bluuebunny/crossref_metadata_2025_split huggingface dataset:
Characterization and Multiparameter Analysis of Visual Adverse Events in Irofulven Single-Agent Phase I and II Trials
Authors: Raymond Eric , Kahatt Carmen , Rigolet Marie Hélène , Sutherland William , Lokiec François , Alexandre Jérôme , Tombal Bertrand , Elman Michael , Lee Michael S. , MacDonald John R. , Cullen Michael , Misset Jean-Louis , Cvitkovic Esteban 
Published: September 2005

Abstract
Purpose: Irofulven (6-hydroxymethylacylfulvene) is a novel agent, derived from illudin S, with potent apoptotic effects in preclinical models. In the Phase I trial evaluating intermittent weekly schedules, visual symptoms were dose limiting. The aim of this analysis was to better characterize the visual adverse events of irofulven and provide treatment guidelines.
Experimental Design: Clinical data from 277 patients entered in single-agent Phase I to II clinical trials who received irofulven on days 1 and 15 every 4 weeks; days 1, 8, and 15 every 4 weeks; or days 1 and 8 every 3 weeks were included in this multiparameter analysis.
Results: Overall, 74 patients (27%) experienced visual symptoms. The most frequently reported symptoms were flashing lights (12% of patients), blurred vision (9%), and photosensitivity (8%). Grade 3 toxicity was observed in 12 patients (4%). The incidence and severity of visual events were dose dependent, with no grade 3 visual events occurring at doses ≤0.50 mg/kg and grade 1 to 2 events in only 12% and 8% of patients, at doses of ≤0.50 mg/kg and ≤20 mg/m2, respectively. Grade 1 to 2 toxicity was reversible in most patients. Abnormal electroretinogram and abnormal visual fields were noted after irofulven treatment in 24 of 39 patients (62%) and 15 of 26 patients (58%), respectively. All but 1 patient who had electroretinogram assessment received doses &gt;0.50 mg/kg. Clinical examination and visual field assessment were found to be better correlated with symptoms and appear to be more appropriate for surveillance of irofulven retinal symptoms than electroretinograms.
Conclusions: On the basis of retained antitumor activity and reversibility of grade 1 and 2 visual symptoms at lower doses, it appears that an irofulven dose of ≤0.50 mg/kg or ≤20 mg/m2, not to exceed 50 mg in a single dose, given as a 30-minute infusion on days 1 and 8 every 3 weeks or days 1 and 15 every 4 weeks minimizes the frequency and severity of visual symptoms.
Preradiotherapy Hemoglobin Level but not Microvessel Density Predicts Locoregional Control and Survival in Laryngeal Cancer Treated with Primary Radical Radiotherapy
Authors: Haugen Hedda , Magnusson Bengt , Svensson Marie , Mercke Claes 
Published: September 2005

Abstract
Purpose: To evaluate the roles of preradiotherapy hemoglobin level and microvessel density (MVD) as predictive factors for tumor control and survival in patients with laryngeal cancer treated with primary radiotherapy.
Experimental Design: Two hundred and fourteen patients with stage I-IV laryngeal cancer were included in the analysis. Patients were treated with once daily fractionated radiotherapy over 6.5 weeks or twice daily fractionated radiotherapy over 4.5 weeks up to total doses of 62 to 68 Gy. Preradiotherapy hemoglobin levels were obtained from patient journals, and pretreatment tumor biopsies were stained with CD34 antibody for the counting of microvessels. The prognostic implication of preradiotherapy hemoglobin level and MVD on tumor control and survival was tested.
Results: Five-year locoregional control probability was 88.9% for patients with preradiotherapy hemoglobin levels &gt;137.5 g/L (median) and 64.4% for patients with preradiotherapy hemoglobin levels &lt;137.5 g/L (P = 0.01). The corresponding figures for disease-free survival were 87.8 and 62.8% (P = 0.007), respectively, and for overall survival 58.1 and 40.3% (P &lt; 0.001), respectively.
In multivariate analysis, tumor stage and preradiotherapy hemoglobin level were significant prognostic factors for locoregional control and disease-free survival, whereas tumor stage, preradiotherapy hemoglobin-level, gender, and age were significant prognostic factors for overall survival. No correlation was found between MVD and tumor control and survival.
Conclusion: Preradiotherapy hemoglobin level, but not MVD, predicts locoregional control and survival in patients with laryngeal cancer treated with radiotherapy.
Increased Levels of Interleukin-10 in Serum from Patients with Hepatocellular Carcinoma Correlate with Profound Numerical Deficiencies and Immature Phenotype of Circulating Dendritic Cell Subsets
Authors: Beckebaum Susanne , Zhang Xia , Chen Xiao , Yu Zhengya , Frilling Andrea , Dworacki Grzegorz , Grosse-Wilde Hans , Broelsch Christoph Erich , Gerken Guido , Cicinnati Vito R. 
Published: September 2005

