bluuebunny/crossref_metadata_2025_split huggingface dataset:
Association of NCOA3 Polymorphisms with Breast Cancer Risk
Authors: Burwinkel Barbara , Wirtenberger Michael , Klaes Rüdiger , Schmutzler Rita K. , Grzybowska Ewa , Försti Asta , Frank Bernd , Bermejo Justo Lorenzo , Bugert Peter , Wappenschmidt Barbara , Butkiewicz Dorota , Pamula Jolanta , Pekala Wioletta , Zientek Helena , Mielzynska Danuta , Siwinska Ewa , Bartram Claus R. , Hemminki Kari 
Published: September 2005

Abstract
The nuclear receptor coactivator 3 (NCOA3, also known as AIB1) is a coactivator of nuclear receptors like the estrogen receptor. NCOA3 is overexpressed in ∼60% of primary human breast tumors, and high levels of NCOA3 expression are associated with tamoxifen resistance and worse survival rate. In contrast, NCOA3 deficiency suppresses v-Ha-ras–induced breast cancer initiation and progression in mice. Here, we analyzed the influence of NCOA3 coding single nucleotide polymorphisms on breast cancer risk by performing a case-control study using a German and a Polish study population and identified an association between NCOA3 polymorphisms and breast cancer. A joint analysis of the German and the Polish study population revealed a significant protective effect for the 1758G&gt;C (Q586H) and 2880A&gt;G (T960T) variants. In addition, haplotype analysis showed a protective effect of the 1758C-2880A and 1758G-2880G haplotypes (odds ratio 0.79; 95% confidence interval, 0.67-0.93; P = 0.004). Because of the impact of NCOA3 in antiestrogen therapy resistance, these polymorphisms might also influence therapy outcome in breast cancer.
B7-H4 Is Highly Expressed in Ductal and Lobular Breast Cancer
Authors: Tringler Barbara , Zhuo Shaoqiu , Pilkington Glenn , Torkko Kathleen C. , Singh Meenakshi , Lucia M. Scott , Heinz David E. , Papkoff Jackie , Shroyer Kenneth R. 
Published: September 2005

AbstractPurpose: This study was designed to investigate the expression of B7-H4 protein, a member of the B7 family that is involved in the regulation of antigen-specific immune responses, in normal breast and in primary and metastatic breast carcinomas.Experimental Design: Archival formalin-fixed tissue blocks from breast cancers and normal somatic tissues were evaluated for B7-H4 expression by immunohistochemistry with manual and automated image analysis. The proportion of B7-H4-positive cells and the intensity of B7-H4 staining were compared with histologic type, grade, stage, hormone receptor status, and HER-2/neu status.Results: B7-H4 was detected in 165 of 173 (95.4%) primary breast cancers and in 240 of 246 (97.6%) metastatic breast cancers. B7-H4 staining intensity was greater in invasive ductal carcinomas [24.61 relative units (RU)] and in invasive lobular carcinomas (15.23 RU) than in normal breast epithelium (4.30 RU, P = 0.0003). Increased staining intensity was associated with negative progesterone receptor status (P = 0.014) and history of neoadjuvant chemotherapy (P = 0.004), and the proportion of B7-H4-positive cells was associated with negative progesterone receptor (P = 0.001) and negative HER-2/neu (P = 0.024) status. However, there was no statistically significant relationship between the proportion of B7-H4-positive cells or staining intensity and grade, stage, or other clinicopathologic variables. Low levels of B7-H4 expression were also detected in epithelial cells of the female genital tract, lung, pancreas, and kidney, but B7-H4 was generally absent in most other normal somatic tissues.Conclusions: The nearly ubiquitous expression of B7-H4 in breast cancer, independent of tumor grade or stage, suggests a critical role for this protein in breast cancer biology.
Shc Family Expression in Neuroblastoma: High Expression of shcC Is Associated with a Poor Prognosis in Advanced Neuroblastoma
Authors: Terui Elena , Matsunaga Tadashi , Yoshida Hideo , Kouchi Katsunori , Kuroda Hiroaki , Hishiki Tomoro , Saito Takeshi , Yamada Shin-ichi , Shirasawa Hiroshi , Ohnuma Naomi 
Published: September 2005

