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1

Patterson, K. G., and J. D. M. Richards. "The use of radioisotopes in haematology." Blood Reviews 6, no. 1 (March 1992): 1–9. http://dx.doi.org/10.1016/0268-960x(92)90002-8.

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2

Kavakli, Kaan, Ozgur Cogulu, Semih Aydogdu, Hayal Ozkilic, Burak Durmaz, Ozgur Kirbiyik, Ferda Ozkinay, et al. "Prospective Evaluation of Chromosomal Breakages in Hemophiliac Children after Radioisotope Synovectomy with Yttrium90 and Rhenium186." Blood 112, no. 11 (November 16, 2008): 1219. http://dx.doi.org/10.1182/blood.v112.11.1219.1219.

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Abstract Radioisotope Synovectomy (RS) is defined as the intra-articular injection of radioisotopic agents with the aim of fibrosis on hypertrophic synovium in the target joint for hemophilia. Yttrium90 (Y90) and Rhenium186 (Re186) are approved isotopes in Europe. The only radioisotope which approved in the USA for RS is Phosphorus 32 (P32). We have successfully used Y90 and Re186 for 8 years in target joints of hemophiliac patients. For the last 30 years, no malignant transformation has been reported in hemophilia with RS. However, recently, development of acute lymphoblastic leukemia in two hemophiliac children after RS has been reported in the USA. Even though P32 was the responsible radioisotopic agent, safety concerns have arisen due to exposure to all type of radioisotopic agents which may cause chromosomal breakages (CBs) and oncological transformation. The aim of this prospective and Ethics commitee-approved study was to investigate the early genotoxic effect on peripheral blood lymphocytes induced by Y90 and Re186 in children who underwent RS for chronical synovitis. All patients and parents were informed according to Helsinki Decleration. Thirty-three patients with persistent synovitis (23 hemophilia-A, 9 hemophilia-B,1 FVII deficiency) were enrolled to the study. All patients were male except one case. The mean age was 16.4 ±6.2 years (range:8–40). RS was performed as an outpatient procedure by using Y90 for knees (n=9)(5 mCi) and Re186 for elbows and ankles (n=14)(2 mCi)(CIS Bio International/Gif-sur-Yvett Cedex-France). In 6 patients, both agents were used simultaneously in one session. No radioisotope leakage away from the injection site was observed during and after procedure. Heparinised peripheral blood samples were obtained for lymphocyte cultures from all patients at three different time points (prior to RS, after 3 days and after 90 days). Diepoxybutane (DEB) test was used for the evaluation of chromosomal breakages in patients by culturing their blood along with blood from a sex-matched control with a working solution of 11 ug/ml. Five μl pure DEB was added to 5 ml of sterile dH2O. Afterwards, 10 μl of the first solution was added to 1 ml of sterile dH2O. This is the working solution at 11 ug/ml. A total of 50 metaphases from each culture were examined and scored according to the procedure. All cytogenetic analysis were performed in the Medical Genetics Laboratory of Ege University Hospital. Due to technical problems, parameters of 29 patients were evaluated. Chromosomal breakages (CB) were found in 20 patients prior to treatment. We have found CBs in 4 additional patients after 3 days of RS. However, all these CBs were disappeared 90 days after. CBs were found to be persisted in 17 patients. Mean frequency of CBs was (0.0707±0.0829/1000 cells) and was not significantly increased after 3 days (0.0828±0.0747) but significantly decreased at 90 days (0.0379±0.0456). The difference of the results of two radioisotopes were not significant. In conclusion, although RS with Y90 and Re186 does not seem to induce the genotoxic effects significantly on peripheral blood lymphocytes in hemophilic children, the significant decrease in the number of CBs between the 3rd and 90th days may be accepted as a warning for the requirement of risk/benefit ratios which should be taken into account for any individual patient. Therefore medical treatment in hemophilia for synovitis should be suggested before RS and families should be informed properly.
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3

Comor, Jozef. "Positron and alpha-emitting radioisotopes for applications in oncology: Plenary lecture." Archive of Oncology 10, no. 3 (2002): 127. http://dx.doi.org/10.2298/aoo0203127c.

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4

Kuriakose, Philip. "Targeted Therapy for Hematologic Malignancies." Cancer Control 12, no. 2 (April 2005): 82–90. http://dx.doi.org/10.1177/107327480501200203.

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Background: The introduction of monoclonal antibodies, either as native molecules or conjugated to radioisotopes or other toxins, has led to new therapeutic options for patients with hematologic malignancies. In addition, the use of small molecules against specific cell surface receptors, enzymes, and proteins has become an important strategy in the treatment of such disorders. Methods: The author reviewed the published clinical trials of monoclonal antibody and other targeted therapies in hematologic malignancies. Results: Results from several trials demonstrate a therapeutic benefit for the use of monoclonal antibodies (either native or conjugated) and other targeted therapies, used alone or in combination with standard cytotoxic chemotherapy. Conclusions: Targeted therapy of hematologic malignancies seems to be an effective and less toxic approach to the treatment of such disorders. Nevertheless, additional studies are needed to determine where and when such management fits into a therapeutic regimen for any given disorder, whether upfront or as salvage therapy, alone or in combination with chemotherapy (concurrent or sequential).
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5

Waldmann, Thomas. "ABCs of Radioisotopes Used for Radioimmunotherapy: α- and β-Emitters." Leukemia & Lymphoma 44, sup3 (November 2003): S107—S113. http://dx.doi.org/10.1080/10428190310001623685.

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6

Dingli, David, Kah-Whye Peng, Mary E. Harvey, Sompong Vongpunsawad, Elizabeth R. Bergert, Robert A. Kyle, Roberto Cattaneo, John C. Morris, and Stephen J. Russell. "Interaction of Measles Virus Vectors with Auger Electron Emitting Radioisotopes." Blood 106, no. 11 (November 16, 2005): 5525. http://dx.doi.org/10.1182/blood.v106.11.5525.5525.

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Abstract Background: Viral vectors based on the Edmonston strain of measles virus (MV-Edm) selectively destroy all tumor cell lines tested in vitro. The oncolytic activity of the virus is enhanced by expression of the thyroidal sodium iodide symporter (MV-NIS) that allows selective 131I uptake by infected tumor cells and eliminates myeloma tumor xenografts that are resistant to the parent virus. MV-NIS is being considered for therapy of patients with relapsed or refractory multiple myeloma. Advanced myeloma is associated with significant immunosuppression with the potential risk of uncontrolled virus proliferation. The number of agents with activity against MV is limited. Low energy (Auger) electrons have a short path length and selectively damage cells in which the isotope decays. Thus, we hypothesized that the Auger electron emitting isotope 125I, selectively taken up by cells expressing NIS, can be used to control viral proliferation. Methods: A replication competent MV that expressed both a soluble form of carcinoembryonic antigen (CEA) and NIS (MV-NICE) was rescued and characterized. Cells were infected with MV-NICE or control vectors and exposed to 125I with appropriate controls. CEA expression and viral titers were determined at different time points. The role of free radical generation on virus replication was explored. In vivo control of MV-NICE replication with 125I was attempted. Results: MV-NICE replication in vitro is inhibited by the selective uptake of 125I by cells expressing NIS. Extracellular decay of the isotope has no effect on virus proliferation. Auger electron damage is in part mediated by free radicals and abrogated by glutathione. In myeloma xenografts, control of MV-NICE with 125I was not possible under the conditions of the experiment. Conclusion: MV-NICE does not replicate faster in the presence of radiation under our experimental conditions. Auger electron emitting isotopes effectively stop propagation of MV vectors expressing NIS in vitro. Additional work is necessary to translate these observations in vivo.
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7

Maloney, David G. "Follicular NHL: From Antibodies and Vaccines to Graft-versus-Lymphoma Effects." Hematology 2007, no. 1 (January 1, 2007): 226–32. http://dx.doi.org/10.1182/asheducation-2007.1.226.

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AbstractMonoclonal antibody therapy with rituximab in combination with standard chemotherapy has improved the survival of patients with advanced-stage follicular lymphoma (FL). A series of next-generation anti-CD20 antibodies may be less immunogenic and have even greater antitumor activity through augmented interactions with host effector mechanisms responsible for tumor cell kill. Additional approaches with patient-specific immunoglobulin idiotype vaccines; novel monoclonal antibodies binding to biologically active cell-surface antigen are also demonstrating early clinical activity. Antibodies targeting radioisotopes, toxins or drugs are also slowly entering clinical trials and practice. Last, allogeneic stem cell transplantation following reduced-intensity conditioning provides graft-versus-tumor immune responses that may be able to control FL and allow this risky but potentially curative treatment option to older patents or those with comorbidities.
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8

Weber, P., J. Vuilleumier, and G. Guibert. "PO-1647 linac activation of radioisotopes and underground gammaspectroscopic analyses." Radiotherapy and Oncology 161 (August 2021): S1367—S1368. http://dx.doi.org/10.1016/s0167-8140(21)08098-1.

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9

Vlajkovic, Marina, and Milovan Matovic. "Diagnostic nuclear medicine in pediatric oncology-what we should know before scanning?" Archive of Oncology 20, no. 3-4 (2012): 139–42. http://dx.doi.org/10.2298/aoo1204139v.

