bluuebunny/crossref_metadata_2025_split huggingface dataset:
Defining Cancer Cachexia in Head and Neck Squamous Cell Carcinoma
Authors: Richey Luke M. , George Jonathan R. , Couch Marion E. , Kanapkey Brian K. , Yin Xiaoying , Cannon Trinitia , Stewart Paul W. , Weissler Mark C. , Shores Carol G. 
Published: November 2007

Abstract
Purpose: Cancer cachexia is a devastating and understudied illness in patients with head and neck squamous cell carcinoma (HNSCC). The primary objective was to identify clinical characteristics and serum levels of cytokines and cachexia-related factors in patients with HNSCC. The secondary objective was to detect the occurrence of cytokine and cachexia-related factor gene expression in HNSCC tumors.
Experimental Design: For the primary objective, cross-sectional data were obtained from prospectively recruited patients identified as cachexia cases and matching cachexia-free controls. For the secondary objective, a retrospective cohort design with matched controls was used.
Results: Clinical characteristics associated with cancer cachexia in HNSCC were T4 status (P = 0.01), increased C-reactive protein (P = 0.01), and decreased hemoglobin (P &lt; 0.01). Exploratory multiplex analysis of serum cytokine levels found increased interleukin (IL)-6 (P = 0.04). A highly sensitive ELISA confirmed the multiplex result for increased IL-6 in cachectic patients (P = 0.02). Quality of life was substantially reduced in patients with cachexia compared with noncachectic patients (P &lt; 0.01). All tumors of HNSCC patients both with and without cachexia expressed RNA for each cytokine tested and the cachexia factor lipid-mobilizing factor. There were no statistically significant differences between the cytokine and cachexia factor RNA expression of cachectic and noncachectic patients (each P &gt; 0.05). No tumors expressed the cachexia factor proteolysis-inducing factor.
Conclusion: We have identified clinical characteristics and pathophysiologic mechanisms associated with cancer cachexia in a carefully defined population of patients with HNSCC. The data suggest that the acute-phase response and elevated IL-6 are associated with this complex disease state. We therefore hypothesize that IL-6 may represent an important therapeutic target for HNSCC patients with cancer cachexia.
BAG-4/SODD and Associated Antiapoptotic Proteins Are Linked to Aggressiveness of Epithelial Ovarian Cancer
Authors: Annunziata Christina M. , Kleinberg Lilach , Davidson Ben , Berner Aasmund , Gius David , Tchabo Nana , Steinberg Seth M. , Kohn Elise C. 
Published: November 2007

Abstract
Purpose: We hypothesized that elevated expression in ovarian cancer of the BAG family of prosurvival proteins and associated partners would be associated with clinical features of aggressiveness in ovarian cancer.
Experimental Design: Expression patterns of BAG-1, BAG-3, BAG-4, and Bcl-xL were determined by immunohistochemical analysis of tissue samples obtained at diagnosis from 28 women with stage III or stage IV ovarian cancer treated with cisplatin, paclitaxel, and cyclophosphamide after initial cytoreduction. Association of these proteins, BAG-6, heat shock protein 70 (Hsp70), Hsp27, and Bcl-2, with clinical variables was tested in ovarian cancer tissue arrays from Gynecologic Oncology Group tissue bank.
Results: A statistically significant relationship was found between elevated cytoplasmic expression of BAG-4 and improved overall (P = 0.0002) and progression-free survival (P = 0.003) in the prospectively collected samples. Bcl-2 staining was significantly more frequent on the tissue array in lower stage (P = 0.005) and grade (P = 0.0009) tumors, whereas Hsp70 was prominent in higher grade cases (P = 0.002). Furthermore, Bcl-xL was more closely associated with serous compared with endometrioid ovarian cancers (P = 0.004).
Conclusion: Unexpectedly, cytoplasmic expression of BAG-4 and Bcl-2 marked less aggressive ovarian cancer, whereas nuclear Hsp70 suggested more aggressive behavior. Bcl-xL may play a more prominent function in the pathology of serous histology ovarian cancers compared with the endometrioid subtype. The findings presented here support involvement of these proteins in the propagation of ovarian cancer and provide a basis for the development of molecular therapeutics modulating these survival pathways.
Inverse Prognostic Impact of Angiogenic Marker Expression in Tumor Cells versus Stromal Cells in Non–Small Cell Lung Cancer
Authors: Donnem Tom , Al-Saad Samer , Al-Shibli Khalid , Delghandi Marit P. , Persson Magnus , Nilsen Marit N. , Busund Lill-Tove , Bremnes Roy M. 
Published: November 2007

