bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mutation in the Tyrosine Kinase Domain of Epidermal Growth Factor Receptor Is a Predictive and Prognostic Factor for Gefitinib Treatment in Patients with Non–Small Cell Lung Cancer
Authors: Chou Teh-Ying , Chiu Chao-Hua , Li Ling-Hui , Hsiao Chun-Yen , Tzen Chin-Yuan , Chang Kuo-Ting , Chen Yuh-Min , Perng Reury-Perng , Tsai Shih-Feng , Tsai Chun-Ming 
Published: September 2005

Abstract
Purpose: Mutations in epidermal growth factor receptor (EGFR) can be used to predict the tumor response of patients receiving gefitinib for non–small cell lung cancer (NSCLC). We investigated the association between mutations in EGFR tyrosine kinase domain and tumor response and survival in gefitinib-treated NSCLC patients.
Experimental Design: EGFR mutations in exons 18 to 21 were analyzed by DNA sequencing of paraffin-embedded tumor tissues from gefitinib-treated NSCLC patients. The results were correlated with clinical variables.
Results: EGFR mutations were found in 61.1% (33 of 54) of cases; response rate and disease control rate were 56.8% and 68.5%, respectively. There was no significant difference in mutation rates between adenocarcinoma (29 of 43) and nonadenocarcinoma (4 of 11; P = 0.085). However, all four nonadenocarcinomas with EGFR mutations had no response to gefitinib. Presence of EGFR mutations was the only independent predictor for disease control (P = 0.003) and tumor response (P = 0.017) in multivariate analysis; positive predictive values were 87.9% and 70.8% and negative predictive values were 61.9% and 69.2%, respectively. In comparison with patients whose tumor was negative for EGFR mutations, patients with EGFR mutations had better progression-free survival (median, 7.6 versus 1.7 months; P = 0.011) and overall survival (median, 14.7 versus 4.7 months; P = 0.046).
Conclusions: Mutations in EGFR tyrosine kinase correlate with treatment response and survival in gefitinib-treated NSCLC patients and can be used as a predictive and prognostic factor. Thus, analysis of EGFR tyrosine kinase mutations in lung adenocarcinoma is of clinical significance, as it can permit the customization of treatment with EGFR tyrosine kinase inhibitors.
Carbonic Anhydrase IX Expression Predicts Outcome of Interleukin 2 Therapy for Renal Cancer
Authors: Atkins Michael , Regan Meredith , McDermott David , Mier James , Stanbridge Eric , Youmans Amanda , Febbo Philip , Upton Melissa , Lechpammer Mirna , Signoretti Sabina 
Published: September 2005

Abstract
Purpose: Renal cancer response to interleukin 2 (IL-2) therapy and patient survival has been correlated with tumor histology and carbonic anhydrase IX (CAIX) expression. In an effort to confirm and expand these observations, we examined CAIX expression in pathology specimens from renal cancer patients who had previously received IL-2 therapy.
Experimental Design: Paraffin-embedded tissue sections of renal cancer were immunostained with the MN-75 monoclonal antibody to CAIX and expression levels were correlated with histologic findings and clinical outcome.
Results: Tissue specimens were obtained from 66 patients; 27 of whom (41%) had responded to IL-2–based therapy. Fifty-eight specimens were assessed as clear cell, with 56, 33, and 4 having alveolar, granular, and papillary features, respectively. Twenty-four (36%), 31 (47%), and 11 (17%) were classified into good, intermediate, and poor prognosis groups according to the Upton pathology model. Forty-one specimens (62%) had high CAIX expression. Twenty-one of 27 (78%) responding patients had high CAIX expressing tumors compared with 20 of 39 (51%) nonresponders (odds ratio, 3.3; P = 0.04). Median survival was prolonged (P = 0.04) and survival &gt;5 years was only seen in high CAIX expressers. In patients with intermediate pathologic prognosis, all nine responders had high CAIX expression versus 11 of 22 nonresponders. A resultant group with good pathologic prognosis alone or with intermediate pathologic prognosis and high CAIX contained 26 of 27 (96%) responders compared with 18 of 39 (46%) nonresponders (odds ratio, 30; P &lt; 0.01) and exhibited longer median survival (P &lt; 0.01).
Conclusions: CAIX expression seems to be an important predictor of outcome in renal cell carcinoma patients receiving IL-2–based therapy and may enhance prognostic information obtained from pathology specimens.
A Homozygous Mutation in MSH6 Causes Turcot Syndrome
Authors: Hegde Madhuri R. , Chong Belinda , Blazo Maria E. , Chin Lip Hon E. , Ward Patricia A. , Chintagumpala Murali M. , Kim John Y. , Plon Sharon E. , Richards C. Sue 
Published: September 2005

