bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Effects of Taurolidine, a Novel Antineoplastic Agent, on Human Malignant Mesothelioma
Authors: Nici Linda , Monfils Barbara , Calabresi Paul 
Published: September 2005

Abstract
Purpose: Malignant mesothelioma (MM) is a cancer with uniformly poor responses to current therapeutic regimens. This study evaluates whether taurolidine, a novel antineoplastic agent, is effective against human MM cell lines and a murine model of human MM.
Experimental Design: Cell growth inhibition and viability assays were performed on REN, LRK, and H28 cell lines after 24–72-h exposure to 0–200 μm taurolidine. Cell cycle analysis with annexin-V binding, terminal deoxynucleotidyl transferase-mediated nick end labeling assay, electron microscopy, and response to the general caspase inhibitor z-VAD-fmk were performed on MM cell lines after 24–72-h exposure to 50–150 μm taurolidine. Athymic mice were given i.p. injections of 20 × 106 REN cells, followed by i.p. taurolidine (17.5 or 20 mg), 3 days/week for up to 3 weeks. Tumors were assessed at day 30. All statistical tests were two-sided.
Results: A 72-h exposure of MM cells to taurolidine showed IC50 of 28–42.7 μm and 50% viability at 49.8–135 μm. Annexin V assay for apoptosis revealed significant increases in annexin binding after 24–72-h exposure to 50–150 μm taurolidine (P &lt; 0.05), which was significantly inhibited by z-VAD (P &lt; 0.05). MM cells exposed to 50–150 μm taurolidine for 24–72 h showed terminal deoxynucleotidyl transferase-mediated nick end labeling staining consistent with apoptosis, as well as structural evidence of apoptosis via electron microscopy. In vivo, there were significant tumor reductions (62 to &gt;99% reduction) for all dosage regimens compared with untreated controls (P &lt; 0.001). In addition, all control animals exhibited ascites and diaphragmatic tumors while treated animals did not.
Conclusions: Taurolidine has significant antineoplastic activity against MM in vitro and in vivo, in part, due to tumor cell apoptosis. These findings warrant further study for potential clinical usefulness.
Trastuzumab Administration Can Effectively Target Chemotherapy-Resistant Cytokeratin-19 Messenger RNA–Positive Tumor Cells in the Peripheral Blood and Bone Marrow of Patients With Breast Cancer
Authors: Bozionellou Vassiliki , Mavroudis Dimitris , Perraki Maria , Papadopoulos Savvas , Apostolaki Stella , Stathopoulos Efstathios , Stathopoulou Aliki , Lianidou Evi , Georgoulias Vassilis 
Published: September 2005

Abstract
Purpose: The detection of disseminated occult breast cancer cells in peripheral blood and bone marrow is associated with poor prognosis. Since a high proportion of these cells express the HER-2 receptor, we evaluated the effectiveness of the anti-HER-2 antibody trastuzumab (Herceptin) administration to eliminate them.
Experimental Design: Thirty patients with prior chemotherapy exposure were recruited to the study on the basis of having detectable cytokeratin-19 (CK-19) mRNA transcripts by nested reverse transcription (RT)-PCR in the peripheral blood and/or bone marrow. There were 13 patients with stage I, II, or III breast cancer and 17 with stage IV disease. They were treated in two cohorts with either 4 to 8 weekly infusions of trastuzumab at 2 mg/kg (4 mg/kg loading dose; 20 patients) or 2 to 3 infusions every 3 weeks at 6 mg/kg (8 mg/kg loading dose; 10 patients). All of the patients’ samples were also analyzed for HER-2 by nested RT-PCR, but detectable HER-2 messenger RNA (mRNA) was not required for inclusion in the study. After trastuzumab infusions, patients were closely monitored by nested RT-PCR and real-time RT-PCR for the detection of CK-19 mRNA-positive cells.
Results: Before trastuzumab infusions, CK-19 mRNA-positive cells were detected in the peripheral blood (n = 10), bone marrow (n = 14), or both (n = 6). In 25 of 30 patients (83%), HER-2 mRNA expression was detected by nested RT-PCR in the pretrastuzumab CK-19–positive sample. After trastuzumab infusions, overall, 28 of 30 (93%) patients became CK-19 mRNA negative by nested RT-PCR and 20 of 30 (67%) by real-time RT-PCR. After a median follow-up of 6 months (range 2 to 22+), the median duration of CK-19 mRNA negativity by nested RT-PCR was 9, 12, and 6 months for stage I/II, III, and IV disease, respectively.
Conclusions: Therapy-resistant CK-19 mRNA-positive cells in the peripheral blood and bone marrow can be effectively targeted by trastuzumab administration. Further studies are needed to evaluate the prognostic significance of the disappearance of these cells.
A Phase I Trial of Perifosine (NSC 639966) on a Loading Dose/Maintenance Dose Schedule in Patients with Advanced Cancer
Authors: Van Ummersen Lynn , Binger Kim , Volkman Jennifer , Marnocha Rebecca , Tutsch Kendra , Kolesar Jill , Arzoomanian Rhoda , Alberti Dona , Wilding George 
Published: September 2005

