bluuebunny/crossref_metadata_2025_split huggingface dataset:
Decreased Absolute Counts of T Lymphocyte Subsets and Their Relation to Disease in Squamous Cell Carcinoma of the Head and Neck
Authors: Kuss Iris , Hathaway Bridget , Ferris Robert L. , Gooding William , Whiteside Theresa L. 
Published: September 2005

Abstract
Purpose: Apoptosis of circulating CD8+ T cells seen in patients with squamous cell carcinoma of the head and neck [SCCHN (Hoffmann T, et al. Clin Cancer Res 2002;8:2553–62)] suggested a possibility of lymphocyte imbalance. Therefore, absolute numbers and percentages of lymphocyte subsets were examined in the peripheral blood of SCCHN patients and controls.
Experimental Design: Venous blood was obtained from 146 patients with SCCHN and 54 normal volunteers. Absolute numbers of CD3+, CD4+, and CD8+ T lymphocytes were determined using fluorobeads in a flow cytometry-based technique. Percentages of T lymphocyte subsets were also evaluated by flow cytometry. The patients were grouped at the time of blood draw [active versus no evidence of disease (NED), type of therapy administered, and the length of follow-up].
Results: Patients with SCCHN had significantly lower absolute numbers of CD3+ CD4+, and CD8+ T cells than normal controls. However, no differences in the percentages of T-cell subsets between patients and normal controls were observed. Patients with active disease had significantly lower CD3+ and CD4+ T-cell counts than those with NED. Patients who had NED after surgery and radiotherapy had the lowest T-cell counts among the NED cohort. Patients who had NED for &gt;2 years did not recover their T-cell counts, and the T-cell imbalance was evident many years after curative surgery. The tumor-node-metastasis (TNM) stage or site of the disease was not related to the absolute T-cell count. Patients with recurrent disease at the time of blood draw tended to have the lowest CD4+ T-cell counts.
Conclusions: Patients with SCCHN have altered lymphocyte homeostasis, which persists for months or years after curative therapies.
The Relationship of Molecular Markers of p53 Function and Angiogenesis to Prognosis of Stage I Epithelial Ovarian Cancer
Authors: Goodheart Michael J. , Ritchie Justine M. , Rose Stephen L. , Fruehauf John P. , De Young Barry R. , Buller Richard E. 
Published: September 2005

Abstract
Purpose: Multiple angiogenic factors may influence tumor progression and metastasis. Several are modified by the p53 gene. We sought to identify molecular markers for high-risk stage I epithelial ovarian cancers.
Experimental Design: Seventy-seven consecutive stage I epithelial ovarian cancers were evaluated for p53, CD31 microvessel density, thrombospondin-1, vascular endothelial growth factor (VEGF), p21 immunohistochemical staining, and p53 gene mutations. Molecular marker impact upon disease-specific survival, disease recurrence, and distant recurrence was evaluated with Cox regression.
Results: There were 12 deaths from disease. Twelve of the 77 tumors contained p53 mutations—10 missense and 3 null (one tumor had two mutations). Fesddration Internationale des Gynaecologistes et Obstetristes substage (IA/IB versus IC; P &lt; 0.001) and VEGF staining (P = 0.02) were significant in bivariate models with relationship to disease-specific survival. Stage (P = 0.0004), grade (P = 0.008), histology (P = 0.0025), p53 dysfunction (positive stain and/or mutation; P = 0.048), and microvessel density (P = 0.04) were significant in bivariate models with relationship to time to recurrence. In multivariate analyses among stage IC patients, failure to receive chemotherapy and microvessel density were associated with disease-specific survival, time to recurrence, and time to distant recurrence with hazard ratios of 4.8 to 44.1.
Conclusions: The p53-dependent molecular markers of angiogenesis are of limited utility in developing a clinical strategy for postoperative management of stage I ovarian carcinoma. Microvessel density impacts survival and metastasis for high-risk stage IC disease. Adjuvant chemotherapy is necessary, but not sufficient, for cure of high-risk stage I epithelial ovarian cancers.
Development of the Novel Biologically Targeted Anticancer Agent Gefitinib
Authors: Wolf Michael , Swaisland Helen , Averbuch Steven 
Published: September 2005

