bluuebunny/crossref_metadata_2025_split huggingface dataset:
B7-H1 Expression on Non-Small Cell Lung Cancer Cells and Its Relationship with Tumor-Infiltrating Lymphocytes and Their PD-1 Expression
Authors: Konishi Jun , Yamazaki Koichi , Azuma Miyuki , Kinoshita Ichiro , Dosaka-Akita Hirotoshi , Nishimura Masaharu 
Published: September 2005

AbstractPurpose: B7-H1/PD-L1 (B7-H1) and B7-DC/PD-L2 (B7-DC) are ligands for the receptor PD-1, which is known to negatively regulate T-cell activation. In the present study, we investigated the expression of B7-H1 and B7-DC in tumor specimens of non-small cell lung cancer and their relationships with clinicopathological variables and postoperative survival. Furthermore, we examined the correlation between B7-H1 expression on tumor cells and the number of tumor-infiltrating lymphocytes (TILs) or PD-1 expression on TILs.Experimental Design: The expression of B7-H1 and B7-DC in 52 surgically resected specimens of non-small cell lung cancer was evaluated immunohistochemically.Results: Expression of B7-H1 and B7-DC was focally observed in all non-small cell lung cancer tumor specimens. No relationship was found between the expression of B7-H1 or B7-DC and clinicopathological variables or postoperative survival. However, in the same sections evaluated, significantly fewer TILs were identified in B7-H1-positive tumor regions than in B7-H1-negative tumor regions in a subset of five patients (P = 0.01). Moreover, the percentage of TILs expressing PD-1 was significantly lower in B7-H1-positive tumor regions than in B7-H1-negative tumor regions (P = 0.02).Conclusions: The expression of B7-H1 on tumor cells in local areas reciprocally correlated with the number of TILs, and this may contribute to negative regulation in antitumor immune responses in non-small cell lung cancer.
Phase I Study of Tirapazamine Plus Cisplatin/Etoposide and Concurrent Thoracic Radiotherapy in Limited-Stage Small Cell Lung Cancer (S0004)
Authors: Le Quynh-Thu , McCoy Jason , Williamson Stephen , Ryu Janice , Gaspar Laurie E. , Edelman Martin J. , Dakhil Shaker R. , Sides Stanley D. , Crowley John J. , Gandara David R. 
Published: September 2005

Abstract
Purpose: To determine the feasibility and a recommended phase II dose of tirapazamine when combined with chemoradiotherapy in limited-stage small cell lung cancer (LSCLC).
Experimental Design: Concurrent chemoradiotherapy consisted of two cycles of cisplatin, etoposide, and once-daily radiation to 61 Gy. Tirapazamine (260 mg/m2) was given 1 h before cisplatin with planned dose escalation to 330 mg/m2 in the absence of dose-limiting toxicity, defined as ≥33% esophagitis (grade 3 or above). Consolidation therapy consisted of two cycles of tirapazamine (330 mg/m2), cisplatin, and etoposide. Complete responders received prophylactic cranial irradiation.
Results: Thirty patients were enrolled at the 260 mg/m2 tirapazamine dose. All had performance status of 0–1. By comparison with S9713, a predecessor Southwest Oncology Group study in LSCLC that used the same concurrent chemoradiotherapy without tirapazamine, the present trial showed a higher rate of grade 3–4 esophagitis (34% versus 22%), vomiting (34% versus 23%), and febrile neutropenia (7% versus 2%). The consolidation phase was relatively well tolerated, with grade 4 neutropenia in 44% and febrile neutropenia in 5% of patients. There were two treatment-related deaths: one from neutropenic fever and one from respiratory infection. The overall response rate was 80%, and the median survival was 22 months.
Conclusions: Protocol-defined dose-limiting toxicity was observed at the initial tirapazamine dose, precluding dose escalation. Compared with S9713, the addition of tirapazamine increased the incidence of vomiting, neutropenia, and febrile neutropenia, although the overall toxicity profile remained acceptable. In view of the observed favorable survival, further study of tirapazamine in LSCLC is warranted.
Irofulven Cytotoxicity Depends on Transcription-Coupled Nucleotide Excision Repair and Is Correlated with XPG Expression in Solid Tumor Cells
Authors: Koeppel Florence , Poindessous Virginie , Lazar Vladimir , Raymond Eric , Sarasin Alain , Larsen Annette K. 
Published: September 2005

