bluuebunny/crossref_metadata_2025_split huggingface dataset:
Microdistribution of Targeted, Fluorescently Labeled Anti–Carcinoembryonic Antigen Antibody in Metastatic Colorectal Cancer: Implications for Radioimmunotherapy
Authors: Fidarova Elena F. , El-Emir Ethaar , Boxer Geoffrey M. , Qureshi Uzma , Dearling Jason L.J. , Robson Mathew P. , Begent Richard H.J. , Trott Klaus R. , Pedley R. Barbara 
Published: May 2008

Abstract
Purpose: Most radioimmunotherapy studies on radiolabeled antibody distribution are based on autoradiographic and radioluminographic data, which provide a lack of detailed information due to low resolution. We used fluorescently labeled anti–carcinoembryonic antigen (CEA) antibody (A5B7) to investigate quantitatively the kinetics and microdistribution of antibody in a clinically relevant orthotopic colorectal cancer model (LS174T) using high-resolution digital microscopy.
Experimental Design: Nude mice bearing LS174T liver orthotopic tumors received a single i.v. injection of fluorescently labeled A5B7 and were sacrificed at 10 minutes, 1 hour, or 24 hours postinjection. Before sacrifice, mice were injected with the perfusion marker Hoechst 33342. An anti-CD31 antibody was used to detect blood vessel distribution. Cryostat sections were processed with immunofluorescence procedures and analyzed with fluorescence microscopy and image analysis techniques. The fluorescence images were related to morphologic images of the same or adjacent tumor sections.
Results: Fluorescently labeled antibody showed rapid, selective uptake into tumor deposits, with a strong negative correlation with tumor size at 10 minutes and 1 hour (P ≤ 0.01). By 24 hours, the correlation was no longer significant. The study showed movement of antibody across the tumor with time and a tendency to localize more uniformly by later time points (24 hours). The rate of antibody motility was similar in small and large tumor metastases, but small deposits showed more rapid antibody localization. Intratumoral vessels were positively related to tumor size (P ≤ 0.001).
Conclusion: The obtained data suggest that radioimmunotherapy can be highly efficient in an adjuvant or minimal residual disease setting.
Promoter Hypermethylation of Hallmark Cancer Genes in Atypical Adenomatous Hyperplasia of the Lung
Authors: Licchesi Julien D.F. , Westra William H. , Hooker Craig M. , Herman James G. 
Published: May 2008

Abstract
Purpose: According to current models of tumorigenesis, the progression of phenotypic changes culminating in overtly malignant carcinoma is driven by genetic and epigenetic alterations. The recognition of an early form of glandular neoplasia termed atypical adenomatous hyperplasia (AAH), a precursor lesion from which lung adenocarcinomas arise, provides an opportunity for characterizing early epigenetic alterations involved in lung tumorigenesis.
Experimental Design: We evaluated AAHs, adjacent normal lung tissue, and synchronous lung adenocarcinomas for promoter hypermethylation of genes implicated in lung tumorigenesis (p16, TIMP3, DAPK, MGMT, RARβ, RASSF1A, and hTERT).
Results: For individual genes and the number of genes methylated, we observed a significant increase in the frequency of promoter hypermethylation in the histologic progression from normal to AAH, with low-grade or high-grade atypia, and finally to adenocarcinoma (Ptrend ≤ 0.01). Multifocal AAHs from individual patients had distinct patterns of promoter hypermethylation, suggesting divergent epigenetic field defects. There were statistically significant positive associations for the presence of promoter hypermethylation of individual and multiple genes with advanced histology, with odds ratios between 4.3 and 58.5. p16 conveyed the strongest individual association for promoter hypermethylation when comparing tumor or high-grade AAH to low-grade AAH or normal tissue, with an odds ratio of 45.5 (95% confidence interval, 5.8-360.5).
Conclusion: This study shows epigenetic progression in the earliest stages of glandular neoplasia of the lung and has implications for early lung cancer detection.
GS-9219—A Novel Acyclic Nucleotide Analogue with Potent Antineoplastic Activity in Dogs with Spontaneous Non–Hodgkin's Lymphoma
Authors: Reiser Hans , Wang Jianying , Chong Lee , Watkins William J. , Ray Adrian S. , Shibata Riri , Birkus Gabriel , Cihlar Tomas , Wu Sylvia , Li Bei , Liu Xiaohong , Henne Ilana N. , Wolfgang Grushenka H.I. , Desai Manoj , Rhodes Gerald R. , Fridland Arnold , Lee William A. , Plunkett William , Vail David , Thamm Douglas H. , Jeraj Robert , Tumas Daniel B. 
Published: May 2008

