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H. Spiess - One of the best experts on this subject based on the ideXlab platform.
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incidence of malignant diseases in humans injected with Radium 224
Radiation Research, 2010Co-Authors: E Nekolla, Linda Walsh, H. SpiessAbstract:Abstract The “Spiess study” follows the health of 899 persons who received multiple injections of the short-lived α-particle emitter 224Ra mainly between 1945 and 1955 for the treatment of tuberculosis, ankylosing spondylitis and some other diseases. In December 2007, 124 persons were still alive. The most striking health effect, observed shortly after 224Ra injections, was a temporal wave of 57 malignant bone tumors. During the two most recent decades of observation, a significant excess of non-skeletal malignant diseases has become evident. Expected numbers of cases were computed from the age, gender and calendar year distribution of person years at risk and incidence rates from the German Saarland Cancer Registry. Poisson statistics were applied to test for statistical significance of the standardized incidence ratios. Up to the end of December 2007, the total number of observed malignant non-skeletal diseases was 270 (248 specified cases of non-skeletal solid cancers and 22 other malignant diseases, a...
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Life-span study on late effects of 224Ra in children and adults.
Health physics, 2010Co-Authors: H. SpiessAbstract:Between 1945 and 1955, several thousand patients were injected with Peteosthor, a preparation containing Radium-224 ( 224 Ra), as treatment for bone tuberculosis or ankylosing spondylitis. 224 Ra, like 239 Pu, is a bone seeking nuclide. During the course of early experimental work it became clear in 1948 that the short lived α-emitter 224 Ra concentrates predominantly in the growing zones of the bones. Consequently, I released strong official warnings, at the 1950 German Congress of Orthopedics, against Peteosthor, and especially against its administration to juvenile patients—still in their period of growth. Epidemiological investigations were then initiated on a study population that comprises 899 persons (including 217 children or juveniles) who received injections of 224 Ra. The study has now been conducted for a follow-up period of over 60 y. The most striking detrimental health effect following 224 Ra injections are a large number of malignant bone tumors that occurred predominantly in childhood. This finding was the reason for my invitation to the first conference on "Delayed Effects of Bone seeking Radionuclides" in Sun Valley, ID, in September 1967, a meeting that was organized by Charles Mays. I reported on 50 224 Ra-induced bone tumors in children and adults, growth disturbances, osteochondroma, and cataracts, concluding that the younger the age at 224 Ra injection, the more severe the late effects. Up to now 57 malignant bone tumors have been observed while less than one case would have been expected. The peak occurred 8 y after the first 224 Ra injection and the last bone sarcoma arose 46 y after injection. A total of 270 non-skeletal malignant diseases were observed against a statistical expectation of 192 cases, the excess risk of mammary cancers in those treated in childhood being particularly striking. In the past two years increases of non-cancer diseases have become apparent in the exposed group compared to a control group of 166 living members with no exposure to 224 Ra. Although 124 study group members are still alive, only the 81 members with ages at or below the maximum age in the control group were included in this comparison in order to attain approximate age matching. The breakdown of these diseases is kidney insufficiency, 12 (15%) study group members vs. 3 (2%) controls, where 5 (6%) study group members required dialysis vs. 2 (1%) controls; thyroid disease (struma nodosa), 28 (35%) study group members vs. 29 (17%) controls; heart attack, 8 (10%) study group members vs. 4 (2%) controls; coronary heart disease, 9 (11%) study group members vs. 8 (5%) controls.
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Incidence of Malignant Diseases in Humans Injected with Radium-224
Radiation research, 2010Co-Authors: E Nekolla, Linda Walsh, H. SpiessAbstract:The "Spiess study" follows the health of 899 persons who received multiple injections of the short-lived alpha-particle emitter (224)Ra mainly between 1945 and 1955 for the treatment of tuberculosis, ankylosing spondylitis and some other diseases. In December 2007, 124 persons were still alive. The most striking health effect, observed shortly after (224)Ra injections, was a temporal wave of 57 malignant bone tumors. During the two most recent decades of observation, a significant excess of non-skeletal malignant diseases has become evident. Expected numbers of cases were computed from the age, gender and calendar year distribution of person years at risk and incidence rates from the German Saarland Cancer Registry. Poisson statistics were applied to test for statistical significance of the standardized incidence ratios. Up to the end of December 2007, the total number of observed malignant non-skeletal diseases was 270 (248 specified cases of non-skeletal solid cancers and 22 other malignant diseases, among these 16 malignant neoplasms of lymphatic and hematopoietic tissue, six without specification of site) compared to 192 expected cases. Accounting for a 5-year minimum latent period and excluding 13 cases of non-melanoma skin cancer, 231 non-skeletal solid cancers were observed compared to 151 expected cases. Significantly increased cancer rates were observed for breast (32 compared to 9.7), soft and connective tissue (11 compared to 1.0), thyroid (7 compared to 1.0), liver (10 compared to 2.4), kidney (13 compared to 5.0), pancreas (9 compared to 4.1), bladder (16 compared to 8.0), and female genital organs (15 compared to 7.8).
