bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Natural Course of Preneoplastic Lesions in Bronchial Epithelium
Authors: Breuer Roderick H. , Pasic Arifa , Smit Egbert F. , van Vliet Esther , Vonk Noordegraaf Anton , Risse Elle J. , Postmus Pieter E. , Sutedja Thomas G. 
Published: June 2022

Abstract
Purpose: To study the natural history of preneoplastic lesions in the bronchial mucosa of the individuals at risk.
Patients and Methods: White light and autofluorescence bronchoscopy examinations have been done in 52 individuals harboring 134 preneoplastic lesions (WHO criteria). End points were the development of carcinoma in situ (CIS) or squamous cell cancer (SCC) or the highest category of dysplasia up until March 1, 2003 for the remaining preneoplastic lesions.
Results: Distribution and outcome of preneoplastic lesions have been found to be unrelated to various risk factors such as smoking history, past history of cancer, or chronic obstructive pulmonary disease. Nonstepwise changes of preneoplastic lesions are seen. Regression rate has been 54%. Progression to CIS/SCC has been 13.4% (18 of 134) and was for severe dysplasia, significantly higher (P &lt; 0.003) than preneoplastic lesions showing lower-grade dysplasia (squamous metaplasia, mild and moderate dysplasia). Time to progression was not significantly different. However, when analyzed per individual, no significant difference of progression rate between individuals with or without severe dysplasia was seen (39% versus 26%; P = 0.36).
Conclusions: The 54% regression rate of all preneoplastic lesions, 26% to 39% progression rate to CIS/SCC of individuals with lower-grade dysplasia or severe dysplasia with no significant difference in progression rate and time to progression combined with nonstepwise histologic changes unrelated to the initial histologic grading indicate that one cannot differentiate the potentially more malignant preneoplastic lesions among the many preneoplastic lesions present in the bronchial mucosa. The initial WHO classification of any preneoplastic lesion cannot be reliably used for accurate risk assessment of field carcinogenesis.
Tartrate-Resistant Acid Phosphatase 5b is a Useful Serum Marker for Extensive Bone Metastasis in Breast Cancer Patients
Authors: Chao Tsu-Yi , Yu Jyh-Cherng , Ku Chih-Hung , Chen Mary M. , Lee Su-Huei , Janckila Anthony J. , Yam Lung T. 
Published: June 2022

Abstract
Purpose: Previous studies showed that serum tartrate-resistant acid phosphatase 5b (TRACP5b) activity was increased in 70% to 94% of breast cancer (BC) patients with bone metastasis (BM). This study aims to determine whether serum TRACP5b is useful for identifying limited or extensive BM in BC patients.
Experimental Design: Serum TRACP5b activity was measured in 168 BC patients, including 81 who were newly diagnosed with early BC, 20 with extraosseous metastasis, 24 with limited BM, and 43 with extensive BM. Serum TRACP5b activity was also measured monthly in 151 patients with early BC until they developed BM. Four hundred and twenty-seven (427) healthy women ages 18 to 90 served as control. One-way ANOVA was used to compare serum TRACP5b among groups. The sensitivity and specificity of serum TRACP5b as a marker for BM were estimated by receiver operator characteristic (ROC) curves.
Results: Serum TRACP5b increased with age in healthy women ( P &lt; 0.0001). It was significantly elevated in patients with extensive BM compared with all other groups ( P &lt; 0.0001). ROC analysis established a cutoff value of 4.026 units/L to identify patients with extensive BM with a specificity of 98% and a sensitivity of 93% (area under the curve = 0.9807; 95% CI = 0.9698-0.9915). Among the 151 patients with early BC, 6 developed limited BM and 2 developed extensive BM during the follow-up period. Serum TRACP5b remained below the cutoff value in patients with limited BM, but became significantly increased in those whose BM became extensive.
Conclusion: Serum TRACP5b activity is a useful diagnostic marker for extensive BM in patients with BC.
Claudin-10 Expression Level is Associated with Recurrence of Primary Hepatocellular Carcinoma
Authors: Cheung Siu Tim , Leung Ka Ling , Ip Ying Chi , Chen Xin , Fong Daniel Y. , Ng Irene O. , Fan Sheung Tat , So Samuel 
Published: June 2022