Abstract
Purpose: GS-9219, a novel prodrug of the nucleotide analogue 9-(2-phosphonylmethoxyethyl)guanine (PMEG), was designed as a cytotoxic agent that preferentially targets lymphoid cells. Our objective was to characterize the antiproliferative activity, pharmacokinetics, pharmacodynamics, and safety of GS-9219.
Experimental Design: GS-9219 was selected through screening in proliferation assays and through pharmacokinetic screening. The activation pathway of GS-9219 was characterized in lymphocytes, and its cytotoxic activity was evaluated against a panel of hematopoietic and nonhematopoietic cell types. To test whether the prodrug moieties present in GS-9219 confer an advantage over PMEG in vivo, the pharmacokinetics, pharmacodynamics (lymph node germinal center depletion), and toxicity of equimolar doses of GS-9219 and PMEG were evaluated after i.v. administration to normal beagle dogs. Finally, proof of concept of the antitumor efficacy of GS-9219 was evaluated in five pet dogs with spontaneous, advanced-stage non–Hodgkin's lymphoma (NHL) following a single i.v. administration of GS-9219 as monotherapy.
Results: In lymphocytes, GS-9219 is converted to its active metabolite, PMEG diphosphate, via enzymatic hydrolysis, deamination, and phosphorylation. GS-9219 has substantial antiproliferative activity against activated lymphocytes and hematopoietic tumor cell lines. In contrast, resting lymphocytes and solid tumor lines were less sensitive to GS-9219. GS-9219, but not PMEG, depleted the germinal centers in lymphoid tissues of normal beagle dogs at doses that were tolerated. In addition, GS-9219 displayed significant in vivo efficacy in five dogs with spontaneous NHL after a single administration, with either no or low-grade adverse events.
Conclusion: GS-9219 may have utility for the treatment of NHL.
The Bone Marrow Microenvironment as a Tumor Sanctuary and Contributor to Drug Resistance
Authors: Meads Mark B. , Hazlehurst Lori A. , Dalton William S. 
Published: May 2008

Abstract
The bone marrow microenvironment facilitates the survival, differentiation, and proliferation of hematopoietic cells. These cells are supported by fibroblast-like bone marrow stromal cells, osteoblasts, and osteoclasts which secrete soluble factors and extracellular matrix proteins that mediate these functions. This rich environment serves as a safe haven not only for normal and malignant hematopoietic cells, but also for epithelial tumor cells that metastasize to bone, offering protection from chemotherapeutic agents by common mechanisms. Soluble factors produced in the bone marrow, such as stromal cell–derived factor-1 and interleukin-6, mediate homing, survival, and proliferation of tumor cells, and integrin-mediated adhesion sequesters tumor cells to this protective niche. Environment-mediated drug resistance includes a combination of soluble factors and adhesion, and can be subdivided into soluble factor–mediated drug resistance and cell adhesion–mediated drug resistance. Because it is induced immediately by the microenvironment and is independent of epigenetic or genetic changes caused by the selective pressure of drug exposure, environment-mediated drug resistance is a form of de novo drug resistance. In this form of drug resistance, tumor cells are transiently and reversibly protected from apoptosis induced by both chemotherapy and physiologic mediators of cell death. This protection allows tumor cells to survive the insult of chemotherapy, leading to minimal residual disease, and thereby increases the probability for the development of acquired drug resistance.
Associations of Matrix Metalloproteinase-9 Protein Polymorphisms with Lymph Node Metastasis but not Invasion of Gastric Cancer
Authors: Tang Yang , Zhu Jinwei , Chen Ling , Chen Linyin , Zhang Sheng , Lin Jianyin 
Published: May 2008

