bluuebunny/crossref_metadata_2025_split huggingface dataset:
Tetranucleotide Microsatellite Instability in Surgical Margins for Prediction of Local Recurrence of Head and Neck Squamous Cell Carcinoma
Authors: Temam Stephane , Casiraghi Odile , Lahaye Jean-Baptiste , Bosq Jacques , Zhou Xian , Julieron Morbize , Mamelle Gerard , Lee J. Jack , Mao Li , Luboinski Bernard , Benard Jean , Janot Francois 
Published: September 2005

Abstract
Purpose: Postoperative radiotherapy is used to prevent local recurrence of head and neck squamous cell carcinoma in patients with positive surgical margins. We sought to determine whether tetranucleotide microsatellite instability could be detected in surgical margins and used to predict local recurrence.
Experimental Design: We prospectively collected tumor and surgical margin specimens from patients with head and neck squamous cell carcinoma who had undergone surgical resection at Institut Gustave-Roussy during a 1-year period. Margins were considered positive if extensive pathological examination revealed either carcinoma within 5 mm or dysplasia. We tested five tetranucleotide microsatellite markers (UT5085, L17686, D9S753, ACTBP2, and CSF1R) in the tumor specimens and paired surgical margins of the patients whose margins were negative on pathological examination.
Results: Pathological examination revealed that among the 76 patients, 22 had positive margins; therefore, these patients were excluded. Of the 54 remaining patients, 26 (48%) had tumors informative for markers UT5085, L17686, or both; the other 3 markers were not informative. Seven (27%) of the 26 informative tumors had the same instability pattern in the surgical margins. At a median follow-up of 26 months, 5 of the 7 local recurrences occurred in patients with molecularly positive surgical margins. A strong, independent association was found between positive surgical margins and local recurrence (P = 0.01; hazard ratio, 6.49).
Conclusions: Tetranucleotide microsatellite instability in surgical margins may be a useful biomarker to predict local recurrence of head and neck squamous cell carcinoma in patients with apparently disease-free margins.
Liposomal Irinotecan
Authors: Messerer Corrie Lynn , Ramsay Euan C. , Waterhouse Dawn , Ng Rebecca , Simms Eva-Maria , Harasym Natashia , Tardi Paul , Mayer Lawrence D. , Bally Marcel B. 
Published: September 2005

Abstract
Purpose: The purpose is to demonstrate whether an appropriately designed liposomal formulation of irinotecan is effective in treating mice with liver-localized colorectal carcinomas.
Experimental Design: Irinotecan was encapsulated in 1,2-distearoyl-sn-glycero-3-phosphocholine/cholesterol (55:45 molar ratio) liposomes using an ionophore (A23187)-generated transmembrane proton gradient. This formulation was evaluated in vivo by measuring plasma elimination of liposomal lipid and drug after i.v. administration. Therapeutic activity was determined in SCID/Rag-2M mice bearing s.c. LS180 tumors or orthotopic LS174T colorectal metastases.
Results: Drug elimination from the plasma was significantly reduced when irinotecan was administered in the liposomal formulation. At 1 hour after i.v. administration, circulating levels of the liposomal drug were 100-fold greater than that of irinotecan given at the same dose. High-performance liquid chromatographic analysis of plasma samples indicated that liposomal irinotecan was protected from inactivating hydrolysis to the carboxylate form. This formulation exhibited substantially improved therapeutic effects. For the LS180 solid tumor model, it was shown that after a single injection of liposomal irinotecan at 50 mg/kg, the time to progress to a 400-mg tumor was 34 days (as compared with 22 days for animals treated with free drug at an equivalent dose). In the model of colorectal liver metastases (LS174T), a median survival time of 79 days was observed after treatment with liposomal irinotecan (50 mg/kg, given every 4 days for a total of three doses). Saline and free drug treated mice survived for 34 and 53 days, respectively.
Conclusions: These results illustrate that liposomal encapsulation can substantially enhance the therapeutic activity of irinotecan and emphasize the potential for using liposomal irinotecan to treat liver metastases.
Immune Responses to a Class II Helper Peptide Epitope in Patients with Stage III/IV Resected Melanoma
Authors: Wong Raymond , Lau Roy , Chang Jenny , Kuus-Reichel Tina , Brichard Vincent , Bruck Claudine , Weber Jeffrey 
Published: September 2005