Abstract
Perifosine (NSC 639966) is a synthetic, substituted heterocyclic alkylphosphocholine that acts primarily at the cell membrane targeting signal transduction pathways. Early clinical trials were limited because of dose-limiting gastrointestinal toxicity, and parenteral dosing of this class of agents is not possible because of their hemolytic properties; therefore, related compounds with an improved therapeutic index were developed. Toxicity was minimized and efficacy improved by using a loading dose/maintenance dose schedule, and therefore, this schedule was carried into clinical trials. This phase I trial enrolled 42 patients with incurable solid malignancies. The starting doses were 100 mg p.o. × four doses (every 6 hours) load followed by a 50 mg p.o. once daily maintenance dose with escalation of either component in successive dose levels. No treatment related deaths occurred. The maximum-tolerated dose was determined to be 150 mg p.o. × four doses load and 100 mg p.o. once daily maintenance. Dose-limiting toxicities such as nausea, diarrhea, dehydration, and fatigue were seen early during the loading phase and were surmountable with the use of prophylactic 5-HT3 receptor antagonists, dexamethasone, and loperamide. Toxicities during the chronic phase were difficult to manage and, given that pharmacokinetic data showed biologically active serum concentrations (based on preclinical data), raised the question of less frequent maintenance dosing. Pharmacokinetic data confirmed the maintenance of stable drug levels with chronic dosing and the long half-life. One partial response was seen, as were multiple patients with stable disease beyond course 2. These results suggest perifosine activity in sarcoma and perhaps renal cell carcinoma (stable disease in two patients who continued for 6 and 14 courses), thus justifying additional investigation of this agent in a phase II sarcoma trial.
Mina53 as a Potential Prognostic Factor for Esophageal Squamous Cell Carcinoma
Authors: Tsuneoka Makoto , Fujita Hiromasa , Arima Nobuyuki , Teye Kwesi , Okamura Torahiko , Inutsuka Hiroki , Koda Yoshiro , Shirouzu Kazuo , Kimura Hiroshi 
Published: September 2005

AbstractPurpose: We previously identified mina53, a novel Myc target gene. Here we investigated whether mina53 is related to esophageal squamous cell carcinoma (ESCC), a disease with poor prognosis.Experimental Design: Mina53 expression was suppressed in ESCC cell lines by a RNA interference method to investigate whether Mina53 is involved in cell proliferation. Expression of Mina53 was investigated by Western blotting in tissue sections from patients with ESCC. Immunohistochemical analysis of Mina53 was carried out and compared with that using anti–Ki-67 antibody. Finally, the level of Mina53 expression was compared with the length of survival of patients with ESCC.Results: Reduction of mina53 expression by RNA interference suppressed cell proliferation in ESCC cell lines. Western blot analysis of surgically resected ESCC specimens indicated that the expression of Mina53 in tumors was increased compared with that in adjacent nonneoplastic tissues in all four specimens examined. When formalin-fixed specimens from 52 patients with ESCC were stained immunohistochemically, it was found that Mina53 was highly expressed in 83% of specimens. Anti-Mina53 antibody stained tumors more efficiently than antibody against Ki-67, a cell proliferation biomarker, in some cancer specimens. Patients with high expression of Mina53 had shorter survival periods, whereas the expression level of Ki-67 in ESCC showed no relationship to patient outcome.Conclusions: Taken together, our results indicate that expression of Mina53 is a characteristic feature of ESCC and suggest that immunostaining by anti-Mina53 antibody may be useful as a potential prognostic indicator.
Plasma Glutathione
S
-Transferase P1-1 as a Prognostic Factor in Patients with Advanced Non-Hodgkin’s Lymphoma (Stages III and IV)
Authors: Katahira Tatsuro , Takayama Tetsuji , Miyanishi Koji , Hayashi Tsuyoshi , Ikeda Tatsuru , Takahashi Yasuo , Takimoto Rishu , Matsunaga Takuya , Kato Junji , Niitsu Yoshiro 
Published: September 2005

