bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Phase I Clinical and Pharmacokinetic Study of Ro 31-7453 Given as a 7- or 14-Day Oral Twice Daily Schedule Every 4 Weeks in Patients with Solid Tumors
Authors: Salazar Ramon , Bissett Donald , Twelves Chris , Breimer Lars , DeMario Mark , Campbell Sophia , Zhi Jay , Ritland Steve , Cassidy Jim 
Published: September 2005

Abstract
Purpose: This is a dose-finding Phase I study of oral Ro 31-7453, a new class of antimitotic drug with promising preclinical activity in several chemoresistant models.
Experimental Design: Two schedules of oral Ro 31-7453 (every 12 h) given for either 7 or 14 consecutive days repeated every 4 weeks were explored consecutively.
Results: Thirty-seven patients with refractory cancer entered the study (14 on the 7-day schedule and 23 on the 14-day schedule). Median age was 63 years (range, 40–77 years), and median Karnofsky performance status was 80 (range, 60–100); the most frequent diagnosis was colorectal carcinoma (16 patients). Dose levels of 100, 200, 240, and 280 mg/m2 twice daily (bid) for 7 days and 70, 100, 125, and 150 mg/m2 bid for 14 days were explored. A total of 110 cycles were administered, the median number of cycles received was 3 (range, 1–7); six patients completed 6 or more cycles. Myelosuppression and mucositis were dose-limiting with both schedules. Fatigue and gastrointestinal toxicities other than mucositis were frequent but generally mild. The maximum tolerated doses were 200 mg/m2 bid and 125 mg/m2 bid for the 7- and 14-day schedules, respectively. Pharmacokinetic analysis showed rapid absorption and metabolism. The area under the concentration-time curve and trough concentrations of Ro 31-7453 and two active metabolites appeared dose proportional with a t1/2 of ∼9 h and a tmax of ∼4 h. One patient with pretreated lung cancer had a partial response.
Conclusions: Both Ro 31-7453 regimens were feasible, but the 14-day schedule at the recommended dose of 125 mg/m2 bid was selected for further monotherapy Phase II evaluation because of its higher preclinical activity. This regimen is convenient, well tolerated, and has a favorable pharmacokinetic profile.
Thymidylate Synthase Gene Polymorphism Predicts Toxicity in Colorectal Cancer Patients Receiving 5-Fluorouracil-based Chemotherapy
Authors: Lecomte Thierry , Ferraz Jean-Marc , Zinzindohoué Franck , Loriot Marie-Anne , Tregouet David-Alexandre , Landi Bruno , Berger Anne , Cugnenc Paul-Henri , Jian Raymond , Beaune Philippe , Laurent-Puig Pierre 
Published: September 2005

Abstract
Purpose: The target enzyme for 5-fluorouracil (5-FU) is thymidylate synthase (TS). The TYMS gene encoding this enzyme is polymorphic, having either double (2R) or tri-tandem (3R) repeats of a 28-bp sequence in the promoter region and a 6-bp variation in the 3′-untranslated region (3′-UTR). TS expression predicts response to 5-FU-based chemotherapy, and the expression seems to be determined by the TYMS gene promoter. The aim of this study was to investigate the utility of determining these two TYMS gene polymorphisms to predict the toxicity and efficacy of 5-FU treatment in patients with colorectal cancer.
Experimental Design: The determination of TYMS genotypes was performed in tumor and normal tissues by PCR amplification from 90 patients with colorectal cancer who were treated with adjuvant or palliative 5-FU-based chemotherapy. Associations between polymorphisms in the TYMS promoter and in the 3′-UTR gene and clinical outcome of these 90 patients treated with 5-FU based chemotherapy were evaluated individually. The linkage between TYMS promoter and TYMS 3′-UTR region polymorphisms was evaluated and a haplotype analysis was performed.
Results: Individuals who were homozygous for the double repeat in the TYMS promoter region had more severe side effects to 5-FU. Patients with a 2R/2R, a 2R/3R, or a 3R/3R genotype had a grade 3 or 4 toxicity rate of 43, 18, and 3% respectively (P &lt; 0.01). The TYMS promoter and TYMS 3′-UTR polymorphisms were in linkage disequilibrium, and the haplotype 2R/ins 6-bp was significantly associated with a high risk of severe side effects to 5-FU. The TYMS promoter and TYMS 3′-UTR polymorphisms were not associated with a response to 5-FU and survival of patients who received palliative 5-FU-based chemotherapy.
Conclusions: This study demonstrated that TYMS genotyping could be of help in predicting toxicity to 5-FU-based chemotherapy. TYMS genotyping might make it possible to individualize treatment for patients with colorectal cancer.
Phospho-Akt Overexpression in Non–Small Cell Lung Cancer Confers Significant Stage-Independent Survival Disadvantage
Authors: David Odile , Jett James , LeBeau Helena , Dy Grace , Hughes Janet , Friedman Mitchell , Brody Arnold R. 
Published: September 2005