Abstract
The emergence of novel, biologically targeted anticancer agents such as gefitinib (‘Iressa’, ZD1839) has raised the question of how the dose for later-stage clinical development and clinical use is best determined. For cytotoxic drugs, because toxic effects and antitumor activity often fall within the same dose range and are dose dependent, the clinically used dose will depend on the therapeutic window. Therefore, the maximum tolerated dose identified in Phase I trials is typically used to determine the dose level for Phase II and III trials. However, because biologically targeted agents are expected to provide clinical benefits that are not predicted by surrogate end points of toxicity to normal replicating tissue, new Phase I trials have been designed to determine the optimum biological dose for use in further studies.
A large, multifaceted Phase I program was designed to evaluate the pharmacokinetics, safety, efficacy, and targeted biological activity of a once-daily oral dose of gefitinib. The maximum tolerated dose was ≥700 mg/day, although doses as low as 150 mg/day provided (a) plasma concentrations sufficient for pharmacological activity, (b) evidence of targeted biological effect, and (c) antitumor activity. From these observations, two large Phase II trials (‘Iressa’ Dose Evuluation in Advanced Lung Cancer 1 and 2) evaluated 250- and 500-mg/day doses of gefitinib in patients with advanced non-small cell lung cancer (NSCLC). As predicted from the Phase I trials, doses &gt;250 mg/day provided no additional efficacy benefit, whereas adverse effects increased in a dose-dependent manner. Consequently, the recommended dose of gefitinib in NSCLC is 250 mg/day. The early clinical trial development of gefitinib provides a model for the development of novel, noncytotoxic anticancer agents.
SEL1L
and Squamous Cell Carcinoma of the Esophagus
Authors: Granelli Paola , Cattaneo Monica , Ferrero Stefano , Bottiglieri Luca , Bosari Silvano , Fichera Giuseppe , Biunno Ida 
Published: September 2005

Abstract
The gene SEL1L is involved both in human breast and pancreatic cancer progression. It is located on 14q24.3–31, a region known to be lost in invasive cancer of the esophagus. We aimed to assess whether SEL1L could become a useful biomarker for this cancer. We assessed SEL1L mRNA and protein expression in 35 patients and found it to be weak in low-grade and strong in high-grade dysplasia. Although the majority of cancer patients showed differential expression (mRNA and protein) of SEL1L, in five cases it was completely absent; these patients had the worst outcomes. SEL1L immunoreactivity was negative in normal tissue samples from five patients with mild esophagitis as well as in normal mucosa adjacent to the tumor. We hypothesize that SEL1L could influence those cellular changes that mediate the transition from a normal mucosa to a neoplastic lesion and may help in the identification of those patients at higher risk of developing this cancer. The specific impact of SEL1L in esophageal cancer needs further investigation.
Combination of Somatostatin Analog, Dexamethasone, and Standard Androgen Ablation Therapy in Stage D3 Prostate Cancer Patients with Bone Metastases
Authors: Koutsilieris Michael , Mitsiades Constantine S. , Bogdanos John , Dimopoulos Theodoros , Karamanolakis Dimitrios , Milathianakis Constantine , Tsintavis Athanassios 
Published: September 2005

