bluuebunny/crossref_metadata_2025 huggingface dataset:
Clinical Significance of CXC Chemokine Receptor-4 and c-Met in Childhood Rhabdomyosarcoma
Authors: Diomedi-Camassei Francesca , McDowell Heather P. , De Ioris Maria A. , Uccini Stefania , Altavista Pierluigi , Raschellà Giuseppe , Vitali Roberta , Mannarino Olga , De Sio Luigi , Cozzi Denis A. , Donfrancesco Alberto , Inserra Alessandro , Callea Francesco , Dominici Carlo
Published: July 2008

Purpose: The CXC chemokine receptor-4 (CXCR4)/stromal-derived factor-1 and c-Met/hepatocyte growth factor axes promote the metastatic potential of rhabdomyosarcoma cell lines in experimental models, but no data are available on their role in rhabdomyosarcoma tumors. The expressions of CXCR4 and c-Met were evaluated in primary tumors and isolated tumor cells in marrow, and were correlated with clinicopathologic variables and survival.

Experimental Design: Forty patients with recently diagnosed rhabdomyosarcoma were retrospectively enrolled. CXCR4 and c-Met expression was investigated in primary tumors by immunohistochemistry, in isolated marrow-infiltrating tumor cells using double-label immunocytology. Results were expressed as the mean percentage of immunostained tumor cells.

Results: CXCR4 and c-Met were expressed in ≥5% of tumor cells from 40 of 40 tumors, with 14 of 40 cases showing ≥50% of immunostained tumor cells (high expression). High CXCR4 expression correlated with alveolar histology (P = 0.006), unfavorable primary site (P = 0.009), advanced group (P < 0.001), marrow involvement (P = 0.007), and shorter overall survival and event-free survival (P < 0.001); high c-Met expression correlated with alveolar histology (P = 0.005), advanced group (P = 0.04), and marrow involvement (P = 0.02). In patients with a positive diagnosis for isolated tumor cells in marrow (n = 16), a significant enrichment in the percentage of CXCR4-positive (P = 0.001) and c-Met–positive (P = 0.003) tumor cells was shown in marrow aspirates compared with the corresponding primary tumors.

Conclusions: CXCR4 and c-Met are widely expressed in both rhabdomyosarcoma subtypes and, at higher levels, in isolated marrow-infiltrating tumor cells. High levels of expression are associated with unfavorable clinical features, tumor marrow involvement and, only for CXCR4, poor outcome. In rhabdomyosarcoma, CXCR4 and c-Met represent novel exploitable targets for disease-directed therapy.
In vivoOptical Molecular Imaging of Vascular Endothelial Growth Factor for Monitoring Cancer Treatment
Authors: Chang Sung K. , Rizvi Imran , Solban Nicolas , Hasan Tayyaba
Published: July 2008

Purpose: Vascular endothelial growth factor (VEGF) expression is a critical component in tumor growth and metastasis. Capabilities to monitor VEGF expression in vivo can potentially serve as a useful tool for diagnosis, prognosis, treatment planning, monitoring, and research. Here, we present the first report of in vivo hyperspectral molecular imaging strategy capable of monitoring treatment-induced changes in VEGF expression.

Experimental Design: VEGF was targeted with an anti-VEGF antibody conjugated with a fluorescent dye and was imaged in vivo using a hyperspectral imaging system. The strategy was validated by quantitatively monitoring VEGF levels in three different tumors as well as following photodynamic treatment. Specificity of the molecular imaging strategy was tested using in vivo competition experiments and mathematically using a quantitative pharmacokinetic model.

Results: The molecular imaging strategy successfully imaged VEGF levels quantitatively in three different tumors and showed concordance with results from standard ELISA. Changes in tumoral VEGF concentration following photodynamic treatment and Avastin treatment were shown. Immunohistochemistry shows that (a) the VEGF-specific contrast agent labels both proteoglycan-bound and unbound VEGF in the extracellular space and (b) the bound VEGF is released from the extracellular matrix in response to photodynamic therapy. In vivo competition experiments and quantitative pharmacokinetic model-based analysis confirmed the high specificity of the imaging strategy.

Conclusion: This first report of in vivo quantitative optical molecular imaging-based monitoring of a secreted cytokine in tumors may have implications in providing tools for mechanistic investigations as well as for improved treatment design and merits further investigation.
Prognostic Effect of Basal-Like Breast Cancers Is Time Dependent: Evidence from Tissue Microarray Studies on a Lymph Node–Negative Cohort
Authors: Mulligan Anna Marie , Pinnaduwage Dushanthi , Bull Shelley B. , O'Malley Frances P. , Andrulis Irene L.
Published: July 2008

Purpose: To determine whether data obtained from tissue microarrays (TMA) of a prospectively accrued node-negative breast cancer cohort are prognostically informative, we compared data derived from TMA with previously determined molecular markers. Subsequent to this validation, we examined outcome in specific subgroups defined using TMA data.

Experimental Design: A consecutive series of 1,561 patients were followed for recurrence (median follow-up of 107 months). Estrogen receptor, progesterone receptor, p53, and HER2 expression, examined using TMA constructed from 887 tumors, was compared with status evaluated previously by biochemical and molecular methods. The associations with risk of recurrence were examined for biomarkers as well as for HER2, luminal, and basal subgroups defined by immunohistochemical expression.

Results: In line with earlier molecular studies, a significant risk of recurrence was found in patients with HER2 overexpression (relative risk = 2.30; P = 0.002) and p53-positive tumors (relative risk = 1.81; P = 0.005) in univariate Cox model analysis. Although complete concordance between methodologies was not observed for estrogen receptor and progesterone receptor, their associations with disease-free survival were consistent with established prognostic findings. Patients with basal-type tumors fared worse within 36 months of diagnosis but not thereafter.

