bluuebunny/crossref_metadata_2025_split huggingface dataset:
Combination Phase I Trial of a Novel Oral Fluorouracil Derivative S-1 with Low-Dose Cisplatin for Unresectable and Recurrent Gastric Cancer (JFMC27–9902)
Authors: Nakata Bunzo , Mitachi Yasushi , Tsuji Akihito , Yamamitsu Susumu , Hirata Koichi , Shirasaka Tetsuhiko , Hirakawa Kosei 
Published: September 2005

Abstract
Purpose: The Japanese Foundation for Multidisciplinary Treatment of Cancer conducted a Phase I study of a novel oral fluorouracil derivative, S-1, combined with a low dose of cisplatin in unresectable and recurrent gastric cancer.
Experimental Design: S-1 was administered orally at 80–120 mg/body/day, depending on body surface area. One course consisted of consecutive administration for 28 days followed by a rest of 14 days. Low-dose cisplatin was given i.v. on days 1–5, 8–12, 15–19, and 22–26 of each course. The dose escalation of cisplatin began with an initial dose of 1 mg/m2/day as level 1 and was stepped up to 2, 3, 4, and 6 mg/m2/day as level 2, 3, 4, and 5, respectively. The regimen was repeated for at least two courses.
Results: A total of 24 patients was entered in the study. There was no treatment-related death. At level 5, consisting of 5 evaluable patients, dose-limiting toxicity was experienced as grade 3 appetite loss in 2 patients and grade 4 neutropenia in 1 patient. The maximum-tolerated dose of cisplatin was estimated to be 6 mg/m2/day. We decided on a recommended dose of cisplatin of 4 mg/m2/day because the dosage was one level under the maximum-tolerated dose. All 3 patients at level 4 showed partial response, suggesting promising clinical efficacy with this dosage. The serum concentration of cisplatin at level 4 was 918 ± 92 ng/ml on day 26 of the first course.
Conclusions: S-1 with low-dose cisplatin may become an effective regimen with acceptable toxicity for gastric cancer.
QuantitativeRARβ2Hypermethylation
Authors: Jerónimo Carmen , Henrique Rui , Hoque Mohammad O. , Ribeiro Franclim R. , Oliveira Jorge , Fonseca Daniel , Teixeira Manuel R. , Lopes Carlos , Sidransky David 
Published: September 2005

AbstractRetinoic acid receptor β2 (RARβ2) is a tumor suppressor gene frequently hypermethylated in several human neoplasms. To further characterize this epigenetic alteration in prostate cancer progression, we examined tumor tissue from 118 patients with prostate carcinoma (PCa), 38 paired high-grade prostatic intraepithelial neoplasias (HGPIN), and non-neoplastic prostate tissue from 30 patients with benign prostate hyperplasia (BPH), using quantitative methylation-specific PCR. We found RARβ2 hypermethylation in 97.5% of PCa, 94.7% of HGPIN, and 23.3% of BPH. Methylation levels were significantly higher in PCa compared with HGPIN and BPH (P &lt; 0.00001). By establishing an empiric cutoff value, we were able to discriminate between neoplastic and non-neoplastic tissue, with 94.9% sensitivity and 100% specificity. Moreover, RARβ2 methylation levels correlated with higher pathological stage (r = 0.30, P = 0.0009). This quantitative assay represents a novel and promising molecular marker that may augment current approaches for prostate cancer detection.
Estrogen Receptor Status in
BRCA1
- and
BRCA2
-Related Breast Cancer
Authors: Foulkes William D. , Metcalfe Kelly , Sun Ping , Hanna Wedad M. , Lynch Henry T. , Ghadirian Parviz , Tung Nadine , Olopade Olufunmilayo I. , Weber Barbara L. , McLennan Jane , Olivotto Ivo A. , Bégin Louis R. , Narod Steven A. 
Published: September 2005

