bluuebunny/crossref_metadata_2025_split huggingface dataset:
Multiple Mechanisms of Telomere Maintenance Exist in Liposarcomas
Authors: Johnson Jay E. , Varkonyi Robert J. , Schwalm Jaclyn , Cragle Ryan , Klein-Szanto Andres , Patchefsky Arthur , Cukierman Edna , von Mehren Margaret , Broccoli Dominique 
Published: September 2005

AbstractPurpose: Telomeres are specialized nucleoprotein complexes that protect and confer stability upon chromosome ends. Loss of telomere function as a consequence of proliferation-associated sequence attrition results in genome instability, which may facilitate carcinogenesis by generating growth-promoting mutations. However, unlimited cellular proliferation requires the maintenance of telomeric DNA; thus, the majority of tumor cells maintain their telomeres either through the activity of telomerase or via a mechanism known as alternative lengthening of telomeres (ALT). Recent data suggest that constitutive telomere maintenance may not be required in all tumor types. Here we assess the role and requirement of telomere maintenance in liposarcoma.Experimental Design: Tumor samples were analyzed with respect to telomerase activity, telomere length, and the presence of ALT-specific subcellular structures, ALT-associated promyelocytic leukemia nuclear bodies. This multiassay assessment improved the accuracy of categorization.Results: Our data reveal a significant incidence (24%) of ALT-positive liposarcomas, whereas telomerase is used at a similar frequency (27%). A large number of tumors (49%) do not show characteristics of telomerase or ALT. In addition, telomere length was always shorter in recurrent disease, regardless of the telomere maintenance mechanism.Conclusions: These results suggest that approximately one half of liposarcomas either employ a novel constitutively active telomere maintenance mechanism or lack such a mechanism. Analysis of recurrent tumors suggests that liposarcomas can develop despite limiting or undetectable activity of a constitutively active telomere maintenance mechanism.
Combining Etoposide and Dexrazoxane Synergizes with Radiotherapy and Improves Survival in Mice with Central Nervous System Tumors
Authors: Hofland Kenneth Francis , Thougaard Annemette Vinding , Dejligbjerg Marielle , Jensen Lars H. , Kristjansen Paul E.G. , Rengtved Pia , Sehested Maxwell , Jensen Peter Buhl 
Published: September 2005

Abstract
Purpose: The treatment of patients with brain metastases is presently ineffective, but cerebral chemoradiotherapy using radiosensitizing agents seems promising. Etoposide targets topoisomerase II, resulting in lethal DNA breaks; such lesions may increase the effect of irradiation, which also depends on DNA damage. Coadministration of the topoisomerase II catalytic inhibitor dexrazoxane in mice allows for more than 3-fold higher dosing of etoposide. We hypothesized that dexrazoxane combined with escalated etoposide doses might improve the efficacy of cerebral radiotherapy.
Experimental Design: Mice with cerebrally inoculated Ehrlich ascites tumor (EHR2) cells were treated with combinations of etoposide + dexrazoxane + cerebral radiotherapy. Similar chemotherapy and radiation combinations were investigated by clonogenic assays using EHR2 cells, and by DNA double-strand break assay through quantification of phosphorylated histone H2AX (γH2AX).
Results: Escalated etoposide dosing (90 mg/kg) combined with dexrazoxane (125 mg/kg) and cerebral radiotherapy (10 Gy × 1) increased the median survival by 60% (P = 0.001) without increased toxicity, suggesting that escalated etoposide levels may indeed represent a new strategy for improving radiotherapy. Interestingly, 125 mg/kg dexrazoxane combined with normal etoposide doses (34 mg/kg) also increased survival from radiotherapy, but only by 27% (P = 0.002). This indicates a direct dexrazoxane modulation of the combined effects of etoposide and radiation in brain tumors. Further, in vitro, concurrent dexrazoxane, etoposide, and irradiation significantly increased DNA double-strand breaks.
Conclusion: Combining etoposide (high or normal doses) and dexrazoxane synergizes with cerebral radiotherapy and significantly improves survival in mice with central nervous system tumors. This regimen may thus improve radiation therapy of central nervous system tumors.
Induction of CD4+ and CD8+ T-Cell Responses to the Human Stromal Antigen, Fibroblast Activation Protein: Implication for Cancer Immunotherapy
Authors: Fassnacht Martin , Lee Jaewoo , Milazzo Caterina , Boczkowski David , Su Zhen , Nair Smita , Gilboa Eli 
Published: September 2005