Abstract
Heterozygous mutations in one of the DNA mismatch repair genes cause hereditary nonpolyposis colorectal cancer (MIM114500). Turcot syndrome (MIM276300) has been described as the association of central nervous system malignant tumors and familial colorectal cancer and has been reported to be both a dominant and recessive disorder. Homozygous and compound heterozygous mutations in APC, MLH1, MSH2, and PMS2 genes have been reported in five families. Here we describe a nonconsanguineous Pakistani family, including a son with lymphoma and colorectal cancer diagnosed at ages 5 and 8, respectively, and an 8-year-old daughter with glioblastoma multiforme. Both children had features of neurofibromatosis type 1 including atypical café au lait spots and axillary freckling without a family history consistent with neurofibromatosis type 1, familial adenomatous polyposis, or hereditary nonpolyposis colorectal cancer. Mutational analysis was done for MLH1, MSH2, and MSH6 using denaturing high-performance liquid chromatography and sequencing of a blood sample from the daughter. A novel homozygous single base insertion mutation was identified (3634insT) resulting in a premature stop at codon 1,223 in exon 7 of the MSH6 gene. Both parents were found to be heterozygous for the 3634insT mutation. Microsatellite instability testing showed instability in the glioblastoma sample. We report here the first identification of a homozygous mutation in MSH6 in a family with childhood-onset brain tumor, lymphoma, colorectal cancer, and neurofibromatosis type 1 phenotype. Our findings support a role for MSH6 in Turcot syndrome and are consistent with an autosomal recessive mode of inheritance.
Somatic Mutations of EGFR Gene in Squamous Cell Carcinoma of the Head and Neck
Authors: Lee Jong Woo , Soung Young Hwa , Kim Su Young , Nam Hyo Kyung , Park Won Sang , Nam Suk Woo , Kim Min Sik , Sun Dong Il , Lee Youn Soo , Jang Ja June , Lee Jung Young , Yoo Nam Jin , Lee Sug Hyung 
Published: September 2005

Abstract
Purpose: Recently, the kinase domain mutations of epidermal growth factor receptor (EGFR) gene have been identified in non–small-cell lung cancer, and these mutations have been related to the clinical response to the tyrosine kinase inhibitor gefitinib. Gefitinib treatment has also shown clinical benefits in squamous cell carcinoma of the head and neck (SCCHN). The aim of this study was to explore the possibility that SCCHN harbored the EGFR mutations.
Experimental Design: In this study, we analyzed EGFR gene in 41 SCCHN for the detection of the somatic mutations by PCR-single-strand conformational polymorphism analysis.
Results: Overall, we detected three EGFR mutations (7.3%), and all of the mutations were the same in-frame deletion mutation in exon 19 (E746_A750del).
Conclusion: These data indicated that in addition to non–small-cell lung cancer, SCCHN harbors the EGFR gene mutations, and suggested the rationale for the clinical applicability of gefinitib to SCCHN patients.
Definition of an Immunogenic Region Within the Ovarian Tumor Antigen Stratum Corneum Chymotryptic Enzyme
Authors: Bondurant Kristina L. , Crew Mark D. , Santin Alessandro D. , O'Brien Timothy J. , Cannon Martin J. 
Published: September 2005