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peteosthor a medical disaster due to Radium 224
Radiation and Environmental Biophysics, 2002Co-Authors: H. SpiessAbstract:Up to the end of World War II, there was no effective therapy against bone tuberculosis, and even today there is no treatment for ankylosing spondylitis. However, in the 1940s up to about 1956, radiotherapy with "Peteosthor" – a drug containing Thorium X (224Ra) as an effective compound – was introduced in Germany as a presumed cure and it maintained a central place in the treatment of these diseases. In 1948, I was entrusted to assess the new treatment. Animal studies and the clinical evaluation of the patients made me soon realise a number of severe adverse health effects which induced me to pronounce and subsequently repeat warnings against the intravenous administration of high doses of 224Ra, especially because it was then administered predominantly to children and juveniles. As a consequence, this type of treatment was finally abandoned in 1956. But there remained a need to observe and document the resulting late health effects. Already in 1967, our initial follow-up study provided data for about 800 patients with exact information on the 224Ra dose levels administered, administration schemes, and the resulting detrimental effects. A large number of bone sarcomas was the most severe consequence, but even today there is a broad spectrum of other grave health effects. A summary of the major scientific insights which have been achieved in the course of the still on-going epidemiological studies is part of this report.
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induction of malignant bone tumors in Radium 224 patients risk estimates based on the improved dosimetry
Radiation Research, 2000Co-Authors: E Nekolla, Wolfgang Gössner, M Kreisheimer, Albrecht M Kellerer, M Kuseisingschulte, H. SpiessAbstract:Abstract Nekolla, E.A., Kreisheimer, M., Kellerer, A.M., Kuse-Isingschulte, M., Gossner, W. and Spiess, H. Induction of Malignant Bone Tumors in Radium-224 Patients: Risk Estimates Based on the Improved Dosimetry. Mainly between 1945 and 1955, several thousand German patients with ankylosing spondylitis, tuberculosis, or—in a few cases—other diseases received multiple injections of the short-lived α-particle emitter Radium-224. In the early 1950s, the follow-up of 899 patients was initiated, and the study has continued since then. It includes most of the high-dose patients and nearly all of those treated as children or juveniles, i.e. under the age of 21. In the study cohort, 56 malignant bone tumors occurred in a temporal wave that peaked 8 years after exposure, whereas less than one case would have been expected during the follow-up. Most of the malignant bone tumors were osteosarcomas and fibrous-histiocytic sarcomas. A new analysis has now been performed, primarily because an improved dosimetry result...
E Nekolla - One of the best experts on this subject based on the ideXlab platform.
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incidence of malignant diseases in humans injected with Radium 224
Radiation Research, 2010Co-Authors: E Nekolla, Linda Walsh, H. SpiessAbstract:Abstract The “Spiess study” follows the health of 899 persons who received multiple injections of the short-lived α-particle emitter 224Ra mainly between 1945 and 1955 for the treatment of tuberculosis, ankylosing spondylitis and some other diseases. In December 2007, 124 persons were still alive. The most striking health effect, observed shortly after 224Ra injections, was a temporal wave of 57 malignant bone tumors. During the two most recent decades of observation, a significant excess of non-skeletal malignant diseases has become evident. Expected numbers of cases were computed from the age, gender and calendar year distribution of person years at risk and incidence rates from the German Saarland Cancer Registry. Poisson statistics were applied to test for statistical significance of the standardized incidence ratios. Up to the end of December 2007, the total number of observed malignant non-skeletal diseases was 270 (248 specified cases of non-skeletal solid cancers and 22 other malignant diseases, a...
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Incidence of Malignant Diseases in Humans Injected with Radium-224
Radiation research, 2010Co-Authors: E Nekolla, Linda Walsh, H. SpiessAbstract:The "Spiess study" follows the health of 899 persons who received multiple injections of the short-lived alpha-particle emitter (224)Ra mainly between 1945 and 1955 for the treatment of tuberculosis, ankylosing spondylitis and some other diseases. In December 2007, 124 persons were still alive. The most striking health effect, observed shortly after (224)Ra injections, was a temporal wave of 57 malignant bone tumors. During the two most recent decades of observation, a significant excess of non-skeletal malignant diseases has become evident. Expected numbers of cases were computed from the age, gender and calendar year distribution of person years at risk and incidence rates from the German Saarland Cancer Registry. Poisson statistics were applied to test for statistical significance of the standardized incidence ratios. Up to the end of December 2007, the total number of observed malignant non-skeletal diseases was 270 (248 specified cases of non-skeletal solid cancers and 22 other malignant diseases, among these 16 malignant neoplasms of lymphatic and hematopoietic tissue, six without specification of site) compared to 192 expected cases. Accounting for a 5-year minimum latent period and excluding 13 cases of non-melanoma skin cancer, 231 non-skeletal solid cancers were observed compared to 151 expected cases. Significantly increased cancer rates were observed for breast (32 compared to 9.7), soft and connective tissue (11 compared to 1.0), thyroid (7 compared to 1.0), liver (10 compared to 2.4), kidney (13 compared to 5.0), pancreas (9 compared to 4.1), bladder (16 compared to 8.0), and female genital organs (15 compared to 7.8).