Abstract
Purpose: The propensity of tumor cells to escape immune elimination could limit, if not defeat, the long-term benefits of effective immunotherapeutic protocols. Immunologic targeting of tumor stroma could significantly reduce the ability of tumors to evade immune elimination. Murine studies have shown that inducing immunity against angiogenesis-associated products engenders potent antitumor immunity without significant pathology. It is, however, not known whether T cells corresponding to stromal products are present in humans. In this study, we describe a method to screen for human stromal products that have not triggered significant tolerance and could therefore serve as candidate antigens for cancer immunotherapy.
Experimental Design: To identify candidates for human stromal antigens, we used an in vitro–screening method to determine whether dendritic cells transfected with mRNA encoding products, which are overexpressed in the tumor stroma, are capable of stimulating cytotoxic CD8+ (CTL) responses from human peripheral blood mononuclear cells.
Results: CTL responses could be consistently generated against fibroblast activation protein (FAP) but not against matrix metalloproteinase-9 (MMP-9) or MMP-14. To enhance the immunogenicity of the mRNA-translated FAP product, a lysosomal targeting signal derived from lysosome-associated membrane protein-1 (LAMP-1) was fused to the COOH terminus of FAP to redirect the translated product into the class II presentation pathway. Dendritic cells transfected with mRNA encoding the FAP-LAMP fusion product stimulated enhanced CD4+ and CD8+ T-cell responses.
Conclusion: This study identifies FAP, a protease preferentially expressed in tumor-associated fibroblasts, as a candidate human stromal antigen to target in the setting of cancer immunotherapy, and shows that differential expression of stromal products is not a sufficient criteria to indicate its immunogenicity in a vaccination setting.
Effects of Exercise Training on Antitumor Efficacy of Doxorubicin in MDA-MB-231 Breast Cancer Xenografts
Authors: Jones Lee W. , Eves Neil D. , Courneya Kerry S. , Chiu Brian K. , Baracos Vickie E. , Hanson John , Johnson Lorelei , Mackey John R. 
Published: September 2005

Abstract
Purpose: Exercise is becoming readily accepted as a beneficial adjunct therapy to maintain or enhance quality of life in breast cancer patients undergoing adjuvant chemotherapy. An essential precursor to these studies is to investigate whether exercise modulates the antitumor efficacy of chemotherapeutic agents.
Experimental Design: Athymic female mice were transplanted with MDA-MB-231 breast xenografts and randomly assigned to one of four groups (n = 21 per group): (a) control, (b) exercise-only, (c) doxorubicin-only, or (d) exercise + doxorubicin. Exercise groups performed progressive treadmill running up to 18 m/min at 0% grade for 45 minutes, 5 d/wk for 8 weeks.
Results: Tumor growth delay was significantly longer in the doxorubicin-only and exercise + doxorubicin groups compared with the control (median 42 versus 25 days, P = 0.0082; 36 versus 25 days, P = 0.029, respectively) and exercise-only groups (median 42 versus 25 days, P = 0.029; 36 versus 25 days, P = 0.080, respectively). There was no significant difference between the doxorubicin-only and exercise + doxorubicin groups (median 42 versus 36 days, P = 0.33), suggesting that moderate intensity exercise does not significantly influence doxorubicin-induced tumor growth delay.
Conclusion: These studies are essential to fully understand the safety and application of exercise as a supportive intervention in cancer control.
Gemcitabine Selectively Eliminates Splenic Gr-1+/CD11b+ Myeloid Suppressor Cells in Tumor-Bearing Animals and Enhances Antitumor Immune Activity
Authors: Suzuki Eiji , Kapoor Veena , Jassar Arminder Singh , Kaiser Larry R. , Albelda Steven M. 
Published: September 2005

