bluuebunny/crossref_metadata_2025_split huggingface dataset:
Proteomic Analysis of Malignant Ovarian Cancer Effusions as a Tool for Biologic and Prognostic Profiling
Authors: Davidson Ben , Espina Virginia , Steinberg Seth M. , Flørenes Vivi Ann , Liotta Lance A. , Kristensen Gunnar B. , Tropé Claes G. , Berner Aasmund , Kohn Elise C. 
Published: March 2006

Abstract
Purpose: Malignant epithelial ovarian cancer effusions are important in disease dissemination and clinical outcome. The identification of biochemical events active in effusions may improve our identification and application of targeted therapeutics.
Experimental Design: Archival effusion samples for which outcome information was known were studied. Clinical variables were comparable between these groups. Two cohorts of patients with malignant effusion were assessed: those with effusion at presentation (Tap1) or at first recurrence (Tap2). Expression and activated fraction of selected signaling proteins were quantitated on serial protein microarrays using validated antibodies. Proteomic results and clinical variables were analyzed by univariate analysis followed by Cox proportional hazards model analysis.
Results: Malignant effusions (&gt;80% malignant cells) were distinguished from benign effusions by higher expression of AKT, activated extracellular signal-regulated kinase, activated (P ≤ 0.001) and total cAMP-responsive element binding protein (P = 0.01), and JNK (P = 0.03). Malignant pleural effusions could not be differentiated from ascites by signaling profiles. Both had signal expression clusters for survival, proliferation and metastasis, and injury pathways. Cox proportional hazards model analysis revealed high p38 and pEGFR/EGFR ratio as jointly associated with poor survival in Tap1 cases (both P ≤ 0.002). Phospho-JNK quantity was associated with worse outcome in Tap2 patients (P = 0.004), when taking other factors into consideration.
Conclusions: Proliferation, survival, and apoptosis signaling dysregulation can be identified in ovarian cancer effusion samples. Biochemical characterization of clinical effusions may provide either predictive and/or correlative information on patient outcome from which to further understand the mechanisms of effusion development and target clinical intervention.
Full-Dose 90Y Ibritumomab Tiuxetan Therapy Is Safe in Patients with Prior Myeloablative Chemotherapy
Authors: Jacobs Samuel A. , Vidnovic Nicholas , Joyce Judith , McCook Barry , Torok Frank , Avril Norbert 
Published: March 2006

Abstract
Purpose: Targeted radioimmunotherapy with yttrium-90 (90Y)–labeled ibritumomab tiuxetan (Zevalin, IDEC-Biogen, San Diego, CA) has shown significant activity in the treatment of relapsed or refractory CD20+ non–Hodgkin's lymphoma. Eligibility criteria used in phase I trials, and adopted in phase II and III trials, excluded patients with prior myeloablative therapy. We treated eight patients with 90Y ibritumomab tiuxetan who had prior autologous stem cell transplant, but met all other treatment criteria.
Experimental Design: Eight patients with CD20+ non–Hodgkin's lymphoma had extensive prior therapy including myeloablative chemotherapy but did not receive total body irradiation. Each had bone marrow cellularity of &gt;15%, platelet count of &gt;100,000/mm3, and one had documented lymphomatous bone marrow involvement of &lt;25%. The standard course of 0.3 to 0.4 mCi/kg of 90Y ibritumomab tiuxetan was administered to patients at full dose. 18-Flouro-deoxyglucose positron emission tomography/computed tomography scans were done at pretreatment and ∼12 weeks after treatment to assess patient response. Maximum toxicities were monitored and classified according to the Common Terminology Criteria for Adverse Events (ver. 3.0).
Results: Toxicities observed included grade 4 thrombocytopenia in three of eight evaluable patients and grade 4 neutropenia in one of eight evaluable patients. One patient had a neutropenic fever; all patients were off blood product support 12 weeks post-zevalin. Complete response by 18-flouro-deoxyglucose positron emission tomography/computed tomography imaging occurred in one of seven evaluable patients and one patient treated as consolidation had no evidence of disease.
Conclusion: Our experience suggests that 90Y ibritumomab tiuxetan treatment is safe for use in patients with prior myeloablative therapy when the general inclusion criteria are fulfilled. In this small series, the response rates, however, are limited. Nevertheless, 90Y ibritumomab tiuxetan treatment may provide clinical benefit in carefully selected extensively pretreated patients.
Determining Maximal Tolerable Dose of the Monoclonal Antibody BR96 Labeled with 90Y or 177Lu in Rats: Establishment of a Syngeneic Tumor Model to Evaluate Means to Improve Radioimmunotherapy
Authors: Mårtensson Linda , Wang Zhongmin , Nilsson Rune , Ohlsson Tomas , Senter Peter , Sjögren Hans-Olov , Strand Sven-Erik , Tennvall Jan 
Published: March 2006