Abstract
The biological features and prognosis of neuroblastoma, a neural crest-derived pediatric tumor, are closely associated with expression of the Trk receptor. Because the Shc family proteins (ShcA, ShcB, and ShcC) are adaptors for various receptors, including Trk receptors, and are regulators of neuronal cell development, we speculated that they may play a role in neuroblastoma. Therefore, in this study, we used semiquantitative reverse transcription-PCR to examine the expression of these three genes in 15 neuroblastoma cell lines, an all-trans-retinoic acid–treated neuroblastoma cell line, and 52 tumor samples. In neuroblastoma cell lines and tumor samples, shcA was ubiquitously and highly expressed. Little expression of shcA was observed. Also, shcB was hardly expressed in neuroblastoma cell lines, but its expression in RT-BM-1 cells was enhanced after all-trans-retinoic acid–induced differentiation, and it was highly expressed in low-stage tumors (P = 0.0095). This suggests that ShcB participates in cellular differentiation and may correlate with a favorable prognosis in neuroblastoma. Finally, the expression of shcC was observed in most of the neuroblastoma cell lines and in some stage 4 patients. Patients with a high expression of shcC had a very poor prognosis (P &lt; 0.0001) and amplification of MYCN, and all died within 31 months after diagnosis. Therefore, ShcC seems to be associated with an aggressive tumor phenotype, perhaps by enhancing TrkB signals. Our results suggest that the expressions of shcB and shcC are important biological factors in neuroblastoma and are useful prognostic indicators.
Cleavage of L1 in Exosomes and Apoptotic Membrane Vesicles Released from Ovarian Carcinoma Cells
Authors: Gutwein Paul , Stoeck Alexander , Riedle Svenja , Gast Daniela , Runz Steffen , Condon Thomas P. , Marmé Alexander , Phong Minh-Chau , Linderkamp Otwin , Skorokhod Alexander , Altevogt Peter 
Published: September 2005

Abstract
Purpose: The L1 adhesion molecule (CD171) is overexpressed in human ovarian and endometrial carcinomas and is associated with bad prognosis. Although expressed as a transmembrane molecule, L1 is released from carcinoma cells in a soluble form. Soluble L1 is present in serum and ascites of ovarian carcinoma patients. We investigated the mode of L1 cleavage and the function of soluble L1.
Experimental Design: We used ovarian carcinoma cell lines and ascites from ovarian carcinoma patients to analyze soluble L1 and L1 cleavage by Western blot analysis and ELISA.
Results: We find that in ovarian carcinoma cells the constitutive cleavage of L1 proceeds in secretory vesicles. We show that apoptotic stimuli like C2-ceramide, staurosporine, UV irradiation, and hypoxic conditions enhance L1-vesicle release resulting in elevated levels of soluble L1. Constitutive cleavage of L1 is mediated by a disintegrin and metalloproteinase 10, but under apoptotic conditions multiple metalloproteinases are involved. L1 cleavage occurs in two types of vesicles with distinct density features: constitutively released vesicles with similarity to exosomes and apoptotic vesicles. Both types of L1-containing vesicles are present in the ascites fluids of ovarian carcinoma patients. Soluble L1 from ascites is a potent inducer of cell migration and can trigger extracellular signal-regulated kinase phosphorylation.
Conclusions: We suggest that tumor-derived vesicles may be an important source for soluble L1 that could regulate tumor cell function in an autocrine/paracrine fashion.
Effects of Nonselective Cyclooxygenase Inhibition with Low-Dose Ibuprofen on Tumor Growth, Angiogenesis, Metastasis, and Survival in a Mouse Model of Colorectal Cancer
Authors: Yao Min , Zhou Wei , Sangha Simren , Albert Andrew , Chang Albert J. , Liu Thomas C. , Wolfe M. Michael 
Published: September 2005