Abstract
Purpose: The serine protease stratum corneum chymotryptic enzyme (SCCE) is overexpressed by ovarian tumor cells, but is not expressed by normal tissues, suggesting that SCCE may be an attractive target for immunotherapy. In this study, we tested the hypothesis that dendritic cells loaded with SCCE peptides will induce ovarian tumor antigen–specific CD8+ CTL responses and antigen-specific CD4+ helper T cell responses.
Experimental Design: Computer algorithms were used to identify candidate HLA-A2.1-restricted CD8+ CTL epitopes and HLA-DR-binding CD4+ helper T cell epitopes within SCCE. CD8+ CTL stimulated with peptide-loaded dendritic cells were tested against targets expressing endogenous SCCE, including HLA-A2.1-matched ovarian tumor cells. Dendritic cells were also loaded with an extended SCCE peptide, SCCE 110-139, which encompassed a defined CD8+ CTL epitope and multiple candidate CD4+ T helper cell epitopes.
Results: CD8+ CTL specific for SCCE 123-131 lysed autologous macrophages infected with an SCCE-expressing recombinant adenovirus, and also lysed HLA-A2.1-matched, SCCE-expressing ovarian tumor cells. Dendritic cells loaded with SCCE 5-13 peptide stimulated an HLA-A2.1-restricted CD8+ CTL response, but with a reduced level of lysis against ovarian tumor cells. Dendritic cells loaded with SCCE 110-139 induced antigen-specific CD4+ T cell and CD8+ T cell responses. Although SCCE 110-139-loaded dendritic cells processed and presented the 123-131 epitope, the dominant CD8+ CTL response was directed against alternative epitopes within SCCE 110-139.
Conclusions: The 110-139 region of SCCE incorporates multiple CD8+ CTL and CD4+ helper T cell epitopes, and represents an attractive target antigen for immunotherapy of ovarian cancer.
p38MAPK-Dependent Sensitivity of Ewing's Sarcoma Family of Tumors to Fenretinide-Induced Cell Death
Authors: Myatt Stephen S. , Redfern Christopher P.F. , Burchill Susan A. 
Published: September 2005

Abstract
Purpose: There is an urgent need for new therapeutic strategies in Ewing's sarcoma family of tumors (ESFT). In this study, we have evaluated the effect of fenretinide [N-(4-hydroxyphenyl)retinamide] in ESFT models.
Experimental Design: The effect of fenretinide on viable cell number and apoptosis of ESFT cell lines and spheroids and growth of s.c. ESFT in nu/nu mice was investigated. The role of the stress-activated kinases p38MAPK and c-Jun NH2-terminal kinase in fenretinide-induced death was investigated by Western blot and inhibitor experiments. Accumulation of reactive oxygen species (ROS) and changes in mitochondrial transmembrane potential were investigated by flow cytometry.
Results: Fenretinide induced cell death in all ESFT cell lines examined in a dose- and time-dependent manner. ESFT cells were more sensitive to fenretinide than the neuroblastoma cell lines examined. Furthermore, fenretinide induced cell death in ESFT spheroids and delayed s.c. ESFT growth in mice. p38MAPK was activated within 15 minutes of fenretinide treatment and was dependent on ROS accumulation. Inhibition of p38MAPK activity partially rescued fenretinide-mediated cell death in ESFT but not in SH-SY5Y neuroblastoma cells. c-Jun NH2-terminal kinase was activated after 4 hours and was dependent on ROS accumulation but not on activation of p38MAPK. After 8 hours, fenretinide induced mitochondrial depolarization (Δψm) and release of cytochrome c into the cytoplasm in a ROS- and p38MAPK-dependent manner.
Conclusions: These data show that the high sensitivity of ESFT cells to fenretinide is dependent in part on the rapid and sustained activation of p38MAPK. The efficacy of fenretinide in preclinical models demands the evaluation of fenretinide as a potential therapeutic agent in ESFT.
In vivo Bioavailability and Pharmacokinetics of a c-MYC Antisense Phosphorodiamidate Morpholino Oligomer, AVI-4126, in Solid Tumors
Authors: Devi Gayathri R. , Beer Tomasz M. , Corless Christopher L. , Arora Vikram , Weller Doreen L. , Iversen Patrick L. 
Published: September 2005