Abstract
Background: Irofulven is a novel alkylating agent with promising clinical activity, particularly toward ovarian and hormone-refractory prostate cancers. To facilitate additional clinical development, we have aimed to identify biological markers associated with sensitivity to the compound.
Methods: Fibroblasts derived from patients with xeroderma pigmentosum or Cockayne’s syndrome along with a panel of 20 human cancer cell lines (eight different tumor types) were examined to establish the importance of nucleotide excision repair proteins in the sensitivity to irofulven.
Results: Human cells deficient in nucleotide excision repair are up to 30-fold more sensitive to the cytotoxic effects of irofulven compared with repair-proficient controls, clearly indicating that nucleotide excision repair plays a crucial role in the sensitivity to the drug. Interestingly, our results show that irofulven-induced lesions are recognized by transcription-coupled repair but not by global genome repair. Another unique feature is the pronounced sensitivity of XPD and XPB helicase-deficient cells to the drug. Comparison of the IC50 values for irofulven, cisplatin, and ecteinascidin 743 with the expression levels of ERCC1, XPD, and XPG genes in different solid tumor cell lines shows no correlation between the expression levels of any of the three nucleotide excision repair proteins and the sensitivity to ecteinascidin 743. In contrast, expression of the XPG endonuclease was correlated with the cytotoxicity for irofulven and, to a lesser degree, for cisplatin. Importantly, XPG expression was also correlated with cellular nucleotide excision repair activity.
Conclusions: Increasing evidence indicates that compromised nucleotide excision repair activity is frequent in several solid tumor types. The results presented here suggest that XPG expression in such tumors may be a useful marker to predict their sensitivity to irofulven.
Overexpression of Collagen XVIII Is Associated with Poor Outcome and Elevated Levels of Circulating Serum Endostatin in Non–Small Cell Lung Cancer
Authors: Iizasa Toshihiko , Chang Hao , Suzuki Makoto , Otsuji Mizuto , Yokoi Sana , Chiyo Masako , Motohashi Shinichiro , Yasufuku Kazuhiro , Sekine Yasuo , Iyoda Akira , Shibuya Kiyoshi , Hiroshima Kenzo , Fujisawa Takehiko 
Published: September 2005

Abstract
Purpose: The aim of this study was to determine whether collagen XVIII expression is correlated with circulating serum endostatin and whether this has any prognostic value in patients with non–small cell lung cancer (NSCLC).
Experimental Design: Serum endostatin levels were measured quantitatively by a competitive enzyme immunoassay, and collagen XVIII expression in tumor tissue was investigated with an immunohistochemical method in a series of 94 patients who underwent surgery for NSCLC.
Results: Sixty cases (63.8%) had positive immunohistochemical staining with anticollagen XVIII polyclonal antibodies, including strongly positive staining in 11 (11.7%) cases. The mean (± SD) serum endostatin level was 41.6 ± 34.4 ng/ml in the patient group and 16.3 ± 10.3 ng/ml in the control group (P &lt; 0.0001). The 11 cases who were strongly collagen XVIII-positive had significantly higher serum endostatin levels than the cases who were negative or weakly positive (P = 0.0297). The 5-year survival rates of negative, weakly positive, and strongly positive patients were 77.8%, 56.9%, and 43.8%, respectively. The cases with strongly positive collagen XVIII expression had a significantly poorer outcome than cases with negative expression (P = 0.0027). A multivariate analysis with Cox proportional hazards model for disease-specific survival revealed that expression of collagen XVIII (strongly positive versus negative; weakly positive versus negative), tumor classification, and regional lymph node classification were independent prognostic factors.
Conclusions: Our results suggest that expression of collagen XVIII in tumor tissue is strongly associated with a poorer outcome in NSCLC and correlates with elevated levels of circulating serum endostatin.
Phase I and Pharmacokinetic Study of the Oral Fluoropyrimidine S-1 on a Once-Daily-for-28-Day Schedule in Patients with Advanced Malignancies
Authors: Chu Quincy Siu-Chung , Hammond Lisa A. , Schwartz Garry , Ochoa Leonel , Rha Sun-Young , Denis Louis , Molpus Kathleen , Roedig Brian , Letrent Stephen P. , Damle Bharat , DeCillis Arthur P. , Rowinsky Eric K. 
Published: September 2005