AbstractIncreased levels of interleukin (IL)-10 have been described as a negative prognostic indicator for survival in patients with various types of cancer. IL-10 exerts tolerogenic and immunosuppressive effects on dendritic cells, which are crucial for the induction of an antitumor immune response. Blood dendritic cell antigen (BDCA)-2 and BDCA-4 are specifically expressed by CD123bright CD11c− plasmacytoid dendritic cells; whereas BDCA-1 and BDCA-3 define 2 distinct subsets of CD11c+ myeloid dendritic cells. In this study, the T-helper cell (Th)1/Th2 cytokine serum profile of 65 hepatocellular carcinoma patients was assessed. We found that serum levels of IL-10 were substantially increased in hepatocellular carcinoma patients as compared with controls. Peripheral blood mononuclear cells from healthy volunteers were exposed to recombinant human (rh)IL-10 in vitro to additionally characterize its impact on distinct blood dendritic cell subsets. A dramatic decrease of all myeloid dendritic cell (MDC) and plasmacytoid dendritic cell (PDC) subsets was detectable after 24 hours of continuous rhIL-10 exposure. Moreover, the expression of HLA-DR, CD80 and CD86, was significantly reduced on rhIL-10-treated dendritic cell subsets. Direct ex vivo flow cytometric analysis of various dendritic cell subpopulations in peripheral blood from hepatocellular carcinoma patients revealed an immature phenotype and a substantial reduction of circulating dendritic cells that was associated with increased IL-10 concentrations in serum and with tumor progression. These findings confirm a predominantly immunosuppressive role of IL-10 for circulating dendritic cells in patients with hepatocellular carcinoma and, thus, may indicate novel aspects of tumor immune evasion.
Inhibition of Proliferation and Induction of Apoptosis by 25-Hydroxyvitamin D3-3β-(2)-Bromoacetate, a Nontoxic and Vitamin D Receptor-Alkylating Analog of 25-Hydroxyvitamin D3 in Prostate Cancer Cells
Authors: Swamy Narasimha , Chen Tai C. , Peleg Sara , Dhawan Puneet , Christakos Sylvia , Stewart LaMonica V. , Weigel Nancy L. , Mehta Rajendra G. , Holick Michael F. , Ray Rahul 
Published: September 2005