Abstract
Purpose: To evaluate therapeutic strategies, it is essential to use biological models reflecting important aspects of the clinical situation. The aim of the present study was to compare the maximal tolerable dose of the monoclonal antibody BR96 labeled with 90Y or 177Lu in immunocompetent rats. Maximal tolerable dose was defined as the highest activity that allows 100% of the animals to survive without clinical signs, such as infections, bleeding, or diarrhea, and with &lt;20% loss in body weight.
Experimental Design: Increasing activity levels of BR96 labeled with 90Y or 177Lu were administered to groups of rats. Blood parameters, body weight, and general performance were monitored for 8 weeks.
Results: Two days postinjection, all groups had decreased leukocyte counts down to 5% to 15% of initial values. Initiation of recovery (at 14-21 days) showed a dose-response relationship. All groups, except the group given the highest activity of 90Y, had complete resolution in their leukopenia. The decrease in platelets was delayed to days 7 to 14 postinjection with a dose-dependent response regarding both severity of the nadir (10-40% of initial value) and the start of recovery. Animals in the groups given the highest activities of both 90Y and 177Lu exhibited skin infections on day 21.
Conclusions: The results showed good reproducibility and dose-dependent toxicity for both radionuclides, indicating that the maximal tolerable dose for 177Lu–BR96 (1,000 MBq/kg) is 1.7 times that for 90Y–BR96 (600 MBq/kg) in rats. This model makes it feasible to evaluate strategies to escalate therapeutic doses to tumors without increasing normal tissue toxicity.
Pretargeting of Carcinoembryonic Antigen–Expressing Tumors with a Biologically Produced Bispecific Anticarcinoembryonic Antigen × Anti-Indium–Labeled Diethylenetriaminepentaacetic Acid Antibody
Authors: van Schaijk Frank G. , Oosterwijk Egbert , Soede Annemieke C. , Broekema Matthias , Frielink Cathelijne , McBride William J. , Goldenberg David M. , Corstens Frans H.M. , Boerman Otto C. 
Published: March 2006

Abstract
Purpose: The aim of these studies was to develop a pretargeting strategy for CEA-expressing cancers using biologically produced bispecific monoclonal antibodies (bsMAb). The bsMAbs used in this system have affinity for the carcinoembryonic antigen on the one hand, and for indium-labeled diethylenetriaminepentaacetic acid (DTPA), on the other.
Experimental Design: Stable quadroma clones producing bsMAb MN-14xDTIn-1 were isolated. LS174T tumor–bearing mice were injected with 1 to 100 μg of bsMAb followed by 1 to 60 ng of an 111In-labeled bivalent peptide [Ac-Phe-Lys(DTPA)-Tyr-Lys(DTPA)-NH2]. Mice were killed at 24 hours postinjection and the biodistribution of the radiolabel was determined. The biodistribution of diDTPA labeled with four different radionuclides (111In, 99mTc, nonresidualizing 125I, and residualizing 125I) was determined at various time points postinjection following pretargeting of LS174T tumors with bsMAb MN-14xDTIn-1.
Results: Optimal tumor targeting was observed when tumors were pretargeted with 10 μg of bsMAb MN-14xDTIn-1 and when 6 ng of a radiolabeled peptide was given 72 hours later. The uptake of the four radiolabels in LS174T tumors at 4 hours postinjection was similar. However, at later time points, the 111In-label and residualizing 125I-label were better retained in the tumor than the nonresidualizing 125I label. Although the absolute uptake in the tumor (in terms of percentage of injected dose per gram of tissue) was 5-fold lower than the uptake obtained with directly labeled MN-14, the pretargeting strategy revealed much higher tumor-to-blood ratios due to the rapid clearance of the radiolabel from the circulation as compared with 111In-MN-14 (445 ± 90 and 5.3 ± 1.1, respectively, at 72 hours postinjection).
Conclusions: Effective targeting of carcinoembryonic antigen-expressing tumors was achieved with a newly produced bispecific antibody. The 111In-labeled l-amino acid peptide and 125I-d-amino acid peptide were better retained in the tumor than the 99mTc- and 125I-l-amino acid peptide. Very high tumor-to-blood ratios were obtained due to rapid background clearance.
Improved Tumor Targeting by Combined Use of Two Antitenascin Antibodies
Authors: Petronzelli Fiorella , Pelliccia Angela , Anastasi Anna Maria , D'Alessio Valeria , Albertoni Claudio , Rosi Antonio , Leoni Barbara , De Angelis Clara , Paganelli Giovanni , Palombo Giovanna , Dani Maria , Carminati Paolo , De Santis Rita 
Published: March 2006

