bluuebunny/crossref_metadata_2025_split huggingface dataset:
Structural and Functional Features of the B-Cell Receptor in IgG-Positive Chronic Lymphocytic Leukemia
Authors: Potter Kathleen N. , Mockridge C. Ian , Neville Louise , Wheatley Isla , Schenk Michael , Orchard Jennifer , Duncombe Andrew S. , Packham Graham , Stevenson Freda K. 
Published: March 2006

Abstract
Purpose: To determine the origin and relationship of the rare IgG+ variant of chronic lymphocytic leukemia (CLL) to the two common IgM+IgD+ subsets that are distinguished by expression of unmutated or mutated VH genes, with the former having a worse prognosis.
Experimental Design: IgG+ CLL cells were characterized using phenotypic, functional, and immunogenetic analyses.
Results: IgG+ CLL was phenotypically similar to mutated IgM+IgD+ CLL (M-CLL) and variably expressed CD38 (4 of 14). ZAP-70, a tyrosine kinase preferentially expressed in unmutated CLL, was found in only 2 of 14 cases. The ability to signal via surface IgM (sIgM) varies between the main subsets of CLL and is associated with expression of ZAP-70. In IgG+ CLL, 9 of 14 responded to engagement of sIgG with no apparent requirement for expression of CD38 or ZAP-70. However, signal capacity correlated with intensity of sIgG expression. Most switched immunoglobulin variable region genes were somatically mutated without intraclonal variation, and no case expressed activation-induced cytidine deaminase. Derivation from a postgerminal center B cell is, therefore, likely, and a relationship with M-CLL is suggested. This is supported by a shared biased usage of the V4-34 gene. Similar bias in normal B cells developed with age, providing an expanded population for transforming events. However, conserved sequences detected in the CDR3 of V4-34-encoded γ chains were not found M-CLL, indicating no direct path of isotype switch from M-CLL.
Conclusion: IgG+ CLL is likely to arise from an age-related expanded pool of B cells, on a path parallel to M-CLL, and perhaps with a similar clinical course.
Lomeguatrib, a Potent Inhibitor of O6-Alkylguanine-DNA-Alkyltransferase: Phase I Safety, Pharmacodynamic, and Pharmacokinetic Trial and Evaluation in Combination with Temozolomide in Patients with Advanced Solid Tumors
Authors: Ranson Malcolm , Middleton Mark R. , Bridgewater John , Lee Siow Ming , Dawson Martin , Jowle Debra , Halbert Gavin , Waller Sue , McGrath Helen , Gumbrell Lindsey , McElhinney R. Stanley , Donnelly Dorothy , McMurry T. Brian H. , Margison Geoffrey P. 
Published: March 2006

Abstract
Purpose: A major mechanism of resistance to temozolomide involves the DNA repair protein O6-alkylguanine-DNA-alkyltransferase (ATase). The main aims of this phase I trial were to determine an ATase-depleting dose (ADD) of lomeguatrib, a potent pseudosubstrate inhibitor, and to define a suitable dose of temozolomide to be used in combination with lomeguatrib in patients with advanced cancer.
Experimental Design: Lomeguatrib was administered at dose levels of 10 to 40 mg/m2 days 1 to 5, as a single agent, and also in combination with temozolomide. Once the ADD of lomeguatrib was identified, the dose of temozolomide in combination was increased, in successive patient cohorts, from 50 to 175 mg/m2 on days 1 to 5 of a 28-day cycle to define the maximal tolerated dose and dose-limiting toxicity of the combination.
Results: Thirty-eight patients with advanced solid tumors were enrolled. More than 95% ATase depletion within 4 hours of the first dose was achieved in peripheral blood mononuclear cells at lomeguatrib doses of ≥10 mg/m2/d i.v. or ≥20 mg/m2/d orally, and tumor biopsies showed ≥92% ATase depletion. At the ADD of lomeguatrib i.v., the maximal tolerated dose of temozolomide in combination was 150 mg/m2 days 1 to 5. The dose limiting toxicity of the combination of lomeguatrib and temozolomide was myelosuppression. The toxicity of lomeguatrib alone was minimal. In 23 patients with measurable disease, one complete response was seen and 12 patients had stable disease for at least 3 months.
Conclusion: This first administration of lomeguatrib to man successfully established an oral ADD of lomeguatrib and identified a combination regimen with temozolomide suitable for future clinical evaluation.
Methods for Gene Expression Profiling in Clinical Trials of Adjuvant Breast Cancer Therapy
Authors: Paik Soonmyung 
Published: March 2006

