H. , Domchek Susan M. , Schultze Joachim L. , George Daniel J. , Hoar Kara M. , Chen Dih-Yih , Stephans Katherine F. , Masutomi Kenkichi , Loda Massimo , Xia Zhinan , Anderson Karen S. , Hahn William C. , Nadler Lee M. 
Published: September 2005

AbstractPurpose: High-level expression of the telomerase reverse transcriptase (hTERT) in &gt;85% of human cancers, in contrast with its restricted expression in normal adult tissues, points to hTERT as a broadly applicable molecular target for anticancer immunotherapy. CTLs recognize peptides derived from hTERT and kill hTERT+ tumor cells of multiple histologies in vitro. Moreover, because survival of hTERT+ tumor cells requires functionally active telomerase, hTERT mutation or loss as a means of escape may be incompatible with sustained tumor growth.Experimental Design: A Phase I clinical trial was performed to evaluate the clinical and immunological impact of vaccinating advanced cancer patients with the HLA-A2-restricted hTERT I540 peptide presented with keyhole limpet hemocyanin by ex vivo generated autologous dendritic cells.Results: As measured by peptide/MHC tetramer, enzyme-linked immunospot, and cytotoxicity assays, hTERT-specific T lymphocytes were induced in 4 of 7 patients with advanced breast or prostate carcinoma after vaccination with dendritic cells pulsed with hTERT peptide. Tetramer-guided high-speed sorting and polyclonal expansion achieved highly enriched populations of hTERT-specific cells that killed tumor cells in an MHC- restricted fashion. Despite concerns of telomerase activity in rare normal cells, no significant toxicity was observed. Partial tumor regression in 1 patient was associated with the induction of CD8+ tumor infiltrating lymphocytes.Conclusions: These results demonstrate the immunological feasibility of vaccinating patients against telomerase and provide rationale for targeting self-antigens with critical roles in oncogenesis.
Rapamycin Inhibits the Growth and Metastatic Progression of Non-Small Cell Lung Cancer
Authors: Boffa Daniel J. , Luan Fulung , Thomas Dolca , Yang Hua , Sharma Vijay K. , Lagman Milagros , Suthanthiran Manikkam 
Published: September 2005

Abstract
Purpose: Lung cancer has a dismal prognosis and comprises 5.5% of post-transplant malignancies. We explored whether rapamycin inhibits the growth and metastatic progression of non-small cell lung cancer (NSCLC).
Experimental Design: Murine KLN-205 NSCLC was used as the model tumor in syngeneic DBA/2 mice to explore the effect of rapamycin on tumor growth and metastastic progression. We also examined the effect of rapamycin on cell cycle progression, apoptosis, and proliferation using murine KLN-205 NSCLC cells and human A-549 NSCLC cells as targets. The in vivo and in vitro effects of cyclosporine and those of rapamycin plus cyclosporine were also investigated.
Results: Rapamycin but not cyclosporine inhibited tumor growth; s.c. tumor volume was 1290 ± 173 mm3 in untreated DBA/2 mice, 246 ± 80 mm3 in mice treated with rapamycin, and 1203 ± 227 mm3 in mice treated with cyclosporine (P &lt; 0.001). Rapamycin but not cyclosporine prevented the formation of distant metastases; eight of eight untreated mice and four of six mice treated with cyclosporine developed pulmonary metastases whereas only one of six mice treated with rapamycin developed pulmonary metastases (P = 0.003). In vitro, rapamycin induced cell cycle arrest at the G1 checkpoint and blocked proliferation of both KLN-205 and A-549 cells but did not induce apoptosis. Cyclosporine did not prevent cell cycle progression and had a minimal antiproliferative effect on KLN-205 and A-549 cells.
Conclusions: The immunosuppressive macrolide rapamycin but not cyclosporine prevents the growth and metastatic progression of NSCLC. A rapamycin-based immunosuppressive regimen may be of value in recipients of allografts.
Clinical Significance of Dysadherin Expression in Gastric Cancer Patients
Authors: Shimada Yutaka , Yamasaki Seiji , Hashimoto Yosuke , Ito Tetsuo , Kawamura Jun-ichiro , Soma Toshiya , Ino Yoshinori , Nakanishi Yukihiro , Sakamoto Michiie , Hirohashi Setsuo , Imamura Masayuki 
Published: September 2005