Abstract
Purpose: In the pretargeted antibody-guided radioimmunotherapy (PAGRIT) system, the combined use of two different antibodies directed against the same tumor antigen could represent a valid approach for improving tumor targeting and therapeutic efficacy. We developed a novel monoclonal antitenascin antibody, ST2485, and studied its biochemical and functional properties by in vitro and in vivo assays. We then investigated the first of the three-step therapy combining ST2485 with another antitenascin antibody, ST2146, previously described, to increase accumulation of biotinylated antibodies at the tumor site.
Experimental Design: Studies of immunoreactivity, affinity, immunohistochemistry, and biodistribution in xenograft model were carried out on ST2485. Analysis of the ST2485 and ST2146 combination was preliminary carried out by ELISA and BiaCore tests and then by in vivo distribution studies after administration of the radiolabeled biotinylated antibodies, followed by a chase with avidin as clearing agent.
Results: ST2485 was found to be a suitable antibody for therapeutic applications. Indeed, for its behavior in all tests, it was comparable with ST2146 and better than BC2, an antibody already used for clinical trials. The additivity of ST2146 and ST2485 in tenascin C binding, shown by in vitro tests, was confirmed by biodistribution studies in a xenograft model where tumor localization of the antibodies was near the sum of each antibody alone, with a tumor-to-blood ratio higher than 24.
Conclusion: The results reported in this study suggest that a monoclonal antitenascin antibody mixture can improve tumor targeting. This strategy could represent progress for therapeutic approaches such as PAGRIT.
Direct Antilymphoma Effects on Human Lymphoma Cells of Monotherapy and Combination Therapy with CD20 and HLA-DR Antibodies and 90Y-Labeled HLA-DR Antibodies
Authors: DeNardo Gerald L. , Tobin Evan , Chan Kaylund , Bradt Bonnie M. , DeNardo Sally J. 
Published: March 2006

AbstractPurpose: Monoclonal antibodies (mAb) in combination and mAbs combined with a radionuclide (radioimmunotherapy) have both been more effective in patients than mAb monotherapy.Experimental Design: Using assays of cell growth and viability, the dose response and temporal characteristics of CD20 (rituximab) and HLA-DR (Lym-1) mAbs, singly and in combination, and of 90Y-conjugated Lym-1 mAb have been characterized in five human lymphoma cell lines (B35M, Raji, SU-DHL-4, SU-DHL-6, and Ramos) spanning Burkitt's to diffuse large cell lymphoma. Although Ramos had a lower HLA-DR density, these cell lines were otherwise selected because of high cell surface CD20 and HLA-DR abundance. Assays of cell growth and death were done using microscopy and trypan blue dye.Results: Lym-1 and rituximab, used singly, showed direct antilymphoma effects; those of Lym-1 were often more potent than those of rituximab. Combinations of these mAbs were more effective, sometimes synergistic, than either mAb singly, even in more resistant SU-DHL-4 cells. Conjugation of 90Y to Lym-1 also augmented potency in all cell lines and overcame resistance to both Lym-1 and rituximab in Ramos cells.Conclusions: Lym-1 exhibited substantially greater direct antilymphoma effects than rituximab in lymphoma cells in culture. Combination of Lym-1 with rituximab or 90Y increased potency and overcame treatment resistance in lymphoma cells. Greater use of combination therapies of this type to increase potency and range of effectiveness seems likely to improve patient outcome.
Radioimmunotherapy with [131I]cG250 in Patients with Metastasized Renal Cell Cancer: Dosimetric Analysis and Immunologic Response
Authors: Brouwers Adrienne H. , Buijs Wilhelmina C.A.M. , Mulders Peter F.A. , de Mulder Pieter H.M. , van den Broek Wim J.M. , Mala Carola , Oosterwijk Egbert , Boerman Otto C. , Corstens Frans H.M. , Oyen Wim J.G. 
Published: March 2006