Abstract
Purpose: The vascular endothelial growth factors (VEGF-A, -C, -D) and the VEGF receptors (VEGFR-1, -2, and -3) are important molecular markers in angiogenesis and lymphangiogenesis. This study elucidates the prognostic significance of these molecular markers in tumor cells as well as in the tumor stroma of resected non–small cell lung cancer tumors.
Experimental Design: Tumor tissue samples from 335 resected patients with stage I to IIIA disease were obtained and tissue microarrays were constructed from duplicate cores of tumor cells and surrounding stromal tissue from each resected specimen. Immunohistochemistry was used to evaluate the expression of each molecular marker. Microvessel density was assessed by CD34 immunohistochemical staining.
Results: In univariate analyses, high tumor cell expression of VEGF-A (P = 0.0005), VEGFR-1 (P = 0.013), VEGFR-2 (P = 0.006), and VEGFR-3 (P = 0.0003) were negative prognostic indicators for disease-specific survival (DSS). In tumor stroma, however, high expression of VEGF-A (P = 0.017), VEGF-C (P = 0.003), VEGF-D (P = 0.009), VEGFR-1 (P = 0.01), and VEGFR-2 (P = 0.019) correlated with good prognosis. There was no significant correlation between microvessel density and DSS. In multivariate analyses, high expression in tumor cells of VEGFR-3 (P = 0.007) was an independent negative prognostic factor for DSS, whereas in stromal cells, high VEGF-C (P = 0.004) expression had an independent positive survival impact.
Conclusion: These are the first tissue microarray data in non–small cell lung cancers showing a positive prognostic impact by highly expressed angiogenic markers in tumor stroma, with VEGF-C as a major independent prognostic indicator.
Inhibition of Protein Kinase Cβ by Enzastaurin Enhances Radiation Cytotoxicity in Pancreatic Cancer
Authors: Spalding Aaron C. , Watson Richard , Davis Mary E. , Kim Alex C. , Lawrence Theodore S. , Ben-Josef Edgar 
Published: November 2007

AbstractPurpose: Aberrant activation of protein kinase Cβ (PKCβ) by pancreatic cancer cells facilitates angiogenesis and tumor cell survival. Targeting PKCβ with enzastaurin, a well-tolerated drug in clinical trials, would be expected to radiosensitize pancreatic tumors through direct antitumor and antivascular effects.Experimental Design: We tested the hypothesis that enzastaurin radiosensitizes pancreatic cancer cells in culture and in vivo through inhibition of PKCβ. We analyzed pancreatic cancer xenografts for growth delay and microvessel density after treatment with enzastaurin, radiation, or both. We determined the effect of radiation and enzastaurin on glycogen synthase kinase 3β, a mediator of cell death in culture and in vivo.Results: At concentrations attained in patients, enzastaurin reduced levels of active PKCβ measured by phosphorylation at Thr500 in culture and in xenografts. Enzastaurin alone did not affect pancreatic cancer cell survival, proliferation, or xenograft growth. However, enzastaurin radiosensitized pancreatic cancer cells in culture by colony formation assay. Enzastaurin alone decreased microvessel density of pancreatic cancer xenografts without appreciable effects on tumor size. When combined with radiation, enzastaurin increased radiation-induced tumor growth delay with a corresponding decrease in microvessel density. Enzastaurin inhibited radiation-induced phosphorylation of glycogen synthase kinase 3β at Ser9 in pancreatic cancer cells in culture and in tumor xenografts, suggesting a possible mechanism for the observed radiosensitization.Conclusions: Enzastaurin inhibits PKCβ in pancreatic cancer cells in culture, enhancing radiation cytotoxicity. Additional antivascular effects of enzastaurin were observed in vivo, resulting in greater radiosensitization. These results provide the rationale for a clinical trial in locally advanced pancreatic cancer combining enzastaurin with radiation.
[18F]Galacto-RGD Positron Emission Tomography for Imaging of αvβ3 Expression on the Neovasculature in Patients with Squamous Cell Carcinoma of the Head and Neck
Authors: Beer Ambros J. , Grosu Anca-Ligia , Carlsen Janette , Kolk Andreas , Sarbia Mario , Stangier Isabelle , Watzlowik Petra , Wester Hans-Jürgen , Haubner Roland , Schwaiger Markus 
Published: November 2007