Abstract
Purpose: Hepatocellular carcinoma (HCC) patients with the same clinicopathologic features can have remarkably different disease outcomes after curative hepatectomy. To address this issue, we evaluated the cDNA microarray gene expression profiles of HCCs and identified claudin-10 expression level was associated with disease recurrence. The aim of the current study is to validate the microarray data by an alternative research method applicable for routine practice.
Experimental Design: Quantitative reverse transcription–PCR (RT-PCR) was used to validate the microarray data on claudin-10 expression level. The assay was repeated on a separate HCC sample set to consolidate the prognostic significance of claudin-10.
Results: Claudin-10 expression level by quantitative RT-PCR and by microarray measurement showed a high concordance (r = 0.602, P &lt; 0.001). Quantitative RT-PCR was repeated on a separate HCC sample set and the association of claudin-10 expression with recurrence was again confirmed (hazard ratio, 1.2; 95% confidence interval, 1.0-1.4; P = 0.011). By multivariable Cox regression analysis, claudin-10 expression and pathologic tumor-node-metastasis stage were independent factors for prediction of disease recurrence.
Conclusion: Claudin-10 expression of HCC can be used as a molecular marker for disease recurrence after curative hepatectomy.
Interlaboratory Comparability Study of Cancer Gene Expression Analysis Using Oligonucleotide Microarrays
Authors: Dobbin Kevin K. , Beer David G. , Meyerson Matthew , Yeatman Timothy J. , Gerald William L. , Jacobson James W. , Conley Barbara , Buetow Kenneth H. , Heiskanen Mervi , Simon Richard M. , Minna John D. , Girard Luc , Misek David E. , Taylor Jeremy M.G. , Hanash Samir , Naoki Katsuhiko , Hayes D. Neil , Ladd-Acosta Christine , Enkemann Steven A. , Viale Agnes , Giordano Thomas J. 
Published: June 2022

Abstract
A key step in bringing gene expression data into clinical practice is the conduct of large studies to confirm preliminary models. The performance of such confirmatory studies and the transition to clinical practice requires that microarray data from different laboratories are comparable and reproducible. We designed a study to assess the comparability of data from four laboratories that will conduct a larger microarray profiling confirmation project in lung adenocarcinomas. To test the feasibility of combining data across laboratories, frozen tumor tissues, cell line pellets, and purified RNA samples were analyzed at each of the four laboratories. Samples of each type and several subsamples from each tumor and each cell line were blinded before being distributed. The laboratories followed a common protocol for all steps of tissue processing, RNA extraction, and microarray analysis using Affymetrix Human Genome U133A arrays. High within-laboratory and between-laboratory correlations were observed on the purified RNA samples, the cell lines, and the frozen tumor tissues. Intraclass correlation within laboratories was only slightly stronger than between laboratories, and the intraclass correlation tended to be weakest for genes expressed at low levels and showing small variation. Finally, hierarchical cluster analysis revealed that the repeated samples clustered together regardless of the laboratory in which the experiments were done. The findings indicate that under properly controlled conditions it is feasible to perform complete tumor microarray analysis, from tissue processing to hybridization and scanning, at multiple independent laboratories for a single study.
Stage-Specific Characterization of the Vascular Endothelial Growth Factor Axis in Prostate Cancer: Expression of Lymphangiogenic Markers Is Associated with Advanced-Stage Disease
Authors: Kaushal Varsha , Mukunyadzi Perkins , Dennis Richard A. , Siegel Eric R. , Johnson Donald E. , Kohli Manish 
Published: June 2022

Abstract
Purpose: The vascular endothelial growth factor (VEGF) family plays a critical role in tumor angiogenesis and lymphangiogenesis. We characterized, at the mRNA and protein levels, the expression of VEGF-A and VEGF-D and their cognate receptors, VEGFR-1, VEGFR-2, and VEGFR-3 in early- and advanced-stage prostate cancer specimens.
Experimental Design: The levels of VEGF-A and VEGF-D mRNA in early- and advanced-stage specimens were compared using an angiogenic gene array and were confirmed by quantitative real-time PCR. Receptor protein levels and activation status were determined by immunoblotting. Spatial expression of the proteins was evaluated using immunohistochemistry with fresh and archival tissues from benign prostatic hypertrophy specimens, early-stage prostate specimens, and advanced-stage metastatic specimens. Circulating plasma levels of these growth factors were measured using ELISAs.
Results: We observed that expression patterns of VEGF isotypes corresponded to the prostate cancer stage: high expression of angiogenic growth factor VEGF-A was observed in early-stage prostate specimens, whereas high expression of lymphangiogenic growth factor VEGF-D was associated with advanced-stage metastatic disease. All VEGF receptors were present at variable levels in all specimens, but their activation states varied in a stage-specific manner. VEGFR-1 and, to a limited extent, VEGFR-2 were activated in early-stage specimens, whereas VEGFR-2 and VEGFR-3 were activated in advanced-stage specimens.
Conclusions: Our results suggest that lymphangiogenic markers, such as VEGF-D and VEGFR-2 and VEGFR-3, may be better than angiogenic markers as targets of therapeutic intervention in advanced-stage prostate disease.
Epidermal Growth Factor Receptor Gene Polymorphisms Predict Pelvic Recurrence in Patients with Rectal Cancer Treated with Chemoradiation
Authors: Zhang Wu , Park David J. , Lu Bo , Yang Dong Yun , Gordon Michael , Groshen Susan , Yun Jim , Press Oliver A. , Vallböhmer Daniel , Rhodes Katrin , Lenz Heinz-Josef 
Published: June 2022