Abstract
The 25-hydroxyvitamin D3 (25-OH-D3) is a nontoxic and low-affinity vitamin D receptor (VDR)-binding metabolic precursor of 1,25-dihydroxyvitamin D3 [1,25(OH)2D3]. We hypothesized that covalent attachment of a 25-OH-D3 analog to the hormone-binding pocket of VDR might convert the latter into transcriptionally active holo-form, making 25-OH-D3 biologically active. Furthermore, it might be possible to translate the nontoxic nature of 25-OH-D3 into its analog. We showed earlier that 25-hydroxyvitamin D3-3-bromoacetate (25-OH-D3-3-BE) alkylated the hormone-binding pocket of VDR. In this communication we describe that 10−6 mol/L of 25-OH-D3-3-BE inhibited the growth of keratinocytes, LNCaP, and LAPC-4 androgen-sensitive and PC-3 and DU145 androgen-refractory prostate cancer cells, and PZ-HPV-7 immortalized normal prostate cells with similar or stronger efficacy as 1,25(OH)2D3. But its effect was strongest in LNCaP, PC-3, LAPC-4, and DU145 cells. Furthermore, 25-OH-D3-3-BE was toxic to these prostate cancer cells and caused these cells to undergo apoptosis as shown by DNA-fragmentation and caspase-activation assays. In a reporter assay with COS-7 cells, transfected with a 1α,25-dihydroxyvitamin D3-24-hydroxylase (24-OHase)-construct and VDR-expression vector, 25-OH-D3-3-BE induced 24-OHase promoter activity. In a “pull down assay” with PC-3 cells, 25-OH-D3-3-BE induced strong interaction between VDR and general transcription factors, retinoid X receptor, and GRIP-1. Collectively, these results strongly suggested that the cellular effects of 25-OH-D3-3-BE were manifested via 1,25(OH)2D3/VDR signaling pathway. A toxicity study in CD-1 mice showed that 166 μg/kg of 25-OH-D3-3-BE did not raise serum-calcium beyond vehicle control. Collectively, these results strongly suggested that 25-OH-D3-3-BE has a strong potential as a therapeutic agent for androgen-sensitive and androgen-refractory prostate cancer.
MAP2K4/MKK4 Expression in Pancreatic Cancer
Authors: Xin Wei , Yun Ki J. , Ricci Francesca , Zahurak Marianna , Qiu Wanglong , Su Gloria H. , Yeo Charles J. , Hruban Ralph H. , Kern Scott E. , Iacobuzio-Donahue Christine A. 
Published: September 2005

Abstract
MKK4 (MAP2K4/SEK1) is a member of the mitogen-activated protein kinase family, originally identified as a kinase involved in the stress-activated protein kinase pathway by directly phosphorylating c-Jun NH2-terminal kinase. MKK4 genetic inactivation has been observed in a subset of pancreatic carcinomas, implicating deregulation of the stress-activated protein kinase pathway in pancreatic carcinogenesis. We evaluated Mkk4 protein expression patterns by immunohistochemical labeling in a series of 60 resected primary infiltrating pancreatic adenocarcinomas (24 cases with known MKK4 genetic status), and 14 different tissue arrays representing the primary carcinoma and all of the gross metastases from 26 patients that died of metastatic pancreatic cancer. Among the surgically resected carcinomas, focal or diffuse-positive immunolabeling for Mkk4 protein was found in 52 of 60 cases (86.7%). Among the eight carcinomas with negative Mkk4 immunolabeling, three harbored a homozygous deletion or intragenic mutation of the MKK4 gene, in contrast to none of the 52 cases with positive Mkk4 immunolabeling (P &lt; 0.01). Loss of Mkk4 immunolabeling showed a trend toward shorter survival, with Mkk4-positive carcinomas having half the risk of death than Mkk4-negative carcinomas (P = 0.09). Mkk4 immunolabeling patterns were also evaluated among unresectable primary and metastatic cancer tissues from autopsy specimens, indicating intact Mkk4 immunolabeling in 88.8% of the unresectable primary carcinomas as compared with 63.3% of distant metastases (P &lt; 0.001). Our data indicate that the loss of Mkk4 protein expression in pancreatic carcinomas may be more frequent than suggested by the rates of genetic inactivation alone and that MKK4 loss may contribute to disease progression. The correlation of MKK4 genetic status with immunolabeling patterns validate this approach for the evaluation of MKK4 status in routine histologic sections and may provide useful information regarding patient prognosis.
Phase II Feasibility and Pharmacokinetic Study of Concurrent Administration of Trastuzumab and High-Dose Chemotherapy in Advanced HER2+ Breast Cancer
Authors: Nieto Yago , Vredenburgh James J. , Shpall Elizabeth J. , Bearman Scott I. , McSweeney Peter A. , Chao Nelson , Rizzieri David , Gasparetto Christina , Matthes Steve , Barón Anna E. , Jones Roy B. 
Published: September 2005