Abstract
Purpose: To determine whether the nonselective and relatively inexpensive nonsteroidal anti-inflammatory drug ibuprofen would be effective in inhibiting colorectal cancer and might improve mortality in a mouse model.
Experimental Design: The effects of ibuprofen on tumor growth inhibition and animal survival have been examined in both mouse and human colorectal cancer tumor models. Angiogenesis was measured by in vitro endothelial cell tube formation and immunohistochemistry.
Results: Ibuprofen significantly inhibited cell proliferation in mouse (MC-26) and human (HT-29) colorectal cancer cell lines. In vitro angiogenesis assays also indicated that ibuprofen decreased both cell proliferation and tube formation. The administration of chow containing 1,360 ppm ibuprofen, which achieved an average plasma concentration of ibuprofen lower than the peak level achieved in humans at therapeutic doses, inhibited tumor growth by 40% to 82%. Fewer liver metastases were found in the ibuprofen group compared with the control group. In combination therapy with the standard antineoplastic agents, 5-fluorouracil, or irinotecan (CPT-11), tumor volumes in the groups with ibuprofen ± CPT-11 or 5-fluorouracil were smaller than in the control group. Ibuprofen was similar to the cyclooxygenase-2 selective inhibitor rofecoxib in its ability to suppress tumor growth and improve overall survival.
Conclusions: Ibuprofen, in part by modulating tumor angiogenesis, decreases both tumor growth and metastatic potential in mice. The ibuprofen doses were in the low range of therapeutic human plasma concentrations. Ibuprofen potentiates the antitumor properties of CPT-11 and improves survival of mice without increasing gastrointestinal toxicity.
Blockade of Paracrine Supply of Insulin-Like Growth Factors Using Neutralizing Antibodies Suppresses the Liver Metastasis of Human Colorectal Cancers
Authors: Miyamoto Shin'ichi , Nakamura Michio , Shitara Kenya , Nakamura Kazuyasu , Ohki Yuji , Ishii Genichiro , Goya Masato , Kodama Keiji , Sangai Takafumi , Maeda Hiroyuki , Shi-chuang Zhang , Chiba Tsutomu , Ochiai Atsushi 
Published: September 2005

Abstract
Environmental stimuli, such as organ-specific growth factors, can influence the metastatic potential of a tumor. The liver is the main source of insulin-like growth factors (IGFs). The importance of IGF signal in hepatic metastasis has been clarified mainly by IGF-I receptor targeting strategies. This study aims to confirm these precedent reports by novel tool, neutralizing antibodies against IGFs and to show that IGFs are promising therapeutic targets for hepatic metastasis in vivo. Hepatic metastasis was induced by intrasplenic injection of human colorectal cancer cell line, HT29. The antimetastatic effects of three antibodies (anti-mouse IGF-I, anti-mouse IGF-II, and anti-human/mouse IGF-II designated KM1468) were tested singly or in combination in the early phase of metastasis. The dose escalation effect of KM1468 and its survival benefit were examined in the early and late phases of metastasis. The mechanism of IGF neutralization was investigated with immunohistochemistry. Dual neutralization of paracrine IGF-I and IGF-II showed modest additive antimetastatic effects than single neutralization of IGF-I or IGF-II. In any phase of metastasis, neutralization led to significant tumor growth inhibition and longer survival. Dose escalation of KM1468 influenced survival only in the late phase of metastasis. Apoptosis increased significantly in the antibody-treated group compared with the control group (P = 0.0025) In conclusion, IGFs are promising therapeutic targets for hepatic metastases of colorectal cancers. However, the IGF dependency is probably variable in the metastatic process.
Prognostic Role of a Multigene Reverse Transcriptase-PCR Assay in Patients with Node-Negative Breast Cancer Not Receiving Adjuvant Systemic Therapy
Authors: Esteva Francisco J. , Sahin Aysegul A. , Cristofanilli Massimo , Coombes Kevin , Lee Sang-Joon , Baker Joffre , Cronin Maureen , Walker Michael , Watson Drew , Shak Steven , Hortobagyi Gabriel N. 
Published: September 2005