Abstract
Purpose: Akt is a signal transduction protein that plays a central role in inhibiting apoptosis in a variety of cell types including human cancer cells. In cell lines derived from human non–small cell lung cancers (NSCLCs), Akt has been shown to confer chemoresistance by inhibition of apoptosis in response to different chemotherapeutic agents including platinum-based agents, which are often the first-line therapy for NSCLCs. Only 20% to 30% of patients with NSCLC treated with chemotherapy have clinical evidence of response. The purpose of this study is to determine whether or not overexpression of activated Akt [i.e., phosphorylated Akt (pAkt)] is correlated with survival.
Experimental Design: We studied tumors from 61 patients with NSCLC in three tissue microarrays. All patients were followed for a period of 10 years or until death. The arrays were studied immunohistochemically with antibodies against pAkt, p53, and Ki-67.
Results: There was a statistically significant difference in survival between the 14 patients with strong pAkt staining and the 47 patients with weak to absent pAkt staining both by log-rank (P = 0.0416) and Breslow analysis (P = 0.0446). Difference in survival time with respect to pAkt status was also statistically significant even after accounting for stage at diagnosis (P = 0.004). Neither p53 nor Ki-67 was a statistically significant prognostic factor.
Conclusions: Overexpression of pAkt is an independent prognostic factor. Additional studies of human NSCLCs are warranted to drive the development of targeted tumor-specific antineoplastic therapies.
Vitamin D Receptor Gene Polymorphisms and Breast Cancer Risk
Authors: Guy Michelle , Lowe Lorraine C. , Bretherton-Watt Deborah , Mansi Janine L. , Peckitt Clare , Bliss Judith , Wilson Rosalind Given , Thomas Valerie , Colston Kay W. 
Published: September 2005

Abstract
Purpose: The steroid hormone 1,25-dihydroxyvitamin D3 is thought to protect against breast cancer. The actions of 1,25-dihydroxyvitamin D3 are mediated via the vitamin D receptor (VDR), and a number of polymorphisms in the VDR gene have been identified. These result in distinct genotypes, some of which may alter susceptibility to breast cancer. We have investigated whether specific VDR gene polymorphisms are associated with breast cancer risk in a United Kingdom Caucasian population.
Experimental Design: In a retrospective case-control study, female breast cancer patients (n = 398) and control women (n = 427) were recruited, and three VDR polymorphisms were determined.
Results: The 3′ VDR polymorphisms BsmI and variable-length poly(adenylate) sequence were both significantly associated with breast cancer risk; odds ratios (adjusted for age menopausal status and hormone replacement therapy usage) for bb genotype versus BB genotype = 1.92 (95% confidence interval, 1.20–3.10; P &lt; 0.01) and for LL versus SS = 1.94 (95% confidence interval, 1.20–3.14; P &lt; 0.01). A 5′ VDR gene variant, FokI, was not associated with breast cancer risk when analyzed in isolation (P &gt; 0.05). However, FokI did modulate the increased risk associated with the bb/LL genotype such that possession of one or more F alleles together with the bb/LL genotype augmented breast cancer risk. Furthermore, the highest proportion of bb and FFLL/FfLL genotypes occurred in women with metastatic breast cancer.
Conclusions: VDR polymorphisms are associated with breast cancer risk and may be associated with disease progression. Additional investigations into how different genotypes may affect the functional mechanisms of the VDR will provide a better strategy for identifying women at risk of breast cancer and for developing improved treatments.
Immunohistochemical and Clinical Characterization of the Basal-Like Subtype of Invasive Breast Carcinoma
Authors: Nielsen Torsten O. , Hsu Forrest D. , Jensen Kristin , Cheang Maggie , Karaca Gamze , Hu Zhiyuan , Hernandez-Boussard Tina , Livasy Chad , Cowan Dave , Dressler Lynn , Akslen Lars A. , Ragaz Joseph , Gown Allen M. , Gilks C. Blake , van de Rijn Matt , Perou Charles M. 
Published: September 2005