Abstract
Phosphorodiamidate morpholino oligomers (PMO) inhibit targeted gene expression by preventing ribosomal assembly, thereby preventing mRNA translation. AVI-4126, a PMO targeted against c-MYC, has been extensively characterized in multiple cancer and other disease models and is currently in human clinical trials. A phase I clinical study was conducted to address the issue of PMO bioavailability in malignant tumors surgically excised from patients with adenocarcinoma of prostate and breast 1 day after i.v. administration of a single dose of 90 mg AVI-4126 PMO. The study objectives were to evaluate safety, to determine AVI-4126 concentration in tissue samples of the tumors, and to examine the distribution of AVI-4126 (margin versus tumor core). Significant concentrations of intact PMO similar to the animal models were detected in both human prostate and breast tumor tissues with increased distribution in the tumor core for the vascular breast tumors. No serious adverse events (graded according to National Cancer Institute Common Toxicity Criteria) were reported. Another phase I study was conducted in normal human volunteers to assess AVI-4126 plasma pharmacokinetics following single i.v. administration of 90 mg AVI-4126. Data from both human studies indicated similar plasma concentration-time profile. These studies show PMO bioavailability in tumor tissue and establish the feasibility of using PMO targeting specific genes in human cancer clinical trials.
Preclinical Evaluation of Gemcitabine Combination Regimens for Application in Acute Myeloid Leukemia
Authors: Shanks Ryan H. , Rizzieri David A. , Flowers James L. , Colvin O. Michael , Adams David J. 
Published: September 2005

Abstract
The DNA antimetabolite gemcitabine is an anticancer agent with shown preclinical and clinical utility and a low toxicity profile. In this study, we sought to identify and optimize drug partners for binary and tertiary combinations with gemcitabine for use in the treatment of acute myelogenous leukemia (AML). Drug interaction was assessed by growth inhibition assay with metabolic end points. The combination index method was used to evaluate combinations of gemcitabine with fludarabine, paclitaxel, chlorambucil, doxorubicin, mitoxantrone, and SN-38 in U937 human AML cells. A three-dimensional method was used to determine the effect of dose ratio and schedule on drug interaction. Mechanisms underlying interactions related to cell cycle effects and apoptosis were assessed by flow cytometric and caspase-3 and -7 assays, respectively. The most synergistic binary combination was gemcitabine + fludarabine. The most synergistic tertiary combination was gemcitabine + fludarabine + paclitaxel, where the interaction was sequence dependent with paclitaxel given before gemcitabine + fludarabine, producing a 2-fold increase in synergy. Cell cycle analysis did not reveal a significant G2-M arrest, suggesting that the synergistic effect of paclitaxel in this combination, which produced the greatest caspase activation, might be independent of microtubule stabilization. In contrast, the gemcitabine + fludarabine + mitoxantrone combination was synergistic and schedule independent. Moreover, few ratios of gemcitabine + fludarabine to mitoxantrone were antagonistic, which could be important for clinical translation. In conclusion, synergistic interactions with gemcitabine occurred with several drugs, the most promising being gemcitabine + fludarabine, gemcitabine + fludarabine + paclitaxel, and gemcitabine + fludarabine + mitoxantrone. These findings provided a rationale for clinical trials of gemcitabine + fludarabine and gemcitabine + mitoxantrone where responses were observed in heavily pretreated AML patients.
Up-Regulation of EphB4 in Mesothelioma and Its Biological Significance
Authors: Xia Guangbin , Kumar S. Ram , Masood Rizwan , Koss Michael , Templeman Claire , Quinn David , Zhu Sutao , Reddy Ramachandra , Krasnoperov Valery , Gill Parkash S. 
Published: September 2005