Conclusions: This study shows the clinical validity of TMA in evaluating the importance of prognostic markers in this cohort. Furthermore, it shows a marked time-dependent effect in tumor subgroups, most notable within the basal subgroup. Our data suggest that patients with basal-like tumors may be broadly separable into two clinically distinctive groups: those likely to experience disease recurrence in the short term and those that will experience long-term survival.
Moscatilin Induces Apoptosis in Human Colorectal Cancer Cells: A Crucial Role of c-Jun NH2-Terminal Protein Kinase Activation Caused by Tubulin Depolymerization and DNA Damage
Authors: Chen Tzu-Hsuan , Pan Shiow-Lin , Guh Jih-Hwa , Liao Cho-Hwa , Huang Der-Yi , Chen Chien-Chih , Teng Che-Ming
Published: July 2008

Purpose: To study the effect of moscatilin (purified from the stem of orchid Dendrobrium loddigesii) on the proliferation of human colorectal cancer HCT-116 cells in vitro and in vivo.

Experimental Design: The growth inhibition of moscatilin was screened on several human cancer cell lines. The effect of moscatilin on tubulin was detected in vitro. Following moscatilin treatment on HCT-116 cells, c-Jun NH2-terminal protein kinase (JNK) and caspase activation was studied by Western blot analysis, and DNA damage was done by Comet assay. Specific JNK inhibitor SP600125 was cotreated to reverse moscatilin-induced apoptosis. Tumor growth inhibition of moscatilin was done on HCT-116 xenograft models.

Results: Moscatilin induced a time-dependent arrest of the cell cycle at G2-M, with an increase of cells at sub-G1. Moscatilin inhibited tubulin polymerization, suggesting that it might bind to tubulins. Moscatilin also induced the phosphorylation of JNK1/2. SP600125 significantly inhibited the activation of caspase-9 and caspase-3 and the subsequent moscatilin-induced apoptosis. The data suggest that JNK activation may contribute to moscatilin-mediated apoptosis signaling. A parallel experiment showed that SP600125 significantly inhibits Taxol- and vincristine-induced HCT-116 cell apoptosis. This suggests that the JNK activation may be a common mechanism for tubulin-binding agents. Moreover, moscatilin induces DNA damage, phosphorylation of H2AX and p53, and up-regulation of p21. Our HCT-116 xenograft models show the in vivo efficacy of moscatilin.

Conclusions: In summary, our results suggest that moscatilin induces apoptosis of colorectal HCT-116 cells via tubulin depolymerization and DNA damage stress and that this leads to the activation of JNK and mitochondria-involved intrinsic apoptosis pathway.
Efficacy of Superoxide Dismutase Mimetic M40403 in Attenuating Radiation-Induced Oral Mucositis in Hamsters
Authors: Murphy Christopher K. , Fey Edward G. , Watkins Brynmor A. , Wong Vivien , Rothstein David , Sonis Stephen T.
Published: July 2008

Purpose: M40403 is a small-molecule superoxide dismutase mimetic that has shown efficacy in animal model disease states in which superoxide anions are thought to play a key role. Radiation treatment and chemotherapy for cancer generate free oxygen radicals that are hypothesized to trigger unwanted side effects in healthy tissue. For some patients undergoing these antineoplastic treatments, one of the most prevalent side effects is oral mucositis, which is a painful, often dose-limiting condition. Preclinical and clinical studies of this condition have shown the positive effect of treatment with compounds that decrease free oxygen radicals. This study investigated the efficacy M40403 in a clinically relevant hamster model of acute, radiation-induced oral mucositis.

Methods: Oral mucositis was induced in hamsters by irradiation of the cheek pouch. The ability of i.p. administered M40403 to decrease the duration and severity of oral mucositis was assessed after treatment at different doses and dosing schedules. Oral mucositis was scored using the WHO grading scale.

Results: Compared with placebo-treated animals, those irradiated on day 0 and treated twice daily with 30 mg/kg M40403 had significantly less severe and shorter duration mucositis over a range of treatment schedules, including from days -1 to 3, day 0 to 3, and day 0 alone. Similar efficacy was achieved at doses of 10 and 3 mg/kg twice daily on days -1 to 3.

Conclusions: These results implicate free oxygen radicals in the onset of oral mucositis and also provide the basis for further development of M40403 in the prevention of this condition in at-risk cancer patients.
A Pharmacodynamic Model for the Time Course of Tumor Shrinkage by Gemcitabine + Carboplatin in Non–Small Cell Lung Cancer Patients
Authors: Tham Lai-San , Wang Lingzhi , Soo Ross A. , Lee Soo-Chin , Lee How-Sung , Yong Wei-Peng , Goh Boon-Cher , Holford Nicholas H.G.
Published: July 2008

Purpose: This tumor response pharmacodynamic model aims to describe primary lesion shrinkage in non–small cell lung cancer over time and determine if concentration-based exposure metrics for gemcitabine or that of its metabolites, 2′,2′-difluorodeoxyuridine or gemcitabine triphosphate, are better than gemcitabine dose for prediction of individual response.

Experimental Design: Gemcitabine was given thrice weekly on days 1 and 8 in combination with carboplatin, which was given only on day 1 of every cycle. Gemcitabine amount in the body and area under the concentration-time curves of plasma gemcitabine, 2′,2′-difluorodeoxyuridine, and intracellular gemcitabine triphosphate in white cells were compared to determine which best describes tumor shrinkage over time. Tumor growth kinetics were described using a Gompertz-like model.

Results: The apparent half-life for the effect of gemcitabine was 7.67 weeks. The tumor turnover time constant was 21.8 week·cm. Baseline tumor size and gemcitabine amount in the body to attain 50% of tumor shrinkage were estimated to be 6.66 cm and 10,600 mg. There was no evidence of relapse during treatment.