Abstract
Purpose: Expression profiling studies classified breast carcinomas into estrogen receptor (ER)+/luminal, normal breast-like, HER2 overexpressing, and basal-like groups, with the latter two associated with poor outcomes. Currently, there exist clinical assays that identify ER+/luminal and HER2-overexpressing tumors, and we sought to develop a clinical assay for breast basal-like tumors.
Experimental Design: To identify an immunohistochemical profile for breast basal-like tumors, we collected a series of known basal-like tumors and tested them for protein patterns that are characteristic of this subtype. Next, we examined the significance of these protein patterns using tissue microarrays and evaluated the prognostic significance of these findings.
Results: Using a panel of 21 basal-like tumors, which was determined using gene expression profiles, we saw that this subtype was typically immunohistochemically negative for estrogen receptor and HER2 but positive for basal cytokeratins, HER1, and/or c-KIT. Using breast carcinoma tissue microarrays representing 930 patients with 17.4-year mean follow-up, basal cytokeratin expression was associated with low disease-specific survival. HER1 expression was observed in 54% of cases positive for basal cytokeratins (versus 11% of negative cases) and was associated with poor survival independent of nodal status and size. c-KIT expression was more common in basal-like tumors than in other breast cancers but did not influence prognosis.
Conclusions: A panel of four antibodies (ER, HER1, HER2, and cytokeratin 5/6) can accurately identify basal-like tumors using standard available clinical tools and shows high specificity. These studies show that many basal-like tumors express HER1, which suggests candidate drugs for evaluation in these patients.
Pilot Study of the Mechanism of Action of Preoperative Trastuzumab in Patients with Primary Operable Breast Tumors Overexpressing HER2
Authors: Gennari Roberto , Menard Sylvie , Fagnoni Francesco , Ponchio Luisa , Scelsi Mario , Tagliabue Elda , Castiglioni Fabio , Villani Laura , Magalotti Cesare , Gibelli Nadia , Oliviero Barbara , Ballardini Bettina , Prada Gianantonio Da , Zambelli Alberto , Costa Alberto 
Published: September 2005