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Cancer is second only to trauma as a cause of death in children, accounting for approximately 10% of all childhood deaths. The application of radioisotopes in the treatment of malignant diseases in children consists of detecting and estimating the degree of tumour spread by application of tumour-specific and non-specific radiopharmaceuticals, as well as the treatment of some malignant diseases. Paramount to any successful nuclear medicine examination is the establishment of acquisition protocols that allow high quality images to be obtained while ALARA principles are followed. Pediatric-specific issues should be anticipated and addressed in the planning of the studies to maximize the utility of the technique in this challenging group of patients, so the goal of this article is to summarize general prerequisites for the application of nuclear medicine diagnostic procedures in pediatric oncology patients.
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10

Holvoet, Paul, Hugo Cleemput, and Désiré Collen. "Assay of Human Tissue-Type Plasminogen Activator (t-PA) with an Enzyme-Linked Immunosorbent Assay (ELISA) Based on Three Murine Monoclonal Antibodies to t-PA." Thrombosis and Haemostasis 54, no. 03 (1985): 684–87. http://dx.doi.org/10.1055/s-0038-1660097.

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SummaryAn enzyme-linked immunosorbent assay (ELISA) for the measurement of human tissue-type plasminogen activator (t-PA) was developed. Microtiter plates were coated with a mixture of two monoclonal antibodies and bound t-PA was quantitated with a third monoclonal antibody linked to peroxidase. The lower limit of sensitivity of the assay was 0.2 ng of t-PA per ml. The concentration of antigen in citrated plasma of human subjects was found to be 3.4 ± 0.8 ng/ml. The assay had a good reproducibility with values of 3.8, 6.5 and 4.9 percent respectively for the intra-, inter-assay and inter-dilution variation coefficients. The results of the ELISA assay on plasma samples from patients during thrombolytic therapy with t-PA correlated very well, over a wide concentration range, with those obtained with a previously described two-site immuno-radiometric assay (r = 0.96). This ELISA with monoclonal antibodies constitutes a stable and reproducible set of reagents for the measurement of t-PA antigen in biological fluids, avoiding the disadvantages of the use of radioisotopes and of polyclonal antibodies.
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11

Abbas Rizvi, Syed M., A. J. Henniker, G. Goozee, and B. J. Allen. "In vitro testing of the leukaemia monoclonal antibody WM-53 labeled with alpha and beta emitting radioisotopes." Leukemia Research 26, no. 1 (January 2002): 37–43. http://dx.doi.org/10.1016/s0145-2126(01)00096-0.

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12

Jastrzębski, J., J. Choiński, A. Jakubowski, M. Sitarz, A. Stolarz, K. Szkliniarz, A. Trzcińska, and W. Zipper. "Production of and research on medical radioisotopes at the heavy ion laboratory, University of Warsaw." Radiotherapy and Oncology 118 (February 2016): S52—S53. http://dx.doi.org/10.1016/s0167-8140(16)30109-8.

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13

Kropp, GL, S. Fucharoen, and SH Embury. "Asymmetrically primed selective amplification/temperature shift fluorescence polymerase chain reaction to detect the hemoglobin Constant Spring mutation." Blood 78, no. 1 (July 1, 1991): 26–29. http://dx.doi.org/10.1182/blood.v78.1.26.26.

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Abstract Hemoglobin (Hb) Constant Spring is an alpha-thalassemic hemoglobinopathy that is a major cause of severe alpha-thalassemia in Southeast Asians. The difficulty of diagnosing Hb Constant Spring using standard electrophoretic methods has led to interest in DNA-dependent diagnostic methods. The methods developed have had to contend with the high degree of homology of the alpha 2-globin gene (the site of the Hb Constant Spring mutation) and the alpha 1-globin gene. We have developed a single reaction polymerase chain reaction-based method that uses asymmetric priming and a temperature shift to accomplish dual ends, selective amplification of alpha 2 but not alpha 1 DNA and discrimination of normal and Hb Constant Spring alpha 2 genes by allele- specific fluorescence polymerase chain reaction. Advantages of this method over previous approaches include avoiding radioisotopes, precluding the need for electrophoresis, and serving as its own control for successful amplification. It is readily applicable to routine diagnosis, population screening, and prenatal diagnosis.
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14

Kropp, GL, S. Fucharoen, and SH Embury. "Asymmetrically primed selective amplification/temperature shift fluorescence polymerase chain reaction to detect the hemoglobin Constant Spring mutation." Blood 78, no. 1 (July 1, 1991): 26–29. http://dx.doi.org/10.1182/blood.v78.1.26.bloodjournal78126.

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Hemoglobin (Hb) Constant Spring is an alpha-thalassemic hemoglobinopathy that is a major cause of severe alpha-thalassemia in Southeast Asians. The difficulty of diagnosing Hb Constant Spring using standard electrophoretic methods has led to interest in DNA-dependent diagnostic methods. The methods developed have had to contend with the high degree of homology of the alpha 2-globin gene (the site of the Hb Constant Spring mutation) and the alpha 1-globin gene. We have developed a single reaction polymerase chain reaction-based method that uses asymmetric priming and a temperature shift to accomplish dual ends, selective amplification of alpha 2 but not alpha 1 DNA and discrimination of normal and Hb Constant Spring alpha 2 genes by allele- specific fluorescence polymerase chain reaction. Advantages of this method over previous approaches include avoiding radioisotopes, precluding the need for electrophoresis, and serving as its own control for successful amplification. It is readily applicable to routine diagnosis, population screening, and prenatal diagnosis.
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15

Hirsch, Ariel E., David C. Medich, Barry S. Rosenstein, Christopher B. Martel, and Joshua A. Hirsch. "Radioisotopes and vertebral augmentation: Dosimetric analysis of a novel approach for the treatment of malignant compression fractures." Radiotherapy and Oncology 87, no. 1 (April 2008): 119–26. http://dx.doi.org/10.1016/j.radonc.2008.01.010.

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16

Villard, Linda, Anna Romer, Nicolas Marincek, Philippe Brunner, Michael T. Koller, Christian Schindler, Quinn K. T. Ng, et al. "Cohort Study of Somatostatin-Based Radiopeptide Therapy With [90Y-DOTA]-TOC Versus [90Y-DOTA]-TOC Plus [177Lu-DOTA]-TOC in Neuroendocrine Cancers." Journal of Clinical Oncology 30, no. 10 (April 1, 2012): 1100–1106. http://dx.doi.org/10.1200/jco.2011.37.2151.

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Purpose Radiopeptide therapy is commonly performed with a single radioisotope. We aimed to compare the effectiveness of somatostatin-based radiopeptide therapy with a single versus a combination of radioisotopes. Patients and Methods In a cohort study, patients with metastasized neuroendocrine cancer were treated with repeated cycles of 90yttrium-labeled tetraazacyclododecane-tetraacetic acid modified Tyr-octreotide ([90Y-DOTA]-TOC) or with cycles alternating between [90Y-DOTA]-TOC and 177lutetium-labeled DOTA-TOC ([177Lu-DOTA]-TOC) until tumor progression or permanent toxicity. Multivariable Cox regression and competing risk regression were used to study predictors of survival and renal toxicity in patients completing three or more treatment cycles. Results A total of 486 patients completed three or more treatment cycles; 237 patients received [90Y-DOTA]-TOC and 249 patients received [90Y-DOTA]-TOC + [177Lu-DOTA]-TOC. Patients receiving [90Y-DOTA]-TOC + [177Lu-DOTA]-TOC had a significantly longer survival than patients receiving [90Y-DOTA]-TOC alone (5.51 v 3.96 years; hazard ratio, 0.64; 95% CI, 0.47 to 0.88; P = .006). The rates of severe hematologic toxicities (6.3% v 4.4%; P = .25) and severe renal toxicity (8.9% v 11.2%; P = .47) were comparable in both groups. Conclusion [90Y-DOTA]-TOC + [177Lu-DOTA]-TOC was associated with improved overall survival compared with [90Y-DOTA]-TOC alone in patients completing three or more cycles of treatment. Contrary to the current practice in radiopeptide therapy, our results suggest an advantage of using a combination of radioisotopes.
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17

Embury, SH, GL Kropp, TS Stanton, TC Warren, PA Cornett, and FF Chehab. "Detection of the hemoglobin E mutation using the color complementation assay: application to complex genotyping." Blood 76, no. 3 (August 1, 1990): 619–23. http://dx.doi.org/10.1182/blood.v76.3.619.619.

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Abstract The color complementation assay (CCA) is a method of allele-specific DNA amplification by which competitive priming and extension of fluorescently labeled oligonucleotide primers determine the color of DNA amplification product. This diagnostic method precludes the need for radioisotopes, electrophoresis, and multiple high-stringency reaction conditions. The multiplicity of mutant globin genes present in Southeast Asians complicates clinical diagnosis and underscores the importance of DNA-based diagnostic methods. We have applied CCA to distinguish beta A and beta E alleles. Competing 15mer primers were a fluorescein-labeled complement to beta A and a rhodamine-labeled complement to beta E, identical except for their central nucleotides. A common unlabeled primer was used to amplify DNA product, the color of which was determined by the perfectly complementary primer. Color photography and spectrofluorometry, as well as a method of black-white photography that we developed to distinguish fluorescein- and rhodamine- labeled DNA, were used to record results. We applied CCA to define the complex genotype of a Thai woman with thalassemia intermedia, 96% HbE, and 4% HbF whose possible genotypes included several permutations of alpha-thalassemia, beta-thalassemia, and beta E genes. zeta-Globin gene mapping of DNA doubly digested with Bg/II and Asp 718 showed the -alpha 3.7/--SEA genotype, and CCA confirmed homozygous beta E/beta E. The CCA is useful for diagnosing the compound hemoglobin genotypes of Southeast Asians and could be applied also to prenatal diagnosis in this population.
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18

Embury, SH, GL Kropp, TS Stanton, TC Warren, PA Cornett, and FF Chehab. "Detection of the hemoglobin E mutation using the color complementation assay: application to complex genotyping." Blood 76, no. 3 (August 1, 1990): 619–23. http://dx.doi.org/10.1182/blood.v76.3.619.bloodjournal763619.