AbstractThe importance of CD8+ cytolytic T cells for protection from viral infection and in the generation of immune responses against tumors has been well established. In contrast, the role of CD4+ T-helper cells in human infection and in cancer immunity has yet to be clearly defined. In this pilot study, we show that immunization of three resected, high-risk metastatic melanoma patients with a T-helper epitope derived from the melanoma differentiation antigen, melanoma antigen recognized by T cells-1, results in CD4+ T-cell immune responses. Immune reactivity to that epitope was detected by DR4-peptide tetramer staining, and enzyme-linked immunospot assay of fresh and restimulated CD4+ T cells from patients over the course of the 12-month vaccine regimen. The postvaccine CD4+ T cells exhibited a mixed T-helper 1/T-helper 2 phenotype, proliferated in response to the antigen and promiscuously recognized the peptide epitope bound to different human leukocyte antigen-DRβ alleles. For 1 DRβ1*0401+ patient, antigen-specific CD4+ T cells recognized human leukocyte antigen-matched antigen-expressing tumor cells, secreted granzyme B, and also exhibited cytolysis that was MHC class II-restricted. These data establish the immunogenicity of a class II epitope derived from a melanoma-associated antigen and support the inclusion of class II peptides in future melanoma vaccine therapies.
Reversal of the Malignant Phenotype of Gastric Cancer Cells by Inhibition of RhoA Expression and Activity
Authors: Liu Na , Bi Feng , Pan Yanglin , Sun Lijun , Xue Yan , Shi Yongquan , Yao Xuebiao , Zheng Yi , Fan Daiming 
Published: September 2005

Abstract
Purpose: The small GTPase RhoA has been implicated in the regulation of cell morphology, motility, and transformation, but the role of RhoA protein in the carcinogenesis of gastric cancer remains unclear. In the present study, we have analyzed the expression status of the RhoA protein in human gastric cancer cells and tissues and investigated the possible involvement of RhoA in regulating the malignant phenotype of gastric cancer cells.
Experimental Design: RhoA expression was analyzed by immunohistochemistry and Western blot in gastric cancer tissues and cell lines. The RhoA-specific small interfering RNA (siRNA) vector was designed and constructed. We examined the role of RhoA in the malignant phenotype of gastric cancer cells by using siRNA knockdown and dominant-negative RhoA mutant suppression of endogenous RhoA activity.
Results: RhoA was found frequently overexpressed in gastric cancer tissues and cells compared with normal tissues or gastric epithelial cells. RhoA-specific siRNA could specifically and stably reduce RhoA expression up to 90% in AGS cells. Both RhoA-specific siRNA and dominant-negative RhoA expressions could significantly inhibit the proliferation and tumorigenicity of AGS cells and enhance chemosensitivity of the cancer cells to Adriamycin and 5-fluorouracil.
Conclusion: RhoA may play a critical role in the carcinogenesis of gastric cancer, and the interference of RhoA expression and/or activity could provide a novel avenue in reversing the malignant phenotype of gastric cancer cells.
Carbon Ion Radiotherapy for Unresectable Sacral Chordomas
Authors: Imai Reiko , Kamada Tadashi , Tsuji Hiroshi , Yanagi Takeshi , Baba Masayuki , Miyamoto Tadaaki , Kato Shingo , Kandatsu Susumu , Mizoe Jun-etsu , Tsujii Hirohiko , Tatezaki Shin-ichiro ,   for the Working Group for Bone, Soft Tissue Sarcomas
Published: September 2005

Abstract
Purpose: The purpose is to evaluate the efficacy and toxicity of carbon ion radiotherapy for unresectable sacral chordomas.
Experimental Design: We performed a retrospective analysis of 30 patients with unresectable sacral chordomas treated with carbon ion radiotherapy at the Heavy Ion Medical Accelerator in Chiba, Japan. Twenty-three patients presented with no prior treatment, and the remaining 7 patients had locally recurrent disease following previous surgical resection. The median clinical target volume was 546 cm3. The applied carbon ion dose ranged from 52.8 to 73.6 GyE (gray equivalent, median 70.4) in 16 fixed fractions over 4 weeks.
Results: At median follow-up of 30 months (range, 9 to 87 months), 26 patients were still alive and 24 patients remained continuously disease-free. Overall and cause-specific survival rates at 5 years were 52 and 94%, respectively. The overall local control rate at 5years was 96%. Two patients experienced severe skin/soft tissue complications requiring skin grafts. No other treatment-related surgical interventions, including colostomy or urinary diversion, were carried out. All patients have remained ambulatory and able to stay at home after carbon ion radiotherapy.
Conclusions: Carbon ion radiotherapy is effective and safe in the management of patients with unresectable sacral chordomas and offers a promising alternative to surgery.
A Phase I and Pharmacokinetic Study of TAS-108 in Postmenopausal Female Patients with Locally Advanced, Locally Recurrent Inoperable, or Progressive Metastatic Breast Cancer
Authors: Blakely L. Johnetta , Buzdar Aman , Chang Hsiu-Yin , Frye Debra , Theriault Richard , Valero Vicente , Rivera Edgardo , Booser Daniel , Kuritani Jun , Tsuda Masuhiro 
Published: September 2005