Abstract
Purpose: To elucidate the mechanism by which trastuzumab, a humanized monoclonal antibody against HER2 with proven survival benefit in women with HER2-positive metastatic breast cancer, mediates its antitumor activity.
Experimental Design: A pilot study including 11 patients with HER2-positive tumors treated in a neo-adjuvant setting with trastuzumab was performed. Trastuzumab was administered i.v. at a dose of 4 mg/kg followed by three weekly i.v. doses of 2 mg/kg. The primary tumor was surgically removed 7 days after the last treatment. Surgical samples, tumor biopsies, and lymphocytes from these patients were collected for biological studies.
Result: Clinical data indicated one complete pathological remission and four partial remissions using RECIST (Response Evaluation Criteria in Solid Tumors). Trastuzumab was well tolerated and neither serious adverse events nor changes in cardiac function were observed during this short-term treatment and after surgery. The biological data showed that, independent of response, (a) all patients showed high levels of circulating trastuzumab; (b) saturating level of trastuzumab was present in all of the tumors; (c) no down-modulation of HER2 was observed in any tumors; (d) no changes in vessel diameter was observed in any tumors; (e) no changes in proliferation was observed in any tumors; and (f) a strong infiltration by lymphoid cells was observed in all cases. Patients with complete remission or partial remission were found to have a higher in situ infiltration of leukocytes and a higher capability to mediate in vitro antibody-dependent cellular cytotoxicity activity.
Conclusions: The results of this pilot study argue against trastuzumab activity in patients through down-modulation of HER2 but in favor of antibody-dependent cellular cytotoxicity guiding efforts to optimize the use of trastuzumab in breast cancer patients.
A Phase II Clinical and Pharmacodynamic Study of E7070 in Patients with Metastatic, Recurrent, or Refractory Squamous Cell Carcinoma of the Head and Neck
Authors: Haddad Robert I. , Weinstein Lisa J. , Wieczorek Tad J. , Bhattacharya Nandita , Raftopoulos Harry , Oster Martin W. , Zhang Xinxin , Latham Vaughan M. , Costello Rosemary , Faucher Jarrod , DeRosa Carolyn , Yule Murray , Miller Linda P. , Loda Massimo , Posner Marshall R. , Shapiro Geoffrey I. 
Published: September 2005

AbstractPurpose: E7070 is a synthetic sulfonamide cell cycle inhibitor that induces hypophosphorylation of the retinoblastoma (Rb) protein and G1 arrest in vitro. This Phase II study was conducted to explore the efficacy, safety, and pharmacodynamics of E7070 in squamous cell carcinoma of the head and neck (SCCHN).Experimental Design: Patients with metastatic, recurrent, or refractory SCCHN, treated with no more than one prior therapy for recurrent disease, received E7070 at 700 mg/m2 over 1 h every 3 weeks. Pre- and posttreatment tumor fine needle aspirates were subjected to immunohistochemistry with a panel of phospho-specific anti-Rb antibodies. End points included progression-free survival, response rate and duration, overall survival, toxicity profile, and inhibition of Rb phosphorylation.Results: Because none of the first 15 patients achieved progression-free survival &gt; 4 months, the early stopping rule was invoked. Eleven patients had oropharyngeal cancer and 12 were male. Median age was 59 years (range, 49–73 years). Thirty-nine cycles of E7070 were delivered (median, 2.6 cycles/patient; range, 1–5 cycles). Six patients had stable disease after 2 cycles and 2 patients each subsequently received 1, 2, and 3 additional cycles, respectively, before experiencing progression. Immunohistochemistry of tumor cell aspirates from 3 patients demonstrated reduced Rb phosphorylation posttreatment.Conclusions: At this dose and schedule, E7070 is unlikely to be superior over single-agent chemotherapy in SCCHN. However, the data suggest that cdk activity can be inhibited in tumor cells, resulting in posttreatment modulation of Rb phosphorylation. In the absence of cytotoxicity, more frequent administration of E7070 may be required to sustain Rb hypophosphorylation and cytostatic growth arrest.
Microsatellite Instability Testing in Colorectal Carcinoma: Choice of Markers Affects Sensitivity of Detection of Mismatch Repair–Deficient Tumors
Authors: Hatch Stephanie B. , Lightfoot Harry M. , Garwacki Christopher P. , Moore Dominic T. , Calvo Benjamin F. , Woosley John T. , Sciarrotta Janiece , Funkhouser William K. , Farber Rosann A. 
Published: September 2005