Abstract
Purpose: To test the ability of a reverse transcriptase-PCR (RT-PCR) assay, based on gene expression profiles, to accurately determine the risk of recurrence in patients with node-negative breast cancer who did not receive systemic therapy using formalin-fixed, paraffin-embedded tissue. A secondary objective was to determine whether the quantitative RT-PCR data correlated with immunohistochemistry assay data regarding estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 status.
Patients and Methods: We obtained archival paraffin-embedded tissue from patients with invasive breast cancer but no axillary lymph node involvement who had received no adjuvant systemic therapy and been followed for at least 5 years. RNA was extracted from three 10-μm-thick sections. The expression of 16 cancer-related genes and 5 reference genes was quantified using RT-PCR. A gene expression algorithm was used to calculate a recurrence score for each patient. We then assessed the ability of the test to accurately predict distant recurrence-free survival in this population.
Results: We identified 149 eligible patients. Median age at diagnosis was 59 years; mean tumor diameter was 2 cm; and 69% of tumors were estrogen receptor positive. Median follow-up was 18 years. The 5-year disease-free survival rate for the group was 80%. The 21 gene-based recurrence score was not predictive of distant disease recurrence. However, a high concordance between RT-PCR and immunohistochemical assays for estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 status was noted.
Conclusions: RT-PCR can be done on paraffin-embedded tissue to validate the large numbers of genes associated with breast cancer recurrence. However, further work needs to be done to develop an assay to identify the likelihood of recurrent disease in patients with node-negative breast cancer who do not receive adjuvant tamoxifen or chemotherapy.
Phase II Trial of Karenitecin in Patients with Malignant Melanoma: Clinical and Translational Study
Authors: Daud Adil , Valkov Nikola , Centeno Barbara , Derderian Jennifer , Sullivan Patricia , Munster Pamela , Urbas Patricia , DeConti Ronald C. , Berghorn Elmer , Liu Zhenmei , Hausheer Frederick , Sullivan Daniel 
Published: September 2005

Abstract
Purpose: A phase II trial of the novel camptothecin karenitecin (BNP1350) was conducted to determine its efficacy and tolerability in patients with metastatic melanoma. Patients were biopsied to determine topoisomerase expression at baseline and response to therapy.
Patients and Methods: Eligible patients had metastatic melanoma with up to three prior chemotherapy and/or any number of immunotherapy regimens. Treatment consisted of an i.v. infusion of 1 mg/m2 karenitecin daily for 5 days with cycles repeated every 3 weeks. Fine-needle aspiration biopsies were done before treatment and on day 3 to determine topoisomerase expression from patients' tumors.
Results: Forty-three patients were evaluable for response and toxicity. Most patients (72%) had stage M1C disease and were previously exposed to chemotherapy (56%). The investigational agent was well tolerated with limited gastrointestinal side effects or fatigue. The major toxicity seen was reversible noncumulative myelosuppression. One patient had a complete response after 11 months of therapy. No partial responses were seen, but 33% of the patients had disease stabilization lasting ≥3 months. Topoisomerase I, IIα, and IIβ expression and localization were determined in a subset of patients. Topoisomerase I expression was highest, followed by topoisomerase IIβ and topoisomerase IIα.
Conclusion: Karenitecin was a well-tolerated investigational agent in this phase II study; side effects were generally mild and mostly hematologic. Karenitecin has significant activity in metastatic melanoma. Melanoma metastases express high levels of topoisomerase I. We did not observe any compensatory increase in topoisomerase II upon treatment with karenitecin.
Phase II Evaluation of Docetaxel-Modulated Capecitabine in Previously Treated Patients with Non–Small Cell Lung Cancer
Authors: Kindwall-Keller Tamila , Otterson Gregory A. , Young Donn , Neki Anterpreet , Criswell Tamara , Nuovo Gerard , Soong Richie , Diasio Robert , Villalona-Calero Miguel A. 
Published: September 2005