Abstract
Purpose: TAS-108 is a novel steroidal anti-estrogen compound that has a strong binding affinity to the estrogen receptor and, in preclinical studies, has antitumor activity against tamoxifen-resistant breast cancer cell lines. The objective of this study was to investigate the safety and the pharmacokinetics in patients with previously treated advanced breast cancer.
Experimental Design: TAS-108 was administered orally once daily starting at 40 mg/day, with dose escalations of 60, 80, 120, and 160 mg/day. A minimum of three patients were enrolled in each dose level, and, if no drug-related grade 3 or higher adverse events were seen in the first 14 days, the next cohort of patients was treated at the next level. Pharmacokinetic data were obtained on day 1, 2, 15, and 28 of the first course.
Results: A total of 16 patients were enrolled, and most had received six to seven prior therapies. Clinical toxicities included nausea, vomiting, hot flashes, headache, weakness and fatigue; all were grade 1–2. TAS-108 had no effect on endometrial thickness based on trans-vaginal ultrasound evaluation. The average duration of therapy was 17.4 weeks (range, 4–60 weeks). The mean terminal half-life ranged from 8.0 to 10.7 hour in the interval of 12 to 24 hours postdose. The mean Cmax ranged from 2.8 to 21.0 ng/mL and AUC0-t from 15.1 to 148.7 ng·h/mL, this showed a linear correlation with the dose.
Conclusions: TAS-108 was well tolerated in the doses studied with no maximum tolerated dose. The drug has linear pharmacokinetics, and in this heavily treated patient population, there was evidence of biological antitumor activity. A multi-institutional phase II study is planned.
CpG Island Hypermethylation of the DNA Repair Enzyme Methyltransferase Predicts Response to Temozolomide in Primary Gliomas
Authors: Paz Maria F. , Yaya-Tur Ricard , Rojas-Marcos Iñigo , Reynes Gaspar , Pollan Marina , Aguirre-Cruz Lucinda , García-Lopez Jose Luis , Piquer Jose , Safont María-Jose , Balaña Carmen , Sanchez-Cespedes Montserrat , García-Villanueva Mercedes , Arribas Leoncio , Esteller Manel 
Published: September 2005

Abstract
Purpose: The DNA repair enzyme O6-methylguanine DNA methyltransferase (MGMT) inhibits the killing of tumor cells by alkylating agents, and its loss in cancer cells is associated with hypermethylation of the MGMT CpG island. Thus, methylation of MGMT has been correlated with the clinical response to 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) in primary gliomas. Here, we investigate whether the presence of MGMT methylation in gliomas is also a good predictor of response to another emergent alkylating agent, temozolomide.
Experimental Design: Using a methylation-specific PCR approach, we assessed the methylation status of the CpG island of MGMT in 92 glioma patients who received temozolomide as first-line chemotherapy or as treatment for relapses.
Results: Methylation of the MGMT promoter positively correlated with the clinical response in the glioma patients receiving temozolomide as first-line chemotherapy (n = 40). Eight of 12 patients with MGMT-methylated tumors (66.7%) had a partial or complete response, compared with 7 of 28 patients with unmethylated tumors (25.0%; P = 0.030). We also found a positive association between MGMT methylation and clinical response in those patients receiving BCNU (n = 35, P = 0.041) or procarbazine/1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (n = 17, P = 0.043) as first-line chemotherapy. Overall, if we analyze the clinical response of all of the first-line chemotherapy treatments with temozolomide, BCNU, and procarbazine/1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea as a group in relation to the MGMT methylation status, MGMT hypermethylation was strongly associated with the presence of partial or complete clinical response (P &lt; 0.001). Finally, the MGMT methylation status determined in the initial glioma tumor did not correlate with the clinical response to temozolomide when this drug was administered as treatment for relapses (P = 0.729).
Conclusions: MGMT methylation predicts the clinical response of primary gliomas to first-line chemotherapy with the alkylating agent temozolomide. These results may open up possibilities for more customized treatments of human brain tumors.
Lymphatic Vessel Density and Vascular Endothelial Growth Factor-C Expression Correlate with Malignant Behavior in Human Pancreatic Endocrine Tumors
Authors: Rubbia-Brandt Laura , Terris Benoit , Giostra Emile , Dousset Bertrand , Morel Philippe , Pepper Michael S. 
Published: September 2005