Abstract
An association between epidermal growth factor receptor (EGFR) signaling pathway and response of cancer cells to ionizing radiation has been reported. Recently, a polymorphic variant in the EGFR gene that leads to an arginine-to-lysine substitution in the extracellular domain at codon 497 within subdomain IV of EGFR has been identified. The variant EGFR (HER-1 497K) may lead to attenuation in ligand binding, growth stimulation, tyrosine kinase activation, and induction of proto-oncogenes myc, fos, and jun. A (CA)n repeat polymorphism in intron 1 of the EGFR gene that alters EGFR expression in vitro and in vivo has also been described. In the current pilot study, we assessed both polymorphisms in 59 patients with locally advanced rectal cancer treated with adjuvant or neoadjuvant chemoradiation therapy using PCR-RFLP and a 5′-end [γ-33P]ATP-labeled PCR protocol. We tested whether either polymorphism alone or in combination can be associated with local recurrence in the setting of chemoradiation treatment. We found that patients with HER-1 497 Arg/Arg genotype or lower number of CA repeats (both alleles &lt;20) tended to have a higher risk of local recurrence (P = 0.24 and 0.31, respectively). Combined analysis showed the highest risk for local recurrence was seen in patients who possessed both a HER-1 497 Arg allele and &lt;20 CA repeats (P = 0.05, log-rank test). Our data suggest that the HER-1 R497K and EGFR intron 1 (CA)n repeat polymorphisms may be potential indicators of radiosensitivity in patients with rectal cancer treated with chemoradiation.
Loss of p16 Protein Defines High-Risk Patients with Gastrointestinal Stromal Tumors: A Tissue Microarray Study
Authors: Schneider-Stock Regine , Boltze Carsten , Lasota Jerzy , Peters Brigitte , Corless Chris L. , Ruemmele Petra , Terracciano Luigi , Pross Matthias , Insabato Luigi , Di Vizio Dolores , Iesalnieks Igor , Dirnhofer Stefan , Hartmann Arndt , Heinrich Michel , Miettinen Markku , Roessner Albert , Tornillo Luigi 
Published: June 2022

Abstract
Despite clearly defined histologic criteria, the prediction of tumor behavior for patients with gastrointestinal stromal tumors (GIST) still poses a challenge to pathologists. Therefore, searching for alternative markers that allow for better prognostic evaluation is an important task. To determine the practicability of immunohistochemical staining for p16 in clinical cases, we examined p16 protein expression in a group of 284 GISTs, a subset of which had long-term follow-up (median, 45 months; range, 1-204 months). P16 protein expression was ascertained on tissue microarrays as well as on standard sections. Survival analyses were carried out in 157 patients. P16 loss was found in 50% of GISTs, there being no correlation with age, sex, histologic subtype, signs of necrosis, or metastases. Patients having p16-negative tumors had a worse prognosis than those with p16-positive tumors (P = 0.012) with a 2.3-fold relative increased risk of dying of disease. P16 loss identified a subgroup of gastric tumors with a worse prognosis (P = 0.03). The multivariate configural frequency analysis identified two “antitypes,” whose observed frequency was found to be significantly lower than the expected frequency [i.e., marker combinations: p16 positive, no metastases, and death of disease and p16 loss, metastases, and still alive]. The “type” whose observed frequency was significantly higher than the expected frequency consisted of the following marker pattern: p16 loss, necrosis, and death of disease (P &lt; 0.001). In the multivariate Cox regression analysis, p16 loss, necrosis, and metastases each had independent prognostic value. P16 loss is a common molecular abnormality in GISTs and might be used in routine diagnosis to identify patients with high-risk tumors.
Prognostic Significance of CpG Island Methylator Phenotype and Microsatellite Instability in Gastric Carcinoma
Authors: An Changhyeok , Choi In-Seon , Yao James C. , Worah Samidha , Xie Keping , Mansfield Paul F. , Ajani Jaffer A. , Rashid Asif , Hamilton Stanley R. , Wu Tsung-Teh 
Published: June 2022