Abstract
Purpose: Dysadherin, a cancer-associated cell membrane glycoprotein, has been reported to down-regulate E-cadherin expression and promote metastasis. To evaluate the role of dysadherin in gastric cancer, we examined dysadherin and E-cadherin expression in gastric cancer patients.
Experimental Design: Dysadherin and E-cadherin expression were evaluated in 276 gastric cancer patients by immunohistochemistry, and the results were compared with the clinicopathological findings of the subjects.
Results: Dysadherin was not expressed in normal gastric epithelium. Both dysadherin and E-cadherin were localized to the cell membrane. Dysadherin expression was sometimes largely localized to infiltrating tumor cells or cells dissociating. Ninety gastric cancer patients (32.6%) were positive for dysadherin, and 151 patients (54.7%) showed preservation of E-cadherin expression. Expression of dysadherin was associated with moderately differentiated carcinoma and hematogenous metastasis, whereas reduced expression of E-cadherin showed an association with poorly differentiated carcinoma and peritoneal dissemination. As a result, dysadherin positivity and reduced E-cadherin expression were associated with a poor prognosis. In addition, patients with both dysadherin positivity and reduced E-cadherin had the worst prognosis. Multivariate analysis revealed that reduced E-cadherin expression was an independent prognostic factor, but dysadherin expression was not.
Conclusion: Combined analysis of dysadherin and E-cadherin expression may help to predict the prognosis and the mode of metastasis in gastric cancer patients. Patients with dysadherin positivity have a higher risk of hematogenous metastasis, whereas patients with reduced E-cadherin expression have an increased risk of peritoneal dissemination.
Hypoxia and Glucose Metabolism in Malignant Tumors
Authors: Rajendran Joseph G. , Mankoff David A. , O’Sullivan Finbarr , Peterson Lanell M. , Schwartz David L. , Conrad Ernest U. , Spence Alexander M. , Muzi Mark , Farwell D. Greg , Krohn Kenneth A. 
Published: September 2005

Abstract
Purpose: The aim of this study is to compare glucose metabolism and hypoxia in four different tumor types using positron emission tomography (PET). 18F-labeled fluorodeoxyglucose (FDG) evaluates energy metabolism, whereas the uptake of 18F-labeled fluoromisonidazole (FMISO) is proportional to tissue hypoxia. Although acute hypoxia results in accelerated glycolysis, cellular metabolism is slowed in chronic hypoxia, prompting us to look for discordance between FMISO and FDG uptake.
Experimental Design: Forty-nine patients (26 with head and neck cancer, 11 with soft tissue sarcoma, 7 with breast cancer, and 5 with glioblastoma multiforme) who had both FMISO and FDG PET scans as part of research protocols through February 2003 were included in this study. The maximum standardized uptake value was used to depict FDG uptake, and hypoxic volume and maximum tissue:blood ratio were used to quantify hypoxia. Pixel-by-pixel correlation of radiotracer uptake was performed on coregistered images for each corresponding tumor plane.
Results: Hypoxia was detected in all four patient groups. The mean correlation coefficients between FMISO and FDG uptake were 0.62 for head and neck cancer, 0.47 for breast cancer, 0.38 for glioblastoma multiforme, and 0.32 for soft tissue sarcoma. The correlation between the overall tumor maximum standardized uptake value for FDG and hypoxic volume was small (Spearman r = 0.24), with highly significant differences among the different tumor types (P &lt; 0.005).
Conclusions: Hypoxia is a general factor affecting glucose metabolism; however, some hypoxic tumors can have modest glucose metabolism, whereas some highly metabolic tumors are not hypoxic, showing discordance in tracer uptake that can be tumor type specific.
Systemic Therapy of Malignant Human Melanoma Tumors by a Common Cold-Producing Enterovirus, Coxsackievirus A21
Authors: Shafren Darren R. , Au Gough G. , Nguyen Tam , Newcombe Nicole G. , Haley Erin S. , Beagley Leone , Johansson E. Susanne , Hersey Peter , Barry Richard D. 
Published: September 2005