Abstract
Metastatic dissemination of tumor cells to regional lymph nodes is a common early feature of many human cancers including pancreatic adenocarcinoma. In contrast, lymph node metastasis is more variably observed in pancreatic endocrine tumors. The objective of this study was to assess the lymphatic system of human pancreatic endocrine tumors and correlate this to clinical behavior. Immunohistochemistry was performed using antibodies to two recently identified markers of lymphatic endothelium, namely, LYVE-1 and podoplanin, and to the lymphangiogenic factor vascular endothelial growth factor (VEGF)-C. As has been reported previously, we observed that in the normal pancreas, islets of Langerhans are devoid of intra-islet lymphatics, but that lymphatics are present in connective tissue in association with ducts and blood vessels. We found that both benign and malignant pancreatic endocrine tumors contain intratumoral lymphatic vessels. Lymphatic vessel density was related to the size of the tumor in benign tumors and to the presence of liver metastasis but not to lymph node metastasis in malignant tumors. VEGF-C was expressed in tumor cells: 4 of 19 (21%) benign tumors were positive, whereas 6 of 9 (67%) borderline tumors and 9 of 11 (82%) carcinomas were positive. These findings strongly suggest that lymphangiogenesis occurs in pancreatic endocrine tumors and that lymphatic invasion and the development of metastases are associated with VEGF-C expression.
Hierarchical Clustering Analysis of Tissue Microarray Immunostaining Data Identifies Prognostically Significant Groups of Breast Carcinoma
Authors: Makretsov Nikita A. , Huntsman David G. , Nielsen Torsten O. , Yorida Erika , Peacock Michael , Cheang Maggie C. U. , Dunn Sandra E. , Hayes Malcolm , van de Rijn Matt , Bajdik Chris , Gilks C. Blake 
Published: September 2005

Abstract
Prognostically relevant cluster groups, based on gene expression profiles, have been recently identified for breast cancers, lung cancers, and lymphoma. Our aim was to determine whether hierarchical clustering analysis of multiple immunomarkers (protein expression profiles) improves prognostication in patients with invasive breast cancer. A cohort of 438 sequential cases of invasive breast cancer with median follow-up of 15.4 years was selected for tissue microarray construction. A total of 31 biomarkers were tested by immunohistochemistry on these tissue arrays. The prognostic significance of individual markers was assessed by using Kaplan-Meier survival estimates and log-rank tests. Seventeen of 31 markers showed prognostic significance in univariate analysis (P ≤ 0.05) and 4 markers showed a trend toward significance (P ≤ 0.2). Unsupervised hierarchical clustering analysis was done by using these 21 immunomarkers, and this resulted in identification of three cluster groups with significant differences in clinical outcome. χ2 analysis showed that expression of 11 markers significantly correlated with membership in one of the three cluster groups. Unsupervised hierarchical clustering analysis with this set of 11 markers reproduced the same three prognostically significant cluster groups identified by using the larger set of markers. These cluster groups were of prognostic significance independent of lymph node metastasis, tumor size, and tumor grade in multivariate analysis (P = 0.0001). The cluster groups were as powerful a prognostic indicator as lymph node status. This work demonstrates that hierarchical clustering of immunostaining data by using multiple markers can group breast cancers into classes with clinical relevance and is superior to the use of individual prognostic markers.
Prognostic Significance of p16 Protein Levels in Oropharyngeal Squamous Cell Cancer
Authors: Weinberger Paul M. , Yu Z. , Haffty B.G. , Kowalski D. , Harigopal M. , Sasaki C. , Rimm D. L. , Psyrri A. 
Published: September 2005