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The color complementation assay (CCA) is a method of allele-specific DNA amplification by which competitive priming and extension of fluorescently labeled oligonucleotide primers determine the color of DNA amplification product. This diagnostic method precludes the need for radioisotopes, electrophoresis, and multiple high-stringency reaction conditions. The multiplicity of mutant globin genes present in Southeast Asians complicates clinical diagnosis and underscores the importance of DNA-based diagnostic methods. We have applied CCA to distinguish beta A and beta E alleles. Competing 15mer primers were a fluorescein-labeled complement to beta A and a rhodamine-labeled complement to beta E, identical except for their central nucleotides. A common unlabeled primer was used to amplify DNA product, the color of which was determined by the perfectly complementary primer. Color photography and spectrofluorometry, as well as a method of black-white photography that we developed to distinguish fluorescein- and rhodamine- labeled DNA, were used to record results. We applied CCA to define the complex genotype of a Thai woman with thalassemia intermedia, 96% HbE, and 4% HbF whose possible genotypes included several permutations of alpha-thalassemia, beta-thalassemia, and beta E genes. zeta-Globin gene mapping of DNA doubly digested with Bg/II and Asp 718 showed the -alpha 3.7/--SEA genotype, and CCA confirmed homozygous beta E/beta E. The CCA is useful for diagnosing the compound hemoglobin genotypes of Southeast Asians and could be applied also to prenatal diagnosis in this population.
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19

Dhingra, K., M. Talpaz, MG Riggs, PS Eastman, T. Zipf, S. Ku, and R. Kurzrock. "Hybridization protection assay: a rapid, sensitive, and specific method for detection of Philadelphia chromosome-positive leukemias." Blood 77, no. 2 (January 15, 1991): 238–42. http://dx.doi.org/10.1182/blood.v77.2.238.238.

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Abstract The Philadelphia (Ph1) chromosome is present in greater than 90% of patients with chronic myelogenous leukemia (CML) and in 2% to 20% of those with acute leukemias, for which it is an important prognostic marker too. The chimeric BCR-ABL mRNAs resulting from the translocation encode either a 210-Kd or a 190-Kd protein. The techniques used to detect Ph1 chromosome include karyotyping, Southern analysis to demonstrate bcr rearrangement, and polymerase chain reaction to amplify the BCR-ABL transcripts. However, the routine performance of these methods by clinical laboratories is cumbersome, time consuming, and exposes laboratory personnel to radioisotopes. We describe here the clinical application of a new method, the hybridization protection assay (HPA), which uses chemiluminescent acridinium-ester-labeled probes in conjunction with PCR for detection of the amplified BCR-ABL sequences. The method is sensitive, specific, and can reliably distinguish between the transcripts for P190BCR-ABL and P210BCR-ABL. In contrast to the 2 days or longer required for conventional hybridization, HPA analysis can be completed in less than 30 minutes. We have successfully used this method to analyze 60 leukemia samples (34 from Ph1-negative acute leukemias; 6 from Ph1-positive acute leukemias; and 20 from CML) with complete correlation (of BCR-ABL positivity or negativity) with the results of karyotype or Southern Blot analysis of genomic DNA for bcr rearrangement. Therefore, the HPA, in conjunction with PCR, appears to provide a rapid and reliable test for the diagnosis of Ph1-positivity.
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20

Dhingra, K., M. Talpaz, MG Riggs, PS Eastman, T. Zipf, S. Ku, and R. Kurzrock. "Hybridization protection assay: a rapid, sensitive, and specific method for detection of Philadelphia chromosome-positive leukemias." Blood 77, no. 2 (January 15, 1991): 238–42. http://dx.doi.org/10.1182/blood.v77.2.238.bloodjournal772238.

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The Philadelphia (Ph1) chromosome is present in greater than 90% of patients with chronic myelogenous leukemia (CML) and in 2% to 20% of those with acute leukemias, for which it is an important prognostic marker too. The chimeric BCR-ABL mRNAs resulting from the translocation encode either a 210-Kd or a 190-Kd protein. The techniques used to detect Ph1 chromosome include karyotyping, Southern analysis to demonstrate bcr rearrangement, and polymerase chain reaction to amplify the BCR-ABL transcripts. However, the routine performance of these methods by clinical laboratories is cumbersome, time consuming, and exposes laboratory personnel to radioisotopes. We describe here the clinical application of a new method, the hybridization protection assay (HPA), which uses chemiluminescent acridinium-ester-labeled probes in conjunction with PCR for detection of the amplified BCR-ABL sequences. The method is sensitive, specific, and can reliably distinguish between the transcripts for P190BCR-ABL and P210BCR-ABL. In contrast to the 2 days or longer required for conventional hybridization, HPA analysis can be completed in less than 30 minutes. We have successfully used this method to analyze 60 leukemia samples (34 from Ph1-negative acute leukemias; 6 from Ph1-positive acute leukemias; and 20 from CML) with complete correlation (of BCR-ABL positivity or negativity) with the results of karyotype or Southern Blot analysis of genomic DNA for bcr rearrangement. Therefore, the HPA, in conjunction with PCR, appears to provide a rapid and reliable test for the diagnosis of Ph1-positivity.
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21

Laguna, Pawel PL, Piotr Zbikowski, Jaroslaw Cwikla, Anna Klukowska, Jan Walecki, and Michal Matysiak. "Radiosynovectomy in Children with Congenital Haemostatic Defects." Blood 112, no. 11 (November 16, 2008): 4513. http://dx.doi.org/10.1182/blood.v112.11.4513.4513.

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Abstract Aims: To evaluate the clinical benefits of radiosynovectomy (RS) in children with congenital coagulative disorders, reduce bleeds and improve progression free survival (PFS). Methods: 35 patients aged 7 to 17 yrs, (mean age 12.6 yrs) were included in the study. 29 had haemophilia A, (4 with inhibitor factor VIII), 3 had haemophilia B (1 with inhibitor factor IX) and 3 had von Willebrand’s disease. There were 43 therapies including injections into the followed joints: knee 21, elbow 13, ankle 6 and shoulder 3. In 30 cases this was initial therapy and in 5 cases repeat therapy due to recurrence or deterioration. Injected activity of 186Re colloid was dependent on type and size of joints, range: 60–180 MBq. Post therapy imaging was performed in each case 1 h after injection of radioisotopes, and then on day 2 and 3. The number of bleedings into joints per month, improvement of joint movements, and other clinical changes were evaluated before and after therapy in 3 month intervals. US images were used to assess changes in joint effusion and synovial overgrowth. PFS in terms of significant clinical improvement within joints was assessed using standard Kaplan Meier methods. The prognostic significance of selected parameters was tested using discriminate function analysis. Results: After injection of 186Re into joints, post-therapeutic images showed intraarticular distribution of tracer and there was no leakage. A significant reduction in bleeds into joints was noted (before therapy mean 1.8 per month and after treatment mean 0.3 per month, p<0.001). Conclusions: This study suggests that use of 186Re in early stages of arthropatic haemophilia reduces the number of bleeds into joints and improves PFS.
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22

Barlogie, B., J. Epstein, P. Selvanayagam, and R. Alexanian. "Plasma cell myeloma--new biological insights and advances in therapy." Blood 73, no. 4 (March 1, 1989): 865–79. http://dx.doi.org/10.1182/blood.v73.4.865.865.

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Abstract Plasma cell myeloma is a more complex neoplasm than suggested by the relative uniformity of its dominant plasma cells, which represent the terminal stage of normal B-cell differentiation. Phenotypic, molecular, and cellular genetic data favor the presence of a myeloma stem cell early in hematopoietic development so that, as in chronic myelogenous leukemia (CML), a far distance exists between the primordial malignant cell that was the target of malignant transformation and the dominant clinical phenotype. Traces of pre-B, myeloid, and T cells are coexpressed with the mature B-cell phenotype, an occurrence unknown in normal B-cell differentiation. Analogous to CML, disease progression is marked by disease dedifferentiation, occasionally with cessation of myeloma protein production and development instead of extramedullary lymphomalike features with high LDH or myelodysplasia/acute myelogenous leukemia (AML) syndromes. The prognostic importance of serum LDH levels even in newly diagnosed myeloma suggests the early presence of tumor cells with “LDH phenotype,” which, as a result of drug resistance and proliferative advantage, expand preferentially during disease progression. Further characterization of these cells may provide important clues about the ontogeny of multiple myeloma. Myeloma cells express many receptors for different biological signals that might be exploitable for therapy with immunotoxins or radioisotopes. Plasma cells and their precursors also produce a variety of cytokines, some of which have putatively autostimulatory functions (eg, IL-1, IL-5, IL-6) and/or are related to disease manifestations (eg, IL-1 and TNF-beta as OAF). The wealth of cellular expression by plasma cells provides clues for understanding the mechanisms of gene activation and the nature of abnormal growth and differentiation. The accuracy of prognostically relevant staging systems has been refined with the use of new quantitative parameters that reflect tumor mass (ie, serum B2M levels) and biology. Further studies of cellular and molecular biology (ie, CAL- LA, H-ras) may reveal those tumor cell features that define clinical entities, response to therapy, and long-term prognosis. The lack of a major advance in prognosis despite the use of more drugs and more intensive regimens justifies the continued use of standard melphalan- prednisone for patients with a highly favorable prognosis, for the very aged, and for those with a short life expectancy due to other major medical problems. However, a radical departure from standard practice is required to improve the prognosis for younger patients with poor risk features.(ABSTRACT TRUNCATED AT 400 WORDS)
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23

Barlogie, B., J. Epstein, P. Selvanayagam, and R. Alexanian. "Plasma cell myeloma--new biological insights and advances in therapy." Blood 73, no. 4 (March 1, 1989): 865–79. http://dx.doi.org/10.1182/blood.v73.4.865.bloodjournal734865.