Abstract
Purpose: The influence of molecular characteristics in prognosis of gastric cancer remains unclear. The aim of this study was to evaluate the prognostic value of the CpG island methylator phenotype (CIMP) and microsatellite instability (MSI) in gastric cancer.
Experimental Design: We studied the methylation profiles of tumor suppressor gene p16, DNA mismatch repair gene hMLH1, and four CpG islands (MINT1, MINT2, MINT25, and MINT31) using bisulfite/methylation–specific PCR, and MSI using five microsatellite markers in 83 resected gastric carcinomas. The CIMP and MSI status were compared with clinicopathologic features and overall survival.
Results: Concordant methylation of multiple genes/loci (CIMP-high) was present in 31% of tumors and in 4% of non-neoplastic mucosa, CIMP-low in 55% and 17%, and CIMP-negative in 13% and 79%, respectively (P &lt; 0.001). The prevalence of MSI-high, MSI-low, and MS-stable in tumor was 19%, 17%, and 64%, respectively. MSI status was closely associated with hMLH1 hypermethylation and CIMP status (P = 0.001). In univariate analysis, overall survival was predicted by pathologic stage (P &lt; 0.0001), R0 resection (P = 0.0002), MINT31 methylation (P = 0.04), and CIMP-high status (P = 0.04). MSI status of tumor was not a significant predictor of prognosis. Although CIMP status seemed to be a prognostic predictor of gastric cancer, only pathologic stage remained a significant predictor of prognosis on multivariate analysis (P &lt; 0.001).
Conclusions: Our results indicate that there is an association between CIMP status and MSI status in gastric cancer. Concordant methylation of multiple genes/loci (CIMP-H) is associated with better survival but is not an independent predictor of prognosis in resected gastric cancer.
A Phase I and Pharmacokinetic Study of Short Infusions of UCN-01 in Patients with Refractory Solid Tumors
Authors: Dees E. Claire , Baker Sharyn D. , O'Reilly Seamus , Rudek Michelle A. , Davidson Susan B. , Aylesworth Cheryl , Elza-Brown Kathy , Carducci Michael A. , Donehower Ross C. 
Published: June 2022

Abstract
Purpose: To define the maximum tolerated dose and the dose-limiting toxicity of the kinase modulator UCN-01 administered as a short (1-3 hours) infusion to patients with refractory solid tumors and to evaluate the pharmacokinetics of this novel agent.
Experimental Design: Twenty-four patients (15 men, 9 women; median age, 59 years; Eastern Cooperative Oncology Group Performance Status, 0-2) were treated with UCN-01 in this phase I study. Using an accelerated titration design, six dose levels were evaluated ranging from 3 mg/m2 over 3 hours to 95 mg/m2 over 1 to 3 hours administered every 28 days. Plasma, urine, and saliva samples were collected for pharmacokinetic analysis.
Results: Seventy courses were evaluable for toxicity. The most frequent adverse events were grade 1 to 2 nausea, vomiting, hyperglycemia, and hypotension. Hypotension was dose limiting at 95 mg/m2 when UCN-01 was administered over 1 hour. The recommended dose of UCN-01 as a short infusion is 95 mg/m2 over 3 hours for the first course and 47.5 mg/m2 over 3 hours for second and subsequent courses. No objective responses were observed. Mean (SD) pharmacokinetic variable values in nine patients treated at 95 mg/m2 over 3 hours were volume of distribution at steady state, 14 (5.4) L; β half-life, 406 (151) hours; systemic clearance, 0.028 (0.017) L/h; Cmax, 51 (16) μmol/L; and area under the curve, 19,732 (12,195) μmol/L h.
Conclusions: UCN-01 is well tolerated when given at doses of 95 mg/m2 over 3 hours every 28 days with second and subsequent courses given at 50 % of the first course dose.
HLA Class I Antigen Down-Regulation in Primary Ovary Carcinoma Lesions: Association with Disease Stage
Authors: Vitale Marco , Pelusi Giuseppe , Taroni Beatrice , Gobbi Giuliana , Micheloni Cristina , Rezzani Rita , Donato Francesco , Wang Xinhui , Ferrone Soldano 
Published: June 2022