Abstract
Purpose: [18F]Galacto-RGD has been developed for positron emission tomography (PET)–imaging of αvβ3 expression, a receptor involved in angiogenesis and metastasis. Our aim was to study the feasibility of PET imaging with [18F]Galacto-RGD in patients with squamous cell carcinoma of the head and neck (SCCHN).
Experimental Design: Eleven patients with primary diagnosis of SCCHN were examined. After injection of 140 to 200 MBq [18F]Galacto-RGD, static emission scans 60 min post injection from the head to the abdomen (n = 11) and dynamic scans &gt;60 min covering the tumor region (n = 6) for kinetic modeling were acquired. Standardized uptake values (SUV) were measured in tumors, muscle and oral mucosa. Immunohistochemistry was done using an αvβ3-specific antibody (n = 7). Image fusion with magnetic resonance imaging and/or computed tomography (CT) scans (n = 8) and calculation of tumor subvolumes based on SUVs was done using the iPlan software (BrainLAB).
Results: [18F]Galacto-RGD PET identified 10 of 12 tumors, with SUVs ranging from 2.2 to 5.8 (mean, 3.4 ± 1.2). Two tumors &lt;5 mm were missed. Tumor/blood and tumor/muscle ratios were 2.8 ± 1.1 and 5.5 ± 1.6, respectively. Tumor kinetics was consistent with a two-tissue compartmental model with reversible specific binding. Immunohistochemistry confirmed αvβ3 expression in all tumors with αvβ3 being located on the microvessels in all specimens and additionally on tumor cells in one specimen. Image fusion of [18F]Galacto-RGD PET with magnetic resonance imaging/multislice CT and definition of tumor subvolumes was feasible in all cases.
Conclusions: [18F]Galacto-RGD PET allows for specific imaging of αvβ3 expression in SCCHN with good contrast. Image fusion and definition of tumor subvolumes is feasible. This technique might be used for the assessment of angiogenesis and for planning and response evaluation of αvβ3-targeted therapies.
1,1-Bis(3′-Indolyl)-1-(p-Substitutedphenyl)methanes Induce Apoptosis and Inhibit Renal Cell Carcinoma Growth
Authors: York Melissa , Abdelrahim Maen , Chintharlapalli Sudhakar , Lucero Salina D. , Safe Stephen 
Published: November 2007

Abstract
Purpose: 1,1-Bis(3′-indolyl)-1-(p-substitutedphenyl)methanes [methylene-substituted diindolylmethanes (C-DIM)] containing p-trifluoromethyl, p-t-butyl, and p-phenyl substituents activate peroxisome proliferator-activated receptor γ (PPARγ) and inhibit growth of several different cancer cell lines through receptor-dependent and receptor-independent pathways. The purpose of this study is to investigate the anticancer activity of these compounds in renal cell carcinoma.
Experimental Design: The anticancer activity of the p-t-butyl–substituted C-DIM compound (DIM-C-pPhtBu) was investigated in ACHN and 786-0 renal cell carcinoma cell lines and in an orthotopic model for renal carcinogenesis using ACHN cells injected directly into the kidney.
Results: PPARγ is overexpressed in ACHN cells and barely detectable in 786-0 cells, and treatment with DIM-C-pPhtBu induces proteasome-dependent degradation of cyclin D1 and variable effects on p21 and p27 expression in both cell lines. DIM-C-pPhtBu also induced several common proapoptotic responses in ACHN and 786-0 cells, including increased expression of nonsteroidal anti-inflammatory drug-activated gene-1 and endoplasmic reticulum stress, which activates death receptor 5 and the extrinsic pathway of apoptosis. Activation of these responses was PPARγ independent. In addition, DIM-C-pPhtBu (40 mg/kg/d) also inhibited tumor growth in an orthotopic mouse model for renal carcinogenesis, and this was accompanied by induction of apoptosis in renal tumors treated with DIM-C-pPhtBu but not in tumors treated with the corn oil vehicle (control).
Conclusions: DIM-C-pPhtBu and related compounds are cytotoxic to renal cancer cells and activate multiple proapoptotic and growth-inhibitory pathways. The results coupled with in vivo anticancer activity show the potential of DIM-C-pPhtBu and related C-DIMs for clinical treatment of renal adenocarcinoma.
Defective Chromosome Segregation and Telomere Dysfunction in Aggressive Wilms' Tumors
Authors: Stewénius Ylva , Jin Yuesheng , Øra Ingrid , de Kraker Jan , Bras Johannes , Frigyesi Attila , Alumets Jan , Sandstedt Bengt , Meeker Alan K. , Gisselsson David 
Published: November 2007