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Plasma cell myeloma is a more complex neoplasm than suggested by the relative uniformity of its dominant plasma cells, which represent the terminal stage of normal B-cell differentiation. Phenotypic, molecular, and cellular genetic data favor the presence of a myeloma stem cell early in hematopoietic development so that, as in chronic myelogenous leukemia (CML), a far distance exists between the primordial malignant cell that was the target of malignant transformation and the dominant clinical phenotype. Traces of pre-B, myeloid, and T cells are coexpressed with the mature B-cell phenotype, an occurrence unknown in normal B-cell differentiation. Analogous to CML, disease progression is marked by disease dedifferentiation, occasionally with cessation of myeloma protein production and development instead of extramedullary lymphomalike features with high LDH or myelodysplasia/acute myelogenous leukemia (AML) syndromes. The prognostic importance of serum LDH levels even in newly diagnosed myeloma suggests the early presence of tumor cells with “LDH phenotype,” which, as a result of drug resistance and proliferative advantage, expand preferentially during disease progression. Further characterization of these cells may provide important clues about the ontogeny of multiple myeloma. Myeloma cells express many receptors for different biological signals that might be exploitable for therapy with immunotoxins or radioisotopes. Plasma cells and their precursors also produce a variety of cytokines, some of which have putatively autostimulatory functions (eg, IL-1, IL-5, IL-6) and/or are related to disease manifestations (eg, IL-1 and TNF-beta as OAF). The wealth of cellular expression by plasma cells provides clues for understanding the mechanisms of gene activation and the nature of abnormal growth and differentiation. The accuracy of prognostically relevant staging systems has been refined with the use of new quantitative parameters that reflect tumor mass (ie, serum B2M levels) and biology. Further studies of cellular and molecular biology (ie, CAL- LA, H-ras) may reveal those tumor cell features that define clinical entities, response to therapy, and long-term prognosis. The lack of a major advance in prognosis despite the use of more drugs and more intensive regimens justifies the continued use of standard melphalan- prednisone for patients with a highly favorable prognosis, for the very aged, and for those with a short life expectancy due to other major medical problems. However, a radical departure from standard practice is required to improve the prognosis for younger patients with poor risk features.(ABSTRACT TRUNCATED AT 400 WORDS)
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Leslie, Lori A., and Anas Younes. "Antibody-Drug Conjugates in Hematologic Malignancies." American Society of Clinical Oncology Educational Book, no. 33 (May 2013): e108-e113. http://dx.doi.org/10.14694/edbook_am.2013.33.e108.

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Antibody-drug conjugates (ADCs) are agents composed of a monoclonal antibody linked to cytotoxic molecules. By specifically delivering cytotoxic agents to cells expressing surface antigens of interest, ADC technology allows for the targeted use of highly toxic agents resulting in increased efficacy against malignant cells and decreased damage to normal tissue. Effector agents can be small molecules, radioisotopes, proteins, or bacterially derived toxins. Over the past several decades, ADCs have been evaluated in a variety of preclinical models of hematologic malignancies, as well as early-phase clinical trials with limited success. More recently, advancements in linkage technology, improvements in cytotoxin selection, and use of smaller conjugates containing partial rather than complete antibodies have drastically improved the potential clinical value of ADCs. In the future, ADC technology may be used to restore tumor suppressor activity, target the microenvironment, or replace nonfunctional enzymes. In this review we will discuss select ADCs in various stages of development for use in hematologic malignancies including lymphoma, multiple myeloma, and leukemia.
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Valeri, C. Robert, Hollace Macgregor, Albert Giorgio, and Gina Ragno. "Comparison of radioisotope methods and a non-radioisotope method to measure platelet survival in the baboon." Transfusion and Apheresis Science 32, no. 3 (June 2005): 275–81. http://dx.doi.org/10.1016/j.transci.2004.05.008.

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26

Rosenblat, Todd L., Michael R. McDevitt, Neeta Pandit-Taskar, Jorge A. Carrasquillo, Suzanne Chanel, Mark G. Frattini, Steven M. Larson, David A. Scheinberg, and Joseph G. Jurcic. "Phase I Trial of the Targeted Alpha-Particle Nano-Generator Actinium-225 (225Ac)-HuM195 (Anti-CD33) in Acute Myeloid Leukemia (AML)." Blood 110, no. 11 (November 16, 2007): 910. http://dx.doi.org/10.1182/blood.v110.11.910.910.

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Abstract HuM195, a humanized anti-CD33 antibody, targets myeloid leukemia cells and has modest activity alone against AML. To increase the antibody’s potency and allow single cell killing, but avoid the nonspecific cytotoxicity associated with β-emitting isotopes, the α-emitter bismuth-213 (213Bi) was initially conjugated to HuM195. In phase I and II trials, 213Bi-HuM195 was capable of inducing remissions in AML after partial cytoreduction with cytarabine. Therapeutic applications of 213Bi, however, are limited by its 46-minute half-life. The isotope generator, 225Ac, a radiometal which yields 4 α-emitting isotopes and has a 10-day half life, can be conjugated to a variety of antibodies using the bifunctional chelate DOTA-SCN. 225Ac-containing immunoconjugates can kill in vitro at radioactivity doses 1000 times lower than 213Bi analogs and prolong survival of animals in several xenograft models (McDevitt et al. Science 2001). We are conducting a first-in-man phase I dose escalation trial to determine the safety, pharmacology, and biological activity of such an in vivo isotope generator using 225Ac-HuM195. Seven patients (median age, 61 years; range, 46–77) with relapsed (n=3) or refractory (n=4) AML were treated to date. Three had poor-risk cytogenetics. Patients received a single infusion of 225Ac-HuM195 at doses of 0.5 (n=3), 1 (n=3), or 2 μCi/kg (n=1). Total administered activities of 225Ac ranged from 23–170 μCi, and HuM195 doses ranged from 1–1.9 mg. No acute toxicities were seen. One of 2 patients evaluable for neutropenia developed an ANC <500/μL. Grade 4 thrombocytopenia was seen in both patients who were evaluable. Among 4 evaluable patients, resolution of grade 4 leukopenia occurred after a median of 10 days (range, 0–26). Three patients had neutropenic fever. One patient with a prior history of fungal hepatitis developed a grade 3 elevation in alkaline phosphate lasting 6 days after receiving 1 μCi/kg of 225Ac-HuM195. No other grade 3–4 extramedullary toxicities were observed. No evidence of radiation nephritis has been seen, with follow-up to 10 months. To determine pharmacokinetics over 10 days following treatment, we analyzed plasma by gamma counting at 2 energy windows for 2 of the 225Ac daughters, francium-221 (221Fr) and 213Bi. Two phase elimination kinetics were seen with mean plasma half-lives t1/2-α and t1/2-β of 2.9 and 54 hours, respectively. These results are similar to other HuM195 constructs containing long-lived radioisotopes. Antileukemic effects included elimination of peripheral blood blasts in 3 of 6 evaluable patients and dose-related reductions of >33% of BM blasts in 4 patients at 4 weeks following treatment. One patient had 3% bone marrow blasts after therapy. This is the first study to show that targeted therapy with an in vivo α-particle generator is feasible in humans. 225Ac-HuM195 appears safe and has antileukemic activity. Accrual to this trial continues.
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AuBuchon, James P. "Radioisotopic reflections." Transfusion 45, s2 (August 2005): 28S—32S. http://dx.doi.org/10.1111/j.1537-2995.2005.00528.x.

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28

Chu, Bae P., Neeta Pandit-Taskar, Boglarka Gyurkocza, Qing Liang, Daniel Miodownik, Vijay Reddy, Mark S. Berger, and Lawrence T. Dauer. "Feasibility of Administering Anti-CD45 Iodine (131I) Apamistamab [Iomab-B] for Re-Induction and Targeted Conditioning in Older Patients with Active, Relapsed or Refractory AML without Lead-Lined Rooms: Sierra Trial Experience at MSKCC." Blood 134, Supplement_1 (November 13, 2019): 5839. http://dx.doi.org/10.1182/blood-2019-131230.

