bluuebunny/crossref_metadata_2025_split huggingface dataset:
Loss of Heterozygosity of Chromosome 3 Detected with Single Nucleotide Polymorphisms Is Superior to Monosomy 3 for Predicting Metastasis in Uveal Melanoma
Authors: Onken Michael D. , Worley Lori A. , Person Erica , Char Devron H. , Bowcock Anne M. , Harbour J. William 
Published: May 2007

Abstract
Purpose: Loss of chromosome 3 is strongly associated with metastasis in uveal melanoma and has been proposed as the basis for clinical prognostic testing. It is not known whether techniques that identify loss of heterozygosity for chromosome 3 predict metastasis more accurately than those that detect only numerical loss of chromosome 3 (monosomy 3).
Experimental Design: Fifty-three uveal melanomas were analyzed by 28 single nucleotide polymorphisms (SNP) across chromosome 3. SNP was compared with fluorescence in situ hybridization (FISH) and array-based comparative genomic hybridization (aCGH) for metastasis prediction by sensitivity, specificity, and Kaplan-Meier survival analysis, using our validated gene expression-based classifier as a reference standard.
Results: By Kaplan-Meier analysis, only the gene expression-based classifier (P = 0.001) and SNP-based detection of loss of heterozygosity for chromosome 3 (P = 0.04) were significantly associated with metastasis. Sensitivity and specificity were 95.2% and 80.8%, respectively, for SNP, 77.8% and 64.7%, respectively, for FISH, and 85.0% and 72.0%, respectively, for aCGH. Isodisomy 3 was identified by SNP but undetected by aCGH and FISH in three tumors.
Conclusions: Prognostic tests based on SNP platforms, which detect both chromosomal homologues and their subregions, may be superior to techniques that only detect changes in chromosome number. These observations could have important implications for efforts to detect genetic alterations in cancer genomes with CGH-based approaches.
Epidermal Growth Factor Receptor Expression in High-Grade Osteosarcomas Is Associated with a Good Clinical Outcome
Authors: Kersting Christian , Gebert Carsten , Agelopoulos Konstantin , Schmidt Hartmut , van Diest Paul J. , Juergens Heribert , Winkelmann Winfried , Kevric Matthias , Gosheger Georg , Brandt Burkhard , Bielack Stefan , Buerger Horst 
Published: May 2007

Abstract
Purpose: The expression of the epidermal growth factor receptor (EGFR) in osteosarcomas has repeatedly been described. With the introduction of anti-EGFR–targeted therapies in clinical practice, these findings regain increased attention. Experience with anti-EGFR–targeted therapies in other cancers has made clear that besides the expression status of EGFR, a detailed knowledge about gene mutations is of major predictive power. We therefore aimed to explore the EGFR expression and gene mutation status in high-grade osteosarcomas.
Experimental Design: We investigated tumor samples of osteosarcoma patients of all age groups by means of immunohistochemistry (n = 111) and egfr fluorescence in situ hybridization (n = 39). Sixty-three patients were treated according to the Cooperative Osteosarcoma Study Group protocols and complete clinical follow-up was available in these cases.
Results: Ninety-one of 111 (81%) of osteosarcomas revealed an expression of EGFR. EGFR expression showed a dose-response relation with improved event-free and overall survival. This was independent of the degree of tumor regression due to neoadjuvant chemotherapy. Nine of 39 (23%) osteosarcomas showed egfr amplifications by means of fluorescence in situ hybridization. All these cases expressed EGFR. When comparing EGFR expression between primary biopsy and resection specimen (n = 19), viable residual tumor cells in resection specimens revealed a lower EGFR expression and a tendency toward membranous staining compared with the initial biopsy.
Conclusions: In conclusion, expression and amplification of EGFR are frequently observed in high-grade osteosarcomas and are associated with improved prognosis in a dose-responsive way. This implies that low EGFR expression possibly predicts lack of response to conventional treatment in high-grade osteosarcomas and may warrant a more intensive therapeutic approach, although not based on EGFR targeting.
Increasing Anticarcinoma Activity of an Anti-erbB2 Recombinant Immunotoxin by the Addition of an Anti-EpCAM sFv
Authors: Stish Brad J. , Chen Hua , Shu Yanqun , Panoskaltsis-Mortari Angela , Vallera Daniel A. 
Published: May 2007