Abstract
Purpose: Functional inactivation of p16 is an early and frequent event in head and neck squamous cell cancers. In this study, we sought to determine whether p16 expression is of prognostic importance in oropharyngeal squamous cell carcinoma.
Experimental Design: p16 protein expression was evaluated by immunohistochemistry in a tissue microarray composed of 123 oropharyngeal squamous cell cancers with a mean patient follow-up time of 33 months.
Results: p16 overexpression was associated with more advanced Tumor-Node-Metastasis stage and higher histologic grade. Despite this association with unfavorable features, p16 overexpression was associated with decreased 5-year local recurrence rates (11 versus 53%) and increased 5-year disease-free survival (62 versus 19%) and overall survival (60 versus 21%). In multivariate analysis, p16 expression status remained an independent prognostic factor for local recurrence, disease-free survival, and overall survival.
Conclusions: In patients with oropharyngeal squamous cell carcinoma, overexpression of p16 as determined by immunohistochemistry is associated with significantly improved prognosis and lower local recurrence rates.
Isochromosome 17q Is a Negative Prognostic Factor in Poor-Risk Childhood Medulloblastoma Patients
Authors: Pan Edward , Pellarin Malgorzata , Holmes Emi , Smirnov Ivan , Misra Anjan , Eberhart Charles G. , Burger Peter C. , Biegel Jaclyn A. , Feuerstein Burt G. 
Published: September 2005

Abstract
Background: Medulloblastomas are the most common primary malignant childhood intracranial neoplasms. Patients are currently sorted into three risk groups based on clinical criteria: standard, poor, and infant (&lt;18 months old). We hypothesized that genetic copy number aberrations (CNA) predict prognosis and would provide improved criteria for predicting outcome.
Methods: DNA from 35 medulloblastoma patients from four Children's Cancer Group trials was analyzed by comparative genomic hybridization to determine CNAs. The genetic alterations were evaluated using statistical and cluster analyses.
Results: The most frequent CNAs were gains on 17q, 7, 1q, and 7q and losses on 17p, 10q, X, 16q, and 11q. Amplification at 5p15.1-p15.3 was also detected. Isochromosome 17q (i(17)(q10)) was associated with poor overall survival (P = 0.03) and event-free survival (P = 0.04) independent of poor risk group classification. Age &lt;3 tended to be associated with &lt;3 CNAs (P = 0.06). Unsupervised cluster analysis sorted the study patients into four subgroups based on CNAs. Supervised analysis using the program Significance Analysis of Microarrays (SAM) quantitatively validated those CNAs identified by unsupervised clustering that significantly distinguished among the four subgroups.
Conclusions: Medulloblastomas are genetically heterogeneous and can be categorized into separate genetic subgroups by their CNAs using unsupervised cluster analysis and SAM. i(17)(q10) was a significant independent negative prognostic factor. Infant medulloblastomas may be a distinct genetic subset from those of older patients.
High Levels of Phosphorylated Form of Akt-1 in Prostate Cancer and Non-Neoplastic Prostate Tissues Are Strong Predictors of Biochemical Recurrence
Authors: Ayala Gustavo , Thompson Timothy , Yang Guang , Frolov Anna , Li Rile , Scardino Peter , Ohori Makoto , Wheeler Thomas , Harper Wade 
Published: September 2005

Abstract
Akt is a serine-threonine-kinase that phosphorylates proteins in several pathways regulating aspects of metabolism, apoptosis, and proliferation. Akt signaling promotes proliferation and increased cell survival and is thought to play an important role in prostate cancer progression. Tissue microarrays (640 patients) with triplicate cores of non-neoplastic prostate, BPH, and index tumor were immunostained with antibody to Phospho-Akt (Ser473), digitized, and quantified. The expression index (Intensity*Percentage) was used for statistical analysis. P-Akt-1 staining was found in both the non-neoplastic and cancer tissues, predominantly in cytoplasmic locations. High level P-Akt-1 is expressed almost exclusively in cancer. By Kaplan-Meier actuarial model, high expression of P-Akt-1 in prostate cancer was predictive of a higher probability of recurrence on univariate and multivariate analysis. Akt-1 expression was an independent prognostic indicator of biochemical recurrence-free survival when Gleason 6 and 7 patients were analyzed separately. Surprisingly, a high level of P-Akt-1 expression in non-neoplastic tissues is also an independent predictor of biochemical recurrence. This suggests that some patients might have an inherent predisposition to express a high level of P-Akt-1 and, therefore, to have an adverse prognosis. We conclude that P-Akt-1 is most likely involved in the progression of prostate cancer and is an excellent biomarker for biochemical recurrence.