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Langzeituntersuchung zum Risiko maligner Erkrankungen nach intravenöser Behandlung des Morbus Bechterew mit Radium-224
Strahlentherapie und Onkologie : Organ der Deutschen Rontgengesellschaft ... [et al], 2009Co-Authors: Tobias L. Schulte, E Nekolla, Roland R. WickAbstract:Ab Ende der 40er Jahre bis 2005 war die Behandlung des Morbus Bechterew mit intravenos appliziertem Radium-224 (224Ra) ein im deutschsprachigen Raum ubliches Therapieverfahren. In dieser Langzeituntersuchung wurde das Risiko maligner Erkrankungen nach intravenoser Behandlung des Morbus Bechterew mit 224Ra ermittelt. Im Rahmen einer prospektiven Langzeit-Nachbeobachtungsstudie wurden 1 471 Patienten untersucht, die zwischen 1948 und 1975 zur Therapie eines Morbus Bechterew intravenose Injektionen von 224Ra erhalten hatten. Als Vergleich diente eine Kontrollgruppe von 1 324 Bechterew-Patienten, die weder mit 224Ra noch mit Rontgenstrahlen behandelt worden waren. Mit Hilfe standardisierter Fragebogen wurde der Gesundheitszustand der Patienten abgefragt. Die Anzahl registrierter maligner Falle wurde mit jener der Kontrollgruppe sowie mit Erwartungswerten einer Normalpopulation verglichen. Nach einem Nachbeobachtungszeitraum von 26 Jahren liegen in der Expositionsgruppe bei 1 006 Patienten gesicherte Todesursachen vor (Kontrollgruppe: 1 072 Patienten). Unter den mit 224Ra behandelten Patienten zeigten sich im Unterschied zur Kontrollgruppe signifikant erhohte Inzidenzraten fur myeloische Leukamien (zwolf beobachtete Falle vs. 2,9 erwartete Falle; p < 0,001), Nierenkarzinome (18 vs. 9,1 Falle; p < 0,01), Schilddrusenkarzinome (vier vs. 1,2 Falle; p = 0,03) sowie grenzwertig signifikant erhohte Inzidenzraten fur maligne Tumorerkrankungen des weiblichen Genitaltrakts (zehn vs. 5,6 Falle; p = 0,06). Die Haufigkeiten maligner Tumoren der Lunge und des Magen-Darm-Trakts waren nicht erhoht. Lymphatische Leukamien (Expositionsgruppe: acht vs. 2,7 Falle; p < 0,01; Kontrollgruppe: sieben vs. drei Falle; p = 0,03) traten sowohl in der Expositions- als auch in der Kontrollgruppe gehauft auf, wobei in beiden Gruppen insbesondere die Rate an chronisch-lymphatischer Leukamie erhoht war. Die Therapie des Morbus Bechterew mittels 224Ra hat zu erhohten Haufigkeiten myeloischer Leukamien sowie maligner Tumoren der Nieren, Schilddruse und des weiblichen Genitaltrakts gefuhrt. Obwohl diese Therapie mittlerweile nicht mehr durchgefuhrt wird, sollten behandelte Patienten weiterhin nachuntersucht werden.
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Radium-224 Injections - Radiobiological Impact of an Abandoned Therapy for Ankylosing Spondylitis
Radioprotection, 2008Co-Authors: R. Wick, E NekollaAbstract:At the Helmholtz Center Munich, formerly GSF National Research Center for Environment and Health, since 1971 an epidemiological study has been carried out on 1471 ankylosing spondylitis patients treated with repeated intravenous injections of the short lived α-emitter 224 Ra between 1948 and 1975. The then usual therapeutic plan consisted of a total of 10 to 12 injections of about 1 MBq of 224 Ra each, given at weekly intervals. This results in a cumulative α-dose of 0.56 to 0.67 Gy to the marrow-free skeleton (bone surface dose: ~5.5 Gy) of a standard man (70 kg). These patients have been followed together with a control group of 1324 ankylosing spondylitis patients not treated with radioactive drugs and/or X-rays. Until now causes of death have been ascertained for 1006 exposed patients and 1072 controls (mean follow-up time 26.3 yr in the exposed or 24.6 yr in the control group). In particular, in the exposed group we observed 18 cases of kidney cancer (vs. 9.1 cases exp., p=0.006), 7 liver carcinomas (vs. 3.5 cases exp., p=0.06), and 4 malignant thyroid tumours (vs. 1.2 cases exp., p=0.03). In the control group the observed cases for these tumours were in the expected range, apart from a non-significant increase of kidney cancers. The most striking observation, however, were the 19 cases of leukaemia in the exposed group (vs. 6.8 cases exp., p Ra preparations compared to those used until very recently plays an important role for the increased rates of myeloproliferative diseases in the exposed group of this study. The enhanced leukaemia incidence in the exposed group is in line with results from animal experiments in mice having been injected with varying amounts of 224 Ra.