Abstract
Purpose: erbB2, the product of the Her2-neu gene, is a well-established therapeutic target for antibody-based biologicals, but anti-erbB2 antibody-toxin fusion proteins are limited in their activity. The goal of this study was to determine if genetically adding an sFv targeting epithelial cell adhesion molecule (EpCAM) to an anti-Her2 sFv immunotoxin would result in enhanced antitumor activity.
Experimental Design: In vitro studies were done in which the new bispecific immunotoxin DTEpCAM23 was compared with monospecific immunotoxins (DTEpCAM and DT23) to quantitate immunotoxin activity. Mixtures of monospecific immunotoxins were tested to determine if they were as effective as the bispecific immunotoxin. Binding and internalization studies were also done. In vivo, bispecific immunotoxins were given i.t. to athymic nude mice bearing HT-29 human colon cancer flank tumors and i.p. to mice with i.p. tumors.
Results: DTEpCAM23 bispecific immunotoxins showed far greater activity than monospecific immunotoxin (sometimes over 2,000-fold) against most tumor lines. Bispecific immunotoxin was superior and selective in its activity against different carcinoma cell lines. Bispecific immunotoxin had greater activity than monospecific immunotoxin indicating an advantage of having both sFv on the same single-chain molecule. Binding and internalization studies did not explain the differences between bispecific immunotoxin and monospecific immunotoxin activity. Orientation of the sFvs on the molecule had a significant effect on in vitro and in vivo properties. The bispecific immunotoxins were more effective than the monospecific immunotoxin in the flank tumor mouse model.
Conclusions: The synthesis of bispecific immunotoxin created a new biological agent with superior in vitro and in vivo activity (over monospecific immunotoxin), more broad reactivity, more efficacy against tumors in vivo, and diminished toxic effects in mice.
Prospective Assessment of XPD Lys751Gln and XRCC1 Arg399Gln Single Nucleotide Polymorphisms in Lung Cancer
Authors: Giachino Daniela F. , Ghio Paolo , Regazzoni Silvia , Mandrile Giorgia , Novello Silvia , Selvaggi Giovanni , Gregori Dario , DeMarchi Mario , Scagliotti Giorgio V. 
Published: May 2007

Abstract
Purpose: XRCC1 and XPD play key roles in the repair of DNA lesions and adducts. Contrasting findings have been reported on the effect of polymorphisms of these genes on the response to platinum-based chemotherapy in advanced non–small-cell lung cancer (NSCLC). This study aimed to investigate the relationship between the XPD Lys751Gln and XRCC1 Arg399Gln genotypes and outcome in lung cancer patients.
Experimental Design: We genotyped 203 NSCLC and 45 small-cell lung carcinoma (SCLC) patients for the two polymorphisms. Most of the patients (81%) received a platinum-based chemotherapy.
Results: The patients' genotype frequencies did not significantly differ from controls and both groups were in Hardy-Weinberg equilibrium for the two polymorphisms. The XRCC1399 Gln/Gln variant genotype was associated with a higher median survival time (80 weeks versus 54.6 weeks for the Arg/Gln heterozygous and 55.6 weeks for the wild-type Arg/Arg genotype; P = 0.09). At the multivariable analysis adjusted for histology, stage of the disease, performance status, age, and gender, the Gln/Gln genotype was associated with a better survival of borderline significance in the subgroup of patients treated with cisplatin (hazard ratio, 0.55; 95% CI, 0.30-1.00); this association became significant for those with grade 3-4 clinical toxicity (hazard ratio, 0.46; 95% CI, 0.22-0.98). No association between XPD Lys751Gln genotype and clinical outcome was found.
Conclusion: This prospective investigation provides suggestive evidence of a favorable effect of the XRCC1399 Gln/Gln genotype on survival in platinum-treated NSCLC and, for the first time, in SCLC patients also. This contrasts with other authors who did not include non–platinum-treated patients, but it does fit the expectation for a suboptimal ability to remove DNA adducts.
Capsaicin Is a Novel Blocker of Constitutive and Interleukin-6–Inducible STAT3 Activation
Authors: Bhutani Manisha , Pathak Ashutosh K. , Nair Asha S. , Kunnumakkara Ajaikumar B. , Guha Sushovan , Sethi Gautam , Aggarwal Bharat B. 
Published: May 2007