Abstract
Purpose: Based on the preclinical observation of upregulation of thymidine phosphorylase, the last enzymatic step in the conversion of capecitabine to 5-fluorouracil, by docetaxel along with good clinical tolerability of the combination of docetaxel and capecitabine using an optimized schedule in a previous phase I trial, we conducted this phase II study of this combination in patients with refractory or relapsed non–small cell lung cancer (NSCLC).
Patients and Methods: Patients with NSCLC previously treated with at least one platinum- or paclitaxel-based regimen received docetaxel 36 mg/m2 on days 1, 8, and 15 and capecitabine 625 mg/m2 twice daily on days 5 to 18, every 4 weeks. The primary objective of the study was evaluation of progression-free survival (PFS) 26 weeks from initiation of treatment.
Results: Thirty-six evaluable patients received 104 cycles of the combination. Severe toxicities were infrequent with only one patient requiring toxicity-related hospitalization. The 26-week PFS rate was 25% (95% confidence interval, 12-42) with an intent to treat median survival and 1-year survival rate of 9.1 months and 37%, respectively. Among 31 patients with measurable disease (Response Evaluation Criteria in Solid Tumors criteria), eight (26%; 95% confidence interval, 12-45) achieved partial responses.
Conclusion: The combination of capecitabine and weekly docetaxel is well tolerated in previously treated patients with NSCLC. The relatively high 26-week PFS and 1-year survival, as well as the high response rate observed, encourages further evaluation of this regimen in NSCLC, either in randomized trials for refractory patients or as a potential treatment option for chemotherapy naive patients.
Biallelic Deletions in INK4 in Cutaneous Melanoma Are Common and Associated with Decreased Survival
Authors: Grafström Eva , Egyházi Suzanne , Ringborg Ulrik , Hansson Johan , Platz Anton 
Published: September 2005

Abstract
Purpose: Both the retinoblastoma and p53 pathways are often genetically altered in human cancers and their complex regulation is in part mediated by the three gene products p16, p14ARF, and p15 of the INK4 locus on chromosome 9p21. Partial or complete biallelic deletions of the INK4 locus have been recognized in a variety of malignant tumors, including malignant melanoma. We have in the present study measured the frequency of INK4 deletions in a large number of melanoma metastases and determined their association with clinicopathologic variables and survival data.
Experimental Design: Quantitative real-time PCR, as well as fluorescence-based fragment analysis, has been used to perform measurements of the relative allelic concentrations of the INK4 genes in 112 human melanoma tumor samples from 86 patients.
Results: Thirty-eight of 86 melanoma patients (44%) had metastases with biallelic losses in INK4. Ten of 20 patients with multiple metastases showed similar deletion patterns in all analyzed tumors. There was no significant association between any of the clinicopathologic variables and loss of INK4. However, loss of INK4 had an adverse effect on median survival from time of diagnosis. Patients with tumors with diploid INK4 had a median survival of 142 months, whereas those with monoallelic or biallelic loss in INK4 had a median survival of only 47 months (P = 0.006).
Conclusions: Our results point to homozygous deletions in the INK4 region as being one of the most common genetic alterations in malignant cutaneous melanoma. INK4 deletions are associated with an adverse prognosis.
Phase I Pharmacokinetic, Food Effect, and Pharmacogenetic Study of Oral Irinotecan Given as Semisolid Matrix Capsules in Patients with Solid Tumors
Authors: Soepenberg Otto , Dumez Herlinde , Verweij Jaap , de Jong Floris A. , de Jonge Maja J.A. , Thomas José , Eskens Ferry A.L.M. , van Schaik Ron H.N. , Selleslach Johan , ter Steeg Judith , Lefebvre Patricia , Assadourian Sylvie , Sanderink Ger-Jan , Sparreboom Alex , van Oosterom Allan T. 
Published: September 2005