Abstract
Purpose: To evaluate the safety of concurrent treatment with trastuzumab and high-dose chemotherapy (HDC), using cyclophosphamide, cisplatin, and 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), with autologous hematopoietic progenitor cells support, in patients with HER2+ advanced breast cancer.
Experimental Design: Patients with HER2-overexpressing high-risk primary breast cancer (HRPBC; defined as ≥4 involved nodes or inflammatory disease), or metastatic breast cancer (MBC) were eligible. Treatment consisted of a loading dose of trastuzumab at 4 mg/kg (day −5), HDC (days −5 to −2), autologous hematopoietic progenitor cells infusion on day 0, and weekly maintenance trastuzumab (2 mg/kg) from day +1 (minimum of 9 doses). Cardiac monitoring included serial left ventricular ejection fraction measurements before treatment and on days +20 and +65.
Results: Thirty-three patients were prospectively enrolled (13 HRPBC, 20 MBC). Toxicity seemed similar to that expected with this HDC regimen alone. Neutrophils and platelets engrafted promptly. There were no cases of grade 4 or 5 toxicity. One patient experienced symptomatic grade 3 acute cardiac failure on day −4, responsive to treatment. Trastuzumab did not alter the pharmacokinetics of HDC. Eleven of twelve MBC patients with measurable disease (nine of them refractory to previous chemotherapy) experienced an objective response (9 complete and 2 partial responses). At median follow-up of 34 (13–58) months, all HRPBC patients remain alive and free of disease; the MBC group has event-free survival and overall survival rates of 45 and 70%, respectively.
Conclusions: Incorporation of trastuzumab into HDC (cyclophosphamide, cisplatin, and BCNU) is feasible, with no apparent increased toxicity or pharmacokinetic interactions.
A Phase I Open Label Study of the Farnesyltransferase Inhibitor CP-609,754 in Patients with Advanced Malignant Tumors
Authors: Moulder Stacy L. , Mahany John J. , Lush Richard , Rocha-Lima Caio , Langevin Michael , Ferrante Karen J. , Bartkowski Lisa Michele , Kajiji Shama M. , Noe Dennis A. , Paillet Simone , Sullivan Daniel M. 
Published: September 2005

Abstract
Purpose: The purpose of this phase I clinical trial was to determine the maximum-tolerated dose and toxicity of CP-609,754 in patients with solid tumors refractory to standard therapies, to determine the cellular effects of CP-609,754 on its molecular target (farnesyltransferase), and to determine the recommended phase II dose (RP2D) of this agent.
Experimental Design: Consenting patients with adequate bone marrow, liver, and renal function were enrolled with an accelerated dose strategy with single-patient parallel cohorts in whom the drug was given orally either once or twice daily. Once a dose-limiting toxicity was encountered or two patients developed Common Toxicity Criteria ≥ grade 2 toxicities, a modified Fibonacci sequence was initiated. Blood samples were collected during cycle 1 for pharmacokinetic and pharmacodynamic analyses.
Results: A total of 68 cycles of CP-609,754 was administered to 21 patients enrolled in this study. The dose escalation was from 20 mg once daily to 640 mg twice per day, and at the highest dose level, one of six patients developed a dose-limiting toxicity of grade 3 neuropathy. The drug was otherwise well tolerated, and the maximum-tolerated dose was not reached because of the large number of tablets that would have been required for additional dose escalation. Pharmacokinetic analyses showed a proportional increase in exposure with dose, rapid oral absorption, and a half-life of ∼3 hours. Pharmacodynamic results predict a 95% maximal inhibition of peripheral blood mononuclear cell farnesyltransferase activity 2 hours postdose, on average, with a dose of 400 mg twice per day of CP-609,754.
Conclusions: On the basis of the safety findings and the pharmacokinetic and pharmacodynamic analyses, the RP2D of CP-609,754 is ≥640 mg twice per day.
Thymidylate Synthase 5′- and 3′-Untranslated Region Polymorphisms Associated with Risk and Progression of Squamous Cell Carcinoma of the Head and Neck
Authors: Zhang Zhengdong , Shi Qiuling , Sturgis Erich M. , Spitz Margaret R. , Hong Waun Ki , Wei Qingyi 
Published: September 2005