Abstract
Although endocrine therapy is highly effective in the treatment of endocrine receptor–positive breast cancer, chemotherapy has been shown to provide clinical benefit when added to tamoxifen. However, baseline risk after tamoxifen treatment is so low, especially in patients who are axillary node negative, that significant overtreatment will result if chemotherapy is given to every patient. Robust prognostic and predictive markers need to be developed to identify those at high risk of treatment failure. Although comprehensive gene expression profiling methods do offer promise, they require fresh or frozen tumor samples. To take advantage of existing archived tissue blocks with clinical follow-up collected from finished clinical trials, such as National Surgical Adjuvant Breast and Bowel Project trials B-20 and B-14, technologies that allow interrogation of archived blocks for gene expression profiling need to be realized. Recent developments in gene expression profiling technologies are discussed with their implications in clinical management of endocrine receptor–positive breast cancer.
Mobilization of Bone Marrow Stem Cells by Granulocyte Colony-Stimulating Factor Ameliorates Radiation-Induced Damage to Salivary Glands
Authors: Lombaert Isabelle M.A. , Wierenga Pieter K. , Kok Tineke , Kampinga Harm H. , deHaan Gerald , Coppes Robert P. 
Published: March 2006

Abstract
Purpose: One of the major reasons for failure of radiotherapeutic cancer treatment is the limitation in dose that can be applied to the tumor because of coirradiation of the normal healthy tissue. Late radiation-induced damage reduces the quality of life of the patient and may even be life threatening. Replacement of the radiation-sterilized stem cells with unirradiated autologous stem cells may restore the tissue function. Here, we assessed the potential of granulocyte colony-stimulating factor (G-CSF)–mobilized bone marrow–derived cells (BMC) to regenerate and functionally restore irradiated salivary glands used as a model for normal tissue damage.
Experimental Design: Male-eGFP+ bone marrow chimeric female C57BL/6 mice were treated with G-CSF, 10 to 60 days after local salivary gland irradiation. Four months after irradiation, salivary gland morphology and flow rate were assessed.
Results: G-CSF treatment induced homing of large number of labeled BMCs to the submandibular glands after irradiation. These animals showed significant increased gland weight, number of acinar cells, and salivary flow rates. Donor cells expressed surface markers specific for hematopoietic or endothelial/mesenchymal cells. However, salivary gland acinar cells neither express the G-CSF receptor nor contained the GFP/Y chromosome donor cell label.
Conclusions: The results show that BMCs home to damaged salivary glands after mobilization and induce repair processes, which improve function and morphology. This process does not involve transdifferentiation of BMCs to salivary gland cells. Mobilization of BMCs could become a promising modality to ameliorate radiation-induced complications after radiotherapy.
Anastrozole as an Adjuvant Endocrine Treatment for Postmenopausal Patients with Breast Cancer: Emerging Data
Authors: Buzdar Aman U. , Cuzick Jack 
Published: March 2006