Abstract
Purpose: The incidence of malignant melanoma continues to increase worldwide; however, treatment of metastatic melanoma remains unsatisfactory, and there is an urgent need for development of effective targeted therapeutics. A potential biological target on the surface of malignant melanoma cells is the up-regulated expression of intercellular adhesion molecule (ICAM)-1 and decay-accelerating factor (DAF), relative to surrounding benign tissue. Coxsackievirus A21 (a common cold virus) targets and destroys susceptible cells via specific viral capsid interactions with surface-expressed virus receptors comprising ICAM-1 and DAF.
Experimental Design: The oncolytic capacity of a genetically unmodified wild-type common cold-producing human enterovirus (Coxsackievirus A21, CAV21) was assessed against in vitro cultures and in vivo xenografts of malignant human melanoma cells.
Results: In vitro studies established that human melanoma cells endogenously express elevated levels of ICAM-1/DAF and were highly susceptible to rapid viral oncolysis by CAV21 infection, whereas ICAM-1/DAF-expressing peripheral blood lymphocytes were refractile to infection. In vivo studies revealed that the tumor burden of nonobese diabetic severe combined immunodeficient mice bearing multiple s.c. melanoma xenografts was rapidly reduced by oncolysis mediated by a single administration of CAV21. The antitumor activity of CAV21 was characterized by highly efficient systemic spread of progeny CAV21, with oncolysis of tumors also occurring at sites distant to the primary site of viral administration.
Conclusions: Overall, the findings presented herein demonstrate an important proof of principle using administration of replication-competent CAV21 as a potential biological oncolytic agent in the control of human metastatic melanoma.
Human Epidermal Growth Factor Receptor 2 Status Modulates Subcellular Localization of and Interaction with Estrogen Receptor α in Breast Cancer Cells
Authors: Yang Zhibo , Barnes Christopher J. , Kumar Rakesh 
Published: September 2005

Abstract
Purpose: Approximately two-thirds of breast cancer patients respond to endocrine therapy, and this population of patients is estrogen receptor (ER) positive. However, a significant proportion of patients do not respond to hormone therapy. ER hormone responsiveness is widely believed to be influenced by enhanced cross-talk of ER with overexpressed human epidermal growth factor receptor 2 (HER2), and a subgroup of ER-positive tumors coexpress high HER2.
Experimental Design: Breast cancer cells with or without HER2 overexpression were analyzed for ER status, subcellular localization, and interactions with HER2 signaling components by biochemical and immunological methods. Experiments explored the regulatory interactions between the HER2 and ER pathways and the sensitivity of breast cancer cells to tamoxifen.
Results: Stable or transient or natural HER2 overexpression in ER-positive breast cancer cells promoted the nucleus-to-cytoplasm relocalization of ER, enhanced interactions of ER with HER2, inhibited ER transactivation function, and induced resistance to tamoxifen-mediated growth inhibition of breast cancer cells. In addition, HER2 up-regulation resulted in ER interaction with Sos, a component of Ras signaling, and hyperstimulation of the mitogen-activated protein kinase extracellular signal-regulated kinase 1/2 (ERK1/2). Conversely, down-regulation of HER2 by the anti-HER2 monoclonal antibody Herceptin led to suppression of ERK1/2 stimulation, restoration of ER to the nucleus, and potentiation of the growth-inhibitory action of tamoxifen.
Conclusion: The results presented here show for the first time that ER redistribution to the cytoplasm and its interaction with HER2 are important downstream effects of HER2 overexpression, that ERK1/2 is important for ER cytoplasmic localization, and that subcellular localization of ER may play a mechanistic role in determining the responsiveness of breast cancer cells to tamoxifen.
Imatinib Mesylate (Gleevec) Inhibits Ovarian Cancer Cell Growth through a Mechanism Dependent on Platelet-Derived Growth Factor Receptor α and Akt Inactivation
Authors: Matei Daniela , Chang David D. , Jeng Meei-Huey 
Published: September 2005