AbstractPurpose: Capsaicin, a constituent of green and red peppers, has been linked with suppression of tumorigenesis through a mechanism that is not well understood. Because the transcription factor signal transducer and activator of transcription 3 (STAT3) has been closely linked with tumorigenesis, we investigated the effect of this vanilloid on the STAT3 pathway in human multiple myeloma cells.Experimental Design: The effect of capsaicin on both constitutive and interleukin-6–induced STAT3 activation, associated protein kinases, and STAT3-regulated gene products involved in proliferation, survival and angiogenesis, cellular proliferation, and apoptosis in multiple myeloma cells was investigated.Results: We found that capsaicin inhibited constitutive activation of STAT3 in multiple myeloma cells in a dose- and time-dependent manner, with minimum effect on STAT5. Capsaicin also inhibited the interleukin-6–induced STAT3 activation. The activation of Janus-activated kinase 1 and c-Src, implicated in STAT3 activation, was also inhibited by the vanilloid, with no effect on extracellular signal-regulated kinase 1/2 activation. Pervanadate reversed the capsaicin-induced down-regulation of STAT3, suggesting the involvement of a protein tyrosine phosphatase. Capsaicin down-regulated the expression of the STAT3-regulated gene products, such as cyclin D1, Bcl-2, Bcl-xL, survivin, and vascular endothelial growth factor. Finally, capsaicin induced the accumulation of cells in G1 phase, inhibited proliferation, and induced apoptosis, as indicated by caspase activation. Capsaicin also significantly potentiated the apoptotic effects of Velcade and thalidomide in multiple myeloma cells. When administered i.p., capsaicin inhibited the growth of human multiple myeloma xenograft tumors in male athymic nu/nu mice.Conclusion: Overall, these results suggest that capsaicin is a novel blocker of the STAT3 activation pathway, with a potential role in the prevention and treatment of multiple myeloma and other cancers.
AZD2171 Shows Potent Antitumor Activity Against Gastric Cancer Over-Expressing Fibroblast Growth Factor Receptor 2/Keratinocyte Growth Factor Receptor
Authors: Takeda Masayuki , Arao Tokuzo , Yokote Hideyuki , Komatsu Teruo , Yanagihara Kazuyoshi , Sasaki Hiroki , Yamada Yasuhide , Tamura Tomohide , Fukuoka Kazuya , Kimura Hiroshi , Saijo Nagahiro , Nishio Kazuto 
Published: May 2007

AbstractPurpose: AZD2171 is an oral, highly potent, and selective vascular endothelial growth factor signaling inhibitor that inhibits all vascular endothelial growth factor receptor tyrosine kinases. The purpose of this study was to investigate the activity of AZD2171 in gastric cancer.Experimental Design: We examined the antitumor effect of AZD2171 on the eight gastric cancer cell lines in vitro and in vivo.Results: AZD2171 directly inhibited the growth of two gastric cancer cell lines (KATO-III and OCUM2M), with an IC50 of 0.15 and 0.37 μmol/L, respectively, more potently than the epidermal growth factor receptor tyrosine kinase inhibitor gefitinib. Reverse transcription-PCR experiments and immunoblotting revealed that sensitive cell lines dominantly expressed COOH terminus–truncated fibroblast growth factor receptor 2 (FGFR2) splicing variants that were constitutively phosphorylated and spontaneously dimerized. AZD2171 completely inhibited the phosphorylation of FGFR2 and downstream signaling proteins (FRS2, AKT, and mitogen-activated protein kinase) in sensitive cell lines at a 10-fold lower concentration (0.1 μmol/L) than in the other cell lines. An in vitro kinase assay showed that AZD2171 inhibited kinase activity of immunoprecipitated FGFR2 with submicromolar Ki values (∼0.05 μmol/L). Finally, we assessed the antitumor activity of AZD2171 in human gastric tumor xenograft models in mice. Oral administration of AZD2171 (1.5 or 6 mg/kg/d) significantly and dose-dependently inhibited tumor growth in mice bearing KATO-III and OCUM2M tumor xenografts.Conclusions: AZD2171 exerted potent antitumor activity against gastric cancer xenografts overexpressing FGFR2. The results of these preclinical studies indicate that AZD2171 may provide clinical benefit in patients with certain types of gastric cancer.
Enhancement of Docetaxel-Induced Cytotoxicity by Blocking Epidermal Growth Factor Receptor and Cyclooxygenase-2 Pathways in Squamous Cell Carcinoma of the Head and Neck
Authors: Choe Mi Sun , Chen Zhuo , Klass Carmen M. , Zhang Xin , Shin Dong M. 
Published: May 2007