Abstract
The Arimidex, Tamoxifen, Alone or in Combination (ATAC) trial compared the efficacy and safety of anastrozole versus tamoxifen versus the combination as initial adjuvant treatment for early breast cancer in over 9,000 postmenopausal women. Analyses at 33 and 47 months median follow-up showed that anastrozole significantly prolonged disease-free survival and time to recurrence and reduced the incidence of contralateral breast cancer compared with tamoxifen. Results of the completed treatment analysis at 68 months median follow-up confirmed the earlier findings, showing that the absolute difference in disease-free survival continued to increase beyond completion of treatment. Mature safety data from the ATAC trial show that, overall, anastrozole has a favorable safety profile compared with tamoxifen. In the absence of current data on further follow-up or the outcome of trials investigating proactive sequencing of endocrine therapies, we present a model based on several trials, including ATAC. This model suggests that using an aromatase inhibitor as initial adjuvant therapy is a better option than switching to an aromatase inhibitor after ≥2 years of tamoxifen. The relative toxicities of the three approved third-generation aromatase inhibitors, anastrozole, letrozole, and exemestane, are discussed. These data suggest that long-term safety profiles may differ between aromatase inhibitors, although comprehensive comparative data for letrozole and exemestane versus tamoxifen are lacking.
Tumor Epithelial Cell Matrix Metalloproteinase 9 Is a Target for Antimetastatic Therapy in Colorectal Cancer
Authors: Lubbe Wilhelm J. , Zhou Zengyi Y. , Fu Weili , Zuzga David , Schulz Stephanie , Fridman Rafael , Muschel Ruth J. , Waldman Scott A. , Pitari Giovanni M. 
Published: March 2006

Abstract
Background: The current paradigm suggests that matrix metalloproteinase 9 (MMP-9) expressed by stromal cells is a therapeutic target in human colorectal tumors which presumably regulates metastatic disease progression. Conversely, whereas cancer cells within those tumors may induce stromal cells to produce MMP-9 and may be targets for MMP-9 activity, they are not the source of MMP-9 underlying metastasis.
Methods: MMP-9 expression in matched colorectal tumors and normal adjacent mucosa from patients and human colon cancer cell lines was examined by real-time reverse transcription-PCR, laser capture microdissection, immunoelectron microscopy, and immunoblot analysis. The role of colon cancer cell MMP-9 in processes underlying metastasis was explored in vitro by examining degradation of extracellular matrix components by gelatin zymography and formation of locomotory organelles by cell spreading analysis and in vivo by quantifying hematogenous tumor cell seeding of mouse lungs.
Results: Primary colorectal tumors overexpress MMP-9 compared with matched normal adjacent mucosa. In contrast to the current paradigm, MMP-9 is expressed equally by cancer and stromal cells within human colon tumors. Cancer cell MMP-9 regulates metastatic behavior in vitro, including degradation of extracellular matrix components and formation of locomotory organelles. Moreover, this MMP-9 critically regulates hematogenous seeding of mouse lungs by human colon cancer cells in vivo.
Conclusions: These observations reveal that MMP-9 produced by human colon cancer, rather than stromal, cells is central to processes underlying metastasis. They underscore the previously unrecognized potential of specifically targeting tumor cell MMP-9 in interventional strategies to reduce mortality from metastatic colorectal cancer.
Management of Central Nervous System Lymphomas Using Monoclonal Antibodies: Challenges and Opportunities
Authors: Wong Eric T. 
Published: March 2006

AbstractMonoclonal antibodies (mAb) may change the management of central nervous system (CNS) lymphomas. This is due to the fact that traditional chemotherapies lack specificity for B-lymphoma cells and blood-brain barrier prevents adequate chemotherapy dosing in the CNS without significant systemic side effects. But in the past 5 years, the emergence of mAbs against specific receptors on B-lymphoma cells, either as a single agent or in combination with cytotoxic chemotherapies, may offer a better therapeutic index than conventional chemotherapies. The advantages of mAbs include high affinity to targets on lymphoma cells, their lack of pharmacodynamic or pharmacokinetic interactions with other drugs, and a potential for a synergistic therapeutic response when combined with conventional chemotherapies. Our review summarizes the biological behaviors of CNS lymphomas and the challenges and opportunities in using mAbs for CNS lymphomas.
Does Paclitaxel (Taxol) Given after 111In-Labeled Monoclonal Antibodies Increase Tumor-Cumulated Activity in Epithelial Cancers?
Authors: Miers Laird , Lamborn Kathleen , Yuan Aina , Richman Carol , Natarajan Arutselvan , DeNardo Sally , DeNardo Gerald 
Published: March 2006