Abstract
Purpose: Microsatellite instability (MSI) is found in 10% to 15% of sporadic colorectal tumors and is usually caused by defects in DNA mismatch repair (MMR). In 1997, a panel of microsatellite markers including mononucleotide and dinucleotide repeats was recommended by a National Cancer Institute workshop on MSI. We investigated the relationship between instability of these markers and MMR protein expression in a cohort of sporadic colorectal cancer patients.
Experimental Design: Paraffin sections of normal and tumor tissue from 262 colorectal cancer patients were examined for MSI status by PCR amplification and for MMR protein expression using antibodies against hMLH1, hPMS2, hMSH2, and hMSH6.
Results: Twenty-six (10%) of the patients studied had tumors with a high level of MSI (MSI-H). The frequencies of MSI were the same in African-American and Caucasian patients. Each of the MSI-H tumors had mutations in both mononucleotide and dinucleotide repeats and had loss of MMR protein expression, as did two tumors that had low levels of MSI (MSI-L). These two MSI-L tumors exhibited mutations in mononucleotide repeats only, whereas eight of the other nine MSI-L tumors had mutations in just a single dinucleotide repeat. There was not a statistically significant difference in outcomes between patients whose tumors were MMR-positive or MMR-negative, although there was a slight trend toward improved survival among those with MMR-deficient tumors.
Conclusions: The choice of microsatellite markers is important for MSI testing. Examination of mononucleotide repeats is sufficient for detection of tumors with MMR defects, whereas instability only in dinucleotides is characteristic of MSI-L/MMR-positive tumors.
The Cooperative Prostate Cancer Tissue Resource
Authors: Melamed Jonathan , Datta Milton W. , Becich Michael J. , Orenstein Jan M. , Dhir Rajiv , Silver Sylvia , Fidélia-Lambert Marie , Kadjacsy-Balla André , Macias Virgilia , Patel Ashokkumar , Walden Paul D. , Bosland Maarten C. , Berman Jules J. ,   the Cooperative Prostate Cancer Tissue Resource.
Published: September 2005

AbstractPurpose: The Cooperative Prostate Cancer Tissue Resource (CPCTR) is a National Cancer Institute-supported tissue bank that provides large numbers of clinically annotated prostate cancer specimens to investigators. This communication describes the CPCTR to investigators interested in obtaining prostate cancer tissue samples.Experimental Design: The CPCTR, through its four participating institutions, has collected specimens and clinical data for prostate cancer cases diagnosed from 1989 onward. These specimens include paraffin blocks and frozen tissue from radical prostatectomy specimens and paraffin blocks from prostate needle biopsies. Standardized histopathological characterization and clinical data extraction are performed for all cases. Information on histopathology, demography (including ethnicity), laboratory data (prostate-specific antigen values), and clinical outcome related to prostate cancer are entered into the CPCTR database for all cases. Materials in the CPCTR are available in multiple tissue formats, including tissue microarray sections, paraffin-embedded tissue sections, serum, and frozen tissue specimens. These are available for research purposes following an application process that is described on the CPCTR web site (www.prostatetissues.org).Results: The CPCTR currently (as of October 2003) contains 5135 prostate cancer cases including 4723 radical prostatectomy cases. Frozen tissues, in some instances including patient serum samples, are available for 1226 cases. Biochemical recurrence data allow identification of cases with residual disease, cases with recurrence, and recurrence-free cases.Conclusions: The CPCTR offers large numbers of highly characterized prostate cancer tissue specimens, including tissue microarrays, with associated clinical data for biomarker studies. Interested investigators are encouraged to apply for use of this material (www.prostatetissues.org).
Isolated Tumor Cells in Bone Marrow Three Years after Diagnosis in Disease-Free Breast Cancer Patients Predict Unfavorable Clinical Outcome1
Authors: Wiedswang Gro , Borgen Elin , Kåresen Rolf , Qvist Hanne , Janbu Jan , Kvalheim Gunnar , Nesland Jahn M. , Naume Bjørn 
Published: September 2005