AbstractPurpose: The addition of molecular targeted agents to enhance the cytotoxicity of chemotherapeutic agents is a promising strategy in cancer treatment. The combination of cyclooxygenase-2 inhibitors and epidermal growth factor receptor tyrosine kinase inhibitors, such as celecoxib and ZD1839 (gefitinib), was reported to achieve synergistic cell growth inhibition in squamous cell carcinoma of the head and neck. Therefore, we postulated that the addition of celecoxib and ZD1839 to docetaxel, a cytotoxic agent, might further increase antitumor activity.Experimental Design: The combination of celecoxib, ZD1839, and docetaxel was studied for its effect on cell growth and apoptosis by cell growth inhibition and Annexin V assays. The relevant molecular targets of these agents and apoptotic markers were examined by immunoblotting analyses in the presence or absence of these three drugs. Morphologic changes of the microtubule cytoskeleton, a known target of docetaxel, were also evaluated by staining for α-tubulin after the combination treatment.Results: We showed that this triple combination significantly enhanced cell growth inhibition and docetaxel-induced apoptosis. Docetaxel mainly induced caspase-8 activation, whereas the addition of celecoxib and ZD1839 augmented the caspase-8 activation and enhanced caspase-9 activation. One of the underlying mechanisms for augmentation of docetaxel-induced apoptosis by celecoxib and ZD1839 is to further inhibit the activation of prosurvival pathway molecules, such as extracellular signal-regulated kinase and AKT, and the promotion of aberrant apoptosis.Conclusions: Our studies suggest that the combination of docetaxel with a cyclooxygenase-2 inhibitor and an epidermal growth factor receptor tyrosine kinase inhibitor may further improve efficacy of docetaxel and other taxane-based therapies in squamous cell carcinoma of the head and neck.
CYP2C9 and CYP2C19 Polymorphic Forms Are Related to Increased Indisulam Exposure and Higher Risk of Severe Hematologic Toxicity
Authors: Zandvliet Anthe S. , Huitema Alwin D.R. , Copalu William , Yamada Yasuhide , Tamura Tomohide , Beijnen Jos H. , Schellens Jan H.M. 
Published: May 2007

AbstractPurpose: The anticancer agent indisulam is metabolized by the cytochrome P450 of enzymes CYP2C9 and CYP2C19. Polymorphisms of these enzymes may affect the elimination rate of indisulam. Consequently, variant genotypes may be clinically relevant predictors for the risk of developing severe hematologic toxicity. The purposes of this study were to evaluate the effect of genetic variants of CYP2C9 and CYP2C19 on the pharmacokinetics of indisulam and on clinical outcome and to assess the need for pharmacogenetically guided dose adaptation.Experimental Design: Pharmacogenetic screening of CYP2C polymorphisms was done in 67 patients treated with indisulam. Pharmacokinetic data were analyzed with a population pharmacokinetic model, in which drug elimination was described by a linear and a Michaelis-Menten pathway. The relationships between allelic variants and the elimination pharmacokinetic parameters (CL, Vmax, Km) were tested using nonlinear mixed-effects modeling. Polymorphisms causing a high risk of dose-limiting neutropenia were identified in a simulation study.Results: The Michaelis-Menten elimination rate (Vmax) was decreased by 27% (P &lt; 0.0001) for heterozygous CYP2C9*3 mutants. Heterozygous CYP2C19*2 and CYP2C19*3 mutations reduced the linear elimination rate (CL) by 38% (P &lt; 0.0001). The risk of severe neutropenia was significantly increased by these mutations and dose reductions of 50 to 100 mg/m2 per mutated allele may be required to normalize this risk.Conclusions: CYP2C9*3, CYP2C19*2, and CYP2C19*3 polymorphisms resulted in a reduced elimination rate of indisulam. Screening for these CYP2C polymorphisms and subsequent pharmacogenetically guided dose adaptation may assist in the selection of an optimized initial indisulam dosage.
KRASMutation Is an Important Predictor of Resistance to Therapy with Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors in Non–Small-Cell Lung Cancer
Authors: Massarelli Erminia , Varella-Garcia Marileila , Tang Ximing , Xavier Ana C. , Ozburn Natalie C. , Liu Diane D. , Bekele Benjamin N. , Herbst Roy S. , Wistuba Ignacio I. 
Published: May 2007