Abstract
Purpose: BRCA1-related breast cancers are more frequently estrogen receptor (ER) negative than are either BRCA2-related or nonhereditary breast cancers. The relationship between ER status and other clinical features of hereditary breast cancers has not been well studied.
Experimental Design: ER status, grade, and histological tumor type were evaluated in 1131 women with invasive breast cancer, ascertained at 10 centers in North America. There were 208 BRCA1 mutation carriers, 88 BRCA2 carriers, and 804 women without a known mutation. We stratified the patients by mutation status, grade, age, and histological type and calculated the percentage of ER-positive tumors within each stratum.
Results: BRCA1 mutation carriers were more likely to have ER-negative breast cancers than were women in other groups, after adjustment for age, grade, and histological subtype (P &lt; 0.001). Only 3.9% of BRCA1-related breast cancers were ER-positive cancers occurring in women in their postmenopausal years. The direction and magnitude of the change in ER status with increasing age at diagnosis in BRCA1 carriers was significantly different from in BRCA2 carriers (Pintercept = 0.0002, Pslope = 0.04). Notably, changes in ER status with age at diagnosis for BRCA1 carriers and noncarriers were almost identical (Pslope = 0.98).
Conclusions: The strong relationship between the presence of a BRCA1 mutation and the ER-negative status of the breast cancers is neither a consequence of the young age at onset nor the high grade but is an intrinsic property of BRCA1-related cancers. The ER-negative status of these cancers may reflect the cell of origin of BRCA1-related cancers.
Meta-Analysis Suggests Association of L-
myc Eco
RI Polymorphism with Cancer Prognosis
Authors: Spinola Monica , Pedotti Paola , Dragani Tommaso A. , Taioli Emanuela 
Published: September 2005

Abstract
The L-myc EcoRI polymorphism is a noncoding variation in the second intron of the L-myc gene, resulting in S and L alleles. Individuals carrying the S allele tend to have poor prognosis and increased risk of several tumor types, although controversial results have been reported. A meta-analysis of 36 studies on L-myc EcoRI genotyping, including 3563 patients with different types of cancer and 2953 controls, was performed. In lung cancer patients the S/S genotype was significantly associated with lymph node metastasis [odds ratio (OR), 2.8; 95% confidence interval (CI), 1.8–4.3], distant metastasis (OR, 4.7; 95% CI, 2.4–9.2), and stage (OR, 2.3; 95% CI, 1.2–4.4). No association was observed between the S/S genotype and cancer (OR, 1.1; 95% CI, 0.8–1.4). In patients with other cancers, the S/S genotype was significantly associated with tumor recurrence (OR, 2.8; 95% CI, 1.4–6.0), whereas no significant association was seen for the other prognostic parameters. When all types of cancer were examined together, the S/S genotype was associated with lymph node metastasis (OR, 2.3; 95% CI, 1.6–3.3), distant metastasis (OR, 2.9; 95% CI, 1.8–4.6), clinical stage (OR, 1.8; 95% CI, 1.2–2.9), and cancer risk (OR, 1.25; 95% CI, 1.07–1.45). The meta-analysis suggests that the L-myc EcoRI polymorphism is a marker of tumor prognosis in lung cancer and possibly in other types of cancer.
Imiquimod Treatment Induces Expression of Opioid Growth Factor Receptor
Authors: Urosevic Mirjana , Oberholzer Patrick A. , Maier Tanja , Hafner Jürg , Laine Elisabeth , Slade Herbert , Benninghoff Bernd , Burg Günter , Dummer Reinhard 
Published: September 2005