Abstract
Purpose: Androgen ablation-refractory prostate cancer patients (stage D3) develop painful bone metastases and limited responsiveness to conventional therapies, hence the lack of universally accepted “gold standard” treatment for this poor prognosis clinical setting. We tested the safety and efficacy in stage D3 patients of the combination hormonal therapy, which combines administration of somatostatin analog and dexamethasone with standard androgen ablation monotherapy (luteinizing-hormone releasing-hormone analog or orchiectomy).
Experimental Design: Thirty eight patients with stage D3 prostate cancer (mean age 71.8 ± 5.9 years) continued receiving androgen ablation therapy in combination with oral dexamethasone (4 mg daily for the 1st month of treatment, tapered down to 1 mg daily by the 4th month, with 1 mg daily maintenance dose thereafter) and somatostatin analog (20 mg octreotide i.m. injections every 28 days).
Results: Twenty-three of 38 patients (60.5%) receiving this combination regimen had partial responses [PR, ≥50% prostate-specific antigen (PSA) decline], 9 (21.1%) had stable disease, and 7 (18.4%) had progressive disease. In 47.7% (18 of 38) of patients, their serum PSA levels decreased with treatment but did not return to their respective baselines until the end of follow-up (or death from non-prostate cancer-related causes). The median time-to-return to baseline PSA was 12 months (95% CI, 7–17 months), median progression-free survival was 7 months (95% CI, 4.5–9.5 months), median overall survival was 14 months (95% CI, 10.7–17.4 months), and median prostate cancer-specific overall survival (defined as time from onset of combination therapy until prostate cancer-related death) was 16.0 months (95% CI, 11.9–20.1 months). All patients reported significant and durable improvement of bone pain and performance status (for a median duration of 14 months; 95% CI, 9–19 months), without major treatment-related side effects. We observed a statistically significant (P &lt; 0.01) reduction in serum insulin-like growth factor-1 levels at response to the combination therapy. T levels remained suppressed within castration levels at baseline and throughout therapy, including relapse.
Conclusion: The combination therapy of dexamethasone plus somatostatin analog and standard androgen ablation manipulation produces objective clinical responses and symptomatic improvement in androgen ablation-refractory refractory prostate cancer patients.
Gabexate Mesilate Inhibits Colon Cancer Growth, Invasion, and Metastasis by Reducing Matrix Metalloproteinases and Angiogenesis
Authors: Yoon Wan-Hee , Jung Yeon-Joo , Kim Tae-Dong , Li Ge , Park Byoung-Jeon , Kim Ji-Yeon , Lee Young-Chul , Kim Jin-Man , Park Jong-Il , Park Hae-Duck , No Zae-Sung , Lim Kyu , Hwang Byung-Doo , Kim Young S. 
Published: September 2005

Abstract
Gabexate mesilate (GM), a synthetic protease inhibitor, has an antiproteinase activity on various types of plasma serine proteases. However, its role on matrix metalloproteinases (MMPs) has not been identified. In this study, we investigated the effect of GM on MMPs and on the invasion and metastasis of human colon cancer cell lines and neoangiogenesis. The activities of MMPs secreted from these cells were significantly reduced by GM but unaffected by the serine protease inhibitor aprotinin. GM directly inhibited purified progelatinase A derived from T98G human glioblastoma cells. In vitro, GM significantly reduced the invasive ability of colon cancer cells but not cellular motility, whereas aprotinin affected neither. Liver metastatic ability and tumorigenic potential in nude mice were remarkably reduced on treatment with GM. Immunohistochemical analysis of GM-treated tumors in mice showed a marked increase in apoptosis and a significant reduction in tumor angiogenesis. Human umbilical vein endothelial cell proliferation, tube formation, and neoangiogenesis in the rabbit cornea and Matrigel implanted in mice were significantly inhibited by GM. These results suggest that GM is a novel inhibitor of MMPs and that it may inhibit the invasion and metastasis of human colon cancer cells by blocking MMPs and neoangiogenesis.
Conservation of Breast Cancer Molecular Subtypes and Transcriptional Patterns of Tumor Progression Across Distinct Ethnic Populations
Authors: Yu Kun , Lee Chee How , Tan Puay Hoon , Tan Patrick 
Published: September 2005

Abstract
Purpose: Breast cancers can display distinct clinical characteristics in different ethnic populations. Previous studies involving European and United States patients have shown that breast tumors can be divided by their gene expression profiles into distinct “molecular subtypes.” In this report, we surveyed a series of invasive and preinvasive breast tumors from Asian-Chinese patients to investigate whether similar subtypes could also be observed in this ethnic group.
Experimental Design and Results: An analysis of expression profiles generated from 11 nonmalignant breast tissues, 17 ductal carcinomas in situ (DCIS) and 98 invasive carcinomas identified three broad molecular subtypes of breast [estrogen receptor (ER)+, ERBB2+ and ER−] in the Asian-Chinese population. These subtypes were highly similar to the “Luminal,” “ERBB2+,” and “Basal” molecular subtypes defined in previous studies, and the subtype-specific expression signatures were also observed in preinvasive DCIS tumors. By comparing the expression profiles of nonmalignant DCIS and invasive breast cancers for two subtypes (ER+ and ERBB2+), we identified several genes that were regulated in both a common and subtype-specific manner during the normal/DCIS and DCIS/invasive carcinoma transitions. Several of these genes were validated by comparison with another recently published similar, but not identical, study.
Conclusions: Our results suggest that molecularly similar subtypes of breast cancer are indeed broadly conserved between Asian and Caucasian patients, and that these subtypes are already present at the preinvasive stage of carcinogenesis. To our knowledge, this study is among the first to directly compare the expression profiles of breast tumors across two different ethnic populations.
A Phase I Study of Cantuzumab Mertansine Administered as a Single Intravenous Infusion Once Weekly in Patients with Advanced Solid Tumors
Authors: Helft Paul R. , Schilsky Richard L. , Hoke Frank J. , Williams Daphne , Kindler Hedy L. , Sprague Evie , DeWitte Mark , Martino Helen K. , Erickson John , Pandite Lini , Russo Mark , Lambert John M. , Howard Maria , Ratain Mark J. 
Published: September 2005