Abstract
Purpose: To characterize the maximum-tolerated dose, recommended dose, dose-limiting toxicities (DLT), pharmacokinetic profile, and food effect of orally administered irinotecan formulated as new semisolid matrix capsules.
Experimental Design: Irinotecan was given orally in fasted patients once daily for 5 consecutive days and repeated every 3 weeks. Patients were randomly assigned to take the drug along with a high-fat, high-calorie breakfast for the administration at day 1 of the first or second cycle. Dosages tested were 70 and 80 mg/m2/day.
Results: Twenty-five patients received 101 cycles of therapy (median two cycles, range 1-15). During the first cycle, grade 3 delayed diarrhea and grade 3 fever were the DLTs at the dosage of 80 mg/m2/day in three out of five patients. Hematologic and nonhematologic toxicities were mild to moderate. Exposure to the active metabolite SN-38 was relatively high compared with i.v. infusion, but no relevant accumulation was observed. Food had no significant effect on irinotecan pharmacokinetics. One confirmed partial remission and 10 disease stabilizations were observed in previously treated patients. No association was found between the UGT1A1*28 genotype and the risk of severe irinotecan-induced toxicity.
Conclusions: For oral irinotecan, a dose of 70 mg/m2/day for 5 consecutive days every 3 weeks is recommended for further studies. Delayed diarrhea was the main DLT, similar to that observed with intravenously administered irinotecan. This study confirms that oral administration of irinotecan is feasible and may have favorable pharmacokinetic characteristics.
Pilot Study of Concurrent Etoposide and Cisplatin Plus Accelerated Hyperfractionated Thoracic Radiotherapy Followed by Irinotecan and Cisplatin for Limited-Stage Small Cell Lung Cancer: Japan Clinical Oncology Group 9903
Authors: Kubota Kaoru , Nishiwaki Yutaka , Sugiura Takahiko , Noda Kazumasa , Mori Kiyoshi , Kawahara Masaaki , Negoro Shunichi , Watanabe Koshiro , Imamura Fumio , Tamura Tomohide , Saijo Nagahiro 
Published: September 2005

Abstract
Purpose: Irinotecan and cisplatin (IP) significantly improved survival compared with etoposide and cisplatin (EP), in patients with extensive-stage small cell lung cancer (SCLC) in a previous Japan Clinical Oncology Group (JCOG) randomized trial. JCOG9903 was conducted to evaluate the safety of sequentially given IP following concurrent EP plus twice-daily thoracic irradiation (TRT) for the treatment of limited-stage SCLC (LSCLC).
Experimental Design: Between October 1999 and July 2000, 31 patients were accrued from 10 institutions. Thirty patients were assessable for toxicity, response, and survival. Treatment consisted of etoposide 100 mg/m2 on days 1 to 3, cisplatin 80 mg/m2 on day 1, and concurrent twice-daily TRT of 45 Gy beginning on day 2. The IP regimen started on day 29 and consisted of irinotecan 60 mg/m2 on days 1, 8, and 15 and cisplatin 60 mg/m2 on day 1, with three 28-day cycles.
Results: There were no treatment-related deaths. The response rate was 97% (complete response, 37%; partial response, 60%). Median overall survival was 20.2 months; 1-, 2-, and 3-year survival rates were 76%, 41%, and 38%, respectively. Of the 24 patients who started the IP regimen, 22 received two or more cycles. Hematologic toxicities of grade 3 or 4 included neutropenia (67%), anemia (50%), and thrombocytopenia (4%). Nonhematologic toxicities of grade 3 or 4 included diarrhea (8%), vomiting (8%), and febrile neutropenia (8%). Of the 20 patients with recurrence, none had local recurrence alone and only two had both local and distant metastasis as the initial sites of disease progression.
Conclusions: IP following concurrent EP plus twice-daily TRT is safe with acceptable toxicities. A randomized phase III trial comparing EP with IP following EP plus concurrent TRT for LSCLC is ongoing (JCOG0202).