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Background: Patients ≥55 years of age with active, relapsed or refractory acute myeloid leukemia (R/R AML) who have failed standard induction and salvage therapies do not routinely undergo allogeneic hematopoietic cell transplantation (HCT) due to their inability to receive myeloablative conditioning and lack of efficacy. The SIERRA trial is a prospective, randomized, phase 3, open-label, multicenter trial designed to address this significant unmet need. Preliminary results have shown the re-induction and targeted conditioning therapy with Iomab-B can lead to successful engraftment. Because of the administered activity of 131I (300-1030 mCi, mean ~600 mCi), patients are isolated for several days after the drug administration before being discharged. Radiation safety procedures with rolling lead shields and blankets were implemented to ensure compliance with local regulations for therapeutic radioisotopes and the safe administration of Iomab-B. Methods: A corner room with private bathroom was selected as the patient room for drug administration and patient isolation. The room was prepared to prevent radioactive contamination. Rolling lead shields were utilized depending on the room configuration: 2 shields against the patient emitting radiation and closer to the door, or 3 shields total with 1 additional shield by the nurses' work station in the room. Lead blankets were placed under the patient bed. Extensive radiation safety training was provided to nursing staff who interacted with Iomab-B patients. The administration was performed in the room using an automatic pump system with Iomab-B drug vial placed in a lead pig during infusion (4-5 hours). Radiation dose rates at several locations were measured at the completion of administration. Radiation doses to nurses who provided care to patients were monitored with personal dosimeters throughout the course of treatment, while the patients remained in radiation isolation. Results: 10 Iomab-B patients were treated with 788 ± 192 (range: 543-1069 mCi). Exposure survey results were taken within 2 hours after therapeutic infusion outside the patient door (mean 0.64, range 0.06-1.95 mrem/hr) the hallway (0.01 mrem/hr, background levels) adjacent rooms (mean 0.747, range 0.2-1.82 mrem/hr) as well as above (mean 0.986, range 0.5-1.6 mrem/hr) and below (mean 1.398, range 0.81-1.88 mrem/hr) the room. All the exposure survey results were below the regulated public area limit, 2 mrem/hr. The dose to inpatient nurses caring for the patient was 9.42 ± 6.6 (range: 1-27 mrem), which is minimal comparing to annual occupational dose limit of 5,000 mrem. The rooms were surveyed for contamination after the patient was cleared from radiation isolation and removable surface contamination was below 200 dpm/100cm2, lower than the limit of 24,00 dpm/100cm2 Conclusion: The use of rolling lead shields and implementation of specific radiation safety procedures allows for the safe administration of Iomab-B and enable treatment of patients without the need for lead-lined rooms. Table Disclosures Pandit-Taskar: Y Mabs: Consultancy, Honoraria; Fusion Pharmaceuticals: Consultancy, Honoraria; Progenics: Consultancy, Honoraria; Medimmune: Consultancy, Honoraria; Actinium Pharmaceuticals, Inc: Consultancy, Honoraria. Gyurkocza:Actinium Pharmaceuticals: Research Funding. Liang:Actinium Pharmaceuticals: Employment. Reddy:Actinium Pharmaceuticals: Employment. Berger:Actinium Pharmaceuticals, Inc: Employment, Equity Ownership. Dauer:Actinium Pharmaceuticals, Inc: Other: MSKCC - NIH/NCI Cancer Center Support Grant P30 CA008748, Research Funding.
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29

Jurcic, Joseph G., Todd L. Rosenblat, Michael R. McDevitt, Neeta Pandit-Taskar, Jorge A. Carrasquillo, Suzanne M. Chanel, Kevin Zikaras, et al. "Phase I Trial of the Targeted Alpha-Particle Nano-Generator Actinium-225 (225Ac)-Lintuzumab (Anti-CD33; HuM195) in Acute Myeloid Leukemia (AML)." Blood 118, no. 21 (November 18, 2011): 768. http://dx.doi.org/10.1182/blood.v118.21.768.768.

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Abstract Abstract 768 Background: Lintuzumab, a humanized anti-CD33 antibody, targets myeloid leukemia cells and has modest activity against AML. To increase the antibody's potency yet avoid nonspecific cytotoxicity seen with β-emitting isotopes, the α-emitter bismuth-213 (213Bi) was conjugated to lintuzumab. Substantial clinical activity was seen in phase I and II trials, but the use of 213Bi is limited by its 46-min half-life. The isotope generator, 225Ac (t½=10 days), yields 4 α-emitting isotopes and can be conjugated to a variety of antibodies using DOTA-SCN. 225Ac-labeled immunoconjugates kill in vitro at radioactivity doses at least 1,000 times lower than 213Bi analogs and prolong survival in mouse xenograft models of several cancers (McDevitt et al. Science 2001). Methods: We are conducting a first-in-man phase I dose escalation trial to determine the safety, pharmacology, and biological activity of 225Ac-lintuzumab in AML. Results: Fifteen patients (median age, 62 yrs; range, 45–80 yrs) with relapsed (n=10) or refractory (n=5) AML were treated to date. Patients received a single infusion of 225Ac-lintuzumab at doses of 0.5 (n=3), 1 (n=4), 2 (n=3), 3 (n=3), or 4 (n=2) μCi/kg (total administered activity, 23–402 μCi). No acute toxicities were seen. Myelosuppression was the most common toxicity; the median time to resolution of grade 4 leukopenia was 26 days (range, 0–71 days). DLT was seen in 3 patients, including myelosuppression lasting >35 days in 1 patient receiving 4 μCi/kg and death due to sepsis in 2 patients treated at the 3 and 4 μCi/kg dose levels. Febrile neutropenia was seen in 4 patients, and 4 patients had grade 3/4 bacteremia. Extramedullary toxicities were limited to transient grade 2/3 liver function abnormalities in 4 patients. With a median follow-up of 2 mos (range, 1–24 mos), no evidence of radiation nephritis was seen. We analyzed plasma pharmacokinetics by gamma counting at energy windows for 2 daughters of 225Ac, francium-221 (221Fr) and 213Bi. Two-phase elimination kinetics were seen with mean plasma t½-α and t½-β of 1.9 and 35 hours, respectively. These results are similar to other lintuzumab constructs labeled with long-lived radioisotopes. Peripheral blood blasts were eliminated in 9 of 14 evaluable patients (64%), but only at doses of ≥1 μCi/kg. Bone marrow blast reductions were seen in 8 of 12 evaluable patients (67%) at 4 weeks, including 6 patients (50%) who had a blast reduction of ≥50%. Three patients treated with 1, 3, and 4 μCi/kg achieved bone marrow blast reductions to ≤5%. Conclusions: This is the first study to show that therapy with a targeted α-particle generator is feasible in humans. 225Ac-lintuzumab has antileukemic activity across all dose levels. Accrual to this trial continues to define the MTD. Disclosures: Jurcic: Actinium Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding. McDevitt:Actinium Pharmaceuticals, Inc.: Consultancy, Research Funding. Cicic:Actinium Pharmaceuticals, Inc.: Employment, Equity Ownership, Patents & Royalties. Scheinberg:Actinium Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding.
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30

Tang, Yongmin, Haizhong Zhang, Sisi Li, Baiqin Qian, Hongqiang Shen, Chunfang Luo, and Yi Zhang. "Preliminary Study on the Leukemia Targeting by a CD19 Antibody Conjugated with Saline Extracts from Mylabris Phalerata Pallas." Blood 110, no. 11 (November 16, 2007): 4189. http://dx.doi.org/10.1182/blood.v110.11.4189.4189.

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Abstract Introduction and Objectives As a potent ligand for an immunotoxin, many moieties have been tried. However, majority of those moieties were large molecules or proteins which may produce human anti-toxin antibodies or were radioisotopes which may generate the concerns of the radioactive contaminations. Thus a small, non-protein toxin is desired to avoid the above disadvantages. Our hypothesis was that there could be a water soluble toxin in the saline extract of a Chinese medicine Mylabris phalerata Pallas (SEM) and easy to be conjugated with antibody proteins to generate immunotoxin. In this study, the toxin (s) in SEM was used to conjugate with our anti-CD19 monoclonal antibody ZCH-4-2E8 (2E8) protein and targeting efficacy on leukemia cells was tested to elucidate its leukemia-specific targeting efficacy and its mechanisms. Materials and Methods The physical and biological activities of SEM were tested by heat treatment, dialysis, SDS-PAGE and cell culture analyses. SEM was conjugated with 2E8 antibody using direct incubation at 37°C for 24 hours. Targeting efficacy were evaluated by cell culture. Cell apoptosis was analyzed by using Annexin V-FITC/Propidium Iodide double staining and flow cytometry method. Results Different concentrations of SEM at 1:200, 1:400, 1:800 and 1:1600 had different cell growth inhibition on both Nalm-6 and K562 cells non-specifically. The concentration at 1:200 generated the most potent cell kill and all the cells were dead after 72 hr culture. Concentrations below 1:800 or lower generated a minimal efficacy of cell kill and the concentration at 1:1600 showed no significant impact as compared to that of control (P > 0.05). Time course investigations showed that the growth inhibition was increased with incubation time. The IC50 for Nalm-6 cells was 1:805 while that for K562 was 1:689. The prudent toxin was heat stable as treatment of 100°C for 5 min did not diminish its cytotoxic activity. The toxin could be dialyzed through the 10kDa pore-size membrane. Electrophoresis analyses with SDS-PAGE showed no protein bands on the gel after staining with Coomassie brilliant blue. The natural conjugation could occur when CD19 antibody supernatant was incubated with the same volume of 1:200 SEM at 37°C for 24 hr. After 144 hr incubation, the inhibition rate of 2E8-SEM (1:2 of 2E8 supernatant with ≤ 1:400 of SEM) on Nalm-6 cells was 55.11% If normal saline was considered as negative control (0%), which was significantly higher than that of non-SEM conjugated 2E8 antibody at 1:2 of supernatant (16.01% of inhibition rate, P < 0.05). The inhibitions were not observed when 2E8-SEM (12.38% of inhibition, P > 0.05) and non-SEM conjugated 2E8 antibody (8.98% of inhibition, P > 0.05) were co-cultured with CD19- K562 cells at the same conditions as compared to that (0%) of normal saline. The cell death was via apoptotic process based on the flow cytometry analysis using Annexin V-FITC/Propidium Iodide double staining. Conclusions The strong and non-specific cytotoxic water soluble toxin(s) existed in SEM which was able to bind to antibody protein using simple incubation at 37°C showing significant targeting efficacy on Nalm-6 leukemia cells. The further study on this new toxin and the optimal way of conjugation are currently under investigation to improve the binding and the targeting efficacies.
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31

Casucci, Monica, Benedetta Nicolis di Robilant, Laura Falcone, Barbara Camisa, Margherita Norelli, Bernhard Gentner, Pietro Genovese, et al. "Off-Tumor Target Expression Levels Do Not Predict CAR-T Cell Killing: A Foundation For The Safety Of CD44v6-Targeted T Cells." Blood 122, no. 21 (November 15, 2013): 142. http://dx.doi.org/10.1182/blood.v122.21.142.142.