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poster epidemiology Radium 224 injections radiobiological impact of an abandoned ther apy for ankylosing spondylitis
2008Co-Authors: R. Wick, E NekollaAbstract:0.56 to 0.67 Gy to the marrow-free skeleton (bone surface dose: »5.5 Gy) of a standard man (70 kg). These patients have been followed together with a control group of 1324 ankylosing spondylitis patients not treated with radioactive drugs and/or X-rays. Until now causes of death have been ascertained for 1006 exposed patients and 1072 controls (mean follow-up time 26.3 yr in the exposed or 24.6 yr in the control group). In particular, in the exposed group we observed 18 cases of kidney cancer (vs. 9.1 cases exp., p=0.006), 7 liver carcinomas (vs. 3.5 cases exp., p=0.06), and 4 malignant thyroid tumours (vs. 1.2 cases exp., p=0.03). In the control group the observed cases for these tumours were in the expected range, apart from a non-significant increase of kidney cancers. The most striking observation, however, were the 19 cases of leukaemia in the exposed group (vs. 6.8 cases exp., p<0.001) compared to 12 cases of leukaemia in the control group (vs. 7.5 cases exp.). Further sub-classification of the leukaemia cases demonstrated a high increase of myeloid leukaemia in the exposed group (11 cases obs. vs. 2.9 cases exp., p<0.001), and especially a high excess of acute myeloid leukaemia (7 cases obs. vs. 1.8 exp., p=0.003), whereas in the controls the observed cases are within the expected range (4 cases of myeloid leukaemia vs. 3.1 cases exp.). The number of myeloid leukaemia cases in the exposed group is also significantly increased in direct comparison with the control group on basis of a modified Fishertest (p<0.05). It is rather unlikely that the negligibly lower purity of earlier 224 Ra preparations compared to those used until very recently plays an important role for the increased rates of myeloproliferative diseases in the exposed group of this study. The enhanced leukaemia incidence in the exposed group is in line with results from animal experiments in mice having been injected with varying amounts of 224 Ra.
Roland R. Wick - One of the best experts on this subject based on the ideXlab platform.
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Langzeituntersuchung zum Risiko maligner Erkrankungen nach intravenöser Behandlung des Morbus Bechterew mit Radium-224
Strahlentherapie und Onkologie : Organ der Deutschen Rontgengesellschaft ... [et al], 2009Co-Authors: Tobias L. Schulte, E Nekolla, Roland R. WickAbstract:Ab Ende der 40er Jahre bis 2005 war die Behandlung des Morbus Bechterew mit intravenos appliziertem Radium-224 (224Ra) ein im deutschsprachigen Raum ubliches Therapieverfahren. In dieser Langzeituntersuchung wurde das Risiko maligner Erkrankungen nach intravenoser Behandlung des Morbus Bechterew mit 224Ra ermittelt. Im Rahmen einer prospektiven Langzeit-Nachbeobachtungsstudie wurden 1 471 Patienten untersucht, die zwischen 1948 und 1975 zur Therapie eines Morbus Bechterew intravenose Injektionen von 224Ra erhalten hatten. Als Vergleich diente eine Kontrollgruppe von 1 324 Bechterew-Patienten, die weder mit 224Ra noch mit Rontgenstrahlen behandelt worden waren. Mit Hilfe standardisierter Fragebogen wurde der Gesundheitszustand der Patienten abgefragt. Die Anzahl registrierter maligner Falle wurde mit jener der Kontrollgruppe sowie mit Erwartungswerten einer Normalpopulation verglichen. Nach einem Nachbeobachtungszeitraum von 26 Jahren liegen in der Expositionsgruppe bei 1 006 Patienten gesicherte Todesursachen vor (Kontrollgruppe: 1 072 Patienten). Unter den mit 224Ra behandelten Patienten zeigten sich im Unterschied zur Kontrollgruppe signifikant erhohte Inzidenzraten fur myeloische Leukamien (zwolf beobachtete Falle vs. 2,9 erwartete Falle; p < 0,001), Nierenkarzinome (18 vs. 9,1 Falle; p < 0,01), Schilddrusenkarzinome (vier vs. 1,2 Falle; p = 0,03) sowie grenzwertig signifikant erhohte Inzidenzraten fur maligne Tumorerkrankungen des weiblichen Genitaltrakts (zehn vs. 5,6 Falle; p = 0,06). Die Haufigkeiten maligner Tumoren der Lunge und des Magen-Darm-Trakts waren nicht erhoht. Lymphatische Leukamien (Expositionsgruppe: acht vs. 2,7 Falle; p < 0,01; Kontrollgruppe: sieben vs. drei Falle; p = 0,03) traten sowohl in der Expositions- als auch in der Kontrollgruppe gehauft auf, wobei in beiden Gruppen insbesondere die Rate an chronisch-lymphatischer Leukamie erhoht war. Die Therapie des Morbus Bechterew mittels 224Ra hat zu erhohten Haufigkeiten myeloischer Leukamien sowie maligner Tumoren der Nieren, Schilddruse und des weiblichen Genitaltrakts gefuhrt. Obwohl diese Therapie mittlerweile nicht mehr durchgefuhrt wird, sollten behandelte Patienten weiterhin nachuntersucht werden.