Abstract
Purpose: The aim of the study was to explore the value of analyzing bone marrow (BM) for the presence of isolated tumor cell(s) (ITCs) in disease-free breast cancer patients 3 years after diagnosis.
Experimental Design: ITCs in BM at operation was found to be an independent prognostic factor in 817 breast cancer patients. Among these, 356 disease-free patients were analyzed with a second BM after 3 years follow-up (median 40 months, SD 3 months, range 29–52). ITC was detected by immunocytochemistry with anticytokeratine antibodies (AE1/AE3).
Results: The population consisted of 70% T1 and 72% node-negative patients. ITC in BM was detected in 15%. At a median of 25 months since the second BM aspiration (66 months since diagnosis), 32 patients had developed relapse, 12 local and 20 systemic. Of the patients with ITC in BM, 21% relapsed compared with 7% of the ITC-negative patients (P &lt; 0.001). Ten patients died of breast cancer. Survival analyses showed that ITC in BM predicted reduced distant disease-free survival (DDFS) and breast cancer specific survival (BCSS; P &lt; 0.001, log-rank test). Uni-and multivariate analyses of the prognostic value of N, T, estrogen receptor/progesterone receptor, and BM status, histological grade, vascular invasion, p53-, c-erb-B2-, and cathepsin D expression were performed. BM status was the only independent prognostic factor for both DDFS and BCSS, whereas c-erbB-2 and N status were independent for BCSS and vascular invasion and T status for DDFS.
Conclusions: ITC in BM 3 years after diagnosis in disease-free breast cancer patients is an independent prognostic factor. Detection of residual disease by BM analysis at follow-up may unravel insufficient adjuvant treatment. The clinical implications should be further explored.
Matrix Metalloproteinase-2 Status in Stromal Fibroblasts, Not in Tumor Cells, Is a Significant Prognostic Factor in Non–Small-Cell Lung Cancer
Authors: Ishikawa Shinya , Takenaka Kazumasa , Yanagihara Kazuhiro , Miyahara Ryo , Kawano Yozo , Otake Yosuke , Hasegawa Seiki , Wada Hiromi , Tanaka Fumihiro 
Published: September 2005

AbstractPurpose: The purpose is to assess clinical significance of matrix metalloproteinase (MMP)-2 and MMP-9 status, especially MMP-2 status, in stromal cells in non–small-cell lung cancer (NSCLC) because experimental studies have revealed that stromal MMP-2 plays important roles in progression of malignant tumors, but most clinical studies focused on tumoral MMP-2 expression, not stromal MMP-2 expression.Experimental Design: We conducted a retrospective study on MMP-2 and MMP-9 expression as evaluated immunohistochemically in a total of 218 consecutive patients with completely resected pathological stage I–IIIA, NSCLC.Results: Strong MMP-2 expression in tumor cells and stromal fibroblasts were documented in 54 (24.8%) and 132 (60.6%) patients, respectively. Strong MMP-2 expression in stromal fibroblasts was more frequently seen in squamous cell carcinoma (72.7%) than in adenocarcinoma (54.9%; P = 0.016). Tumors showing strong MMP-2 expression in stromal fibroblasts showed a significantly higher intratumoral microvessel density (IMVD) than weak stromal MMP-2 tumors (mean intratumoral microvessel density, 50.9 versus 32.4, P = 0.003). In addition, postoperative prognosis of strong stromal MMP-2 patients was significantly poorer than that of weak stromal MMP-2 patients (5-year survival rate, 77.5 versus 60.2%, P = 0.032), and the prognostic significance was enhanced in squamous cell carcinoma patients but disappeared in adenocarcinoma patients. Multivariate analyses confirmed that strong stromal MMP-2 expression was a significant factor to predict a poor prognosis in squamous cell carcinoma patients, not in adenocarcinoma patients. In contrast, MMP-2 or MMP-9 status in tumor cells was not a significant prognostic factor.Conclusions: MMP-2 status in stromal fibroblasts, not in tumor cells, was a significant prognostic factor associated with angiogenesis in NSCLC.