AbstractPurpose: Imiquimod represents a synthetic local immune response modifier that has demonstrated efficacy in clearing basal cell carcinoma. Via interaction with Toll-like receptor 7 on immune cells, imiquimod induces local production of cytokines, such as interferon (IFN)-α.Experimental Design: To more closely define and elucidate mechanisms leading to basal cell carcinoma clearance in vivo, we examined gene expression profiles of skin basal cell carcinoma before and after treatment with 5% imiquimod cream (Aldara) by using high-density oligonucleotide arrays.Results: We show that imiquimod predominantly induces genes involved in different aspects of immune response. In addition to effects on immunity, imiquimod treatment modulates the expression of genes involved in the control of apoptosis and oncogenesis. Array data indicated that imiquimod treatment induces expression of opioid growth factor receptor, a molecule recently reported to be a target for antitumor antibody responses. Immunohistochemistry revealed in vivo up-regulation of opioid growth factor receptor protein on tumor and on infiltrating cells after treatment. By using basal cell carcinoma cell lines treated with IFN-α or imiquimod, we show that opioid growth factor receptor up-regulation is IFN-α-mediated, rather then directly imiquimod-mediated. By using tissue microarray containing 52 basal cell carcinomas, we demonstrate opioid growth factor receptor expression in almost half of the cases. Expression of opioid growth factor receptor correlated with a longer recurrence-free period in basal cell carcinoma that recurred after radiotherapy (Kaplan-Meier analysis, P = 0.041).Conclusions: In addition to its immunomodulatory and antiproliferative activity, opioid growth factor receptor seems to have a prognostic significance in basal cell carcinoma patients. Our data add to the growing list of basal cell carcinoma-associated tumor antigens.
Expression of ΔNp73 Predicts Poor Prognosis in Lung Cancer
Authors: Uramoto Hidetaka , Sugio Kenji , Oyama Tsunehiro , Nakata Shoji , Ono Kenji , Morita Masaru , Funa Keiko , Yasumoto Kosei 
Published: September 2005

Abstract
Purpose: ΔNp73 is an isoform of the p53 homologue p73, which lacks an NH2-terminal transactivation domain and antagonizes the induction of gene expression by p53/p73. The aim of this study was to detect ΔNp73 expression in lung cancer and to evaluate the relationship between the ΔNp73 expression level and the prognosis of patients with resected lung cancer.
Experimental Design: We used immunohistochemistry to analyze the protein expression of ΔNp73 in paraffin-embedded tumor samples from 132 well-characterized lung cancer patients and compared the expression level of ΔNp73, clinical variables, and survival outcome.
Results: Positive expression of ΔNp73 was detected mainly in the cytoplasm of tumor cells in 77 of 132 patients (58.3%) with lung cancer. The incidence of positive expression of ΔNp73 was 52.2, 50.0, and 70.2% in patients with stage I, II, and III, respectively (P = 0.04). Positive expression of ΔNp73 was associated with gender but not associated with age, histologic type, pathological stage, pathological T status, and pathological N status. Lung cancer patients with positive ΔNp73 expression had a poorer prognosis than those with negative ΔNp73 expression. In addition, multivariate analysis of the clinicopathological characteristics of lung cancer indicated that positive expression of ΔNp73 was a significant independent factor for predicting poor prognosis (P &lt; 0.0001, risk ratio = 3.39).
Conclusions: Expression of ΔNp73 may be a useful marker for predicting poor prognosis of patients who underwent resection of lung cancer.
Characterization of a Folate Transporter in HeLa Cells with a Low pH Optimum and High Affinity for Pemetrexed Distinct from the Reduced Folate Carrier
Authors: Wang Yanhua , Zhao Rongbao , Goldman I. David 
Published: September 2005

Abstract
Studies were undertaken to characterize a low pH transport activity in a reduced folate carrier (RFC)-null HeLa-derived cell line (R5). This transport activity has a 20-fold higher affinity for pemetrexed (PMX; Kt, ∼45 nmol/L) than methotrexate (MTX; Kt, ∼1 μmol/L) with comparable Vmax values. The Ki values for folic acid, ZD9331, and ZD1694 were ∼ 400–600 nmol/L, and the Ki values for PT523, PT632, and trimetrexate were &gt;50 μmol/L. The transporter is stereospecific and has a 7-fold higher affinity for the 6S isomer than the 6R isomer of 5-formyltetrahydrofolate but a 4-fold higher affinity for the 6R isomer than the 6S isomer of dideazatetrahydrofolic acid. Properties of RFC-independent transport were compared with transport mediated by RFC at low pH using HepG2 cells, with minimal constitutive low pH transport activity, transfected to high levels of RFC. MTX influx Kt was comparable at pH 7.4 and pH 5.5 (1.7 versus 3.8 μmol/L), but Vmax was decreased 4.5-fold. There was no difference in the Kt for PMX (∼1.2 μmol/L) or the Ki for folic acid (∼130 μmol/L) or PT523 (∼ 0.2 μmol/L) at pH 7.4 and pH 5.5. MTX influx in R5 and HepG2 transfectants at pH 5.5 was trans-stimulated in cells loaded with 5-formyltetrahydrofolate, inhibited by Cl− (HepG2-B &gt; R5), Na+ independent, and uninhibited by energy depletion. Hence, RFC-independent low pH transport activity in HeLa R5 cells is consistent with a carrier-mediated process with high affinity for PMX. Potential alterations in protonation of RFC or the folate molecule as a function of pH do not result in changes in affinity constants for antifolates. Whereas both activities at low pH have similarities, they can be distinguished by folic acid and PT523, agents for which they have very different structural specificities.
Effect of Rapamycin Alone and in Combination with Antiangiogenesis Therapy in an Orthotopic Model of Human Pancreatic Cancer
Authors: Stephan Susann , Datta Kaustubh , Wang Enfeng , Li Jinping , Brekken Rolf A. , Parangi Sareh , Thorpe Philip E. , Mukhopadhyay Debabrata 
Published: September 2005