Conclusions: Concentration-based exposure metrics for gemcitabine and its metabolites were no better than gemcitabine amount in predicting tumor shrinkage in primary lung cancer lesions. Gemcitabine dose-based models did marginally better than treatment-based models that ignored doses of drug administered to patients. Modeling tumor shrinkage in primary lesions can be used to quantify individual sensitivity and response to antitumor effects of anticancer drugs.
Human CD4+ T Lymphocytes Recognize a Vascular Endothelial Growth Factor Receptor-2–Derived Epitope in Association with HLA-DR
Authors: Sun Yuansheng , Song Mingxia , Jäger Elke , Schwer Christina , Stevanovic Stefan , Flindt Sven , Karbach Julia , Nguyen Xuan D. , Schadendorf Dirk , Cichutek Klaus
Published: July 2008

Purpose: Given the multiple escape mechanisms of tumor cells, immunotherapy targeting tumor-dependent stroma may be an effective cancer treatment strategy. Animal models indicate that inducing immunity to tumor endothelia engenders potent antitumor effects without significant pathology. Recently, the first human tumor endothelial antigen vascular endothelial growth factor receptor-2 (VEGFR-2) recognized by HLA class I–restricted CD8+ T cells has been characterized. In this study, we sought to investigate specific recognition of this molecule by human CD4+ T cells.

Experimental Design: To identify HLA-DR–restricted antigenic peptides on VEGFR-2 recognized by CD4+ T cells of healthy donors and cancer patients.

Results: Nine candidate VEGFR-2 peptides with high binding probability to six common HLA-DRB1 alleles were synthesized using the SYFPEITHI algorithm. One 15-mer peptide (EKRFVPDGNRISWDS), mapping to the 167-181 region of VEGFR-2, stimulated CD4+ T cells in association with several HLA-DR alleles, including DR4 and DR7. Importantly, the epitope could be naturally processed and presented both by HLA-DR–matched antigen-expressing proliferating endothelial cells and by dendritic cells loaded with the native antigen. Furthermore, circulating VEGFR-2–specific CD4+ T cells were detected in 4 of 10 healthy donors and 12 of 40 cancer patients even after single-round peptide stimulation in short-term culture. Patient's T cells could recognize antigen-expressing proliferating endothelial cells in a HLA-DR–restricted fashion.

Conclusion: These findings indicate an important role for the 167-181 region of VEGFR-2 in the stimulation of CD4+ T cell responses to VEGFR-2 protein, and may be instrumental both for the development and monitoring of upcoming antitumor vessel vaccines against different cancers based on VEGFR-2 immunogens.
Gene Expression Profiles of Luteal Phase Fallopian Tube Epithelium from BRCA Mutation Carriers Resemble High-Grade Serous Carcinoma
Authors: Tone Alicia A. , Begley Heather , Sharma Monika , Murphy Joan , Rosen Barry , Brown Theodore J. , Shaw Patricia A.
Published: July 2008

Purpose: To identify molecular alterations potentially involved in predisposition to adnexal serous carcinoma (SerCa) in the nonmalignant fallopian tube epithelium (FTE) of BRCA1/2 mutation carriers, given recent evidence implicating the distal FTE as a common source for SerCa.

Experimental Design: We obtained and compared gene expression profiles of laser capture microdissected nonmalignant distal FTE from 12 known BRCA1/2 mutation carriers (FTEb) and 12 control women (FTEn) during the luteal and follicular phase, as well as 13 high-grade tubal and ovarian SerCa.

Results: Gene expression profiles of tubal and ovarian SerCa specimens were indistinguishable by unsupervised cluster analysis and significance analysis of microarrays. FTEb samples as a group, and four individual FTEb samples from the luteal phase in particular, clustered closely with SerCa rather than normal control FTE. Differentially expressed genes from these four samples relative to other FTEb samples, as well as differentially expressed genes in all FTEb luteal samples relative to follicular samples, were mapped to the I2D protein-protein interaction database, revealing a complex network affecting signaling pathways previously implicated in tumorigenesis. Two candidates, disabled homolog 2 mitogen-responsive phosphoprotein (DAB2) and Ski-like (SKIL), were further validated by real-time reverse transcription–PCR and tissue arrays. FTEb luteal and SerCa samples expressed higher levels of oncogenic SKIL and decreased levels of tumor suppressor DAB2, relative to FTEb follicular samples.

Conclusions: These findings support a common molecular pathway for adnexal SerCa and implicate factors associated with the luteal phase in predisposition to ovarian cancer in BRCA mutation carriers.
Increased Prevalence ofEGFR-Mutant Lung Cancer in Women and in East Asian Populations: Analysis of Estrogen-Related Polymorphisms
Authors: Bell Daphne W. , Brannigan Brian W. , Matsuo Keitaro , Finkelstein Dianne M. , Sordella Raffaella , Settleman Jeff , Mitsudomi Tetsuya , Haber Daniel A.
Published: July 2008

Purpose: Somatic mutations in the epidermal growth factor receptor (EGFR) gene occur in a subset of non–small-cell lung cancer (NSCLC) and are highly predictive of the clinical response to selective EGFR kinase inhibitors. The prevalence of EGFR-mutant NSCLC is appreciably higher in females than in males and in East Asian than in Caucasian populations. We hypothesized that these disparate frequencies may be attributable to underlying genetic modifiers. Given the coincident differences in sex and ethnic origin, we tested allozymatic variants of enzymes involved in estrogen biosynthesis and metabolism, encoded by polymorphic alleles known to differ in frequency between Caucasian and Asian populations, as modifying alleles.

Experimental Design: We genotyped nine polymorphisms in the CYP1A1, CYP17A1, CYP19, HSD17B1, COMT, GSTM1, and GSTT1 genes, in a series of 100 Japanese NSCLCs, selected for equal representation of EGFR wild-type (wt) and EGFR-mutant cases, as well as male and female cases. Associations between polymorphic variants and the EGFR genotype and sex of NSCLC cases were examined using Fisher's exact test of significance.