Abstract
Purpose: In many childhood neoplasms, prognostic subgroups have been defined based on specific chromosome changes. In Wilms' tumor (WT), such subclassification has been hampered by the diverse and relatively unspecific pattern of chromosomal imbalances present in these tumors. Unspecific patterns of cytogenetic imbalances in tumors are often caused by mitotic segregation errors due to short dysfunctional telomeres. As an alternative to cytogenetic classification, we therefore have evaluated whether the rate of telomere-dependent chromosomal instability could influence the clinical course in WT patients.
Experimental Design: Telomere function and mitotic segregation errors were assessed in 12 cultured tumors and in tumor tissue sections from 41 WT patients.
Results: Abnormal telomere shortening was found in cultured cells and in tissue sections from highly aggressive tumors. In vitro, dysfunctional telomeres were associated to specific cell division abnormalities, including anaphase bridges and multipolar mitoses. Assessment of mitotic figures in tissue sections revealed that anaphase bridges and multipolar mitoses were predominantly, but not exclusively, present in high-risk tumors and were predictors of poor event-free and overall survival.
Conclusions: Telomere-dependent mitotic instability is present in a subgroup of WT, predominately consisting of high-risk tumors.
Therapeutic Implications of Leukemic Stem Cell Pathways
Authors: Chumsri Saranya , Matsui William , Burger Angelika M. 
Published: November 2007

Abstract
An emerging concept in cancer biology is that a rare population of cancer stem cells exists among the heterogeneous cell mass that constitutes a tumor. This concept is best understood in human myeloid leukemia. Normal and malignant hematopoietic stem cell functions are defined by a common set of critical stemness genes that regulate self-renewal and developmental pathways. Several stemness factors, such as Notch or telomerase, show differential activation in normal hematopoietic versus leukemia stem cells. These differences could be exploited therapeutically even with drugs that are already in clinical use for the treatment of leukemia. The translation of novel and existing leukemic stem cell–directed therapies into clinical practice, however, will require changes in clinical trial design and the inclusion of stem cell biomarkers as correlative end points.
New Issues in Genetic Counseling of Hereditary Colon Cancer
Authors: Lynch Patrick M. 
Published: November 2007

Abstract
Clinicians face significant challenges in the diagnosis and management of familial colorectal cancer predisposition. Many of the challenges concern the rarity of individual conditions and their unfamiliarity to most clinicians, even those in the subspecialty areas of gastroenterology, colorectal surgery, and medical oncology. Because the World Wide Web now offers a wealth of information, familiarity with available online resources should be a minimal expectation of clinicians. Notably, these same resources are available to the lay public, so a more informed group of patients can be expected and is already being encountered. The web sites noted throughout this article are merely early examples of what should become an opportunity for instant access to the most up-to-date knowledge of rare familial colorectal cancers and their clinical features, molecular diagnostics, and clinical management and prevention. Many professional organizations have produced guidelines (in print and online) for use by practitioners in various specialties. The consistency, growing evidence base, and ready availability of these guidelines to providers and patients alike will likely foster greater recognition of the need to be in compliance with them. Finally, as investigators make progress with the genetics of these rare diseases, one can anticipate a “cooperative group” approach to clinical trials.
Radiosensitization by the Histone Deacetylase Inhibitor PCI-24781
Authors: Banuelos Carmen A. , Banáth Judit P. , MacPhail Susan H. , Zhao Jin , Reitsema Tarren , Olive Peggy L. 
Published: November 2007