Abstract
Purpose: The purpose is to determine the maximum-tolerated dose, assess the toxicities, characterize the pharmacokinetic behavior, and seek preliminary evidence of biological activity of cantuzumab mertansine when administered as a weekly i.v. infusion without interruption.
Experimental Design: Patients with incurable solid tumors that expressed the target antigen for cantuzumab mertansine, CanAg, were treated with doses of cantuzumab mertansine ranging from 40 to 138 mg/m2. The maximum-tolerated dose was defined as the highest dose at which no more than 1 of 6 patients experienced dose-limiting toxicity. Plasma concentrations of cantuzumab mertansine and total humanized antibody were determined, and area under the plasma concentration-time curve (to the last measured concentration) was calculated.
Results: Thirty-nine patients received a total of 280 weekly doses of cantuzumab mertansine. Acute, transient elevation of the hepatic transaminases and reversible fatigue were identified as the dose-limiting toxicities at the highest dose level. The maximum-tolerated dose was determined to be 115 mg/m2/week. Evidence of clinical activity was noted in 3 patients. Pharmacokinetic analyses revealed that the pharmacokinetic variability was moderate, without evidence of dose dependency. Furthermore, the drug had a long terminal half-life (∼40 h).
Conclusions: This study identified a safe and tolerable dose of the novel immunoconjugate prodrug cantuzumab mertansine. The evidence of antitumor activity suggests that additional clinical development is warranted, with a focus on tumors that express high levels of CanAg and which are known to be sensitive to antimicrotubule agents.
A Phase I and Pharmacodynamic Study of Fludarabine, Carboplatin, and Topotecan in Patients With Relapsed, Refractory, or High-Risk Acute Leukemia
Authors: Cooper Brenda W. , Veal Gareth J. , Radivoyevitch Tomas , Tilby Michael J. , Meyerson Howard J. , Lazarus Hillard M. , Koc Omer N. , Creger Richard J. , Pearson Graham , Nowell Geoff M. , Gosky David , Ingalls Stephen T. , Hoppel Charles L. , Gerson Stanton L. 
Published: September 2005

Abstract
Purpose: A novel regimen designed to maximize antileukemia activity of carboplatin through inhibiting repair of platinum-DNA adducts was conducted in poor prognosis, acute leukemia patients.
Experimental Design: Patients received fludarabine (10 to 15 mg/m2 × 5 days), carboplatin (area under the curve 10 to 12 by continuous infusion over 5 days), followed by escalated doses of topotecan infused over 72 hours (fludarabine, carboplatin, topotecan regimen). Twenty-eight patients had acute myelogenous leukemia (7 untreated secondary acute myelogenous leukemia, 11 in first relapse, and 10 in second relapse or refractory), 1 patient had refractory/relapsed acute lymphoblastic leukemia, and 2 patients had untreated chronic myelogenous leukemia blast crisis. Six patients had failed an autologous stem cell transplant. Patients ranged from 19 to 76 (median 54) years. Measurement of platinum-DNA adducts were done in serial bone marrow specimens.
Results: Fifteen of 31 patients achieved bone marrow aplasia. Clinical responses included 2 complete response, 4 complete response with persistent thrombocytopenia, and 2 partial response. Prolonged myelosuppression was observed with median time to blood neutrophils ≥200/μl of 28 (0 to 43) days and time to platelets ≥20,000/μl (untransfused) of 40 (24 to 120) days. Grade 3 or greater infections occurred in all of the patients, and there were 2 infection-related deaths. The nonhematologic toxicity profile was acceptable. Five patients subsequently received allografts without early transplant-related mortality. Maximum tolerated dose of fludarabine, carboplatin, topotecan regimen was fludarabine 15 mg/m2 × 5, carboplatin area under the curve 12, and topotecan 2.55 mg/m2 over 72 hours. An increase in bone marrow, platinum-DNA adduct formation between the end of carboplatin infusion and 48 hours after the infusion correlated with bone marrow response.
Conclusions: Fludarabine, carboplatin, topotecan regimen is a promising treatment based on potential pharmacodynamic interactions, which merits additional study in poor prognosis, acute leukemia patients.
Biological Relevance of Adduct Detection to the Chemoprevention of Cancer
Authors: Sharma Ricky A. , Farmer Peter B. 
Published: September 2005