Abstract
Purpose: Mesothelioma is a rare malignancy that is incurable and carries a short survival despite surgery, radiation, or chemotherapy. This study was designed to identify novel targets for diagnostic, prognostic, and therapeutic approaches.
Experimental Design: The expression and functional significance of the receptor tyrosine kinase EphB4 was studied in vitro and in a murine model of mesothelioma.
Results: EphB4 was highly expressed in mesothelioma cell lines and primary tumor tissues but not in normal mesothelium. Knockdown of EphB4 using small interfering RNA and antisense oligodeoxynucleotide showed reduction in cell survival, migration, and invasion. EphB4 knockdown initiated a caspase-8-mediated apoptosis and down-regulation of the antiapoptotic protein bcl-xl. EphB4 knockdown also resulted in reduced phosphorylation of Akt and down-regulation of matrix metalloproteinase-2 transcription. In addition, murine tumor xenograft studies using EphB4 oligodeoxynucleotides showed a marked reduction in tumor growth accompanied by a specific decline in EphB4 protein levels, reduced cell division, apoptosis in tumor tissue, and decreased microvascular density.
Conclusions: EphB4 is expressed in mesothelioma, provides a survival advantage to tumor cells, and is therefore a potential novel therapeutic target.
Unexpected Association between Induction of Immunity to the Universal Tumor Antigen CYP1B1 and Response to Next Therapy
Authors: Gribben John G. , Ryan David P. , Boyajian Richard , Urban Robert G. , Hedley Mary L. , Beach Kathleen , Nealon Patrick , Matulonis Ursula , Campos Susana , Gilligan Timothy D. , Richardson Paul G. , Marshall Blossom , Neuberg Donna , Nadler Lee M. 
Published: September 2005

Abstract
Purpose: The carcinogen activator cytochrome P450 1B1 (CYP1B1) is expressed on almost all human tumors with rare expression on normal tissues. Anti-CYP1B1–specific T cells kill CYP1B1-expressing tumors, providing the rationale to examine CYP1B1 as a target for immunotherapy.
Experimental Design: ZYC300, a plasmid DNA of CYP1B1 encapsulated in biodegradable poly-dl-lactide-coglycolide microparticles, was used in a phase I clinical trial to treat 17 patients with advanced stage, progressive cancer. ZYC300 was administered i.m. at a fixed dose of 400 μg every other week for up to 12 doses.
Results: Thirteen patients received six vaccinations and five received all 12 doses. No significant adverse events were observed. Six patients developed immunity to CYP1B1, three of whom developed disease stabilization. All but 1 of 11 patients who did not develop immunity to CYP1B1 progressed and did not respond to salvage therapy. Five patients who developed immunity to CYP1B1 required salvage therapy for progressive metastatic disease and showed marked response to their next treatment regimen, most of which lasted longer than 1 year.
Conclusions: The association between immunity to CYP1B1 and response to next salvage therapy was not expected. Because six of the seven patients who had clinical benefit regardless of the nature of salvage therapy had developed immunity to CYP1B1, it seems highly unlikely that this occurred by chance alone. Regardless of the mechanism(s) that induced tumor regression, these findings force us to rethink how the generation of antitumor immunity might be integrated into the treatment of cancer.
Improved Therapeutic Effectiveness by Combining Recombinant CXC Chemokine Ligand 10 with Cisplatin in Solid Tumors
Authors: Li Gang , Tian Ling , Hou Jian-mei , Ding Zhen-yu , He Qiu-ming , Feng Ping , Wen Yan-jun , Xiao Fei , Yao Bing , Zhang Ru , Peng Feng , Jiang Yu , Luo Feng , Zhao Xia , Zhang Lin , Zhou Qiao , Wei Yu-quan 
Published: September 2005