Abstract
Purpose: The oral fluoropyrimidine S-1, which consists of a mixture of a 5-fluorouracil (5-FU) prodrug (tegafur), a dihydropyrimidine dehydrogenase inhibitor [5-chloro-2,4-dihydroxypyrimidine (CDHP)], and an inhibitor of orotate phosphoribosyltransferase [potassium oxonate (oxonic acid)], was developed to increase the feasibility and therapeutic index of 5-FU administered orally. The principal objective of this study was to assess the feasibility of administering S-1 on a once-daily-for-28-day schedule every 5 weeks, determine the maximum tolerated dose, characterize the pharmacokinetics of S-1, and seek evidence of anticancer activity.
Experimental Design: Patients with advanced solid malignancies were treated with escalating doses of S-1 on a once-daily oral schedule for 28 days every 5 weeks. The maximum tolerated dose was defined as the highest dose in which fewer than two of the first six new patients experienced dose-limiting toxicity. The pharmacokinetic profiles of the tegafur, CDHP, and oxonic acid constituents were characterized.
Results: Twenty patients were treated with 72 courses of S-1 at three dose levels ranging from 50 to 70 mg/m2/day. Diarrhea, which was often associated with abdominal discomfort and cramping, was the principal dose-limiting toxicity of S-1 on this protracted schedule. Nausea, vomiting, mucositis, fatigue, and cutaneous effects were also observed but were rarely severe. Myelosuppression was modest and uncommon. A partial response and a 49% reduction in tumor size were observed in patients with fluoropyrimidine- and irinotecan-resistant colorectal carcinoma. The pharmacokinetic data suggested potent inhibition of 5-FU clearance by CHDP, with resultant 5-FU exposure at least 10-fold higher than that reported from equitoxic doses of tegafur modulated by uracil in the oral fluoropyrimidine UFT.
Conclusions: The recommended dose for Phase II studies of S-1 administered once daily for 28 consecutive days every 5 weeks is 50 mg/m2/day. The pharmacokinetic data indicate substantial modulation of 5-FU clearance by CDHP. Based on these pharmacokinetic data, the predictable toxicity profile of S-1, and the low incidence of severe adverse effects at the recommended Phase II dose, evaluations of S-1 on this schedule are warranted in malignancies that are sensitive to the fluoropyrimidines.
Is a Lymph Node Detected by the Dye-Guided Method a True Sentinel Node in Gastric Cancer?
Authors: Osaka Hirohisa , Yashiro Masakazu , Sawada Tetsuji , Katsuragi Kei , Hirakawa Kosei 
Published: September 2005

AbstractPurpose: A sentinel node is defined as the initial lymph node, to which cancer cells metastasize from a primary tumor. Recently, sentinel node navigation surgery has been done using the dye-guided method. However, no study has shown that a lymph node detected by the dye-guided method is the true sentinel node from the viewpoint of micrometastasis. Micrometastases of lymph nodes, in which no metastasis was found by H&E staining, were examined to establish whether a lymph node detected by the dye-guided method is the true sentinel node.Experimental Design: Isosulfan blue was injected endoscopically as the dye-guided method at a submucosal lesion of early gastric cancer. Total 345 lymph nodes, including 150 blue-dyed lymph nodes and 195 nondyed lymph nodes were collected from 57 patients and each was quartered. Two quarters were examined histologically by H&E staining and cytokeratin staining. The other specimens were used for quantitative reverse transcription-PCR of CEA and CK20 mRNAs.Results: Lymph node disease was not found in any of 345 lymph nodes from the 57 patients by routine H&E staining. By contrast, either CEA or CK20 mRNA expression was detected in 21 of 345 lymph nodes obtained from the 10 (18%) of 57 patients by quantitative reverse transcription-PCR. Eight of the 21 micrometastasis-positive lymph nodes were confirmed to be positive for cytokeratin staining. Although micrometastasis of nondyed lymph nodes was found in three cases, these were included in the 10 cases with micrometastasis of blue-dyed nodes, such that there was no patient who only had micrometastasis in nondyed nodes. Six of 10 cases were micrometastasis-positive in a single node; all six were blue-dyed nodes.Conclusion: A lymph node detected by the dye-guided method should be a true sentinel node to which cancer cells metastasize initially.
Using Protein Expressions to Predict Survival in Clear Cell Renal Carcinoma
Authors: Kim Hyung L. , Seligson David , Liu Xueli , Janzen Nicolette , Bui Matthew H. T. , Yu Hong , Shi Tao , Figlin Robert A. , Horvath Steve , Belldegrun Arie S. 
Published: September 2005