Results: Only CYP1A1*2C showed a difference in allele frequency that approached statistical significance. Heterozygotes were underrepresented among EGFR-mutant cases compared with EGFR-wt cases (27% versus 47%, P = 0.08), with a concurrent trend toward overrepresentation of CYP1A1*2CIle/Ile homozygotes among EGFR-mutant cases as compared with EGFR-wt cases (69% versus 51%, P = 0.13).

Conclusion: Within the power of this study, our findings suggest that the selected polymorphic variants in the estrogen biosynthesis and metabolism pathways are unlikely to be major genetic modifiers of the prevalence of EGFR-mutant NSCLC.
DNA Damage Detection and Repair Pathways—Recent Advances with Inhibitors of Checkpoint Kinases in Cancer Therapy
Authors: Ashwell Susan , Zabludoff Sonya
Published: July 2008

Insights from cell cycle research have led to the hypothesis that tumors may be selectivity sensitized to DNA-damaging agents, resulting in improved antitumor activity and a wider therapeutic margin. The theory relies primarily on the observation that the majority of tumors are deficient in the G1-DNA damage checkpoint pathway, resulting in reliance on S and G2 phase checkpoints for DNA repair and cell survival. The S and G2 phase checkpoints are predominantly regulated by checkpoint kinase 1; thus, inhibition of checkpoint kinase 1 signaling impairs DNA repair and increases tumor cell death. Normal tissues, however, have a functioning G1 checkpoint signaling pathway that allows for DNA repair and cell survival. There is now a large body of preclinical evidence showing that checkpoint kinase inhibitors do indeed enhance the efficacy of both conventional chemotherapy and radiotherapy, and several agents have recently entered clinical trials. Excitingly, additional therapeutic opportunities for checkpoint kinase inhibitors continue to emerge as biology outside their pivotal role in cell cycle arrest is further elucidated.
Combined Inhibition of c-Src and Epidermal Growth Factor Receptor Abrogates Growth and Invasion of Head and Neck Squamous Cell Carcinoma
Authors: Koppikar Priya , Choi Seung-Ho , Egloff Ann Marie , Cai Quan , Suzuki Shinsuke , Freilino Maria , Nozawa Hiroshi , Thomas Sufi M. , Gooding William E. , Siegfried Jill M. , Grandis Jennifer R.
Published: July 2008

Purpose: Increased expression and/or activation of epidermal growth factor receptor (EGFR) is associated with tumor progression and poor prognosis in many cancers, including head and neck squamous cell carcinoma (HNSCC). Src family kinases, including c-Src, mediate a variety of intracellular or extracellular signals that contribute to tumor formation and progression. This study was undertaken to elucidate the role of c-Src in the growth and invasion of HNSCC and to determine the effects of combined targeting of EGFR and Src kinases in HNSCC cell lines.

Experimental Design: HNSCC cells were engineered to stably express a dominant-active form of c-Src and investigated in cell growth and invasion assays. The biochemical effects of combined treatment with the Src inhibitor AZD0530, a potent, orally active Src inhibitor with Bcr/Abl activity, and the EGFR kinase inhibitor gefitinib were examined, as well as the consequences of dual Src/EGFR targeting on the growth and invasion of a panel of HNSCC cell lines.

Results: HNSCC cells expressing dominant-active c-Src showed increased growth and invasion compared with vector-transfected controls. Combined treatment with AZD0530 and gefitinib resulted in greater inhibition of HNSCC cell growth and invasion compared with either agent alone.

Conclusions: These results suggest that increased expression and activation of c-Src promotes HNSCC progression where combined targeting of EGFR and c-Src may be an efficacious treatment approach.
Functional Variants of the NEIL1 and NEIL2 Genes and Risk and Progression of Squamous Cell Carcinoma of the Oral Cavity and Oropharynx
Authors: Zhai Xiaodong , Zhao Hui , Liu Zhensheng , Wang Li-E , El-Naggar Adel K. , Sturgis Erich M. , Wei Qingyi
Published: July 2008

Purpose: Human DNA glycosylases NEIL1 and NEIL2 participate in oxidized base excision repair and protect cells from DNA damage. NEIL1 (MIM:608844) and NEIL2 (MIM:608933) variants may affect their protein functions, leading to altered cell death and carcinogenesis. To date, only one reported study has investigated the association between NEIL1 and NEIL2 polymorphisms and cancer risk.

Experimental Design: Genotype and haplotypes of the NEIL1 NT_010194.16:g.46434077G>T (rs7182283) and g.46438282C>G (rs4462560) and NEIL2 NT_077531.3:g.4102971C>G (rs804270) polymorphisms were determined for 872 patients with newly diagnosed squamous cell carcinomas of the oral cavity and oropharynx (SCCOOP) and 1,044 cancer-free non–Hispanic white control subjects frequency-matched by age and sex. Crude and adjusted odds ratios (OR) and 95% confidence intervals (95% CI) were calculated using multivariate logistic regression, and false-positive report probabilities were also calculated.

Results: We found no overall differences in the frequencies of alleles, genotypes, and haplotypes of NEIL1 g.46434077G>T and NEIL1 g.46438282C>G polymorphisms between cases and controls. However, the NEIL2 g.4102971CC genotype was associated with a significantly increased risk of SCCOOP (adjusted OR, 1.30; 95% CI, 1.02-1.65); this increase in risk was the highest among current alcohol drinkers (adjusted OR, 1.87; 95% CI, 1.28-2.72), particularly in patients with oropharyngeal cancer (adjusted OR, 1.35; 95% CI, 1.04-1.76). The NEIL2 g.4102971CC genotype was also significantly associated with SCCOOP of advanced stages.