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Abstract Introduction Off-tumor expression of the target antigen raises justified safety concerns about newly designed chimeric antigen receptors (CARs). We have recently developed a CAR targeting the tumor-promoting antigen CD44v6 and demonstrated potent antitumor effects against acute myeloid leukemia (AML) and multiple myeloma (MM) both in vitro and in vivo. Despite promising activity against epithelial tumors, the administration of the CD44v6-specific mAb used for deriving our CAR (bivatuzumab) showed reversible myelosuppression and mucositis when conjugated with radioisotopes, and severe skin toxicity when conjugated with the potent cytotoxic drug mertansine. Preclinically evaluating the potential off-tumor toxicities of CD44v6-targeted T cells is therefore crucial before they can be safely translated to the clinic. Aim To profile the off-tumor expression of CD44v6 and to verify the susceptibility of expressing cells to CAR-T cell killing. Results Quantitative RT-PCR analysis on a wide panel of cDNA from normal tissues revealed restricted CD44v6 expression on flat stratified epithelia, like the skin, albeit at considerably lower levels compared with primary leukemic blasts. We therefore addressed the issue of keratinocyte recognition in co-culture experiments. Strikingly, at the E:T ratios allowing the potent antitumor effects of CD44v6-targeted T cells, keratinocytes were not killed and there was no cytokine production. Interestingly, comparative analysis of accessory molecules showed that, differently from leukemic blasts, keratinocytes expressed significant lower levels of adhesion/costimulatory molecules, including (ICAM-1, LFA-3 and B7.2), but higher levels of the critical checkpoint molecule PD-L1. Of the different cells of the hematopoietic system analyzed, only circulating CD14+ monocytes expressed CD44v6 and were killed by CD44v6-targeted T cells. Interestingly, by immunohistochemistry, we found no CD44v6 expression on bone-marrow monocytes, lymph-node macrophages, brain microglia, liver Kuppfer cells and dermal macrophages, suggesting a low risk for by-stander toxicity against these tissues. Moreover, CD44v6-targeted T cells did not interfere with the generation of virus-specific CTLs by antigen-specific stimulation in vitro. Importantly, both RT-qPCR and FACS demonstrated lack of CD44v6 expression on hematopoietic stem cells (HSCs) and progenitors. Accordingly, CD44v6-targeted T cells did not interfere with their clonogenic potential in vitro and, in co-culture experiments with whole bone marrow from MM patients, were able to selectively eliminate tumor cells, while sparing HSCs and progenitors. Finally, we tested the potential hematological toxicities of CD44v6-targeted T cells in NSG mice transgenic for human IL-3, SCF and GM-CSF (NSG-3GS). NSG-3GS mice transplanted with human CD34-selected cord blood cells showed enhanced myeloid reconstitution compared to NSG mice, including CD44v6+ monocytes. The infusion of CD44v6-targeted T cells in reconstituted NSG-3G mice resulted in the selective elimination of monocytes, but in the preservation of other cell subsets. Importantly, after in vivo exhaustion of CD44v6-targeted T cells, NSG-3G mice reconstituted monocytes de novo, indicating preservation of the HSC pool. For enabling rapid and conditional ablation of CD44v6-targeted T cells, we have finally co-expressed the CD44v6-CAR with TK or the inducible caspase-9 and validated the suicide gene approach in hyperacute xenogeneic GVHD surrogating maximal toxicity. Conclusions Our results indicate that off-tumor target expression levels do not automatically predict the susceptibility to CAR T-cell killing. Moreover they suggest that, differently from mAb-derived pharmaceuticals, therapeutic doses of suicidal CD44v6-targeted T cells might associate with acceptable and/or reversible toxicities. Disclosures: Bordignon: MolMed SpA: Employment.
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32

Puri, Sonika, Jun-Ki Park, Frank Modersitzki, and David S. Goldfarb. "Radioisotope blood volume measurement in hemodialysis patients." Hemodialysis International 18, no. 2 (November 22, 2013): 406–14. http://dx.doi.org/10.1111/hdi.12105.

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Robinson, Lary A. "Radioisotope-Guided Surgical Biopsy of Suspected Osseous Metastases." Cancer Control 4, no. 6 (November 1997): 516–22. http://dx.doi.org/10.1177/107327489700400605.

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Background Radioisotope bone scanning is frequently used to stage patients with suspected or proven malignancies. Since false-positive results are common, especially in the ribs, open biopsy is often necessary. The conventional approach of visual inspection of the bone scan image to guide the surgeon usually requires excision of a large area of one or two ribs to assure that the biopsy was performed on the correct rib. A more precise method to guide the biopsy is desirable. Methods One technique to localize the suspicious area of bone intraoperatively for accurate biopsy involves percutaneous injection of the bone abnormality with a radioisotope followed by injection of methylene blue into the periosteum and subsequent open surgical biopsy. A more recent technique uses a hand-held gamma probe in a sterile sleeve in the operating room to locate the bone “hot spot” directly in the wound to guide the biopsy. Results Both techniques are effective in pinpointing the bone scan abnormality, but use of the gamma probe is less cumbersome and consumes less time and fewer resources. In one series of 10 patients undergoing gamma probe-guided biopsies of 13 rib and 1 sternal bone scan lesions, this technique showed a sensitivity of 100% in locating the area of abnormal radioisotope uptake. All biopsies yielded an abnormal diagnosis to account for the bone scan abnormality, but only 4 of 14 (29%) demonstrated metastatic tumor. Conclusions Techniques described for radioisotope-guided localization of areas of increased tracer uptake in asymptomatic suspected bone metastases are accurate, sensitive guides to the open biopsy of these bony abnormalities. Due to the high false-positive rates in these asymptomatic but suspicious bone scan abnormalities, a diagnosis should be histologically confirmed.
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34

Yoshimura, Mana. "JS5-4 Recent trends in targeted radioisotope therapy." Annals of Oncology 33 (July 2022): S415. http://dx.doi.org/10.1016/j.annonc.2022.05.392.

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35

Garcia-Robledo, Juan Esteban, David A. Martinez, Pedro Franco-Fuquen, Fabio Vargas Cely, Eider Moreno-Cortes, Rhea Hans, Santanu Bhattacharya, Debabrata Mukhopadhyay, and Januario E. Castro. "Novel Peptide-Based Plectin-1 CAR T-Cells Target Specifically Pancreatic Cancer Cells." Blood 142, Supplement 1 (November 28, 2023): 6846. http://dx.doi.org/10.1182/blood-2023-191254.