Abstract
Purpose: We identified the platelet-derived growth factor receptor α (PDGFRα) as an ovarian cancer-specific gene by microarray hybridization using primary cultures. The purpose of this study is to evaluate whether disruption of the platelet-derived growth factor-regulated growth pathway by Imatinib mesylate (Gleevec), a partially selective PDGFR inhibitor, inhibits growth of ovarian cancer cells expressing PDGFR.
Experimental Design: To investigate the effects of Imatinib mesylate in ovarian cancer, we established an in vitro model by immortalizing primary ovarian cells, which express endogenous PDGFR, and we evaluated the effects of Imatinib on cell proliferation. In addition, we investigated the involvement of Akt in mediating Imatinib-inhibited cell growth inhibition.
Results: We found that 39% of ovarian tumors express PDGFR by immunohistochemistry. We showed that Imatinib inhibits the growth of ovarian cancer cells in a PDGFR-specific manner, at clinically relevant concentrations (IC50 &lt; 1 μm). Imatinib inhibits the growth of three primary ovarian cultures and two immortalized cultures (PDGFR positive), but has no effects on SkOv3 and CaOv3 cell lines (PDGFR negative). Imatinib exerts antiproliferative effects by arresting cells at G0-G1 and preventing progression through S phase. Imatinib inhibits both PDGFRα and Akt phosphorylation at a concentration of 1 μm. Stable expression of constitutively active Akt induces partial resistance to PDGFR inhibition in ovarian cancer cells, as demonstrated by cell proliferation assay and cell cycle analysis.
Conclusions: Our data indicate that Imatinib mesylate inhibits the growth of ovarian cancer cells through PDGFR inactivation. In addition, our results suggest that constitutive Akt activation modulates sensitivity to Imatinib in ovarian cancer cells.
Association of Pre- and Postoperative Plasma Levels of Transforming Growth Factor β1 and Interleukin 6 and Its Soluble Receptor with Prostate Cancer Progression
Authors: Shariat Shahrokh F. , Kattan Michael W. , Traxel Erica , Andrews Ben , Zhu Kuichun , Wheeler Thomas M. , Slawin Kevin M. 
Published: September 2005

AbstractPurpose: We have shown that preoperative plasma levels of transforming growth factor-β1 (TGF-β1), interleukin 6 (IL)-6, and its receptor (IL-6sR) are associated with prostate cancer progression and metastasis. The objectives of this study were to confirm these findings and to examine the association of changes in plasma levels of these markers after surgery with disease progression in a large consecutive cohort of patients.Experimental Design: Plasma levels of TGF-β1, IL-6, and IL-6sR were measured pre- and postoperatively (6–8 weeks after surgery) in 302 consecutive patients who underwent radical prostatectomy for clinically localized disease.Results: Pre- and postoperative levels of TGF-β1 were significantly elevated in patients with extraprostatic extension, seminal vesicle involvement, and metastases to lymph nodes. In contrast, preoperative levels of IL-6 and IL-6sR, but not postoperative levels, were significantly associated with tumor volume, prostatectomy Gleason sum, and metastases to lymph nodes. In a postoperative model that included pre- and postoperative TGF-β1, IL-6, and IL-6sR and standard postoperative parameters, postoperative TGF-β1 and prostatectomy Gleason sum were significant predictors of overall and aggressive disease progression. Although, for all patients, plasma levels of all three markers declined significantly after prostate removal, for patients that experienced disease progression, only IL-6 and IL-6sR levels decreased significantly.Conclusions: For patients undergoing radical prostatectomy, preoperative plasma levels of TGF-β1 and IL-6sR are associated with metastases to regional lymph nodes, presumed occult metastases at the time of primary treatment, and disease progression. After prostate removal, postoperative TGF-β1 level increases in value over preoperative levels for the prediction of disease progression.