Abstract
Purpose: The overall 5-year survival of patients with pancreatic cancer remains &lt;5%. Novel therapeutic strategies are needed. We examined the effect of rapamycin, alone and in combination with antiangiogenesis therapy, on pancreatic cancer in vivo.
Experimental Design: Human pancreatic cancer AsPC-1 cells were orthotopically injected into severe combined immunodeficient/beige mice to evaluate primary tumor growth and liver metastasis after treatment with rapamycin alone or in combination with anti-vascular endothelial growth factor antibody 2C3. Tumor cell proliferation was determined by bromodeoxyuridine incorporation. To detect tumor cell apoptosis, the terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling assay was used. Tumor angiogenesis was investigated by using a monoclonal anti-CD31 antibody. All statistical tests were two-sided.
Results: Rapamycin, alone and in combination with 2C3, strongly inhibited primary and metastatic tumor growth in an orthotopic pancreatic cancer animal model. Furthermore, the combination therapy significantly improved the effect on liver metastasis compared with single treatment with either rapamycin (P = 0.0128) or 2C3 (P = 0.0099). Rapamycin alone inhibited pancreatic tumor cell proliferation, induced apoptosis, and decreased tumor angiogenesis. Nevertheless, the combination therapy showed a significant, stronger inhibition of tumor cell proliferation (P = 0.0002 versus rapamycin alone and P &lt; 0.0001 versus 2C3 alone). The induction of apoptosis was significantly higher than in the rapamycin-treated group (P = 0.0039). Additionally, the combination therapy further improved suppression of tumor cell angiogenesis compared with rapamycin treatment (P = 0.029)
Conclusions: Our studies propose new therapeutic strategies to inhibit both primary and metastatic tumor growth in pancreatic cancer. Considering the fact that liver metastasis is a crucial problem in advanced stages of pancreatic cancer, the combination therapy of rapamycin plus anti-vascular endothelial growth factor antibody 2C3 is a significant advantage compared with single treatment with rapamycin.
NY-ESO-1 Expression and Immunogenicity in Esophageal Cancer
Authors: Fujita Shoichiro , Wada Hisashi , Jungbluth Achim A. , Sato Shuichiro , Nakata Tetsuya , Noguchi Yuji , Doki Yuichiro , Yasui Masayoshi , Sugita Yurika , Yasuda Takushi , Yano Masahiko , Ono Toshiro , Chen Yao-Tseng , Higashiyama Masahiko , Gnjatic Sacha , Old Lloyd J. , Nakayama Eiichi , Monden Morito 
Published: September 2005