Abstract
Purpose: PCI-24781 is a novel broad spectrum histone deacetylase inhibitor that is currently in phase I clinical trials. The ability of PCI-24781 to act as a radiation sensitizer and the mechanisms of radiosensitization were examined.
Experimental Design: Exponentially growing human SiHa cervical and WiDr colon carcinoma cells were exposed to 0.1 to 10 μmol/L PCI-24781 in vitro for 2 to 20 h before irradiation and 0 to 4 h after irradiation. Single cells and sorted populations were analyzed for histone acetylation, H2AX phosphorylation, cell cycle distribution, apoptotic fraction, and clonogenic survival.
Results: PCI-24781 treatment for 4 h increased histone H3 acetylation and produced a modest increase in γH2AX but negligible cell killing or radiosensitization. Treatment for 24 h resulted in up to 80% cell kill and depletion of cells in S phase. Toxicity reached maximum levels at a drug concentration of ∼1 μmol/L, and cells in G1 phase at the end of treatment were preferentially spared. A similar dose-modifying factor (DMF0.1 = 1.5) was observed for SiHa cells exposed for 24 h at 0.1 to 3 μmol/L, and more radioresistant WiDr cells showed less sensitization (DMF0.1 = 1.2). Limited radiosensitization and less killing were observed in noncycling human fibroblasts. Cell sorting experiments confirmed that depletion of S-phase cells was not a major mechanism of radiosensitization and that inner noncycling cells of SiHa spheroids could be sensitized by nontoxic doses. PCI-24781 pretreatment increased the fraction of cells with γH2AX foci 24 h after irradation but did not affect the initial rate of loss of radiation-induced γH2AX or the rate of rejoining of DNA double-strand breaks.
Conclusions: PCI-24781 shows promise as a radiosensitizing agent that may compromise the accuracy of repair of radiation damage.
Multidisciplinary Management of Patients with Advanced Rectal Cancer
Authors: Beart Robert W. 
Published: November 2007

Abstract
The chance of lymph node involvement in T3 and T4 rectal cancers is 20% to 60%, a risk sufficiently high that most clinicians favor mesorectal excision rather than less aggressive approaches. Patients who have a complete clinical response of the primary lesions to neoadjuvant therapy may represent a special case. Total mesorectal excision can be accomplished without sacrifice of the anal sphincters, and continence can be preserved. Evolving understanding of patterns of tumor spread and mechanisms of anal continence have resulted in increased use of continence-preserving procedures. Removal of the anal sphincters seems to be advantageous only if the sphincters are directly involved. A few small series suggest that a segmental sphincter resection could result in good local control and continence preservation, even if the sphincters are involved. Areas of controversy currently include the role of neoadjuvant therapy for high rectal lesions, the role of lateral lymph node dissection, and methods of improving anal continence after rectal resection.
Colon and Rectal Cancer: Laparoscopic or Open?
Authors: Boller Anne-Marie , Nelson Heidi 
Published: November 2007

Abstract
Early experiences with laparoscopic colectomy were unfavorable, with higher than expected rates of wound tumor implants and concerns about short and long-term compromised oncologic outcomes. Several international randomized controlled trials were initiated to address concerns regarding compromised oncologic outcomes. Each of the trials was designed to test the hypothesis that level 1 evidence supports the general feasibility and recovery advantage as well as cancer equivalence of laparoscopic colectomy in curable colon cancer. The following four phase III randomized controlled trials have completed accrual and reported early data on recovery benefits for laparoscopic colectomy: Barcelona, Clinical Outcomes of Surgical Therapy Study Group (COSTSG), Colon Cancer Laparoscopic or Open Resection (COLOR), and Conventional versus Laparoscopic-Assisted Surgery in Colorectal Cancer (CLASICC). These trials have uniformly and consistently shown a significant reduction in the use of narcotics and oral analgesics and length of hospital stay, as well as a faster return of diet and bowel function, with laparoscopic colectomy. Two of the trials, Barcelona and COSTSG, have sufficient maturation and follow-up to report recurrence and survival data, and neither has found a survival disadvantage in patients treated with laparoscopic colectomy. Results of the Barcelona trial suggest a cancer-related survival advantage in patients treated with laparoscopic colectomy, based solely on differences in patients with stage III disease; this is not confirmed by the COSTSG trial. Results of the CLASICC and COLOR trials, as well as 5-year data from the COSTSG trial, should definitively address survival results. The investigational experience with laparoscopic rectal cancer is not as mature; the subset of rectal cancer patients (n = 253) in the CLASICC trial provides the only available randomized controlled trial data. Laparoscopic colectomy in patients with curable cancer is accepted as an alternative to open colectomy, whereas the viability of laparoscopic rectal cancer resection requires further investigation.