Abstract
Purpose: Like most cancers, gastric cancer has a complex multistep etiology that involves both environmental and genetic factors. Matrix metalloproteinase-9 (MMP-9) is frequently overexpressed in gastric cancer. We investigated the effect of the genetic differences in MMP-9 coding region on the occurrence and progression of gastric cancer.
Experimental Design: A case-control study was conducted in a population of 74 patients and 100 healthy people in southeast China. Individuals were genotyped for two single nucleotide polymorphisms (SNP) in MMP-9: R279Q and P574R. Genotypic distributions between patient and control groups were compared for correlations with cancer occurrence. Associations between genotypic distributions and several clinicopathologic features were also analyzed using univariate tests, multivariate logistic regression modeling, and stratified analyses.
Results: Significant associations were revealed between both SNPs and lymph node metastasis [P = 0.012 and 0.025; odds ratio (OR), 3.4 and 2.8, respectively]. After adjustment using logistic regression for the potential confounding effects of gender, age, and location of the tumors, homozygous MMP-9 279RR and 574PP are more evidently associated with lymph node metastasis with ORadjusted of 5.7 [95% confidence interval (95% CI), 1.80-18.34] and 4.2 (95% CI, 1.37-12.69). The homozygous 279R-574P haplotype showed a stronger association by an ORadjusted of 6.1 (95% CI, 1.92-12.29) and was also associated with the 1-year postoperative mortality (ORadjusted, 6.5; 95% CI, 1.18-35.74). Interestingly, our data also suggested that the MMP-9 polymorphisms seem to result in higher risk of lymph node metastasis through a pathway independent of cancer invasion because no positive associations were found between these polymorphisms and cancer invasion (OR, 0.59 &lt; 1). The stratified analyses indicated a synergistic interaction between the MMP-9 polymorphisms and the type of diffuse in affecting lymph node metastasis (OR, 13.4; Pbetween strata = 0.04). Significant association between both SNPs and the overall occurrence of gastric cancer was not observed.
Conclusion: The present study has shown significant associations between the two nonsynonymous MMP-9 polymorphisms with lymph node metastasis in gastric cancer, especially with the diffuse type. The relatively large values of ORs and disassociation with cancer invasion suggest that the genetic differences of MMP-9 protein play an important and specific role in lymph node metastases, and therefore, further investigation of the underlying molecular mechanism is warranted.
CS1, a Potential New Therapeutic Antibody Target for the Treatment of Multiple Myeloma
Authors: Hsi Eric D. , Steinle Roxanne , Balasa Balaji , Szmania Susann , Draksharapu Aparna , Shum Benny P. , Huseni Mahrukh , Powers David , Nanisetti Amulya , Zhang Yin , Rice Audie G. , van Abbema Anne , Wong Melanie , Liu Gao , Zhan Fenghuang , Dillon Myles , Chen Shihao , Rhodes Susan , Fuh Franklin , Tsurushita Naoya , Kumar Shankar , Vexler Vladimir , Shaughnessy John D. , Barlogie Bart , van Rhee Frits , Hussein Mohamad , Afar Daniel E.H. , Williams Marna B. 
Published: May 2008