Abstract
Purpose: This study aims to investigate whether the plasma level of glutathione S-transferase P1-1 (GSTP1-1), which is a phase II detoxifying enzyme known to be a resistance factor for anticancer drugs, could be a prognostic factor of de novo non-Hodgkin lymphoma (NHL) in clinical stages (CSs) III and IV.
Experimental Design: Study population consisted of 80 NHL patients with no prior treatment: 12 patients were at CS I, 14 at CS II, 25 at CS III, and 29 at CS IV. All 54 patients at CS III or CS IV were treated with cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP). Plasma GSTP1-1 concentration was measured by ELISA. We stained lymph node tissues for GSTP1-1 using anti-GSTP1-1 monoclonal antibody 5F and quantitatively assessed the intensity of immunostaining by using the KS-400 image analyzing system.
Results: There was a significant stepwise increment of plasma GSTP1-1 concentration from CS I to CS IV (P &lt; 0.05). Of the 54 patients with CS III or IV treated with CHOP, 28 (52%) had elevated plasma GSTP1-1 levels. Plasma GSTP1-1 concentration tended to correlate with the intensity of GSTP1-1 expression in lymphoma tissues as assessed by immunostaining (P = 0.07). The CR rates in patients at CS III and CS IV treated by CHOP, 55.2% (14 of 26) and 16.0% (5 of 28) for the low and high plasma GSTP1-1 groups, respectively, were significantly different (P &lt; 0.01). For these two groups, the median survival times were 64 and 25 months, respectively (P &lt; 0.01), and the median times to progression were 58 and 12 months, respectively (P &lt; 0.01). There was no significant correlation between plasma GSTP1-1 concentrations and other NHL prognostic indicators in these patients as determined by univariate and multivariate analyses.
Conclusion: These results showed that plasma GSTP1-1 is a useful prognostic factor for CS III and IV advanced NHL. Thus, it may be a promising strategy to treat NHL concomitantly with anticancer drugs and GSTP1-1-specific inhibitors.
Type I Collagen Promotes the Malignant Phenotype of Pancreatic Ductal Adenocarcinoma
Authors: Armstrong Thomas , Packham Graham , Murphy Lindsay B. , Bateman Adrian C. , Conti John A. , Fine David R. , Johnson Colin D. , Benyon R. Christopher , Iredale John P. 
Published: September 2005

Abstract
Purpose: The purpose of this study was to determine the role of functional interactions between pancreatic cancer cells and pancreatic stellate cells (PSCs) in the formation of the desmoplastic reaction (DR) in pancreatic cancer and to characterize the effect of type I collagen (the predominant component of the DR) on pancreatic cancer cell phenotype.
Experimental Design: PSCs and type I collagen were identified in sections of pancreatic cancer using immunohistochemistry, and their anatomic relationship was studied. Interactions among pancreatic cancer cell lines (MIA PaCa-2, Panc-1, and AsPC-1), primary cultures of human PSCs, and type I collagen were investigated in a series of tissue culture models.
Results: In vivo, the DR causes gross distortion of normal pancreas, bringing cancer cells into close contact with numerous PSCs and abundant type I collagen. In tissue culture models of pancreatic cancer, conditioned media from each cell line increased PSC [3H]thymidine incorporation up to 6.3-fold that of controls, and AsPC-1 cells also increased PSC collagen synthesis 1.3-fold. Type I collagen was observed to increase long-term survival of pancreatic cancer cells treated with 5-fluorouracil, by up to 62% in clonogenic assays. This was because type I collagen increased the proliferation of cancer cells ([3H]thymidine incorporation was up to 2.8-fold that of cells cultured on tissue culture plastic) and reduced apoptosis of AsPC-1 cells in response to 5-fluorouracil (by regulating mcl-1).
Conclusions: These experiments elucidate a mechanism by which the DR in pancreatic cancer may form and, via the collagen within it, promote the malignant phenotype of pancreatic cancer cells, suggesting significant detriment to the host.
High LYVE-1–Positive Lymphatic Vessel Numbers Are Associated with Poor Outcome in Breast Cancer
Authors: Bono Petri , Wasenius Veli-Matti , Heikkilä Päivi , Lundin Johan , Jackson David G. , Joensuu Heikki 
Published: September 2005