AbstractPurpose:EGFR gene mutations and increased EGFR copy number have been associated with favorable response to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (EGFR-TKI) in patients with non–small-cell lung cancer (NSCLC). In contrast, KRAS mutation has been shown to predict poor response to such therapy. We tested the utility of combinations of these three markers in predicting response and survival in patients with NSCLC treated with EGFR-TKIs.Experimental Design: Patients with advanced NSCLC treated with EGFR-TKI with available archival tissue specimens were included. EGFR and KRAS mutations were analyzed using PCR-based sequencing. EGFR copy number was analyzed using fluorescence in situ hybridization.Results: The study included 73 patients, 59 of whom had all three potential markers successfully analyzed. EGFR mutation was detected in 7 of 71 patients (9.8%), increased EGFR copy number in 32 of 59 (54.2%), and KRAS mutation in 16 of 70 (22.8%). EGFR mutation (P &lt; 0.0001) but not increased EGFR copy number (P = 0.48) correlated with favorable response. No survival benefit was detected in patients with either of these features. KRAS mutation correlated with progressive disease (P = 0.04) and shorter median time to progression (P = 0.0025) but not with survival. Patients with both EGFR mutation and increased EGFR copy number had a &gt;99.7% chance of objective response, whereas patients with KRAS mutation with or without increased EGFR copy number had a &gt;96.5% chance of disease progression.Conclusion:KRAS mutation should be included as indicator of resistance in the panel of markers used to predict response to EGFR-TKIs in NSCLC.
Intradermal CpG-B Activates Both Plasmacytoid and Myeloid Dendritic Cells in the Sentinel Lymph Node of Melanoma Patients
Authors: Molenkamp Barbara G. , van Leeuwen Paul A.M. , Meijer Sybren , Sluijter Berbel J.R. , Wijnands Pepijn G.J.T.B. , Baars Arnold , van den Eertwegh Alfons J.M. , Scheper Rik J. , de Gruijl Tanja D. 
Published: May 2007

AbstractPurpose: A decrease in the frequency and activation state of dendritic cells in the sentinel lymph node (SLN) has been observed in early stages of melanoma development. This may hinder the generation of effective antitumor T-cell responses and increase the likelihood of metastatic spread. Immunopotentiation of the melanoma SLN may therefore be a valuable adjuvant treatment option. One way to achieve this is through the use of bacterially derived unmethylated cytosine-phosphate-guanine (CpG) DNA sequences that bind Toll-like receptor 9 and activate plasmacytoid dendritic cells (PDC). CpG-activated PDC, in turn, release IFNα and may thus boost T-cell and natural killer cell responses as well as activate conventional myeloid dendritic cells (MDC).Experimental Design: We studied the effects of preoperative local administration of the CpG B-type oligodeoxynucleotide (ODN) PF-3512676 (formerly known as CPG 7909) on dendritic cell and T-cell subsets in the SLN of 23 stage I to III melanoma patients, randomized to receive intradermal injections of either PF-3512676 or saline (NaCl 0.9%).Results: PF-3512676 administration resulted in bulkier SLN, higher yields of isolated SLN leukocytes, and activation of BDCA-2+CD123+ PDC as well as of CD1a+ MDC. In addition, PF-3512676 administration was associated with the presence of a newly identified CD11chiCD123+CD83+TRAIL+ mature SLN-MDC subset, an increased release of a variety of inflammatory cytokines, and lower frequencies of CD4+CD25hiCTLA-4+FoxP3+ regulatory T cells in the SLN.Conclusions: These findings point to the possible utility of the conditioning of SLN by PF-3512676 as an adjuvant immunotherapeutic modality for early-stage melanoma.
Knee-Specific Quality-of-Life Instruments
Authors: Tanner Suzanne M. , Dainty Katie N. , Marx Robert G. , Kirkley Alexandra 
Published: May 2007

Background Knee-specific quality-of-life instruments are commonly used outcome measures. However, they have not been compared for their ability to detect symptoms and disabilities important to patients. Study Design Cohort study (diagnosis); Level of evidence, 1. Methods Subjective portions of 11 knee-specific instruments were consolidated. The frequency and importance of each item were assessed. One hundred fifty-three patients with anterior cruciate ligament ruptures, isolated meniscal tears, or osteoarthritis were polled. Instruments were ranked according to the number of items with high mean importance, high frequency importance product, and low mean importance, and according to the number endorsed by at least 51% of patients. Results For anterior cruciate ligament tears, the Mohtadi quality-of-life instrument scored highest in 3 categories. For meniscal tears, the Western Ontario Meniscal Evaluation Tool scored highly in all 4 categories. For osteoarthritis, the Western Ontario and McMaster Universities Osteoarthritis Index scored highly in 4 categories. Of the general knee instruments, the International Knee Documentation Committee Standard Evaluation Form and the Knee Injury and Osteoarthritis Outcome Score scored favorably. Conclusion The Mohtadi quality-of-life instrument, Western Ontario Meniscal Evaluation Tool, and Western Ontario and McMaster Universities Osteoarthritis Index—disease-specific instruments—contain many items important to patients. Of general knee instruments studied, the International Knee Documentation Committee Standard Evaluation Form and the Knee Injury and Osteoarthritis Outcome Score contain the most items important to patients. Clinical Relevance This study guides clinicians and researchers in selecting instruments that ensure that the patient's perspective is considered for outcome studies involving 3 common knee disorders.