Conclusions: Polymorphisms of the NEIL2 gene may be markers for risk and progression of SCCOOP, particularly in patients with oropharyngeal cancer. Larger studies are needed to confirm our findings.
Multiple Mechanisms of Telomere Maintenance Exist and Differentially Affect Clinical Outcome in Diffuse Malignant Peritoneal Mesothelioma
Authors: Villa Raffaella , Daidone Maria Grazia , Motta Rosita , Venturini Lorenza , De Marco Cinzia , Vannelli Alberto , Kusamura Shigeki , Baratti Dario , Deraco Marcello , Costa Aurora , Reddel Roger R. , Zaffaroni Nadia
Published: July 2008

Purpose: This study aims to investigate the prevalence of the two known telomere maintenance mechanisms, telomerase activity (TA) and alternative lengthening of telomeres (ALT), and to assess their prognostic relevance in diffuse malignant peritoneal mesothelioma (DMPM).

Experimental Design: In 44 DMPM specimens obtained from 38 patients, TA was determined using the telomeric repeat amplification protocol and ALT was detected by assaying ALT-associated promyelocytic leukemia nuclear bodies. The prognostic significance of telomere maintenance mechanisms was analyzed by Cox regression in the overall series and in a subset of 29 patients who underwent a uniform treatment regimen consisting of cytoreductive surgery and hyperthermic i.p. chemotherapy.

Results: Telomere maintenance mechanisms were detectable in 86.4% of DMPM: ALT or TA alone was found in 18.2% or 63.6% of lesions, respectively, whereas two cases (4.6%) were ALT+/TA+. TA and ALT proved to be inversely associated (P = 0.002). In the overall series, TA was prognostic for 4-year relapse (TA+ versus TA−, hazard ratio, 3.30; 95% confidence interval, 1.23-8.86; P = 0.018) and cancer-related death (TA+ versus TA−, hazard ratio, 3.56; 95% confidence interval, 1.03-12.51; P = 0.045), whereas ALT failed to significantly affect clinical outcome. These results held true also in the subset of patients submitted to uniform treatment with cytoreductive surgery and hyperthermic i.p. chemotherapy.

Conclusions: Our results indicate that both known telomere maintenance mechanisms, TA and ALT, are present in DMPM and differentially affect patient prognosis.
Dendritic Cell Vaccination with Xenogenic Polypeptide Hormone Induces Tumor Rejection in Neuroendocrine Cancer
Authors: Papewalis Claudia , Wuttke Margret , Seissler Jochen , Meyer Yvonne , Kessler Caroline , Jacobs Benedikt , Ullrich Evelyn , Willenberg Holger S. , Schinner Sven , Baehring Thomas , Scherbaum Werner A. , Schott Matthias
Published: July 2008

Purpose: No relevant breakthrough has yet been achieved in the identification of tumor antigens in many neuroendocrine cancer types that exist, such as malignant gastrinoma, insulinoma, or medullary thyroid carcinoma. The aim of this study was to proof the concept of dendritic cell immunization with a tumor cell-specific polypeptide hormone as a target molecule in a transgenic mouse model for medullary thyroid carcinoma (Ret/Cal mice).

Experimental Design: Ret/Cal mice were repeatedly immunized for up to 6 months with amino acid–modified (xenogenic) calcitonin-pulsed dendritic cells. Xenogenic calcitonin was chosen for immunization due to its higher immunogenicity as compared with murine calcitonin.

Results: Lymph nodes from control protein-immunized mice did not show any macroscopic abnormalities, whereas tumor peptide-treated mice revealed in general profoundly enlarged lymph nodes. In tetramer analysis of paratumorous lymph nodes, 1.9% to 3.1% of all infiltrating CD8+ T cells were specific for one of three tumor epitopes tested. Analysis of the activated IFN-γ-secreting component in splenic cells revealed an average of 2.8% tumor epitope-specific CD8+ cells. Immunohistochemistry revealed strong CD8+ tumor infiltration in calcitonin-vaccinated mice. In addition, these cells also showed strong in vitro lysis capacity at up to 63.3%. Most importantly, calcitonin-immunized mice revealed largely diminished tumor outgrowth (−74.3%) compared with control mice (P < 0.0001). Likewise, serum calcitonin levels in calcitonin-vaccinated Ret/Cal mice were lower than in the control group.

Conclusion: These results have a major effect, as they are the first to establish a role for xenogenic polypeptide hormones as target molecules for immunotherapy in endocrine malignancies.
Pharmacologic Targets on the Female Urethra
Authors: Canda A. Erdem , Cinar Mehtap G. , Turna Burak , Sahin M. Oguz
Published: July 2008

Introduction: This article reviews the mechanisms affecting contraction and relaxation of the urethra in order to establish a basis for current and future treatments for urinary incontinence in women. Material and Methods: A review of the English literature using MEDLINE was performed between 1970 and 2008 on female urethra pharmacology, urinary incontinence, and mechanisms involved in contraction and relaxation of the female human urethra. Results: α-Adrenoceptors (ARs) cause contraction and β-ARs cause relaxation. Use of selective α-agonist and β-AR blocker agents might have potential for the treatment of stress urinary incontinence. Tolerable doses of cholinergic agonists did not have significant effects on intraurethral pressure. Nitric oxide seems to be the major nonadrenergic-noncholinergic inhibitory transmitter causing relaxation. c-kit-positive interstitial cells seem to regulate urethral tone. The roles of adenosine triphosphate and carbon monoxide have not been fully investigated in humans. Neuropeptides function similarly to the urinary bladder. Prostanoids cause urethral contraction and relaxation depending on their subtypes. Serotonin enhances the strength of urethral sphincteric contractions. The Rho-kinase pathway also appears to be modulating smooth muscle contraction in the urethra. Conclusions: Understanding of the urethral function and pharmacology may lead to the development of promising new agents which might be useful in the management of urinary incontinence in women.
Cytokine Therapy Response as a Selection Criterion for Cytoreductive Nephrectomy in Metastatic Renal Clear-Cell Carcinoma of Intermediate Prognosis
Authors: Bex Axel , Haanen John B.A.G. , Vyth-Dreese Florry A. , Horenblas Simon , de Gast Gijsbert C.
Published: July 2008