Abstract
Purpose: The clinical significance of intratumoral or peritumoral lymph vessel density is not known. LYVE-1, a lymphatic endothelium-specific hyaluronan receptor, is a novel lymphatic vessel marker that is expressed on lymph vessel endothelial cells of both normal and neoplastic tissues.
Experimental Design: We investigated expression of LYVE-1 by immunhistochemistry in 180 unilateral, invasive ductal breast carcinomas and assessed the presence and density of lymph vessels within the tumor and at the tumor periphery.
Results: A minority (12%) of breast carcinomas had intratumoral lymph vessels, whereas peritumoral lymph vessels were identified in almost all cases (94%). No substantial association was found between the number of LYVE-1–positive vessels and the number of CD31 or vascular endothelial growth factor receptor-3–positive vessels, or vascular endothelial growth factor-C expression. The number of metastatic axillary lymph nodes increased in parallel with increasing lymph vessel counts (P = 0.033). A higher than the median lymph vessel count at the tumor periphery was significantly associated with unfavorable distant disease-free survival and overall survival. Women with high peritumoral lymph vessel density had only 58% (95% confidence interval, 46–70%) 5-year distant disease-free survival as compared with 74% (66–83%) among those with a low peritumoral lymph vessel density (P = 0.0088). In contrast, the presence of intratumoral lymph vessels was associated with neither axillary nodal status nor survival. Lymph vessel density was not an independent prognostic factor in a multivariate survival analysis.
Conclusions: A high peritumoral lymph vessel density is associated with a poor outcome in ductal breast cancer.
Increased Angiogenesis and Lymphangiogenesis in Inflammatory
versus
Noninflammatory Breast Cancer by Real-Time Reverse Transcriptase-PCR Gene Expression Quantification
Authors: Van der Auwera Ilse , Van Laere Steven J. , Van den Eynden Gert G. , Benoy Ina , van Dam Peter , Colpaert Cecile G. , Fox Stephen B. , Turley Helen , Harris Adrian L. , Van Marck Eric A. , Vermeulen Peter B. , Dirix Luc Y. 
Published: September 2005

Abstract
Purpose: Inflammatory breast cancer is a distinct and aggressive form of locally advanced breast cancer with unique clinical and pathological features. Recently, histologic evidence of intense angiogenesis was found in inflammatory breast cancer specimens. The aim of this study was to confirm the angiogenic phenotype of inflammatory breast cancer and to investigate its potential to induce lymphangiogenesis.
Experimental Design: Real-time quantitative reverse transcriptase-PCR was used to measure levels of mRNA of tumor angiogenesis and lymphangiogenesis-related factors [vascular endothelial growth factor (VEGF)-A, VEGF-C, VEGF-D, Flt-1, KDR, Flt-4, Ang-1, Ang-2, Tie-1, Tie-2, cyclooxygenase-2, fibroblast growth factor-2 (FGF-2), Egr-1, Prox-1, and LYVE-1] in tumor specimens of 16 inflammatory breast cancer and 20 noninflammatory breast cancer patients. Tissue microarray technology and immunohistochemistry were used to study differential protein expression of some of the angiogenic factors in inflammatory breast cancer and noninflammatory breast cancer. Active lymphangiogenesis was further assessed by measuring lymphatic endothelial cell proliferation.
Results: Inflammatory breast cancer specimens had significantly higher mRNA expression levels than noninflammatory breast cancer specimens of the following genes: KDR (P = 0.033), Ang-1, (P = 0.0001), Tie-1 (P = 0.001), Tie-2 (P = 0.001), FGF-2 (P = 0.002), VEGF-C (P = 0.001), VEGF-D (P = 0.012), Flt-4 (P = 0.001), Prox-1 (P = 0.005), and LYVE-1 (P = 0.013). High mRNA levels of FGF-2 and cyclooxygenase-2 corresponded to increased protein expression by immunohistochemistry. Inflammatory breast cancer specimens contained significantly higher fractions of proliferating lymphatic endothelial cells than noninflammatory breast cancer specimens (P = 0.033).
Conclusions: Using real-time quantitative reverse transcriptase-PCR and immunohistochemistry, we confirmed the intense angiogenic activity in inflammatory breast cancer and demonstrated the presence of active lymphangiogenesis in inflammatory breast cancer. This may help explain the high metastatic potential of inflammatory breast cancer by lymphatic and hematogenous route. Both pathways are potential targets for the treatment of inflammatory breast cancer.
Antibody-Based Profiling of the Phosphoinositide 3-Kinase Pathway in Clinical Prostate Cancer
Authors: Thomas George V. , Horvath Steve , Smith Bradley L. , Crosby Katherine , Lebel Lori A. , Schrage Matthew , Said Jonathan , De Kernion Jean , Reiter Robert E. , Sawyers Charles L. 
Published: September 2005