Abstract
Purpose: A study was designed to define the therapeutic efficacy, safety, and toxicity of two sequential high-dose treatments of radioimmunotherapy with [131I]cG250 in patients with metastasized renal cell carcinoma. Here, we report the dosimetric analysis and the relationship between the development of a human antichimeric antibody response and altered pharmacokinetics.
Experimental Design: Patients (n = 29) with progressive metastatic renal cell carcinoma received a low dose (222 MBq) of [131I]cG250 for dosimetric analysis, followed by the first radioimmunotherapy with 2,220 MBq/m2 [131I]cG250 (n = 27) 1 week later. If no grade 4 hematologic toxicity was observed, a second low dose of [131I]cG250 (n = 20) was given 3 months later. Provided that no accelerated blood clearance was observed, a second radioimmunotherapy of [131I]cG250 was administered at an activity-dose level of 1,110 MBq/m2 (n = 3) or 1,665 MBq/m2 (n = 16). After each administration, whole-body images were obtained and the pharmacokinetics and the development of human antichimeric antibody responses were determined. Radiation-absorbed doses were calculated for whole body, red marrow, organs, and metastases.
Results: No correlation was found between hematologic toxicity and radiation-absorbed dose to the whole body or bone marrow, nor administered activity (MBq and MBq/kg). The tumor-absorbed doses varied largely. An inverse relation between tumor size and radiation-absorbed dose was found. Most tumor lesions received &lt;10 Gy, whereas only lesions &lt;5 g absorbed &gt;50 Gy. A relatively high number of patients developed a human antichimeric antibody response (8 of 27) with altered pharmacokinetics, hampering additional radioimmunotherapies in four of these patients.
Conclusions: Dosimetric analysis did not adequately predict the degree of bone marrow toxicity. When human antichimeric antibody developed, the rapid clearance of radioactivity from the blood and body prohibited further treatment. According to the calculated absorbed dose in metastatic lesions, future radioimmunotherapy studies with radiolabeled cG250 should aim at treatment of small-volume disease or treatment in an adjuvant setting.
Nuclear Imaging of Met-Expressing Human and Canine Cancer Xenografts with Radiolabeled Monoclonal Antibodies (MetSeekTM)
Authors: Hay Rick V. , Cao Brian , Skinner R. Scot , Su Yanli , Zhao Ping , Gustafson Margaret F. , Qian Chao-Nan , Teh Bin T. , Knudsen Beatrice S. , Resau James H. , Shen Shuren , Waters David J. , Gross Milton D. , Vande Woude George F. 
Published: March 2006

Abstract
Purpose: Met, an oncogene product and receptor tyrosine kinase, is a keystone molecule for malignant progression in solid human tumors. We are developing Met-directed imaging and therapeutic agents, including anti-Met monoclonal antibodies (MetSeekTM). In this study, we compared two antibodies, Met5 and Met3, for nuclear imaging of human and canine Met-expressing tumor xenografts in nude mice.
Experimental Design: Xenografts representing cancers of three different human tissue origins and metastatic canine prostate cancer were raised s.c. in host athymic nude mice. Animals were injected i.v. with I-125-Met5 or I-125-Met3, posterior total body gamma camera images were acquired for several days postinjection, and quantitative region-of-interest activity analysis was done.
Results: PC-3, SK-LMS-1/HGF, and CNE-2 xenografts imaged with I-125-Met5 were compared with PC-3, SK-LMS-1/HGF, and DU145 xenografts imaged with I-125-Met3. Nuclear imaging contrast was qualitatively similar for I-125-Met5 and I-125-Met3 in PC-3 and SK-LMS-1/HGF host mice. However, by region-of-interest analysis, the set of human tumors imaged with I-125-Met3 exhibited a pattern of rapid initial tumor uptake followed by a continuous decline in activity, whereas the set of human tumors imaged with I-125-Met5 showed slow initial uptake, peak tumor-associated activity at 1 day postinjection, and persistence of activity in xenografts for at least 5 days. GN4 canine prostate cancer xenografts were readily imaged with I-125-Met5.
Conclusions: We conclude that radioiodinated Met3 and Met5 offer qualitatively similar nuclear images in xenograft-bearing mice, but quantitative considerations indicate that Met5 might be more useful for radioimmunotherapy. Moreover, canine prostate cancer seems to be a suitable model for second-stage preclinical evaluation of Met5.
Application of High Amplitude Alternating Magnetic Fields for Heat Induction of Nanoparticles Localized in Cancer
Authors: Ivkov Robert , DeNardo Sally J. , Daum Wolfgang , Foreman Allan R. , Goldstein Robert C. , Nemkov Valentin S. , DeNardo Gerald L. 
Published: March 2006