Aims: To assess the strategy of using an absence of progression at metastatic sites following initial cytokine therapy outcome as a selection criterion for nephrectomy in patients with synchronous metastatic renal carcinoma and an intermediate prognosis according to the Memorial Sloan Kettering prognostic index classification. Materials and Methods: A combined retrospective analysis of patients with clear-cell subtype from studies of initial cytokine treatment response to assist with selection of patients for nephrectomy. We analyzed survival times, UCLA integrated staging system scores, number of nephrectomies and risk of progression to unresectability of the primary tumor during treatment. Results: There were 33 patients in total. Nephrectomies were not performed in 10 (30%) patients whose cancers had progressed at metastatic sites. Median survival time was 4 months with none of the patients dying of local tumor progression. The median survival time of the 21 patients with nonprogressive cancer and the primary removed was 17 months. Of those, 8 had a survival time ≤1 year (median 8.5 months) and a progression-free survival time of 4 months and 13 had a survival time >1 year (median 25 months). The median progression-free survival time was 7 months (4–57 months). Four of the 5 objective responses at metastatic sites (5/33, 14%) occurred in those surviving >1 year. Conclusions: We propose that progression at metastatic sites during initial immunotherapy may be used to identify patients with a short survival time and who are unlikely to benefit from nephrectomy.
Activation of PI3K Is Associated with Reduced Survival in Renal Cell Carcinoma
Authors: Merseburger Axel S. , Hennenlotter Joerg , Kuehs Ursula , Simon Perikles , Kruck Stephan , Koch Eva , Stenzl Arnulf , Kuczyk Markus A.
Published: July 2008

Objectives: The epidermal growth factor receptor- (EGFR) activated phosphatidylinositol 3-kinase (PI3K)/protein kinase B (PKB/Akt) pathway is associated with tumorigenesis and progression. The aims of the present study were to determine the expression patterns of Akt pathway parameters PI3K, phosphatase and tensin homolog (PTEN), phosphor-Akt (p-Akt) and their combination, for their possible prognostic value in renal cell carcinoma (RCC). PTEN dephosphorylates the liquid product of PI3K. Methods: Tumor samples from 176 RCC patients were investigated for PTEN, p-Akt and PI3K expression by immunohistochemistry. Expression levels were correlated to clinical variables and postoperative outcome by uni- and multivariate statistical analysis. Results: The various expression levels within the tumor samples were independent of histological grade and tumor stage, due to different levels of activation of the PI3K/p-Akt pathway. The activation of PI3K protein was found to be significantly associated with reduced survival times (p = 0.0304, multivariate analysis). Analysis of combined biomarker expressions showed that decreased long-term survival was correlated with PTEN low/p-Akt high expression (p < 0.05). Conclusions: Activation of the PI3K pathway is significantly associated with adverse clinical outcome in RCC. Analysis of biomarker combinations might identify high-risk patients and a subsequent need to adapt treatment modalities. Molecular pathways regulating PI3K activation appear to be promising targets for drug development in the clinical management of RCC patients.
Comparative Promoter Methylation Analysis of p53 Target Genes in Urogenital Cancers
Authors: Christoph Frank , Hinz Stefan , Weikert Steffen , Kempkensteffen Carsten , Schostak Martin , Miller Kurt , Schrader Mark
Published: July 2008

Introduction: The methylation status of selected new p53 target genes in bladder, kidney and testicular cancer was investigated to find similarities in methylation frequency and individual levels of methylation with regard to the histopathological classification and biological behavior. Material and Methods: The patients’ samples were evaluated using real-time methylation-specific PCR (MSP) investigating the methylation status of APAF-1, CASP-8, DAPK-1 and IGFBP-3. Included were 103 patients with bladder cancer, 85 patients with kidney cancer and 42 patients with testicular cancer in non-advanced and advanced tumor stages. Non-cancerous tissue from 49 patients was used as control. Results: Methylation frequency was highest for APAF-1 (88–100%) and DAPK-1 (17–86%) through all the different tumor types. Highest APAF-1 and DAPK-1 levels of methylation were found in the advanced tumor groups. In normal tissue, methylation frequency and methylation levels were significantly lower. APAF-1 methylation was also frequent in normal testicular tissue but to lower methylation levels as in cancerous tissue. APAF-1 and IGFBP-3 methylation levels were significantly higher in recurrent superficial and muscle-invasive bladder tumors. Methylation levels of APAF-1 also correlated with higher risk for recurrent metastatic disease in non-advanced tumors of the kidney. Conclusions: The methylation profile observed demonstrates a substantial role of the APAF-1 gene in tumorigenesis. The different methylation pattern in testicular cancer might represent a different methylotype of this cancer. The extent of promoter methylation may be a promising target for application as a tumor marker in urogenital cancer disease.
Does the Expression of Fascin-1 and Tumor Subclassification Help to Assess the Risk of Recurrence and Progression in T1 Urothelial Urinary Bladder Carcinoma?
Authors: Soukup V. , Babjuk M. , Dušková J. , Pešl M. , Szakáczová M. , Zámečník L. , Dvořáček J.
Published: July 2008