Abstract
Purpose: CXC chemokine ligand 10 (CXCL10) is a potent inhibitor of angiogenesis. We wonder whether the combination of CXCL10 with cisplatin would improve the therapeutic antitumor efficacy.
Experiment Design: We evaluated the antitumor activity of the combination therapy in the immunocompetent C57BL/6 and BALB/c mice bearing LL/2 Lewis lung cancer and CT26 colon adenocarcinoma, respectively. Mice were treated with either CXCL10 s.c. at 25 μg per kg per day once daily for 30 days, cisplatin cycled twice (5 mg/kg i.p. on days 14 and 21 after the initiation of CXCL10), or both agents together. Tumor volume and survival time were observed. Antiangiogenesis of CXCL10 in vivo were determined by alginate capsule models and CD31 immunohistochemistry. Histologic analysis and assessment of apoptotic cells were also conducted in tumor tissues.
Results: CXCL10 + cisplatin reduced tumor growth in LL/2 and CT26 tumor model, respectively, more effectively, although cisplatin or CXCL10 individually resulted in suppression of tumor growth and improved survival time of tumor-bearing mice. CXCL10 successfully inhibited angiogenesis as assessed by alginate model and CD31 (P &lt; 0.05). Histologic analysis of tumors exhibited that CXCL10 in combination with cisplatin led to the increased rate of apoptosis, tumor necrosis, and elevated lymphocyte infiltration.
Conclusions: Our data suggest that the combination of CXCL10, a well-tolerated angiogenesis inhibitor, with cisplatin can enhance the antitumor activity. The present findings may be of importance to the further exploration of the potential application of this combined approach in the treatment of lung and colon carcinoma.
Effects of Chemotherapy on the Cytogenetic Constitution of Wilms' Tumor
Authors: Schlomm Thorsten , Gunawan Bastian , Schulten Hans-Jürgen , Sander Björn , Thangavelu Karthinathan , Graf Norbert , Leuschner Ivo , Ringert Rolf-Hermann , Füzesi László 
Published: September 2005

Abstract
The management of Wilms' tumors consists of a combination of surgery, chemotherapy, and possibly radiotherapy. To date, chemotherapy is being risk stratified according to histologic subtype and stage. Although the cytogenetic characteristics of Wilms' tumors are well established, the cytogenetic effects related to chemotherapy are widely unknown. We herein report on comparative genomic hybridization findings in 41 primary Wilms' tumors of blastemal type, of which 19 had received preoperative chemotherapy (PCT group) and 22 did not (non-PCT group). Overall, imbalances could be detected in 32 tumors, with +1q (17 cases), +7q (10 cases), +7p (6 cases), and −7p (6 cases) as the most common changes. Among these, +7q and −7p were both significantly associated with metastatic disease at the time of surgery (P = 0.002 and 0.007, respectively), and +7q was also associated with higher stage (stages III + IV; P = 0.003). There were significant differences in the cytogenetic constitution of tumors between the two treatment groups. As a trend, tumors in the preoperative-chemotheraphy group had fewer changes (mean, 2.7) than those in the non-preoperative-chemotheraphy group (mean, 3.8), and the frequencies of imbalances at 7p or +7q, respectively, were significantly lower compared with tumors in the non-preoperative-chemotheraphy group (2 of 19 versus 10 of 22, P = 0.019; 1 of 19 versus 9 of 22, P = 0.011). In contrast, −1q was common in both the preop-CT group (10 of 19) and the non-preop-CT group (7 of 22). The results suggest that Wilms' tumor clones with +1q are not obliterated by preoperative chemotherapy, whereas cytogenetically more complex clones with +7q and/or imbalances at 7p seem more responsive and are more likely to be eliminated by chemotherapeutic treatment.