Abstract
Purpose: To investigate TAP1, TAP2, and HLA class I antigen expression in primary ovarian carcinoma lesions and to assess the clinical significance of defects in the expression of these molecules.
Experimental Design: Fifty-one formalin-fixed, paraffin-embedded primary ovarian carcinoma lesions were stained with affinity-purified rabbit anti-TAP1 and anti-TAP2 antibodies and with anti-HLA class I heavy chain monoclonal antibody (mAb) HC-10 using the immunoperoxidase reaction. The results of immunohistochemical staining were correlated with the histopathologic characteristics of the lesions and with patients' survival.
Results: Ovarian surface epithelium, thecal cells of follicles, and stromal cells were stained by anti-TAP1, anti-TAP2, and anti-HLA class I antigen xenoantibodies with a homogeneous pattern. In contrast, no staining of lutheinic cells by these antibodies was detected. Forty-one and 32 out of 51 primary ovarian carcinoma lesions were stained by anti-TAP1 and anti-TAP2 xenoantibodies and by anti-HLA class I antigen mAb HC-10, respectively. The staining patterns by anti-TAP1 and anti-TAP2 xenoantibodies were completely concordant, but did not correlate with that by anti-HLA class I heavy chain mAb HC-10. TAP1 and TAP2 expression was associated neither with the histopathologic characteristics of the lesions nor with clinical variables. On the other hand, HLA class I antigen down-regulation was associated with disease stage: the odds ratio of stage III for HLA class I antigen negative patients was 7.6 (95% confidence interval, 1.9-30.5; P= 0.007), whereas for TAP negative patients was 5.1 (95% confidence interval, 0.9-28.4; P = 0.07). Follow up was available for 39 out of the 51 patients. Multivariate analysis showed that both grading and staging were associated with a higher risk of death, whereas TAP and HLA class I antigen phenotypes were not.
Conclusions: The lack of association between TAP and HLA class I antigen expression is compatible with the possibility that multiple mechanisms underlie HLA class I antigen down-regulation in primary ovarian carcinoma lesions. The potential role of immunologic events in the clinical course of ovarian carcinoma suggests that the association between HLA class I antigen down-regulation and disease progression may reflect the escape of tumor cells from immune recognition and destruction.
Pharmacodynamic Analysis of Target Inhibition and Endothelial Cell Death in Tumors Treated with the Vascular Endothelial Growth Factor Receptor Antagonists SU5416 or SU6668
Authors: Davis Darren W. , Takamori Ryan , Raut Chandrajit P. , Xiong Henry Q. , Herbst Roy S. , Stadler Walter M. , Heymach John V. , Demetri George D. , Rashid Asif , Shen Yu , Wen Sijin , Abbruzzese James L. , McConkey David J. 
Published: June 2022

Abstract
Purpose: To determine the effects of small molecule inhibitors of vascular endothelial growth factor receptor (VEGFR)-2 (SU5416 and SU6668) on receptor phosphorylation in tumor xenografts and in paired tumor biopsies obtained in three clinical trials in patients with advanced solid malignancies.
Experimental Design: The dose-dependent effects of SU6668 on angiogenesis and tumor growth were investigated in orthotopic L3.6pl pancreatic tumors. Excisional or 18G core biopsies were obtained from patients before and after therapy with SU5416 or SU6668. Laser scanning cytometry–mediated analysis was used to quantify levels of phosphorylated and total VEGFRs and platelet-derived growth factor receptors (PDGFR), tumor microvessel densities, vessel sizes, and endothelial and tumor cell apoptosis.
Results: Significant inhibition of tumor microvessel density and growth and increased apoptosis were observed at SU6668 maximum tolerated dose (100 mg/kg) in L3.6pl xenografts. At 6 hours post therapy, SU6668 reduced VEGFR and PDGFR phosphorylation in the tumors by 50% and 92%, respectively, but levels rebounded beyond the baselines by 24 hours. Levels of phosphorylated VEGFR-2 and PDGFR also decreased significantly (≈50%) 6 hours after therapy in 1 of 6 primary human tumors treated with SU6668, but these effects were not associated with increased apoptosis. A significant increase in endothelial cell apoptosis was observed in one tumor exposed to SU5416 and was associated with an increase in vessel size, but these changes occurred without an increase in tumor cell death.
Conclusions: SU5416 and SU6668 displayed biological activity in xenografts. However, neither drug produced marked biological activity in primary patient tumors.