Introduction: To evaluate the prognostic value of T1 subclassification and fascin-1 expression in T1 human urothelial cell carcinoma of the bladder. Materials and Methods: In a prospective study with 105 consecutive patients, T1 tumors were subclassified into 2 groups according to the depth of tumor invasion. The tunica muscularis mucosae was used as a landmark. The expression of fascin-1 was examined by using an anti-fascin-1 mouse monoclonal antibody and was evaluated semiquantitatively for both intensity and distribution. The patients were followed up for 27.3 ± 13.7 months. Results: The T1 tumor subclassification was feasible in 99 patients (94%). T1a tumor was detected in 77 patients (73%), T1b tumor in 22 patients (21%). An invasive tumor was found in 5 patients (4.8%) during the restaging transurethral resection of the bladder. The risk of understaging in patients with T1b tumor was 18%. There was not a significant difference in time to the recurrence in the T1a and the T1b group. The progression-free survival rates were significantly different between both groups (p = 0.0034). No correlation was found between fascin-1 positivity and the depth of tumor invasion. Fascin-1 positivity did not correlate with recurrence or the progression-free intervals. In the multivariate analysis, only the extent of lamina propria invasion was an independent predictor of the tumor progression. The fascin positivity was not an independent prognostic factor relating to the risk of recurrence or progression. Conclusion: The finding of T1b tumor was connected with a significantly higher risk of progression and understaging. The fascin-1 expression did not correlate with the depth of tumor invasion or with the tumor recurrence or progression.
Kohki Tea Protects the Rabbit Bladder from Ischemia/Reperfusion-Induced Contractile Dysfunction
Authors: Levin Robert M. , Leggett Robert E. , Whitbeck Catherine , Matsumoto Seiji , Ohto Nobuaki , Ikeda Takao , Mizutani Kenji , Higurashi Akifumi
Published: July 2008

Objectives: Results of several studies indicated that ischemia/reperfusion is an etiological factor in obstructive bladder dysfunction. Kohki tea pretreatment was shown to reduce the dysfunctions induced by partial outlet obstruction in rabbits. The current study was designed to determine if pretreatment of rabbits with Kohki tea could prevent the contractile dysfunctions induced by bilateral ischemia followed by reperfusion. Methods: New Zealand white rabbits were separated into several groups; one half of each group was pretreated by oral gavage for 3 weeks with Kohki tea and the other half was treated with vehicle (water). Experimental groups were subjected to bilateral ischemia for either 1 or 3 h followed by reperfusion for either 1 h or 1 week (4 groups). The results from the experimental groups were compared to the groups of rabbits receiving sham operations. Results: Under all experimental conditions, Kohki tea significantly reduced the contractile dysfunctions induced by ischemia and ischemia followed by reperfusion. Conclusions: This data is consistent with the concept that Kohki tea acts by protecting the bladder smooth muscle and mucosa from cellular damage caused by ischemia/reperfusion.
Gonadotropin-Releasing Hormone (GnRH) and GnRH Receptor in Bladder Cancer Epithelia and GnRH Effect on Bladder Cancer Cell Proliferation
Authors: Bahk Jong Yoon , Kim Myeong Ok , Park Moon Seok , Lee Hae Young , Lee Jeong-Hee , Chung Bong Chul , Min Seung Ki
Published: July 2008

Introduction: Gonadotropin-releasing hormone (GnRH) is the pivotal hormone in the hypothalamopituitary gonadal axis. Recently, localization of extrahypothalamic GnRHs and GnRH receptors has been made in several organs but not in the bladder. We studied the extrahypothalamic GnRH and GnRH receptor in bladder cancer epithelia, and the role of GnRH on bladder cancer cell proliferation. Material and Methods: Normal human bladder mucosa, human transitional bladder cancer tissue, and 4 bladder cancer cell lines were used. For culture media, normal or charcoal-stripped serum with exogenous GnRH of different concentrations (0, 10–3, 10–5, and 10–7M) were supplemented. For detection of GnRH and the GnRH receptor and its mRNAs, RNase protection assay, in situ hybridization, and immunocytochemistry were performed. Cellular proliferation was measured by hemocytometer and the cell cycle by flow cytometer. Results: GnRH and GnRH receptor mRNA expression were detected in all cancer cell lines and human bladder cancer tissues. GnRH and GnRH receptors were localized in bladder cancer epithelial cells, but the density was not even. There were no significant differences (p > 0.05) in proliferation, and no significant change (p > 0.05) in cell cycle with GnRH supplements compared to controls. Conclusion: The bladder epithelia produce GnRH and the GnRH receptor in both normal and malignant tissues, but GnRH does not induce proliferation or cell cycle change of bladder cancer cells.
False Positive 18F-FDG PET Scan in Adrenal Oncocytoma
Authors: Acar C. , Akkas B.E. , Sen I. , Sozen S. , Kitapci M.T.
Published: July 2008

18F-FDG whole-body positron emulsion tomography (18F-FDG PET) has become an established imaging modality for a variety of cancers. Today, 18F-FDG PET is utilized to differentiate benign from malignant non-functioning adrenal masses. In this report, a 25-year-old woman presented with a 2-month history of left flank pain. Abdominal CT revealed a left 6.5 × 4.5 cm adrenal mass with regular margins and focal calcification. To make a differential diagnosis, 18F-FDG PET was performed. Preoperative laboratory studies showed that the mass was non-functioning. A left adrenalectomy was performed through a left subcostal incision. The final pathologic evaluation revealed adrenal oncocytoma. We present the disassociation between preoperative 18F-FDG PET and pathologic findings of a benign adrenocortical oncocytoma.
Neoadjuvant Therapy with Sorafenib in Advanced Renal Cell Carcinoma with Vena Cava Extension Submitted to Radical Nephrectomy
Authors: Di Silverio Franco , Sciarra Alessandro , Parente Ulderico , Andrea Alfarone , Von Heland Magnus , Panebianco Valeria , Passariello Roberto
Published: July 2008