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Introduction: Pancreatic ductal adenocarcinoma (PDAC) is one of the most devastating cancers, and therapies to treat this malignancy have not evolved rapidly to fulfill the need of affected patients. PDAC, like many solid malignancies, is considered a “cold immunological tumor” where the lack of targetable tumor-associated antigens has hampered the development of successful immunotherapies. Despite newer treatment approaches, PDAC patients with advanced disease have a dismal prognosis. Therefore, there is an urgent need to develop new therapies. Plectin-1 is a high molecular weight protein (∼500 kDa) that participates in cytoskeleton network organization linking intermediate filaments to microtubules and microfilaments. Plectin-1 is aberrantly expressed in the PDAC cellular membrane, contributes to PDAC pathogenesis, and confers a poor prognosis. Plectin-1-targeting peptides (PTP) in mice and humans have been successfully explored for their use in PDAC imaging and targeted payload delivery (small molecules, radioisotopes, and chemotherapy). We sought to take advantage of the specific binding of PTP and develop a peptide-based plectin-1 chimeric antigen receptor (CAR), and test T-cell transduced with this construct in vitro against PDAC cell lines. Methods: Using in silico tools, we optimized different pepto-CAR constructs and selected one that showed the highest levels of cytotoxicity against plectin-1-expressing PDAC cell lines. A myc tag was incorporated in the hinge region for flow cytometry or western blot detection. The intracellular signaling domain of these CAR sequences included 4-1BB and the zeta chain of the CD3 molecule ( Figure 1A). Plasmids containing the CAR sequence were packaged on lentivirus particles using HEK293T cells. Purified plectin-1 CAR lentiviruses were used to transduce T-cells derived from human peripheral blood T-cells obtained and purified from healthy donor whole blood. The expanded CAR T-cells were used for cytotoxic experiments against different cell lines. Results: Expression of plectin-1 CAR was confirmed by flow cytometry using an anti-myc tag antibody ( Figure 1B). Plectin-1 expression was analyzed in different pancreatic cancer cell lines, and the BxPC-3 cells showed the highest expression level ( Figure 1B). Using a luciferase-based assay, we plated 50,000 BxPC-3 cells per well in duplicates with different effector-to-target (E:T) ratios. After 24 hours, luciferin was added, and the plate was read using a luminometer. As a negative control for effector cells, we use T-cells without a CAR ( Figure 1B), and for the target cells, we use the plectin-1 negative lung cancer cell line A549 ( Figure 1B). Plectin-1 CAR T-cells effectively killed BxPC-3 cells at different E:T ratios in a specific manner compared with controls using unmodified T-cells. Furthermore, no cytotoxicity was observed against plectin-1 negative A549 cells ( Figure 1A). Conclusion: Our results show that a novel peptide-based CAR construct design against plectin-1 can induce specific cytotoxicity on plectin-1 expressing PDAC cell line BxPC-3. Furthermore, these data demonstrate the feasibility of using a CAR with a peptide-based antigen binding domain instead of the traditional antibody-derived scFv. This novel peptide-based CAR design offers alternatives for cellular therapy bioengineering. Moreover, our results can significantly impact immune-oncology therapeutic applications, particularly in challenging diseases like pancreatic cancer. Figure 1 . A) In the above section, the Plectin-1 CAR construct is depicted. Cytotoxicity of unmodified T-cells and Plectin-1 CAR T-cells against BxPC-3 and A549 is shown below. B) Expression of Plectin-1 CAR in unmodified T-cells and Plectin-1 CAR T-cells is shown on the left. The expression of plectin-1 antigen on the surface of BxPC-3 cells and A549 cells is shown on the right. PTP: plectin-1 targeting peptide.
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DOKAL, I. S., M. DEENMAMODE, and S. M. LEWIS. "Radioisotope studies in monitoring of Gaucher's disease and its treatment." Clinical & Laboratory Haematology 11, no. 2 (June 1989): 91–96. http://dx.doi.org/10.1111/j.1365-2257.1989.tb00188.x.

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37

Barker, R. N., K. M. Casswell, M. E. Reid, R. J. Sokol, and C. J. Elson. "Identification of autoantigens in autoimmune haemolytic anaemia by a non-radioisotope immunoprecipitation method." British Journal of Haematology 82, no. 1 (September 1992): 126–32. http://dx.doi.org/10.1111/j.1365-2141.1992.tb04604.x.

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38

Fitscha, Peter, Alfred Keiler, John O'Gracy, Bernhard A. Peskar, and Helmut Sinzinger. "Isradipine decreases arterial thrombogenicity in rabbits a morphometric and radioisotopic study." Thrombosis Research 74, no. 3 (May 1994): 175–83. http://dx.doi.org/10.1016/0049-3848(94)90106-6.

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39

Barlow, R., D. Bruton, R. Edgecock, and C. Johnstone. "A compact high current accelerator for radioisotope production." Radiotherapy and Oncology 118 (February 2016): S38—S39. http://dx.doi.org/10.1016/s0167-8140(16)30078-0.

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40

Sauls, C. D., and C. T. Caskey. "Applications of recombinant DNA to pathologic diagnosis." Clinical Chemistry 31, no. 6 (June 1, 1985): 804–11. http://dx.doi.org/10.1093/clinchem/31.6.804.

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Abstract Recombinant DNA techniques are contributing to the understanding of the pathogeneses of genetic, neoplastic, and viral diseases, and are used in the diagnosis of certain genetic and viral diseases. Such techniques will have wider application in the future and will play an increasing role in the clinical laboratory. The technology of this field rests upon the cleavage of DNA by certain enzymes, restriction endonucleases, and upon the ability to locate specific sequences of nucleotides in a cleaved DNA sample by using known fragments of DNA ("probes") labeled with radioisotopes or biotin. To produce useful probes, one "clones" multiple copies of the same DNA fragment in bacteria. The use of DNA probes in the clinical laboratory is valuable in antenatal diagnosis, genetic counseling, and post-natal diagnosis of genetic diseases, especially hematologic diseases and inborn errors of metabolism. DNA probes can also be used to detect viral genetic material in clinical specimens.
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41

Jiao, Y., and Q. Lv. "327P Defining ≥10% radioisotope-hot stained nodes as sentinel lymph nodes by “blue dye + radioisotope” dual-tracer method for sentinel lymph node biopsy leads to the overdetection and excessive excision." Annals of Oncology 34 (October 2023): S314. http://dx.doi.org/10.1016/j.annonc.2023.09.523.

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42

Li, Xiangan, Kaoru Hatanaka, Ling Guo, Motoo Tsushima, Yukihiko Kitamura, and Akira Yamamoto. "A Sensitive Peroxidase Staining Immunoblotting Method for Measuring Total Protein S in Human Plasma." Thrombosis and Haemostasis 69, no. 04 (1993): 331–34. http://dx.doi.org/10.1055/s-0038-1651607.

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SummaryIn plasma, protein S is found in its free form and as a complex with C4b-binding protein. After 125I-protein S was added tonormal human plasma and applied to SDS-8% polyacrylamide gel electrophoresis, the autoradiogram of the gel showed only one single band at free protein S position. Applying this evidence, we have developed a peroxidase staining Western Blotting method to quantitate total protein S in human plasma which consists of sodium dodecyl sulfate polyacrylamide gel electrophoresis followed by blotting to nitrocellulose membrane and a sensitive avidin-biotinylated peroxidase staining method (ABC technique). The measurement of protein S by the immunoblotting was reproducible and the coefficient of variation was 7%. As little as 1 ng of protein S could be detected. C4b-binding protein did not affect the measurement of protein S. Compared to other immunoassays, this peroxidase staining immunoblotting method has the advantage of directly estimating the apparent molecular weight of protein of interest, eliminating nonspecific stain and having high sensitivity without using radioisotope.
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43

Fiz, Francesco, Samine Sahbai, Cristina Campi, Matthias Weissinger, Helmut Dittmann, Cecilia Marini, Michele Piana, Gianmario Sambuceti, and Christian la Fougère. "Tumor Burden and Intraosseous Metabolic Activity as Predictors of Bone Marrow Failure during Radioisotope Therapy in Metastasized Prostate Cancer Patients." BioMed Research International 2017 (2017): 1–10. http://dx.doi.org/10.1155/2017/3905216.

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Rationale. Radium-223-Dichloride (Ra-223) is an alpha-emitter, used to treat bone metastases. Patients with high metastatic burden and/or with increased trabecular bone uptake could present a higher incidence of hematologic toxicity. We hypothesized that these two factors are predictors of bone marrow failure. Material and Methods. A computer algorithm discriminated between trabecular bone (BVol) and tumor metastases (MVol) within pretherapeutic whole-body skeletal SPECT/CT (N=47). The program calculated the metastatic invasion percent (INV%) as the MVol/(MVol+BVol) ratio and extracted the BVol mean counts. BVol counts were correlated to % drop of hemoglobin (Hb), leukocytes (WBC), and platelets (PLT) after 3/6 Ra-223 cycles. Patient-specific and computational-derived parameters were tested as predictors of hematologic toxicity with MANOVA. Results. BVol counts correlated with drop of Hb (R = 0,65, p<0.01) and PLT (R = 0,45, p<0.01). Appendicular BVol counts showed a better correlation (p<0.05, p<0.01, and p<0.001 for Hb, WBC, and PLT, resp.). INV% directly correlated with BVol counts (R = 0.68, p<0.001). At MANOVA, grade III/IV toxicity was predicted by INV% (p<0.01), by long-bone invasion (p<0.005), and by BVol counts (p<0.05). Conclusions. In patients with significant bone tumor burden, degree of bone invasion and trabecular bone uptake are predictors of subsequent bone marrow failure.
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44

Kavakli, Kaan, Semih Aydogdu, Yusuf Duman, Memduh Taner, Guray Saydam, Kazim Capaci, Aysenur Oktay, Can Balkan, and Deniz Yilmaz. "Radioisotope Synovectomy for Treating Chronic Synovitis in Inhibitor Patients with Hemophilia." Blood 108, no. 11 (November 16, 2006): 4005. http://dx.doi.org/10.1182/blood.v108.11.4005.4005.