AbstractPurpose: Myeloid suppressor (Gr-1+/CD11b+) cells accumulate in the spleens of tumor-bearing mice where they contribute to immunosuppression by inhibiting the function of CD8+ T cells and by promoting tumor angiogenesis. Elimination of these myeloid suppressor cells may thus significantly improve antitumor responses and enhance effects of cancer immunotherapy, although to date few practical options exist.Experimental Design: The effect of the chemotherapy drug gemcitabine on the number of (Gr-1+/CD11b+) cells in the spleens of animals bearing large tumors derived from five cancer lines grown in both C57Bl/6 and BALB/c mice was analyzed. Suppressive activity of splenocytes from gemcitabine-treated and control animals was measured in natural killer (NK) cell lysis and Winn assays. The impact of myeloid suppressor cell activity was determined in an immunogene therapy model using an adenovirus expressing IFN-β.Results: This study shows that the chemotherapeutic drug gemcitabine, given at a dose similar to the equivalent dose used in patients, was able to dramatically and specifically reduce the number of myeloid suppressor cells found in the spleens of animals bearing large tumors with no significant reductions in CD4+ T cells, CD8+ T cells, NK cells, macrophages, or B cells. The loss of myeloid suppressor cells was accompanied by an increase in the antitumor activity of CD8+ T cells and activated NK cells. Combining gemcitabine with cytokine immunogene therapy using IFN-β markedly enhanced antitumor efficacy.Conclusions: These results suggest that gemcitabine may be a practical strategy for the reduction of myeloid suppressor cells and should be evaluated in conjunction with a variety of immunotherapy approaches.
Study Design Issues and Early Stage Non–Small Cell Lung Cancer
Authors: Schiller Joan H. 
Published: September 2005

Abstract
The most common type of clinical trial in oncology enrolls patients with advanced disease. End points for phase II trials in advanced disease typically include response rate or time to progression, based upon the presumption that these may serve as surrogates for the ultimate end point of improved survival. Unique problems arise with the design of adjuvant trials, for which response rates clearly are not appropriate end points. In addition, survival is much longer, making rapid completion of phase III trials difficult. For lung cancer, the proportion of patients with stage I and II disease is much lower than with other types of cancer, and the absolute number of these patients is relatively low. To conduct large adjuvant trials in lung cancer more efficiently, we need to optimize our trials as much as possible. “Targeted therapies,” by definition, inhibit a specific target, thus offering the theoretical advantage of enriching the patient population by restricting enrollment to patients whose tumor expresses the target of interest. Education of health care professionals regarding the benefits of adjuvant therapies, to decrease a sense of nihilism and to increase referrals, and international collaborations may also be necessary to increase accrual.
Localized Non–Small Cell Lung Cancer: Adjuvant Radiotherapy in the Era of Effective Systemic Therapy
Authors: Bogart Jeffrey A. , Aronowitz Jesse N. 
Published: September 2005

Abstract
Investigators in Europe, Canada, and the United States recently established a definitive role for adjuvant systemic chemotherapy following resection of early-stage non–small cell lung cancer (NSCLC). This was no small accomplishment, as upward of 20 randomized trials had previously been conducted. The role of postoperative radiotherapy (PORT) has been studied with far less vigor in the modern era. A 1998 meta-analysis of randomized trials suggesting that PORT was detrimental to survival included studies of doubtful quality. The value of PORT should be considered in the same context as recent chemotherapy trials. Advances in imaging have improved the accuracy of staging, patient selection, and target definition. Modern dosimetry and accelerator technologies have advanced the capacity to deliver radiation to the target with less tissue toxicity. Evolving philosophies in dosing and fractionation should improve the therapeutic ratio. Finally, it is reasonable to assume that the importance of local control will be enhanced in the setting of better systemic therapies. We will review the data on PORT and address critical issues in the design of trials to assess the role of modern radiotherapy in the integrated approach to management of early-stage NSCLC.
Clinical Issues in the Management of Early Lung Cancer
Authors: Mulshine James L. 
Published: September 2005