Abstract
Purpose: Paclitaxel synergized radiolabeled monoclonal antibodies, enhancing therapeutic effect in studies in mice with human xenografts. Paclitaxel was also observed to increase tumor uptake in imaging studies of 111In-DOTA-Gly3Phe-m170 in patients with breast and prostate cancers. Further evaluations of tissue-cumulated activities, therapeutic indices, and pharmacokinetics were done using data for patients with breast and prostate cancer and for mice with human breast cancer xenografts.
Experimental Design: In radioimmunotherapy trials, 12 patients with breast or prostate cancer were given two imaging doses (5 mCi each) of 111In-DOTA-Gly3Phe-m170 1 week apart. Five of these patients were given a single dose of paclitaxel i.v. (75 mg/m2) 2 days after the second dose of 111In. In a subsequent study, athymic mice with human breast cancer xenografts were given 111In-DOTA-Gly3Phe-ChL6 alone, or in combination with daily paclitaxel i.p. (300 μg) one or more times. Pharmacokinetics were studied for at least 6 days in patients and 5 days in mice. Cumulated activities were determined for tumors and normal tissues.
Results: Tumor-cumulated activity for every patient in the paclitaxel-treated group increased for the second dose of 111In-DOTA-Gly3Phe-m170. The median ratio of cumulated activities in tumors for imaging dose 2 to those for dose 1 was 1.0 (0.8-1.3) in patients that were not given paclitaxel and 1.3 (1.2-1.4) in patients given paclitaxel. Normal tissue-cumulated activities were not different for the two doses. Mice given paclitaxel 1 day after 111In-DOTA-Gly3Phe-ChL6 also showed an increase in tumor-cumulated activity, 22.9 (± 1.3) versus 19.4 (± 3.3) μCi h/g/μCi (P = 0.05). Cumulated activities of normal tissues were similar for all groups of mice.
Conclusions: Paclitaxel given 1 to 2 days after 111In-DOTA-Gly3Phe-monoclonal antibody increased the tumor-cumulated activity in patients and in mice with epithelial cancers and did not alter cumulated activities in normal tissues.
Preliminary Results of the Safety of Immunotherapy with Gemtuzumab Ozogamicin following Reduced Intensity Allogeneic Stem Cell Transplant in Children with CD33+ Acute Myeloid Leukemia
Authors: Roman Elizabeth , Cooney Erin , Harrison Lauren , Militano Olga , Wolownik Karen , Hawks Ria , Foley Sandi , Satwani Prakash , Unal Elif , Bhatia Monica , Bradley Brigid , Del Toro Gustavo , George Diane , Garvin James , van de Ven Carmella , Cairo Mitchell S. 
Published: March 2006

Abstract
Purpose: Myeloablative allogeneic stem cell transplantation (SCT) has been successful in the treatment of childhood acute myeloid leukemia (AML), but may be associated with significant toxicity and recurrent disease. Reduced-intensity allogeneic SCT may offer a less toxic approach to patients with AML. Targeted immunotherapy with gemtuzumab ozogamicin has been shown to be safe, well tolerated in children, and, as a single agent, gemtuzumab ozogamicin has induced responses in 30% of patients with recurrent CD33+ AML. There are no safety data with gemtuzumab ozogamicin post allogeneic SCT in children. Therefore, we explored the feasibility and toxicity of targeted immunotherapy following reduced-intensity allogeneic SCT in children with CD33+ AML.
Experimental Design: Eight patients with CD33+ AML received a reduced-intensity allogeneic SCT following fludarabine 30 mg/m2 for 6 days and busulfan 3.2 mg/kg (&lt;4 years, 4 mg/kg/d) for 2 days. Donor sources included six 6/6 HLA-matched related peripheral blood stem cells, one 6/6 sibling cord blood, and one 4/6 unrelated cord blood.
Results: Day 30 and day 60 donor chimerisms in seven of eight evaluable patients were 96 ± 2% (n = 7) and 94 ± 3% (n = 6), respectively. Five of six patients (too early for one patient) received two doses of gemtuzumab ozogamicin and one patient received only one dose. After each dose, all patients developed grade 4 neutropenia, with recovery on median days 16 and 13, respectively, after dose 1 and dose 2. Grade 4 thrombocytopenia was only observed in 2 of 11 gemtuzumab ozogamicin courses. No patients have developed dose-limiting toxicity secondary to gemtuzumab ozogamicin.
Conclusions: The administration of gemtuzumab ozogamicin post reduced-intensity allogeneic SCT in children with average risk AML is feasible and well tolerated with minimal toxicity. The maximal tolerated dose has yet to be determined for gemtuzumab ozogamicin post reduced-intensity allogeneic SCT in children with CD33+ AML. Additional studies in a larger group of patients will be required to adequately assess the safety of this approach.
Enhanced Efficacy of Radioimmunotherapy with 90Y-CHX-A″-DTPA-hu3S193 by Inhibition of Epidermal Growth Factor Receptor (EGFR) Signaling with EGFR Tyrosine Kinase Inhibitor AG1478
Authors: Lee Fook T. , Mountain Angela J. , Kelly Marcus P. , Hall Cathrine , Rigopoulos Angela , Johns Terrance G. , Smyth Fiona E. , Brechbiel Martin W. , Nice Edouard C. , Burgess Antony W. , Scott Andrew M. 
Published: March 2006