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Langzeituntersuchung zum Risiko maligner Erkrankungen nach intravenöser Behandlung des Morbus Bechterew mit Radium-224
Strahlentherapie und Onkologie, 2009Co-Authors: Tobias L. Schulte, Elke A. Nekolla, Roland R. WickAbstract:Background and Purpose: In German-speaking countries, the intravenous treatment of ankylosing spondylitis (AS) with Radium-224 (^224Ra) was common between the late 1940s and 2005. In this long-term investigation, the risk of malignant diseases following intravenous ^224Ra treatment for AS was assessed. Patients and Methods: In a prospective long-term study, 1,471 patients with AS who were treated with ^224Ra between 1948 and 1975 have been followed together with a control group of 1,324 AS patients treated neither with radioactive drugs nor with X-rays. Standardized questionnaires to evaluate the patients’ health status were used. Observed numbers of malignant diseases were compared with those of the control group as well as with expected numbers for a normal population. Results: After 26 years of follow-up, causes of death have been certified for 1,006 patients of the exposure group (control group: 1,072 patients). Significantly increased rates of myeloid leukemia (12 cases observed vs. 2.9 expected; p < 0.001), kidney cancer (18 vs. 9.1; p < 0.01), thyroid cancer (4 vs. 1.2; p = 0.03) and borderline significantly increased rates of cancer of female genital organs (10 vs. 5.6; p = 0.06) were found in the exposure group in contrast to no significant increases of these diseases in the control group. Rates of pulmonary and gastrointestinal malignancies were not increased. Lymphatic leukemia (exposure group: 8 vs. 2.7; p < 0.01; control group: 7 vs. 3; p = 0.03) was significantly elevated due to a high rate of chronic lymphatic leukemia in both, the exposure as well as the control group. Conclusion: Treatment of AS with ^224Ra led to increased incidences of myeloid leukemia and malignancies of kidneys, thyroid and female genital organs. Although this kind of therapy is now abandoned, there is a need for close follow-up of patients who received it. Hintergrund und Ziel: Ab Ende der 40er Jahre bis 2005 war die Behandlung des Morbus Bechterew mit intravenös appliziertem Radium-224 (^224Ra) ein im deutschsprachigen Raum übliches Therapieverfahren. In dieser Langzeituntersuchung wurde das Risiko maligner Erkrankungen nach intravenöser Behandlung des Morbus Bechterew mit ^224Ra ermittelt. Patienten und Methodik: Im Rahmen einer prospektiven Langzeit-Nachbeobachtungsstudie wurden 1 471 Patienten untersucht, die zwischen 1948 und 1975 zur Therapie eines Morbus Bechterew intravenöse Injektionen von ^224Ra erhalten hatten. Als Vergleich diente eine Kontrollgruppe von 1 324 Bechterew-Patienten, die weder mit ^224Ra noch mit Röntgenstrahlen behandelt worden waren. Mit Hilfe standardisierter Fragebögen wurde der Gesundheitszustand der Patienten abgefragt. Die Anzahl registrierter maligner Fälle wurde mit jener der Kontrollgruppe sowie mit Erwartungswerten einer Normalpopulation verglichen. Ergebnisse: Nach einem Nachbeobachtungszeitraum von 26 Jahren liegen in der Expositionsgruppe bei 1 006 Patienten gesicherte Todesursachen vor (Kontrollgruppe: 1 072 Patienten). Unter den mit ^224Ra behandelten Patienten zeigten sich im Unterschied zur Kontrollgruppe signifikant erhöhte Inzidenzraten für myeloische Leukämien (zwölf beobachtete Fälle vs. 2,9 erwartete Fälle; p < 0,001), Nierenkarzinome (18 vs. 9,1 Fälle; p < 0,01), Schilddrüsenkarzinome (vier vs. 1,2 Fälle; p = 0,03) sowie grenzwertig signifikant erhöhte Inzidenzraten für maligne Tumorerkrankungen des weiblichen Genitaltrakts (zehn vs. 5,6 Fälle; p = 0,06). Die Häufigkeiten maligner Tumoren der Lunge und des Magen-Darm-Trakts waren nicht erhöht. Lymphatische Leukämien (Expositionsgruppe: acht vs. 2,7 Fälle; p < 0,01; Kontrollgruppe: sieben vs. drei Fälle; p = 0,03) traten sowohl in der Expositions- als auch in der Kontrollgruppe gehäuft auf, wobei in beiden Gruppen insbesondere die Rate an chronisch-lymphatischer Leukämie erhöht war. Schlussfolgerung: Die Therapie des Morbus Bechterew mittels ^224Ra hat zu erhöhten Häufigkeiten myeloischer Leukämien sowie maligner Tumoren der Nieren, Schilddrüse und des weiblichen Genitaltrakts geführt. Obwohl diese Therapie mittlerweile nicht mehr durchgeführt wird, sollten behandelte Patienten weiterhin nachuntersucht werden.