Abstract
Lung cancer is commonly diagnosed after metastatic spread, when therapies are rarely curative, providing an impetus for continued research directed at exploring approaches for cost-effective early lung cancer detection. Recently published pilot studies across three continents support a benefit of spiral computed tomography (CT) in detecting earlier stage non–small cell lung cancer. Improved resolution of early lung cancer is a result of significant changes in CT imaging hardware and software. The status and implications of these developments are reviewed. Many aspects of the management of screening for early lung cancer could be informed by optimizing the downstream clinical management of potential lung cancers identified by CT screening. The first and most critical issue is whether or not this improved detection rate is clearly associated with a reduction in lung cancer–related mortality. However, other related issues such as cost-benefit evaluations are also considered. If smaller, truly localized primary cancer can be routinely detected, then options for less morbid interventions would also be desirable. The rapid improvement in resolution and cost of spiral CT has provided a powerful impetus to reconsider the possibilities for achieving safe, economical, and meaningful early lung cancer detection.
Integration of Novel Therapeutics into Combined Modality Therapy of Locally Advanced Non–Small Cell Lung Cancer
Authors: Gandara David , Narayan Samir , Lara Primo N. , Goldberg Zelanna , Davies Angela , Lau Derrick H.M. , Mack Philip , Gumerlock Paul , Vijayakumar Srinivasan 
Published: September 2005

Abstract
Novel therapeutic agents (NTA) directed against a wide array of newly described molecular targets are now entering clinical investigation, many in the treatment of non–small cell lung cancer (NSCLC). The great majority of these clinical trials have been directed toward patients with advanced stage (metastatic) disease. More recently, study of NTAs has turned toward earlier-stage disease. Locally advanced, or stage III, NSCLC represents a large and heterogeneous group of patients and several clinically distinct substages. During the last 15 years, randomized clinical trials have shown improved survival with sequential chemoradiation compared with radiation alone and, more recently, the superiority of concurrent versus sequential chemoradiation. As NTAs have increasingly shown clinical activity against NSCLC, questions of how to incorporate them into clinical trials in stage III disease, whether they should be given together with radiotherapy, substituting for chemotherapy, or whether they should be added to current chemoradiation strategies, all remain as issues. Here, we describe conceptual issues, preclinical rationale, and ongoing or planned clinical trials incorporating NTAs into current treatment paradigms for unresectable stage III NSCLC.
Computed Tomography Screening for Lung Cancer: Principles and Results
Authors: Henschke Claudia I. 
Published: September 2005

Abstract
In modern healthcare, one of the most public, most important, and at the same time complicated and scientifically demanding topics is screening for a cancer. Mammographic screening for breast cancer has been, in the last few years, a particularly hotly disputed topic in scientific and public policy circles, with similar confusion and frustration widely reported and thus disseminated by the mass media. Most remarkably, this debacle has taken place against the backdrop of, and despite,a truly enormous amount of completed research designed to address the usefulness of such screening. To avoid a “mammography” debacle for lung cancer, the fundamental principles of screening need to be presented as we have come to think of them. Although it is generally accepted that low-dose computed tomography (CT) screening leads to early diagnosis of lung cancer in a high percentage of the cases, the logical consequence of the current knowledge is that annual CT screening prevents death from lung cancer. Thus, it is not whether CT screening is effective, rather the magnitude of its benefit which needs to be determined. We will illustrate our approach by discussing the Early Lung Cancer Action Project and its New York and International sequels.
Laparoscopic and Partial Nephrectomy
Authors: Novick Andrew C. 
Published: September 2005

Abstract
Radical nephrectomy is the gold standard curative operation for patients with localized renal cell carcinoma (RCC). Since its introduction in 1990, laparoscopic radical nephrectomy is being increasingly done at numerous institutions worldwide. In the hands of experienced laparoscopic urological surgeons and with adherence to established principles of open radical nephrectomy, laparoscopic radical nephrectomy is now a standard of care for patients with T1–3a N0 M0 RCC. Intermediate-term outcome data indicate equivalent cancer-free survival to open radical nephrectomy in such cases. Nephron-sparing surgery (NSS) is now an established approach for patients with localized RCC when there is a clinically relevant need to preserve renal function. NSS is also indicated in patients with a single, small, unilateral, localized RCC when the opposite kidney is completely normal. The technical success rate with NSS for RCC is excellent, and long-term patient survival free of cancer is comparable with that obtained after radical nephrectomy. We recently reviewed the results of NSS in 107 patients with localized sporadic RCC treated at the Cleveland Clinic before 1988 who were followed up for a minimum of 10 years. Long-term preservation of renal function was achieved in 93% of patients, and the 10-year cancer specific survival rate was 73%. Although open surgical partial nephrectomy remains the gold standard for nephron-sparing treatment of RCC, laparoscopic partial nephrectomy is now available in selected cases. The optimal indications for laparoscopic NSS are in patients with a relatively small and peripheral renal tumor. In such cases, laparoscopic NSS is proving to be an effective, minimally invasive therapeutic approach with respect to renal functional outcome, with additional advantages of reduced postoperative narcotic use, earlier hospital discharge, and a faster convalescence. The laparoscopic approach is associated with longer warm renal ischemia time, more major intraoperative complications, and more postoperative urological complications. Continued efforts are required to develop laparoscopic renal hypothermia techniques and to facilitate intrarenal suturing while minimizing the warm ischemia time.
Dendritic Cell-Tumor Fusion Vaccines for Renal Cell Carcinoma
Authors: Avigan David 
Published: September 2005