Abstract
Purpose: Monoclonal antibodies and tyrosine kinase inhibitors specific for the epidermal growth factor receptor (EGFR) have been shown to enhance the effect of external beam radiation on EGFR-positive tumors. The effect of EGFR signaling abrogation by EGFR tyrosine kinase inhibitor on the efficacy of radioimmunotherapy has not been reported previously. This study investigated the effect of EGFR tyrosine kinase inhibition on the efficacy of radioimmunotherapy in a human cancer xenograft model.
Experimental Design: The humanized anti–Lewis Y antibody hu3S193 and the EGFR tyrosine kinase inhibitor AG1478 were studied. BALB/c nude mice were engrafted with A431 squamous carcinoma cells. Initial biodistribution properties of the 90Y-CHX-A″-DTPA-hu3S193 were evaluated in this model. In therapy experiments, cohorts of four to five xenografted mice were treated with saline as placebo, 0.4 mg AG1478 i.p. (six doses over 2 weeks), single i.v. injections of unlabeled hu3S193, or 90Y-CHX-A″-DTPA-hu3S193 (12.5, 25, 50, or 100 μCi). The combination of 0.4 mg AG1478 i.p. and 25 μCi 90Y-CHX-A″-DTPA-hu3S193 i.v. was subsequently evaluated in the A431 model.
Results: 90Y-CHX-A″-DTPA-hu3S193 retained excellent immunoreactivity after radiolabeling. The biodistribution study showed excellent uptake in tumor (90.33 ± 38.84%ID/g) peaking at 24 to 72 hours after injection and with prolonged retention. 90Y-CHX-A″-DTPA-hu3S193 significantly inhibited A431 xenograft growth at 25, 50, and 100 μCi doses. The combination of 0.4 mg AG1478 with a single dose of 25 μCi 90Y-CHX-A″-DTPA-hu3S193 resulted in a significant enhancement of efficacy compared with either agent alone (P = 0.013).
Conclusions: The efficacy of radioimmunotherapy with 90Y-CHX-A″-DTPA-hu3S193 is significantly enhanced by EGFR tyrosine kinase inhibitor AG1478. Further investigations of dosing regimens using EGFR tyrosine kinase inhibitors and radioimmunotherapy in the treatment of EGFR expressing tumors are warranted.
Radioimmunotherapy of Prostate Cancer Using 90Y- and 177Lu-Labeled J591 Monoclonal Antibodies: Effect of Multiple Treatments on Myelotoxicity
Authors: Vallabhajosula Shankar , Goldsmith Stanley J. , Kostakoglu Lale , Milowsky Mathew I. , Nanus David M. , Bander Neil H. 
Published: March 2006