Yona Keisari - One of the best experts on this subject based on the ideXlab platform.
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The treatment of solid tumors by alpha emitters released from (224)Ra-loaded sources-internal dosimetry analysis.
Physics in medicine and biology, 2010Co-Authors: Lior Arazi, Tomer Cooks, Michael Schmidt, Yona Keisari, Itzhak KelsonAbstract:Diffusing alpha-emitters radiation therapy (DART) is a proposed new form of brachytherapy, allowing the treatment of solid tumors by alpha particles. DART utilizes implantable sources carrying small activities of Radium-224, which continually release into the tumor radon-220, polonium-216 and lead-212 atoms, while Radium-224 itself remains fixed to the source. The released atoms disperse inside the tumor by diffusive and convective processes, creating, through their alpha emissions, a high-dose region measuring several mm in diameter about each source. The efficacy of DART has been demonstrated in preclinical studies on mice-borne squamous cell carcinoma and lung tumors and the method is now being developed toward clinical trials. This work studies DART safety with respect to the dose delivered to distant organs as a result of lead-212 leakage from the tumor through the blood, relying on a biokinetic calculation coupled to internal dose assessments. It is found that the dose-limiting organs are the kidneys and red bone marrow. Assuming a typical source spacing of approximately 5 mm and a typical Radium-224 activity density of 0.4-0.8 MBq g(-1) of tumor tissue, it is predicted that tumors weighing up to several hundred grams may be treated without reaching the tolerance dose in any organ.
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Local control of lung derived tumors by diffusing alpha-emitting atoms released from intratumoral wires loaded with Radium-224.
International journal of radiation oncology biology physics, 2009Co-Authors: Tomer Cooks, Lior Arazi, Michael Schmidt, Itzhak Kelson, Hadas Bittan, E. Lazarov, Yona KeisariAbstract:Diffusing alpha-emitters radiation therapy (DART) is a new form of brachytherapy enabling the treatment of solid tumors with alpha radiation. The present study examines the antitumoral effects resulting from the release of alpha emitting radioisotopes into solid lung carcinoma (LL2, A427, and NCI-H520). An in vitro setup tested the dose-dependent killing of tumor cells exposed to alpha particles. In in vivo studies, radioactive wires (0.3 mm diameter, 5 mm long) with (224)Ra activities in the range of 21-38 kBq were inserted into LL/2 tumors in C57BL/6 mice and into human-derived A427 or NCI-H520 tumors in athymic mice. The efficacy of the short-lived daughters of (224)Ra to produce tumor growth retardation and prolong life was assessed, and the spread of radioisotopes inside tumors was measured using autoradiography. The insertion of a single DART wire into the center of 6- to 7-mm tumors had a pronounced retardation effect on tumor growth, leading to a significant inhibition of 49% (LL2) and 93% (A427) in tumor development and prolongations of 48% (LL2) in life expectancy. In the human model, more than 80% of the treated tumors disappeared or shrunk. Autoradiographic analysis of the treated sectioned tissue revealed the intratumoral distribution of the radioisotopes, and histological analysis showed corresponding areas of necrosis. In vitro experiments demonstrated a dose-dependent killing of tumors cells exposed to alpha particles. Short-lived diffusing alpha-emitters produced tumor growth retardation and increased survival in mice bearing lung tumor implants. These results justify further investigations with improved dose distributions.