Abstract
Purpose: As kinase inhibitors transition from the laboratory to patients, it is imperative to develop biomarkers that can be used in the clinic. The primary objectives are to identify patients most likely to benefit from molecularly targeted therapies and to document modulation of the drug target. Constitutive activation of the phosphoinositide 3-kinase (PI3K) pathway and its downstream effectors, as a result of PTEN loss or by other mechanisms, occurs in a high proportion of prostate cancers, making it an ideal template for the design of clinical trials involving PI3K pathway inhibitors. Prostate cancers also present unique organ-specific challenges, in that tumors are heterogeneous and diagnostic tissue is extremely limited.
Experimental Design: Working within these limitations, we have developed a set of immunohistochemical assays that define activation of the PI3K pathway in clinical samples.
Results and Conclusions: Using both univariate and multivariate analyses, we show that loss of PTEN is highly correlated with the activation of AKT, and this, in turn, is associated with the phosphorylation of S6, one of its main effectors. These three antibodies are potentially able to define a molecular signature of PTEN loss and/or AKT pathway activation in prostate cancer.
The Use of Real-Time Reverse Transcription-PCR for Prostate-Specific Antigen mRNA to Discriminate between Blood Samples from Healthy Volunteers and from Patients with Metastatic Prostate Cancer
Authors: Patel Kinnari , Whelan Peter J. , Prescott Stephen , Brownhill Samantha C. , Johnston Colin F. , Selby Peter J. , Burchill Susan A. 
Published: September 2005

Abstract
Purpose: A clinical role for nonquantitative reverse transcription-PCR (RT-PCR) using prostate-specific antigen in blood samples from patients with prostate cancer remains undefined. Assay variation and detection of prostate-specific antigen mRNA illegitimate transcription may explain inconsistent results between studies. Defining levels of prostate-specific antigen mRNA expression in blood samples from healthy volunteers and patients with prostate cancer would allow cutoffs to be established to distinguish the two groups.
Experimental Design: Quantitative real-time RT-PCR for prostate-specific antigen mRNA was established and levels of prostate-specific antigen mRNA measured in bloods samples from healthy volunteers (n = 21) and patients with localized (n = 27) and metastatic (n = 40) prostate cancer.
Results: Levels of prostate-specific antigen mRNA were significantly higher in blood samples from patients with metastatic prostate cancer than in blood samples from patients with localized prostate cancer (P &lt; 0.001) or in blood samples from healthy volunteers (P &lt; 0.01); levels between patients with localized prostate cancer and healthy volunteers were no different. Assay sensitivity to detect patients with metastatic prostate cancer was 68% with specificity of 95%. In patients with newly diagnosed metastatic prostate cancer, monitoring response to hormonal therapy was possible with this assay. No correlation between levels of prostate-specific antigen mRNA and serum prostate-specific antigen protein levels was found, suggesting that prostate-specific antigen mRNA and serum prostate-specific antigen protein levels reflect different features of prostate cancer, i.e., circulating tumor cells and total tumor bulk, respectively.
Conclusions: Quantitative RT-PCR discriminates patients with metastatic prostate cancer from healthy volunteers and patients with localized prostate cancer but cannot discriminate patients with localized prostate cancer from healthy volunteers. A role for quantitative RT-PCR has been identified in the assessment and monitoring of patients with metastatic prostate cancer.