AbstractPurpose: We generated a humanized antibody, HuLuc63, which specifically targets CS1 (CCND3 subset 1, CRACC, and SLAMF7), a cell surface glycoprotein not previously associated with multiple myeloma. To explore the therapeutic potential of HuLuc63 in multiple myeloma, we examined in detail the expression profile of CS1, the binding properties of HuLuc63 to normal and malignant cells, and the antimyeloma activity of HuLuc63 in preclinical models.Experimental Design: CS1 was analyzed by gene expression profiling and immunohistochemistry of multiple myeloma samples and numerous normal tissues. HuLuc63-mediated antimyeloma activity was tested in vitro in antibody-dependent cellular cytotoxicity (ADCC) assays and in vivo using the human OPM2 xenograft model in mice.Results: CS1 mRNA was expressed in &gt;90% of 532 multiple myeloma cases, regardless of cytogenetic abnormalities. Anti-CS1 antibody staining of tissues showed strong staining of myeloma cells in all plasmacytomas and bone marrow biopsies. Flow cytometric analysis of patient samples using HuLuc63 showed specific staining of CD138+ myeloma cells, natural killer (NK), NK-like T cells, and CD8+ T cells, with no binding detected on hematopoietic CD34+ stem cells. HuLuc63 exhibited significant in vitro ADCC using primary myeloma cells as targets and both allogeneic and autologous NK cells as effectors. HuLuc63 exerted significant in vivo antitumor activity, which depended on efficient Fc-CD16 interaction as well as the presence of NK cells in the mice.Conclusions: These results suggest that HuLuc63 eliminates myeloma cells, at least in part, via NK-mediated ADCC and shows the therapeutic potential of targeting CS1 with HuLuc63 for the treatment of multiple myeloma.
Hematogenous Metastasis in Gastric Cancer Requires Isolated Tumor Cells and Expression of Vascular Endothelial Growth Factor Receptor-1
Authors: Mimori Koshi , Fukagawa Takeo , Kosaka Yoshimasa , Kita Yoshiaki , Ishikawa Kenji , Etoh Tsuyoshi , Iinuma Hisae , Sasako Mitsuru , Mori Masaki 
Published: May 2008

Abstract
Purpose: Recent studies of cancer metastasis have focused on the role of premetastatic gene expression and circulating tumor cells. We did a blind prospective study in gastric cancer to assess the significance of isolated tumor cells (ITC) and to test the hypothesis that vascular endothelial growth factor receptor-1 (VEGFR-1) is expressed within the bone marrow at tumor-specific, premetastatic sites.
Experimental Design: Both bone marrow and peripheral blood samples from 810 gastric cancer patients were collected at the Central Hospital, National Cancer Center (Tokyo, Japan). The samples were transferred to Kyushu University Hospital (Beppu, Japan) where they were analyzed by quantitative real-time reverse transcription-PCR for three epithelial cell markers, carcinoembryonic antigen, cytokeratin-19, and cytokeratin-7, as well as VEGFR-1.
Results: ITCs were observed in peripheral blood and bone marrow even in early stages of gastric cancer. The frequency of ITC in bone marrow was significantly associated with the stage of disease by ANOVA (P &lt; 0.01). Gastric cancer metastasized when ITCs were observed in the presence of VEGFR-1. In the 380 patients who were ITC negative and showed low VEGFR-1 expression, synchronous (at the time of surgery) and heterochronous (recurrent) metastases were not observed.
Conclusions: ITCs circulate even in early stages of disease. Furthermore, elevated expression of VEGFR-1 facilitates the establishment of hematogenous metastases in gastric cancer. This study indicates that the simultaneous presence of ITC and VEGFR-1 expression at premetastatic sites is clinically significant for disease progression.
Epidermal Growth Factor Receptor Blockade in Combination with Conventional Chemotherapy Inhibits Soft Tissue Sarcoma Cell Growth In vitro and In vivo
Authors: Ren Wenhong , Korchin Borys , Zhu Quan-Sheng , Wei Caimiao , Dicker Adam , Heymach John , Lazar Alexander , Pollock Raphael E. , Lev Dina 
Published: May 2008