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local control of lung derived tumors by diffusing alpha emitting atoms released from intratumoral wires loaded with Radium 224
International Journal of Radiation Oncology Biology Physics, 2009Co-Authors: Tomer Cooks, Michael Schmidt, Itzhak Kelson, Hadas Bittan, E. Lazarov, L Arazi, Yona KeisariAbstract:Purpose Diffusing alpha-emitters radiation therapy (DART) is a new form of brachytherapy enabling the treatment of solid tumors with alpha radiation. The present study examines the antitumoral effects resulting from the release of alpha emitting radioisotopes into solid lung carcinoma (LL2, A427, and NCI-H520). Methods and Materials An in vitro setup tested the dose-dependent killing of tumor cells exposed to alpha particles. In in viv o studies, radioactive wires (0.3 mm diameter, 5 mm long) with 224 Ra activities in the range of 21-38 kBq were inserted into LL/2 tumors in C57BL/6 mice and into human-derived A427 or NCI-H520 tumors in athymic mice. The efficacy of the short-lived daughters of 224 Ra to produce tumor growth retardation and prolong life was assessed, and the spread of radioisotopes inside tumors was measured using autoradiography. Results The insertion of a single DART wire into the center of 6- to 7-mm tumors had a pronounced retardation effect on tumor growth, leading to a significant inhibition of 49% (LL2) and 93% (A427) in tumor development and prolongations of 48% (LL2) in life expectancy. In the human model, more than 80% of the treated tumors disappeared or shrunk. Autoradiographic analysis of the treated sectioned tissue revealed the intratumoral distribution of the radioisotopes, and histological analysis showed corresponding areas of necrosis. In vitro experiments demonstrated a dose-dependent killing of tumors cells exposed to alpha particles. Conclusions Short-lived diffusing alpha-emitters produced tumor growth retardation and increased survival in mice bearing lung tumor implants. These results justify further investigations with improved dose distributions.
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Interstitial wires releasing diffusing alpha emitters combined with chemotherapy improved local tumor control and survival in squamous cell carcinoma-bearing mice.
Cancer, 2009Co-Authors: Tomer Cooks, Lior Arazi, Michael Schmidt, Itzhak Kelson, Margalit Efrati, Gideon Marshak, Yona KeisariAbstract:BACKGROUND: The objective of this study was to examine the combined effect of diffusing alpha-emitter radiation therapy (DART) together with the chemotherapeutic agent cisplatin on tumor development. METHODS: BALB/c mice bearing squamous cell carcinoma tumors were treated with Radium 224 (224Ra-)–loaded stainless steel wires, releasing short-lived, alpha-emitting atoms from their surface. A concomitant regimen of cisplatin doses (5 mg/kg per dose) was given intravenously for the evaluation of the combined effect. Animals were monitored for tumor growth and survival. RESULTS: First, the authors observed that alpha particles and cisplatin inhibited SQ2 cell proliferation in vitro and promoted apoptosis. Treatment of tumor-bearing mice indicated that, when a regimen of 2 separate doses of cisplatin was given concomitantly with a single intratumoral 224Ra-loaded wire, there was moderate tumor growth inhibition relative to what was observed from each treatment alone. When tumors were treated with 2 radioactive wires positioned near the tumor base and a similar drug administration, the growth arrest effect intensified, and there also was a significant increase in survival rates. The combined treatment reduced both local tumor growth and metastatic spread to the lungs. CONCLUSIONS: Antitumor activity and overall survival of metastatic tumor-bearing mice were improved significantly by the combined treatment. These results highlight the potential benefit of alpha radiation-based radiotherapy in combination with chemotherapeutic drugs for anticancer treatment. Cancer 2009. © 2009 American Cancer Society.
Itzhak Kelson - One of the best experts on this subject based on the ideXlab platform.
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The treatment of solid tumors by alpha emitters released from (224)Ra-loaded sources-internal dosimetry analysis.
Physics in medicine and biology, 2010Co-Authors: Lior Arazi, Tomer Cooks, Michael Schmidt, Yona Keisari, Itzhak KelsonAbstract:Diffusing alpha-emitters radiation therapy (DART) is a proposed new form of brachytherapy, allowing the treatment of solid tumors by alpha particles. DART utilizes implantable sources carrying small activities of Radium-224, which continually release into the tumor radon-220, polonium-216 and lead-212 atoms, while Radium-224 itself remains fixed to the source. The released atoms disperse inside the tumor by diffusive and convective processes, creating, through their alpha emissions, a high-dose region measuring several mm in diameter about each source. The efficacy of DART has been demonstrated in preclinical studies on mice-borne squamous cell carcinoma and lung tumors and the method is now being developed toward clinical trials. This work studies DART safety with respect to the dose delivered to distant organs as a result of lead-212 leakage from the tumor through the blood, relying on a biokinetic calculation coupled to internal dose assessments. It is found that the dose-limiting organs are the kidneys and red bone marrow. Assuming a typical source spacing of approximately 5 mm and a typical Radium-224 activity density of 0.4-0.8 MBq g(-1) of tumor tissue, it is predicted that tumors weighing up to several hundred grams may be treated without reaching the tolerance dose in any organ.
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Local control of lung derived tumors by diffusing alpha-emitting atoms released from intratumoral wires loaded with Radium-224.