AbstractPurpose: An accurate system for predicting survival for patients with solid tumors will allow for better patient selection for both established and novel therapies. We propose a staging system for clear cell variants of renal cell carcinoma (RCC) that includes molecular predictors and standard clinical predictors such as tumor-node-metastasis (TNM) stage, histological grade, and performance status (PS).Experimental Design: A custom tissue array was constructed using clear cell RCC from 318 patients, representing all stages of localized and metastatic RCC, and immunohistochemically stained for molecular markers Ki67, p53, gelsolin, CA9, CA12, PTEN, EpCAM, and vimentin. We present a strategy for evaluating individual candidate markers for prognostic information and integrating informative markers into a multivariate prognostic system.Results: The overall median follow-up and the median follow-up for surviving patients were 28 and 55 months, respectively. A prognostic model based primarily on molecular markers included metastasis status, p53, CA9, gelsolin, and vimentin as predictors and had high discriminatory power: its statistically validated concordance index (C-index) was found to be 0.75. A prognostic model based on a combination of clinical and molecular predictors included metastasis status, T stage, Eastern Cooperative Oncology Group PS, p53, CA9, and vimentin as predictors and had a C-index of 0.79, which was significantly higher (P &lt; 0.05) than that of prognostic models based on grade alone (C = 0.65), TNM stage alone (C = 0.73), or the University of California Los Angeles integrated staging system (C = 0.76).Conclusions: Protein expressions obtained using widely available technology can complement standard clinical predictors such as TNM stage, histological grade, and PS.
Enhancement of Xenograft Tumor Radiosensitivity by the Histone Deacetylase Inhibitor MS-275 and Correlation with Histone Hyperacetylation
Authors: Camphausen Kevin , Scott Tamalee , Sproull Mary , Tofilon Philip J. 
Published: September 2005

Abstract
Purpose: Histone deacetylase (HDAC) inhibitors are undergoing clinical evaluation in cancer therapy. Because HDAC modulation has been shown to enhance the radiosensitivity of tumor cells in vitro, we investigated the effects of the HDAC inhibitor MS-275 on the radioresponse of DU145 prostate carcinoma xenografts.
Experimental Design: As an indicator of HDAC inhibition in vivo, the histone acetylation status in tumor lysates was determined after two, four, and six injections of MS-275 delivered at 12-hour intervals, as well as 24 and 48 hours after the last injection. Tumor growth delay studies were then performed using this DU-145 xenograft model with radiation administered to leg tumors after the fourth dose of MS-275, which corresponded to the time of maximum histone hyperacetylation.
Results: An increase in histone hyperacetylation was detected in each tumor after two injections of MS-275 with a maximum hyperacetylation occurring after four to six injections. In tumor growth delay studies, the combination of MS-275 and radiation resulted in a greater than additive inhibition of tumor growth as compared with the individual modalities. As alternative sources for an indicator of drug radiosensitizing activity, histone hyperacetylation was determined in a series of normal tissues, including lymphocytes. Each of the normal tissues also had a maximal histone hyperacetylation after four to six injections of MS-275.
Conclusions: These studies show that MS-275 enhances the radiosensitivity of DU145 xenografts and suggest that histone hyperacetylation status can serve as a useful marker for drug radiosensitizing activity.
T Cell–Dependent Antibody Responses against Aberrantly Expressed Cyclin B1 Protein in Patients with Cancer and Premalignant Disease
Authors: Suzuki Hiroyuki , Graziano Daniel F. , McKolanis John , Finn Olivera J. 
Published: September 2005

AbstractPurpose: Cyclin B1–derived peptides were shown by us to be targets of tumor-specific CD8+ T cells in patients with breast and head and neck cancer. We obtained further evidence of cyclin B1 immunogenicity and its potential to serve as a tumor-specific antigen by analyzing its ability to elicit T cell–dependent humoral immune responses in vivo in patients with different types of tumors.Experimental Design: Recombinant cyclin B1 protein from two different sources was purified and used as antigen in ELISA assays to test sera from patients with breast, pancreatic, colon, and lung cancer for the presence of anti-cyclin B1 antibody. We also analyzed patients with benign lung disease, premalignant disease, and a known history of heavy smoking.Results and Conclusions: Cyclin B1 elicits helper T cell–dependent antibody responses in vivo. Tumors with higher level of cyclin B1 expression elicit higher anti-cyclin B1 antibody levels. Antibodies in patients with breast and colon cancer are primarily of the IgG isotype whereas patients with pancreatic and lung cancer have in addition anti-cyclin B1 IgA. Cyclin B1–specific IgG was also detected in long-term smokers and in patients with preneoplastic lung disease. Immune responses to aberrantly expressed cyclin B1 in tumors and premalignant lesions should be further explored as diagnostic and prognostic markers, in addition to their immunotherapeutic potential.
Truncating
BRCA1
Mutations Are Uncommon in a Cohort of Hereditary Prostate Cancer Families with Evidence of Linkage to 17q Markers
Authors: Zuhlke Kimberly A. , Madeoy Jennifer J. , Beebe-Dimmer Jennifer , White Kirsten A. , Griffin Angela , Lange Ethan M. , Gruber Stephen B. , Ostrander Elaine A. , Cooney Kathleen A. 
Published: September 2005