Abstract
Purpose: Folate deficiency and reduced DNA repair capacity are established risk factors for squamous cell carcinoma of the head and neck (SCCHN). We hypothesized that polymorphisms of the thymidylate synthase (TYMS) gene, which regulates a key enzyme in folate metabolism required for DNA synthesis and repair, are associated with SCCHN risk.
Experimental Design: In a hospital-based case-control study of 704 SCCHN cases and 1,085 controls, frequency matched by age, sex, and ethnicity, we genotyped the TSER (thymidylate synthase in the 5′-untranslated enhanced region) and TS3′UTR (thymidylate synthase in the 3′-untranslated region) polymorphisms.
Results: The TS3′UTR 0bp/0bp genotype was associated with a significantly decreased risk of SCCHN [adjusted odd ratio (OR) = 0.67, 95% confidence interval (CI) = 0.47–0.94] compared with the 6bp/6bp genotype, but the TSER polymorphism had no main effect on risk of SCCHN. When we evaluated the two polymorphisms together by the number of protective alleles (the TSER 3R and TS3′UTR 0bp alleles), we found that the combined genotypes with four protective alleles (the TSER 3R3R and TS3′UTR 0bp/0bp) was associated with significantly decreased SCCHN risk (OR = 0.60, 95% CI = 0.37–0.98). In addition, the TS3′UTR 0bp genotypes were associated in an allele dose-dependent manner with a decreased risk of overall stage IV oral cancer (OR = 0.84, 95% CI = 0.52–1.34 for the 6bp/0bp genotype and OR = 0.26, 95% CI = 0.08–0.87 for the 0bp/0bp genotype; Ptrend = 0.035).
Conclusion: The TSER and TS3′UTR polymorphisms are associated with SCCHN risk. The TSER 3R and TS3′UTR 0bp alleles seemed to jointly protect against SCCHN. In particular, the 0bp allele seemed to protect against oral cancer progression.
Detection of Methylated Apoptosis-Associated Genes in Urine Sediments of Bladder Cancer Patients
Authors: Friedrich Martin G. , Weisenberger Daniel J. , Cheng Jonathan C. , Chandrasoma Shahin , Siegmund Kimberly D. , Gonzalgo Mark L. , Toma Marieta I. , Huland Hartwig , Yoo Christine , Tsai Yvonne C. , Nichols Peter W. , Bochner Bernard H. , Jones Peter A. , Liang Gangning 
Published: September 2005

Abstract
Purpose: There is increasing evidence for a fundamental role for epigenetic silencing of apoptotic pathways in cancer. Changes in DNA methylation can be detected with a high degree of sensitivity, so we used the MethyLight assay to determine how methylation patterns of apoptosis-associated genes change during bladder carcinogenesis and whether DNA methylation could be detected in urine sediments.
Experimental Design: We analyzed the methylation status of the 5′ regions of 12 apoptosis-associated genes (ARF, FADD, TNFRSF21, BAX, LITAF, DAPK, TMS-1, BCL2, RASSF1A, TERT, TNFRSF25, and EDNRB) in 18 bladder cancer cell lines, 127 bladder cancer samples, and 37 samples of adjacent normal bladder mucosa using the quantitative MethyLight assay. We also analyzed the methylation status in urine sediments of 20 cancer-free volunteers and 37 bladder cancer patients.
Results: The 5′ regions of DAPK, BCL2, TERT, RASSFIA, and TNFRSF25 showed significant increases in methylation levels when compared with nonmalignant adjacent tissue (P ≤ 0.01). Methylation levels of BCL2 were significantly associated with tumor staging and grading (P ≤ 0.01), whereas methylation levels of RASSF1A and ARF were only associated with tumor stage (P ≤ 0.04), and TERT methylation and EDNRB methylation were predictors of tumor grade (P ≤ 0.02). To investigate clinical usefulness for noninvasive bladder cancer detection, we further analyzed the methylation status of the markers in urine samples of patients with bladder cancer. Methylation of DAPK, BCL2, and TERT in urine sediment DNA from bladder cancer patients was detected in the majority of samples (78%), whereas they were unmethylated in the urine sediment DNA from age-matched cancer-free individuals.
Conclusions: Our results indicate that methylation of the 5′ region of apoptosis-associated genes is a common finding in patients with bladder carcinoma. The ability to detect methylation not only in bladder tissue, but also in urine sediments, suggests that methylation markers are promising tools for noninvasive detection of bladder cancers. Our results also indicate that some methylation markers, such as those in regions of RASSF1A and TNFRSF25, might be of limited use for detection because they are also methylated in normal bladder tissues.
Antifolate Resistance in a HeLa Cell Line Associated With Impaired Transport Independent of the Reduced Folate Carrier
Authors: Zhao Rongbao , Chattopadhyay Shrikanta , Hanscom Marie , Goldman I. David 
Published: September 2005