Abstract
Purpose: Although NY-ESO-1 was isolated from an esophageal carcinoma patient, its expression in this type of cancer and its immunogenicity in esophageal cancer patients have not yet been fully elucidated. We report here the frequency of NY-ESO-1 mRNA and protein expression in esophageal cancer and the presence of NY-ESO-1-specific immune response in patients.
Experimental Design: One hundred twenty three esophageal squamous cell carcinoma specimens were analyzed for the expression of NY-ESO-1 mRNA by conventional and real-time reverse transcription-PCR and the expression of protein by immunohistochemistry and Western blot. Sera and peripheral blood lymphocytes from 51 patients were analyzed for the NY-ESO-1 antibody production by enzyme-linked immunosorbent assay and NY-ESO-1 T cell response by enzyme-linked immunospot assay. Survival analyses were also performed.
Results: NY-ESO-1 mRNA was expressed in 41 of 123 (33%) esophageal squamous cell carcinoma specimens, and its expression was found at higher frequency in well-differentiated and moderately differentiated type of cancer. No mRNA copy was detected in any of the adjacent normal tissues. Twenty-one of 24 (87.5%) NY-ESO-1 mRNA-positive tumors were stained positively by immunohistochemistry. Correlation between the level of NY-ESO-1 mRNA expression and the degree of immunohistochemistry positivity was observed. Antibody production was observed in 2 patients with tumors that showed protein expression. Furthermore, a CD8 T-cell response against NY-ESO-1 was observed in 1 of the 2 seropositive patients.
Conclusions: The high expression frequency of NY-ESO-1 mRNA and protein indicates NY-ESO-1 as a feasible vaccine target in esophageal cancer.
Cellular Uptake and Intracellular Levels of the Bcl-2 Antisense G3139 in Cultured Cells and Treated Patients with Acute Myeloid Leukemia
Authors: Dai Guowei , Chan Kenneth K. , Liu Shujun , Hoyt Dale , Whitman Susan , Klisovic Marko , Shen TianSheng , Caligiuri Michael A. , Byrd John , Grever Michael , Marcucci Guido 
Published: September 2005

Abstract
Purpose: Down-regulation of Bcl-2 by the antisense G3139, currently under clinical evaluations, could restore chemosensitivity in otherwise resistant malignant cells. To date, the mechanism of intracellular accumulation of G3139 following in vivo administration remains to be elucidated. This study aimed to assess whether detectable intracellular concentrations of G3139 are achievable in vivo and how these relate to Bcl-2 down-regulation.
Experimental Design: Cellular uptake of G3139 was studied in leukemia myeloid cell lines and blasts collected from treated patients using a newly developed, novel, and highly sensitive ELISA-based assay. Real-time reverse transcription-PCR was used to quantify Bcl-2 mRNA changes in treated cells.
Results: The assay was fully validated and showed a limit of quantification of 50 pmol/L. When exposed to 0.33 to 10 μmol/L G3139, K562 cells exhibited intracellular concentrations in the range of 2.1 to 11.4 pmol/mg protein. When G3139 was delivered with cationic lipids, a 10- to 25-fold increase of the intracellular concentrations was observed. There was an accumulation of G3139 in the nuclei, and the ratio of nucleus to cytoplasm was increased 7-fold by cationic lipids. Intracellular concentrations of G3139 were correlated with Bcl-2 mRNA down-regulation. Robust intracellular concentrations of G3139 were achieved in vivo in bone marrow (range, 3.4-40.6 pmol/mg protein) and peripheral blood mononuclear cells (range, 0.47-19.4 pmol/mg protein) from acute myeloid leukemia patients treated with G3139.
Conclusions: This is the first evidence that measurable intracellular levels of G3139 are achievable in vivo in acute myeloid leukemia patients and that Bcl-2 down-regulation is likely to depend on the achievable intracellular concentrations rather than on plasma concentrations.
MEN4901/T-0128, a New Camptothecin Derivative–Carboxymethyldextran Conjugate, Has Potent Antitumor Activities in a Panel of Human Tumor Xenografts in Nude Mice
Authors: Fujita Fumiko , Koike Masako , Fujita Masahide , Sakamoto Yasuo , Okuno Satoshi , Kawaguchi Takayuki , Yano Shigeru , Yano Toshiro , Kiuchi Satoko , Fujiwara Toshihisa , Kudoh Shinzoh , Kakushima Masatoshi 
Published: September 2005