Abstract
Purpose: Bone marrow is the dose-limiting organ in radioimmunotherapy. Fractionated dose regimens may decrease myelotoxicity and increase greater total administered dose. We have studied the effect of two or three treatments of 177Lu-J591 and 90Y-J591 monoclonal antibodies (mAb) on myelotoxicity.
Experimental Design: J591 is a deimmunized anti-PSMA mAb. Seven groups of patients with prostate cancer (n = 35) received 10 to 75 mCi/m2 of 177Lu-J591 and five additional groups (n = 28) received 5 to 20 mCi/m2 of 90Y-J591. Fifteen patients received two to three treatments of 177Lu-J591 (30, 45, or 60 mCi/m2) and four patients received two or three doses of 90Y-J591 (17.5 or 20 mCi/m2). Re-treatment consisted of patients receiving the same 177Lu or 90Y dose as their initial cycle. Time between treatments was 2 to 4 months.
Results: The single dose maximum tolerated dose was 70 mCi/m2 with 177Lu-J591 and 17.5 mCi/m2 with 90Y-J591. With a single dose of 177Lu, no severe toxicity was observed below 60 mCi/m2. With 177Lu, two doses of 45 or 60 mCi/m2, totaling 90 to 120 mCi/m2, proved to be quite toxic. Three doses of 30 mCi/m2 (total 90 mCi/m2), however, were well tolerated. With 90Y, four patients tolerated two to three doses of 17.5 or 20 mCi/m2. Thrombocytopenia increased at higher doses and after repeat treatments. At higher doses, the nadir was lower and the time to reach nadir was longer. Time for recovery of platelets seems related to the total dose.
Conclusions: Multiple (two or three) administrations of 177Lu-J591 (30-60 mCi/m2) or 90Y-J591 (17.5 mCi/m2) over a 4- to 6-month period were tolerated by the patients with manageable thrombocytopenia. Although a single large dose may deliver optimal radiation dose to kill a larger fraction of tumor cells, fractionated therapy offers the advantage of lower myelotoxicity and prolonged tumor response. With 177Lu-J591, dose fractionation in combination with taxanes should be considered as an alternative approach to achieve optimal therapeutic efficacy in patients with prostate cancer.
Antiproliferative activity of angiotensin II receptor blocker through cross-talk between stromal and epithelial prostate cancer cells
Authors: Uemura Hiroji , Ishiguro Hitoshi , Nagashima Yoji , Sasaki Takeshi , Nakaigawa Noboru , Hasumi Hisashi , Kato Shingo , Kubota Yoshinobu 
Published: March 2006

AbstractWe showed previously that angiotensin II activated the proliferation of prostate cancer cells and that angiotensin II receptor blockers (ARB) could inhibit it. Here, we investigated whether angiotensin II exerts mitogenic effects on the cross-talk between stromal and cancer cells and whether an ARB can inhibit tumor growth through actions on stromal cells. Cell proliferation and interleukin-6 secretion of prostate stromal PrSC cells stimulated with angiotensin II, tumor necrosis factor-α, or epidermal growth factor were examined in the absence and presence of ARB. We examined the effect of ARB on mitogen-activated protein kinase (MAPK) phosphorylation of PrSC and PC-3 cells treated with conditioned medium of PrSC cells and determined the effect of ARB on tumor growth induced by paracrine factors from PrSC cells. Angiotensin II activated the cell proliferation and interleukin-6 secretion of PrSC cells, and ARB inhibited it. Angiotensin II, tumor necrosis factor-α, or epidermal growth factor induced MAPK phosphorylation in PrSC cells, and this phosphorylation was inhibited by ARB. Conditioned medium of PrSC cells with angiotensin II activated MAPK phosphorylation in PC-3 cells, and ARB-treated conditioned medium of PrSC cells inhibited it. The tumor growth and angiogenesis of a mixture of PC-3 with PrSC were inhibited by ARB administration, whereas those of PC-3 xenografts were not inhibited. ARB exerted an antiproliferative effect on prostate cancer through paracrine factors from stromal cells. Because prostate stromal cells are thought to be involved in the initiation and development of prostate cancer, the present data suggest the possibility that ARBs are a novel therapeutic class of agents for prostate cancer.