AbstractPrior studies from this laboratory documented the prevalence of methotrexate (MTX) transport activity with a low pH optimum in human solid tumor cell lines. In HeLa cells, this low pH activity has high affinity for pemetrexed [PMX (Alimta)] and is reduced folate carrier (RFC)-independent because it is not diminished in a RFC-null subline (R5). R5 cells also have residual transport activity, with high specificity for PMX, at neutral pH. In the current study, a R5 subline, R1, was selected under MTX selective pressure at a modest reduction in pH. There was markedly decreased MTX and PMX transport at both pH 5.5 and pH 7.4. When MTX was removed, there was a slow return of transport activity, and when MTX was added back, there was loss of transport at both pH values within 8 weeks. In R1 cells, there was a marked decrease in accumulation of PMX, MTX, and folic acid along with a decrease in growth inhibition by these and other antifolates that require a facilitative process to gain entry into cells. These data demonstrate that (i) RFC-independent transport in HeLa cells at low and neutral pH contributes to antifolate activity (in particular, to PMX activity) and can be diminished by antifolate selective pressure and (ii) the loss of these activities results in marked resistance to PMX, an agent for which there is little or no loss of activity when transport mediated by RFC is abolished. These observations suggest that transport activity in RFC-null HeLa R5 cells at neutral and low pH may reflect the same carrier-mediated process.
Immunocytochemical Identification of VPAC1, VPAC2, and PAC1 Receptors in Normal and Neoplastic Human Tissues with Subtype-Specific Antibodies
Authors: Schulz Solveig , Röcken Christoph , Mawrin Christian , Weise Wolfgang , Höllt Volker , Schulz Stefan 
Published: September 2005

Abstract
Human tumors frequently overexpress receptors for vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating peptide (PACAP). However, none of the VIP/PACAP receptor proteins has been visualized individually in human tumors. Here, we developed and characterized a panel of antipeptide antibodies to the carboxyl-terminal regions of the VIP/PACAP receptor subtypes vasoactive intestinal peptide receptor (VPAC)1, VPAC2, and pituitary adenylate cyclase-activating peptide receptor (PAC)1. Specificity of the antisera was shown by the following: (1) detection of broad bands migrating at Mr 50,000 to 70,000 in Western blots of membranes from receptor-expressing tumors and receptor-transfected cells; (2) cell surface staining of VIP/PACAP receptor-transfected cells; (3) translocation of VIP/PACAP receptor immunostaining in transfected cells after agonist exposure; and (4) abolition of tissue immunostaining by preadsorbtion of the antibodies with their immunizing peptides. The distribution of VIP/PACAP receptors was investigated in 98 human tumors and their tissues of origin. VPAC1, VPAC2, and PAC1 receptors were clearly located at the plasma membrane of the tumor cells in a variety of human neoplasms. In the gastrointestinal tract, VPAC1 receptor immunoreactivity was abundant in the mucosa and myenteric neurons; VPAC2 receptor immunoreactivity was detected in neuroendocrine cells, blood vessels, and smooth muscle; and PAC1 receptor immunoreactivity was found in myenteric neurons. This is the first localization of all of the VIP/PACAP receptor subtypes in human formalin-fixed, paraffin-embedded tissues. VIP/PACAP receptor visualization with this simple and rapid immunohistochemical method will facilitate identification of tumors with a sufficient receptor overexpression for diagnostic or therapeutic intervention.