Abstract
Adducts arise from the chemical modification of bases in DNA or amino acids in proteins by toxic chemicals. Many chemicals known to be carcinogenic in humans have been shown to form adducts or to cause oxidative damage to genomic DNA in model systems. Biomarkers of carcinogenesis reflect biological events that take place between exposure to external or endogenous carcinogens and the subsequent development of cancer. Therapeutic intervention for the purpose of cancer chemoprevention may modify these biomarkers. In this article, the potential efficacy of DNA adducts as biomarkers of carcinogenesis and chemoprevention is discussed using criteria defined for phases of biomarker development. The sensitivity of adduct detection in histologically normal tissue offers opportunities for the early detection of carcinogenesis. Extensive evidence for aflatoxin B1 adducts as biomarkers of risk and progression of hepatic carcinogenesis and for oxidative DNA adducts as biomarkers of the development of prostate carcinogenesis is reviewed together with the clinical trials measuring these adducts as biomarkers of the efficacy of chemoprevention. Favorable modification of oxidative DNA adducts by dietary intervention and chemoprevention has been demonstrated in preclinical and clinical studies. Protein adducts and DNA adducts in blood constituents or urine may act as useful surrogates for the target organ. Additional information regarding reliability, reproducibility, specificity, and confounding variables are required at the clinical level to validate adducts as suitable biomarkers of chemoprevention.
“We do not administer antihypertensive drugs to patients in clinical trials without checking their blood pressure, so why should we give antioxidants without checking that they have decreased oxidant status (B. Halliwell, Lancet 2000:355:1179–80)?”
Activation of the Akt/Mammalian Target of Rapamycin/4E-BP1 Pathway by ErbB2 Overexpression Predicts Tumor Progression in Breast Cancers
Authors: Zhou Xiaoyan , Tan Ming , Stone Hawthorne Valerie , Klos Kristine S. , Lan Keng-Hsueh , Yang Ying , Yang Wentao , Smith Terry L. , Shi Daren , Yu Dihua 
Published: September 2005

Abstract
The Akt/mammalian target of rapamycin (mTOR)/4E-BP1 pathway is considered to be a central regulator of protein synthesis, involving the regulation of cell proliferation, differentiation, and survival. The inhibitors of mTOR as anticancer reagents are undergoing active evaluation in various malignancies including breast cancer. However, the activation status of the Akt/mTOR/4E-BP1 pathway and its potential roles in breast cancers remain unknown. Thus, we examined 165 invasive breast cancers with specific antibodies for the phosphorylation of Akt, mTOR, and 4E-BP1 by immunohistochemistry and compared them with normal breast epithelium, fibroadenoma, intraductal hyperplasia, and ductal carcinoma in situ. We discovered that the phosphorylation of Akt, mTOR, and 4E-BP1 increased progressively from normal breast epithelium to hyperplasia and abnormal hyperplasia to tumor invasion. Phosphorylated Akt, mTOR, and 4E-BP1 were positively associated with ErbB2 overexpression. Survival analysis showed that phosphorylation of each of these three markers was associated with poor disease-free survival independently. In vitro, we further confirmed the causal relationship between ErbB2 overexpression and mTOR activation, which was associated with enhanced invasive ability and sensitivity to a mTOR inhibitor, rapamycin. Our results, for the first time, demonstrate the following: (a) high levels of phosphorylation of Akt, mTOR, and 4E-BP1 in breast cancers, indicating activation of the Akt/mTOR/4E-BP1 pathway in breast cancer development and progression; (b) a link between ErbB2 and the Akt/mTOR/4E-BP1 pathway in breast cancers in vitro and in vivo, indicating the possible role of Akt/mTOR activation in ErbB2-mediated breast cancer progression; and (c) a potential role for this pathway in predicting the prognosis of patients with breast cancer, especially those treated with mTOR inhibitors.