Abstract
Purpose: The purpose of the present study was to evaluate the antitumor activity and pharmacokinetic profile of MEN4901/T-0128 in nude mice bearing human tumor xenografts in comparison with irinotecan (CPT-11) and T-2513.
Experimental Design: We have determined the antitumor activity of MEN4901/T-0128, CPT-11, and T-2513 in BALB/cA Jcl nude mice bearing human gastric (H-81), colon (H-110), lung (Mqnu-1, H-74), esophageal (H-204), liver (H-181), and pancreatic (H-48) cancer lines, which had been serially transplanted s.c. and maintained in nude mice, and characterized the pharmacokinetic profile of MEN4901/T-0128 in nude mice bearing human gastric carcinoma St-4.
Results: MEN4901/T-0128 administered i.v. showed a marked antitumor activity in each of these tumor models, producing tumor shrinkage in the models of H-204 and H-181 carcinomas at its maximum tolerated dose of 80 mg/kg (expressed as T-2513) weekly for 4 weeks (q7d × 4) and tumor-shrinking or marked growth-inhibitory effects in the models of H-81, H-110, Mqnu-1, H-74, and H-48 carcinomas at 1/3 of its maximum tolerated dose (q7d × 4). Pharmacokinetic analysis showed that MEN4901/T-0128 had an extended plasma half-life with sustained tumor levels of T-2513, which may explain the superior activity of MEN4901/T-0128 in vivo.
Conclusions: Because the efficacies of some drugs in this human cancer-nude mouse panel correlated well with their clinical outcomes in patients with the same type of cancers, the findings provide direct support that MEN4901/T-0128 is more efficacious than CPT-11 and is an excellent candidate for clinical trials for the treatment of solid tumors.
A Phase II, Pharmacokinetic, and Biological Correlative Study of Oblimersen Sodium and Docetaxel in Patients with Hormone-Refractory Prostate Cancer
Authors: Tolcher Anthony W. , Chi Kim , Kuhn John , Gleave Martin , Patnaik Amita , Takimoto Chris , Schwartz Garry , Thompson Ian , Berg Kristin , D'Aloisio Susan , Murray Nevin , Frankel Stanley R. , Izbicka Elzbieta , Rowinsky Eric 
Published: September 2005

Abstract
Purpose: To determine the antitumor activity and safety of oblimersen sodium, a phosphorothioate antisense oligonucleotide directed to the bcl-2 mRNA, with docetaxel in patients with hormone-refractory prostate cancer (HRPC) and to determine if relevant pharmacokinetic and pharmacodynamic variables of oblimersen or docetaxel influence response to this therapy.
Experimental Design: Patients with HRPC were treated with oblimersen sodium by continuous i.v. infusion on days 1 to 8 with docetaxel given i.v. over 1 hour on day 6 every 3 weeks. Plasma samples were analyzed to characterize the pharmacokinetic variables of both oblimersen and docetaxel, and paired collections of peripheral blood mononuclear cells were collected to determine Bcl-2 protein expression pretreatment and post-treatment.
Results: Twenty-eight patients received 173 courses of oblimersen (7 mg/kg/d continuous i.v. infusion on days 1-8) and docetaxel (75 mg/m2 i.v. on day 6). Prostate-specific antigen responses were observed in 14 of 27 (52%) patients, whereas 4 of 12 (33%) patients with bidimensionally measurable disease had objective responses. The mean oblimersen steady-state concentration (Css) was a significant determinant of antitumor activity; mean Css values were higher in responders compared with nonresponders (6.24 ± 1.68 versus 4.27 ± 1.22; P = 0.008). The median survival of all patients was 19.8 months. Bcl-2 protein expression decreased a median of 49.9% in peripheral blood mononuclear cells post-treatment, but the individual incremental change did not correlate with either oblimersen Css or response.
Conclusions: Oblimersen combined with docetaxel is an active combination in HRPC patients demonstrating both an encouraging response rate and an overall median survival. The absence of severe toxicities at this recommended dose, evidence of Bcl-2 protein inhibition, and encouraging antitumor activity in HPRC patients warrant further clinical evaluation of this combination, including studies to optimize oblimersen Css.