Abstract
Purpose: The epidermal growth factor receptor (EGFR) is highly expressed in many human soft tissue sarcomas (STS). However, EGFR blockade has not apparently been used for human STS therapy; therefore, we examined the in vitro and in vivo effects and the underlying mechanisms before considering EGFR blockade as a therapy for STS patients.
Experimental Design: Human STS tissues and cell lines were used to study EGFR expression and activation. Western blot analysis was used to evaluate effects of EGFR activation on downstream signaling. Cell culture assays were used to assess the effect of EGF stimulation as well as EGFR blockade (using an EGFR tyrosine kinase inhibitor, Iressa; AstraZeneca) on STS cell growth, apoptosis, and chemosensitivity. An in vivo study (HT1080 human fibrosarcoma cell line in nude/nude mice: Iressa, doxorubicin, Iressa + doxorubicin, vehicle) was used to examine tumor growth; pEGFR, proliferating cell nuclear antigen, and terminal deoxyribonucleotide transferase–mediated nick-end labeling staining helped assess the effect of therapy in vivo on STS EGFR activation, proliferation, and apoptosis.
Results: EGFR was expressed and activated in STS cell lines and tumors, probably due to ligand binding rather than EGFR mutation. Stimulation caused activation of AKT and mitogen-activated protein kinase pathways. EGFR blockade inhibited these effects and also caused increased apoptosis, a p53-independent G0-G1 cell cycle arrest, and decreased cyclin D1 expression. In vivo, Iressa + doxorubicin had markedly synergistic anti-STS effects.
Conclusion: EGFR blockade combined with conventional chemotherapy results in anti-human STS activity in vitro and in vivo, suggesting the possibility that combining these synergistic treatments will improve anti-STS therapy.
Phase II, Open-Label Study Evaluating the Activity of Imatinib in Treating Life-Threatening Malignancies Known to Be Associated with Imatinib-Sensitive Tyrosine Kinases
Authors: Heinrich Michael C. , Joensuu Heikki , Demetri George D. , Corless Christopher L. , Apperley Jane , Fletcher Jonathan A. , Soulieres Denis , Dirnhofer Stephan , Harlow Amy , Town Ajia , McKinley Arin , Supple Shane G. , Seymour John , Di Scala Lilla , van Oosterom Allan , Herrmann Richard , Nikolova Zariana , McArthur and Grant ,   for the Imatinib Target Exploration Consortium Study B2225
Published: May 2008

Abstract
Purpose: To evaluate the activity of imatinib in treating advanced, life-threatening malignancies expressing one or more imatinib-sensitive tyrosine kinases.
Experimental Design: This was a phase II, open-label, single arm study. Patients ≥15 years old with malignancies showing histologic or molecular evidence of expression/activation of imatinib-sensitive tyrosine kinases were enrolled. Patients were treated with 400 or 800 mg/d imatinib for hematologic malignancy and solid tumors, respectively. Treatment was continued until disease progression or unacceptable toxicity. The primary objective was to identify evidence of imatinib activity with tumor response as the primary end point.
Results: One hundred eighty-six patients with 40 different malignancies were enrolled (78.5% solid tumors, 21.5% hematologic malignancies). Confirmed response occurred in 8.9% of solid tumor patients (4 complete, 9 partial) and 27.5% of hematologic malignancy patients (8 complete, 3 partial). Notable activity of imatinib was observed in only five tumor types (aggressive fibromatosis, dermatofibrosarcoma protuberans, hypereosinophilic syndrome, myeloproliferative disorders, and systemic mastocytosis). A total of 106 tumors were screened for activating mutations: five KIT mutations and no platelet-derived growth factor receptor mutations were found. One patient with systemic mastocytosis and a partial response to therapy had a novel imatinib-sensitive KIT mutation (D816T). There was no clear relationship between expression or activation of wild-type imatinib-sensitive tyrosine kinases and clinical response.
Conclusion: Clinical benefit was largely confined to diseases with known genomic mechanisms of activation of imatinib target kinases. Our results indicate an important role for molecular characterization of tumors to identify patients likely to benefit from imatinib treatment.
Safety and Immunogenicity Study of NY-ESO-1b Peptide and Montanide ISA-51 Vaccination of Patients with Epithelial Ovarian Cancer in High-Risk First Remission
Authors: Diefenbach Catherine S.M. , Gnjatic Sacha , Sabbatini Paul , Aghajanian Carol , Hensley Martee L. , Spriggs David R. , Iasonos Alexia , Lee Helen , Dupont Bo , Pezzulli Sandra , Jungbluth Achim A. , Old Lloyd J. , Dupont Jakob 
Published: May 2008