Abstract
Renal cell carcinoma is a malignant disease that demonstrates resistance to standard chemotherapeutic agents. A promising area of investigation is the use of cancer vaccines to educate host immunity to specifically target and eliminate malignant cells. Dendritic cells (DCs) are potent antigen-presenting cells that are uniquely effective in generating primary immune responses. DCs that are manipulated to present tumor antigens induce antitumor immunity in animal models and preclinical human studies. A myriad of strategies have been developed to effectively load tumor antigen onto DCs, including the introduction of individual peptides, proteins, or tumor-specific genes, as well as the use of whole tumor cells as a source of antigen. A promising approach for the design of cancer vaccines involves the fusion of whole tumor cells with DCs. The DC-tumor fusion presents a spectrum of tumor-associated antigens to helper and cytotoxic T-cell populations in the context of DC-mediated costimulatory signals. In animal models, vaccination with DC-tumor fusions resulted in protection from tumor challenge and regression of established metastatic disease. We have conducted phase 1 dose escalation studies in which patients with metastatic breast and renal cancer underwent vaccination with DC-tumor fusions. Twenty-three patients underwent vaccination with autologous DC-tumor fusions. Vaccination was well tolerated without substantial treatment-related toxic effects. Immunologic responses and disease regression were observed in a subset of patients. Future studies will explore the effect of DC maturation and cytokine adjuvants on vaccine potency.
Genetic Basis of Cancer of the Kidney
Authors: Linehan W. Marston , Vasselli James , Srinivasan Ramaprasad , Walther McClellan M. , Merino Maria , Choyke Peter , Vocke Cathy , Schmidt Laura , Isaacs Jennifer S. , Glenn Gladys , Toro Jorge , Zbar Berton , Bottaro Donald , Neckers Len 
Published: September 2005

Abstract
Studies during the past two decades have shown that kidney cancer is not a single disease; it is made up of a number of different types of cancer that occur in this organ. Clear cell renal carcinoma is characterized by mutation of the VHL gene. The VHL gene product forms a heterotrimeric complex with elongin C, elongin B, and Cul-2 to target hypoxia-inducible factors 1 and 2α for ubiquitin-mediated degradation. VHL−/− clear cell renal carcinoma overexpresses epidermal growth factor receptor and transforming growth factor α. Both hypoxia-inducible factor 1α and the epidermal growth factor receptor are potential therapeutic targets in clear cell renal carcinoma. Studies of the hereditary form of renal cell carcinoma (RCC) associated with hereditary papillary renal carcinoma (HPRC) determined that the c-Met proto-oncogene on chromosome 7 is the gene for HPRC and for a number of sporadic papillary RCCs. The HPRC c-Met mutations are activating mutations in the tyrosine kinase domain of the gene. The gene for a new form of hereditary RCC (Birt Hogg Dubé syndrome) associated with cutaneous tumors, lung cysts, and colon polyps or cancer has recently been identified. Studies are currently under way to determine what type of gene BHD is and how damage to this gene leads to kidney cancer. Individuals affected with hereditary leiomyomatosis renal cell carcinoma are at risk for the development of cutaneous leiomyomas, uterine leiomyomas (fibroids), and type 2 papillary RCC. The HLRC gene has been found to be the Krebs cycle enzyme, fumarate hydratase. Studies are under way to understand the downstream pathway of this cancer gene.