Abstract
Objective: Magnetic nanoparticles conjugated to a monoclonal antibody can be i.v. injected to target cancer tissue and will rapidly heat when activated by an external alternating magnetic field (AMF). The result is necrosis of the microenvironment provided the concentration of particles and AMF amplitude are sufficient. High-amplitude AMF causes nonspecific heating in tissues through induced eddy currents, which must be minimized. In this study, application of high-amplitude, confined, pulsed AMF to a mouse model is explored with the goal to provide data for a concomitant efficacy study of heating i.v. injected magnetic nanoparticles.
Methods: Thirty-seven female BALB/c athymic nude mice (5-8 weeks) were exposed to an AMF with frequency of 153 kHz, and amplitude (400-1,300 Oe), duration (1-20 minutes), duty (15-100%), and pulse ON time (2-1,200 seconds). Mice were placed in a water-cooled four-turn helical induction coil. Two additional mice, used as controls, were placed in the coil but received no AMF exposure. Tissue and core temperatures as the response were measured in situ and recorded at 1-second intervals.
Results: No adverse effects were observed for AMF amplitudes of ≤700 Oe, even at continuous power application (100% duty) for up to 20 minutes. Mice exposed to AMF amplitudes in excess of 950 Oe experienced morbidity and injury when the duty exceeded 50%.
Conclusion: High-amplitude AMF (up to 1,300 Oe) was well tolerated provided the duty was adjusted to dissipate heat. Results presented suggest that further tissue temperature regulation can be achieved with suitable variations of pulse width for a given amplitude and duty combination. These results suggest that it is possible to apply high-amplitude AMF (&gt;500 Oe) with pulsing for a time sufficient to treat cancer tissue in which magnetic nanoparticles have been embedded.
Fractionated Locoregional Low-Dose Radioimmunotherapy Improves Survival in a Mouse Model of Diffuse-Type Gastric Cancer Using a 213Bi-Conjugated Monoclonal Antibody
Authors: Bloechl Stefanie , Beck Roswitha , Seidl Christof , Morgenstern Alfred , Schwaiger Markus , Senekowitsch-Schmidtke Reingard 
Published: March 2006

Abstract
Purpose: Locoregional radioimmunotherapy of i.p. tumor cell dissemination of diffuse-type gastric cancer using the α-emitter 213Bi displayed good therapeutic results after a single application depending on the time interval between tumor cell inoculation and injection of the 213Bi-immunoconjugate. The aim of the present study was to compare single versus double i.p. injection of a tumor-specific antibody (d9MAb) conjugated with low activities of 213Bi in terms of therapeutic efficacy and toxicity.
Experimental Design: Nude mice were inoculated i.p. with 1 × 107 human gastric cancer cells (HSC45-M2) expressing tumor-specific mutant d9-E-cadherin (d9-E-cad). After tumor cell inoculation, the mice were injected i.p. with a single injection at day 1 or 8, or double injections at days 1 and 8 or days 8 and 15 with 0.37, 0.74, or 1.48 MBq 213Bi-d9MAb. Therapeutic efficacy was determined by median survival, and toxicity was evaluated by leukocyte and platelet counts. The development of i.p. carcinomatosis was monitored by carcinoembryonic antigen concentrations in the serum of the mice.
Results: The median survival of treated animals increased, depending on the time interval (days) between tumor cell inoculation and therapy, and the injected activity, from 22 days of untreated mice to 48 days (0.37 MBq, 1 day), 84 days (0.37 MBq, 1 and 8 days), 37 days (0.37 MBq, 8 days), 46 days (0.37 MBq, 8 and 15 days), 42 days (0.74 MBq, 8 days), 78 days (0.74 MBq, 8 and 15 days), and 44 days (1.48 MBq, 8 days). The injected activities did not reduce leukocyte and platelet counts. Carcinoembryonic antigen, which was not detectable in the serum of tumor-free mice, increased after tumor cell inoculation and tumor proliferation and decreased after each therapeutic application of 213Bi-d9MAb.
Conclusions: Double application of only 0.37 MBq of 213Bi-d9MAb at days 1 and 8 after tumor cell inoculation significantly prolonged median survival in nude mice suffering from i.p. tumor cell dissemination compared with a single injection. Even in an advanced stage of the disease, double injection of 0.74 MBq at days 8 and 15 was superior to a single injection of 1.48 MBq at day 8 without any sign of toxicity.