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Abstract Hemophilic arthropathy, caused by chronic synovitis is the most common musculoskeletal complication of recurrrent hemarthrosis in hemophilia patients. However, in patients with target joints and chronical synovitis, local directed therapy is more useful than systemic treatment. Radioisotope Synovectomy (RS) consists of destruction of synovial tissue by intra-articular injection of a radioisotope agent. RS has gained acceptance worldwide for 10 years after favourable reports in respect of efficacy and safety. The most frequent and serious complication in hemophilia-A is the development of inhibitors. Due to problems for hemostasis and limited treatment modalities, arthropathy risk is higher in these patients. For last 6 years, we have performed 163 RS procedures in 109 children and young adults in our center. In this report, we present our experience in inhibitor patients (16 cases and 28 joints). All cases were severe hemophilia-A (FVIII&lt;2%). Thirteen patients had high responder (HR)(5–400 BU/ml), three had low responder (LR)(2–5 BU/ml) inhibitor. All patients had target joints and grade-II (n=8) and grade-III (n=20) synovitis. We have used intra-articularly 5 mCi Yttrium 90 for knees (n=16) and 2 mCi Yttrium 90 (n=7) or Rhenium 186 (n=5) for small joints (Schering-CIS, France). The age range was 3–26 years (mean 14.6±6.1yr). We have 4 patients below 10 years. The knees injected 16, elbows 7, ankles 3 and shoulders in 2 joints. Written informed consent was mandatory. For HR patients; recombinant FVIIa (Novoseven) was used (90 mcg/bw / in 2-h interval) in three consecutive doses except one case for 15 joints in 9 patients. Activated PCC (FEIBA) was used (75 IU/bw / in 12 h of interval) in 2 or 3 consecutive doses for 4 patients in 8 joints. High dose FVIII were used for 3 LR patients in 5 joints. Overnight hospitalization was applied. Mean follow-up period after procedure was 2.5 years (range: 6 month-5 year). The efficacy of procedure was evaluated by comparing joint bleedings and signs for synovitis. Seventy-five percent of inhibitor patients had satisfactory results. Pre-procedure joint bleeds were 7.9±3.2 (range: 4–16) for 6 months. After RS, during the first year hemarthroses were significantly decreased as (0.4±1.1). In cases with grade-II synovitis outcome was more better than grade-III synovitis as expected. In two patients, procedure was needed to be repeated due to insufficient effect. After repeated applications, outcome was satisfactory. In other two patients, late recurrence of synovitis was observed after 2 years. One of them, intra-articular injection was repeated and synovitis has improved. No complications have seen. Recently, some suspicions arose due to two children who had had the radioisotope synovectomy using with P32 subsequently developed acute leukemia (ALL) in the USA. However, we have used Y90 and Re186 and no malignancy have reported in the literature and not observed in our study group for 6 years. In conclusion, RS is efficient also in inhibitor patients as far as other patients. RS is cost-effective and easy to perform and hence highly recommended for inhibitor patients. RS seems to be invaluable for treatment of chronic synovitis of inhibitor patients for preventing hemophilic arthropathy.
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KAVAKLİ, K., S. AYDOGDU, M. TANER, Y. DUMAN, C. BALKAN, D. Y. KARAPİNAR, G. SAYDAM, K. CAPACİ, and A. OKTAY. "Radioisotope synovectomy with rhenium186in haemophilic synovitis for elbows, ankles and shoulders." Haemophilia 14, no. 3 (May 2008): 518–23. http://dx.doi.org/10.1111/j.1365-2516.2008.01691.x.

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46

Skoro-Sajer, Nika, Alexander Becherer, Walter Klepetko, Meinhard Kneussl, Gerald Maurer, and Irene Lang. "Longitudinal analysis of perfusion lung scintigrams of patients with unoperated chronic thromboembolic pulmonary hypertension." Thrombosis and Haemostasis 92, no. 07 (2004): 201–7. http://dx.doi.org/10.1160/th03-11-0727.

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SummaryChronic thromboembolic pulmonary hypertension (CTEPH) is the result of single or recurrent pulmonary thromboemboli that are thought to develop into organized pulmonary arterial obstructions by recurrent embolism and in situ thrombosis. Radioisotopic ventilation-perfusion scanning (V/Q scan) is a safe and highly sensitive test for pulmonary thromboembolic disease. The aim was to assess the natural history of thrombus expansion. We performed a prospective quantitative evaluation of ventilation/perfusion scintigrams (V/Q scans) in 20 patients with severe unoperated CTEPH. The baseline V/Q scan of each patient served as a reference for the second scan 21.7 ± 8.2 months later. Planar images with intravenous 99mTc-labeled human albumin macroaggregates were reconstructed in six standard projections. Perfusion scans were analyzed by a semiquantitative evaluation. In parallel, hemodynamics and clinical condition were prospectively observed. Lung perfusion scintigrams analyzed by a semi-quantitative method in patients with severe unoperated CTEPH show an apparent decrease of segmental flow abnormalities over time, paralleling right ventricular decline.
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47

Jacobs, Samuel A., Anthony M. Harrison, Steven H. Swerdlow, Kenneth A. Foon, Norbert Avril, Nick Vidnovic, Kenneth S. McCarty, and Wayne Saville. "Cellular Localization Pattern of Yttrium 90 (90Y) Ibritumomab Tiuxetan (Zevalin®) in a Patient with Low-Grade Non-Hodgkin’s Lymphoma (NHL)." Blood 104, no. 11 (November 16, 2004): 4569. http://dx.doi.org/10.1182/blood.v104.11.4569.4569.

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Abstract Ytrrium 90 (90Y) ibritumomab tiuxetan (Zevalin®) is indicated for the treatment of relapsed or refractory low-grade, follicular, or transformed B-cell NHL at relapse or upon confirmation of refractory disease. Long-term responses in excess of 6 years have been observed following ibritumomab tiuxetan administration, underscoring the efficacy of this selective treatment modality. Dosing guidelines for 90Y ibritumomab tiuxetan were established in phase 1/2 trials and are dependent on body mass and platelet count, with the maximum recommended dose being 32 mCi. Biodistribution is evaluated by whole-body imaging prior to the delivery of the therapeutic dose using the gamma emitter indium 111 (111In) as the imaging radioimmunoconjugate. Current imaging methodology for the ibritumomab tiuxetan regimen has several limitations. First, the correlation between 111In ibritumomab tiuxetan dosimetry and either toxicity or tumor response is poor, and clinical parameters such as platelet count, patient weight, and percentage lymphomatous bone marrow involvement have been much more accurate. Further, while gamma (or PET/SPECT) imaging provides a visual evaluation of uptake in the blood pool and relevant organs, it cannot resolve biodistribution to the cellular level. This is particularly relevant for discriminating between radioisotope uptake in malignant and nonmalignant tissues. In order to assess the uniformity of cellular localization of 90Y ibritumomab tiuxetan, we performed autoradiographic analyses of lymph node tissue and bone marrow sampled after ibritumomab tiuxetan therapy. We also proposed to semi-quantify the energy doses delivered to lymphomatous tissue in an effort to better understand mechanisms of cellular sensitivity or resistance to this form of radioimmunotherapy. Following standard delivery of the ibritumomab tiuxetan regimen, bone marrow and lymph node tissues were sampled from a patient who presented with CD20+ NHL, bulky peripheral lymph nodes, and positive bone marrow involvement. Samples were collected 4 days after the administration of 90Y ibritumomab tiuxetan and immediately processed. Prepared sections were stained with hematoxylin and eosin (H&E) for histologic examination and then submitted for autoradiographic preparation with Kodak NBT-3 nuclear emulsion at 42o C, Kodak D-19 developer, and sodium thiosulphate fixative. Within lymph node tissue, radioisotope uptake was preferentially localized to lymphoma cells. An absence of significant localization in the histologically normal sections of bone marrow was also noted. The observed distribution patterns in the lymph node suggested that distribution of 90Y ibritumomab tiuxetan was localized to the cell membrane of lymphoma cells, with limited stromal and intravascular involvement. We are currently quantifying the density of radioisotope aggregation within malignant cells to assess whether a sufficient quantity of nuclide is recruited to achieve a crossfire effect on neighboring, unlabeled cells. Our results confirm that in vivo,90Y ibritumomab tiuxetan selectively targets tumor tissue with little binding to normal bone marrow and lymph node tissue, including stroma and vasculature. Additional patients with CD20+ NHL are being studied to verify the cellular localization pattern of 90Y ibritumomab tiuxetan.
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48

Lindbom, Lennart, and Ellinor Kenne. "Imaging inflammatory plasma leakage in vivo." Thrombosis and Haemostasis 105, no. 05 (2011): 783–89. http://dx.doi.org/10.1160/th10-10-0635.

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SummaryIncreased vascular permeability and consequent plasma leakage from postcapillary venules is a cardinal sign of inflammation. Although the movement of plasma constituents from the vasculature to the affected tissue aids in clearing the inflammatory stimulus, excessive plasma extravasation can lead to hospitalisation or death in cases such as influenza-induced pneumonia, burns or brain injury. The use of intravital imaging has significantly contributed to the understanding of the mechanisms controlling the vascular permeability alterations that occur during inflammation. Today, intravital imaging can be performed using optical and non-optical techniques. Optical techniques, which are generally used in experimental settings, include traditional intravital fluorescence microscopy and near-infrared fluorescence imaging. Magnetic resonance (MRI) and radioisotopic imaging are used mainly in the clinical setting, but are increasingly used in experimental work, and can detect plasma leakage without optics. Although these methods are all able to visualise inflammatory plasma leakage in vivo, the spatial and temporal resolution differs between the techniques. In addition, they vary with regards to invasiveness and availability. This overview discusses the use of imaging techniques in the visualisation of inflammatory plasma leakage.
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49

Brogsitter, Claudia, and Jörg Kotzerke. "Radioisotope-antibody conjugates selectively target bone marrow prior to stem cell therapy." Radiotherapy and Oncology 102, no. 2 (February 2012): 321. http://dx.doi.org/10.1016/j.radonc.2011.06.041.

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50

Viertl, D., F. Buchegger, J. O. Prior, Ph Morel, O. Ratib, L. Bühler, Th Stora, and CERN-MEDICIS collaboration. "MEDICIS-PROMED: MEDICIS-Produced Radioisotope Beams for Medicine an Innovative Training Networ." Radiotherapy and Oncology 118 (February 2016): S87. http://dx.doi.org/10.1016/s0167-8140(16)30178-5.

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