Abstract
Purpose: A genome-wide scan of 175 hereditary prostate cancer families from the University of Michigan Prostate Cancer Genetics Project provided evidence of prostate cancer linkage to 17q markers near the BRCA1 gene. To examine the possibility that germ-line BRCA1 mutations were associated with hereditary prostate cancer, individuals from 93 families with evidence of linkage to chromosome 17q were screened for germ-line BRCA1 mutations.
Experimental Design: One individual from each of the 93 families, the majority with three or more cases of prostate cancer, were screened for BRCA1 mutations with denaturing high-performance liquid chromatography (HPLC). Fragments exhibiting denaturing HPLC variant patterns were additionally analyzed by direct sequencing.
Results: Sixty-five of the individuals selected for sequencing from 65 unrelated families were determined to have wild-type BRCA1 sequence by denaturing HPLC. One individual from a family with both prostate and ovarian cancer was found to have a truncating BRCA1 mutation (3829delT). An additional 27 germ-line variants were identified, including 15 missense variants.
Conclusions: These sequencing results suggest that BRCA1 truncating mutations do not account for the linkage evidence on chromosome 17 observed in University of Michigan Prostate Cancer Genetics Project families. A recently completed combined genome scan has also detected linkage to 17q22, and studies are ongoing to identify the relevant prostate cancer susceptibility gene in this region.
Aberrant Promoter Hypermethylation of Multiple Genes in Gallbladder Carcinoma and Chronic Cholecystitis
Authors: Takahashi Takao , Shivapurkar Narayan , Riquelme Erick , Shigematsu Hisayuki , Reddy Jyotsna , Suzuki Makoto , Miyajima Kuniharu , Zhou Xian , Bekele B. Nebiyou , Gazdar Adi F. , Wistuba Ignacio I. 
Published: September 2005

Abstract
Purpose: Aberrant methylation of 5′ gene promoter regions is an epigenetic phenomenon that is a major mechanism for silencing of tumor suppressor genes in many cancer types. There is limited information about the molecular changes involved in the pathogenesis of gallbladder carcinoma (GBC), including methylation status.
Experimental Design: We investigated the aberrant promoter methylation profile of 24 known or suspected tumor suppressor genes in 50 GBCs and compared those results with the findings in 25 chronic cholecystitis (CC) specimens without cancer. The methylation-specific polymerase chain reaction and combined restriction analysis methods were used to detect methylation, and the results were confirmed by sequencing of cloned polymerase chain reaction products.
Results: In GBC, gene methylation frequencies varied from 0% to 80%. Ten genes demonstrated relatively high frequencies of aberrant methylation: SHP1 (80%), 3-OST-2 (72%), CDH13 (44%), P15INK4B (44%), CDH1 (38%), RUNX3 (32%), APC (30%), RIZ1 (26%), P16INK4A (24%), and HPP1 (20%). Eight genes (P73, RARβ2, SOCS-1, DAPK, DcR2, DcR1, HIN1, and CHFR) showed low frequencies (2–14%) of methylation, and no methylation of the remaining six genes (TIMP-3, P57, RASSF1A, CRBP1, SYK, and NORE1) was detected. In CC, methylation was detected for seven genes: SHP1 (88%), P15INK4B (28%), 3-OST-2 (12%), CDH1 (12%), CDH13 (8%), DcR2 (4%), and P16INK4A (4%). Significantly higher frequencies of methylation in GBC compared with CC were detected for eight genes (3-OST-2, CDH13, CDH1, RUNX3, APC, RIZ1, P16INK4A, and HPP1). Of those, four genes showed frequent methylation (&gt;30%) in GBCs. The mean methylation index, an expression of the amount of methylated genes by case, was significantly higher in GBC (0.196 ± 0.013) compared with CC (0.065 ± 0.008; P &lt; 0.001).
Conclusions: Our study constitutes the most comprehensive methylation profile report available in GBC and demonstrates that this neoplasm has a distinct pattern of abnormal gene methylation. Whereas gallbladders from healthy individual were not available, our finding of methylation in CC cases without cancer suggests that this phenomenon represents an early event in the pathogenesis of GBC.