A 71-year-old man with advanced left renal cell carcinoma (lymph node involvement and vena cava thrombus) was submitted to 6 months of neoadjuvant treatment with sorafenib before open radical nephrectomy. After sorafenib treatment and before surgery a new CT scan confirmed the presence of a 9.0 cm in diameter solid mass in the left kidney but a reduction in thrombus extension, limited to the left renal vein. At histological examination after radical nephrectomy, over 90% of the renal mass was substituted by necrotic tissue.
Strangulation Caused by a Small Bowel Epiploic Appendage: Report of a Case
Authors: Nemoto Hiroshi , Yoshizawa Yasuo , Hibi Kenji , Saito Mitsuo , Ishibashi Kazuyoshi , Sanada Yutaka , Tate Genshu
Published: July 2008

While many recent cases of colonic epiploic appendage causing acute abdomen have been reported, such appendages of the small bowel are extremely rare. We present a 59-year-old woman in whom a small bowel epiploic appendage caused volvulus. She presented with abdominal pain and vomiting in the absence of previous abdominal operations. A diagnosis of small bowel obstruction from strangulation was made. Laparotomy disclosed bloody peritoneal fluid and a closed loop of strangulated small intestine. An adherent band composed of an epiploic appendage and intestine had completely encircled a loop of jejunum, leading to obstruction. This band was released, and approximately 80 cm of gangrenous bowel was resected. Four epiploic appendages 5–6 cm in length were attached to the ileum at the mesenteric border, beginning at a point 70 cm proximal to the terminal ileum.
Geophagy in New World Monkeys (Platyrrhini): Ecological and Geographic Patterns
Authors: Ferrari Stephen F. , Veiga Liza M. , Urbani Bernardo
Published: July 2008

Geophagy has been recorded in an increasing number of New World monkeys (Platyrrhini) over recent years, permitting a tentative analysis of ecological patterns. While geophagy has now been recorded in species representing all 4 platyrrhine families and a majority of genera, there is a marked tendency for it to occur in the larger-bodied Pitheciidae and Atelidae. Howlers (Alouatta) are responsible for almost a third of reports, which are concentrated in the more frugivorous species, Alouatta belzebul and Alouatta seniculus. Geophagy may also be relatively common in the spider monkeys (Ateles) and the pitheciids, which are specialised frugivores and seed predators, respectively. An overview of the available data points to a marked Amazonian bias, allowing for geographical differences in the number of species and field studies. This pattern is demonstrated most emphatically by Alouatta, for which there are almost as many reports as field studies in the Amazon basin, in stark contrast with Central American sites, which have a long tradition of fieldwork, but no published records of geophagy. There are also relatively few reports from the Brazilian Atlantic forest. Despite the growth in reports, and the patterns identified here, the functional aspects of geophagy in the platyrrhines still remain unclear.
Development of Functional If Channels in mMSCs after Transfection with mHCN4: Effects on Cell Morphology and Mechanical Activity in vitro
Authors: Tong Shifei , Yao Qing , Wan Ying , Zhou Jianzhi , Shu Maoqin , Zhong Li , Li Yonghua , Zhang Qian , YinDai Jiajia , Song Zhiyuan
Published: July 2008

Objective: To study the functional properties of If channels and the changes in mechanical activity of mouse mesenchymal stem cells (mMSCs) transfected with mHCN4. Methods: mMSCs were purified by using CD11b-immunomagnetic microbeads and transfected with pMSCV-mHCN4-EGFP or pMSCV-EGFP. We examined the kinetic characteristics of the mHCN4 channel. The morphological changes of positively transfected mMSCs were investigated at the same time. Results: The If current recorded from the experimental group was sensitive to extracellular Cs+ (–44.5 ± 4.2 vs. –5.5 ± 1.0 pA/pF, p < 0.001). The half-maximal activation was –99.0 ± 5.8 mV. The time constant of activation was 451 ± 61 ms under –140 mV. The control cells did not show the current under the same conditions. The absolute values of half-maximal activation decreased in the presence of cAMP or cGMP in the experimental group (–78.6 ± 10.4 and –85.7 ± 8.6 vs. –99.0 ± 5.8 mV, respectively, p < 0.05). mMSCs transfected with pMSCV-mHCN4-EGFP could form spontaneous beating cells. Extracellular Cs+ decreased the beating rate significantly (196 ± 50 vs. 66 ± 23 bmp, p < 0.01). Conclusions: Functional If channels can be reconstructed in mMSCs infected with mHCN4. mMSCs modified by successful transfection with mHCN4 can differentiate so as to develop spontaneous mechanical activity.
Definitions of the Term ‘Recovered’ in Schizophrenia and Other Disorders
Authors: Færden Ann , Nesvåg Ragnar , Marder Stephen R.
Published: July 2008

Background: The use of the term ‘recovered’ in outcome studies of schizophrenia has for a long time been problematic because of the many different definitions in use. In the present study different definitions of recovered in schizophrenia are reviewed and compared with similar definitions in other fields of medicine. Sampling and Methods: A literature searchwas done for criteria-based definitions of recovered as used in follow-up studies of patients with schizophrenia during the last 50 years and the current use of the term in other fields of medicine. Results: In medicine, only the field of psychiatry defines the term recovered to be synonymous with no or minimal signs of illness. Other fields only apply the term when studying the outcome of a specific function. In psychiatry, only the field of schizophrenia includes both symptoms and functioning in the definition. All but 1 of the 18 definitions found in use in the field of schizophrenia required minimal or no symptoms, while all differed in defining functional recovery. Recovered was seldom defined as following from a state of remission, and studies varied in requiring a stable phase. Conclusion: When using the term in the field of schizophrenia, a distinction should be made between symptomatic and functional recovery in order to place it in line with other fields of medicine. To avoid confusing the process of recovery from the state of being recovered, the term recovered should be reserved for use in outcome studies, following from a time in remission. We suggest 2 years.