AbstractPurpose: The cancer-testis antigen NY-ESO-1 is expressed by &gt;40% of advanced epithelial ovarian cancers and is a promising immunotherapeutic target. In this study, we describe the effects of vaccination with the HLA-A*0201–restricted NY-ESO-1b peptide on patients with epithelial ovarian cancer in high-risk first remission.Experimental Design: After primary surgery and chemotherapy, high-risk epithelial ovarian cancer patients in first clinical remission received NY-ESO-1b peptide and Montanide every 3 weeks for five vaccinations. Tumor expression was evaluated by immunohistochemistry. Toxicity was monitored using National Cancer Institute Common Toxicity Criteria Scale Version 2. NY-ESO-1 specific humoral immunity (ELISA), T-cell immunity (tetramer and ELISPOT), and delayed-type hypersensitivity were assessed on weeks 0, 1, 4, 7, 10, 13, and 16.Results: Treatment-related adverse events included grade 1 fatigue, anemia, pruritus, myalgias, and hyperthyroidism and grade 2 hypothyroidism. There were no grade 3/grade 4 adverse events. Three of four patients (75%) with NY-ESO-1–positive tumor showed T-cell immunity by tetramer (0.6-9.5%) and ELISPOT (range, 35-260 spots). Four of five patients (80%) with NY-ESO-1–negative tumor showed T-cell immunity by tetramer (1.0-12.1%) and/or ELISPOT (range, 35-400 spots). With a median follow-up of 11.3 months, six of nine patients (67%) have recurred, with a median progression-free survival of 13 months (95% confidence interval, 11.2 months–not reached). Three of nine patients remain in complete clinical remission at 25, 38, and 52 months.Conclusion: Vaccination of high-risk HLA-A*0201–positive epithelial ovarian cancer patients with NY-ESO-1b and Montanide has minimal toxicity and induces specific T-cell immunity in patients with both NY-ESO-1–positive and NY-ESO-1–negative tumors. Additional study is warranted.
Light Delivery over Extended Time Periods Enhances the Effectiveness of Photodynamic Therapy
Authors: Seshadri Mukund , Bellnier David A. , Vaughan Lurine A. , Spernyak Joseph A. , Mazurchuk Richard , Foster Thomas H. , Henderson Barbara W. 
Published: May 2008

Abstract
Purpose: The rate of energy delivery is a principal factor determining the biological consequences of photodynamic therapy (PDT). In contrast to conventional high-irradiance treatments, recent preclinical and clinical studies have focused on low-irradiance schemes. The objective of this study was to investigate the relationship between irradiance, photosensitizer dose, and PDT dose with regard to treatment outcome and tumor oxygenation in a rat tumor model.
Experimental Design: Using the photosensitizer HPPH (2-[1-hexyloxyethyl]-2-devinyl pyropheophorbide), a wide range of PDT doses that included clinically relevant photosensitizer concentrations was evaluated. Magnetic resonance imaging and oxygen tension measurements were done along with the Evans blue exclusion assay to assess vascular response, oxygenation status, and tumor necrosis.
Results: In contrast to high-incident laser power (150 mW), low-power regimens (7 mW) yielded effective tumor destruction. This was largely independent of PDT dose (drug-light product), with up to 30-fold differences in photosensitizer dose and 15-fold differences in drug-light product. For all drug-light products, the duration of light treatment positively influenced tumor response. Regimens using treatment times of 120 to 240 min showed marked reduction in signal intensity in T2-weighted magnetic resonance images at both low (0.1 mg/kg) and high (3 mg/kg) drug doses compared with short-duration (6-11 min) regimens. Significantly greater reductions in pO2 were observed with extended exposures, which persisted after completion of treatment.
Conclusions: These results confirm the benefit of prolonged light exposure, identify vascular response as a major contributor, and suggest that duration of light treatment (time) may be an important new treatment variable.