International journal of radiation oncology biology physics, 2009Co-Authors: Tomer Cooks, Lior Arazi, Michael Schmidt, Itzhak Kelson, Hadas Bittan, E. Lazarov, Yona KeisariAbstract:Diffusing alpha-emitters radiation therapy (DART) is a new form of brachytherapy enabling the treatment of solid tumors with alpha radiation. The present study examines the antitumoral effects resulting from the release of alpha emitting radioisotopes into solid lung carcinoma (LL2, A427, and NCI-H520). An in vitro setup tested the dose-dependent killing of tumor cells exposed to alpha particles. In in vivo studies, radioactive wires (0.3 mm diameter, 5 mm long) with (224)Ra activities in the range of 21-38 kBq were inserted into LL/2 tumors in C57BL/6 mice and into human-derived A427 or NCI-H520 tumors in athymic mice. The efficacy of the short-lived daughters of (224)Ra to produce tumor growth retardation and prolong life was assessed, and the spread of radioisotopes inside tumors was measured using autoradiography. The insertion of a single DART wire into the center of 6- to 7-mm tumors had a pronounced retardation effect on tumor growth, leading to a significant inhibition of 49% (LL2) and 93% (A427) in tumor development and prolongations of 48% (LL2) in life expectancy. In the human model, more than 80% of the treated tumors disappeared or shrunk. Autoradiographic analysis of the treated sectioned tissue revealed the intratumoral distribution of the radioisotopes, and histological analysis showed corresponding areas of necrosis. In vitro experiments demonstrated a dose-dependent killing of tumors cells exposed to alpha particles. Short-lived diffusing alpha-emitters produced tumor growth retardation and increased survival in mice bearing lung tumor implants. These results justify further investigations with improved dose distributions.
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local control of lung derived tumors by diffusing alpha emitting atoms released from intratumoral wires loaded with Radium 224
International Journal of Radiation Oncology Biology Physics, 2009Co-Authors: Tomer Cooks, Michael Schmidt, Itzhak Kelson, Hadas Bittan, E. Lazarov, L Arazi, Yona KeisariAbstract:Purpose Diffusing alpha-emitters radiation therapy (DART) is a new form of brachytherapy enabling the treatment of solid tumors with alpha radiation. The present study examines the antitumoral effects resulting from the release of alpha emitting radioisotopes into solid lung carcinoma (LL2, A427, and NCI-H520). Methods and Materials An in vitro setup tested the dose-dependent killing of tumor cells exposed to alpha particles. In in viv o studies, radioactive wires (0.3 mm diameter, 5 mm long) with 224 Ra activities in the range of 21-38 kBq were inserted into LL/2 tumors in C57BL/6 mice and into human-derived A427 or NCI-H520 tumors in athymic mice. The efficacy of the short-lived daughters of 224 Ra to produce tumor growth retardation and prolong life was assessed, and the spread of radioisotopes inside tumors was measured using autoradiography. Results The insertion of a single DART wire into the center of 6- to 7-mm tumors had a pronounced retardation effect on tumor growth, leading to a significant inhibition of 49% (LL2) and 93% (A427) in tumor development and prolongations of 48% (LL2) in life expectancy. In the human model, more than 80% of the treated tumors disappeared or shrunk. Autoradiographic analysis of the treated sectioned tissue revealed the intratumoral distribution of the radioisotopes, and histological analysis showed corresponding areas of necrosis. In vitro experiments demonstrated a dose-dependent killing of tumors cells exposed to alpha particles. Conclusions Short-lived diffusing alpha-emitters produced tumor growth retardation and increased survival in mice bearing lung tumor implants. These results justify further investigations with improved dose distributions.
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Interstitial wires releasing diffusing alpha emitters combined with chemotherapy improved local tumor control and survival in squamous cell carcinoma-bearing mice.
Cancer, 2009Co-Authors: Tomer Cooks, Lior Arazi, Michael Schmidt, Itzhak Kelson, Margalit Efrati, Gideon Marshak, Yona KeisariAbstract:BACKGROUND: The objective of this study was to examine the combined effect of diffusing alpha-emitter radiation therapy (DART) together with the chemotherapeutic agent cisplatin on tumor development. METHODS: BALB/c mice bearing squamous cell carcinoma tumors were treated with Radium 224 (224Ra-)–loaded stainless steel wires, releasing short-lived, alpha-emitting atoms from their surface. A concomitant regimen of cisplatin doses (5 mg/kg per dose) was given intravenously for the evaluation of the combined effect. Animals were monitored for tumor growth and survival. RESULTS: First, the authors observed that alpha particles and cisplatin inhibited SQ2 cell proliferation in vitro and promoted apoptosis. Treatment of tumor-bearing mice indicated that, when a regimen of 2 separate doses of cisplatin was given concomitantly with a single intratumoral 224Ra-loaded wire, there was moderate tumor growth inhibition relative to what was observed from each treatment alone. When tumors were treated with 2 radioactive wires positioned near the tumor base and a similar drug administration, the growth arrest effect intensified, and there also was a significant increase in survival rates. The combined treatment reduced both local tumor growth and metastatic spread to the lungs. CONCLUSIONS: Antitumor activity and overall survival of metastatic tumor-bearing mice were improved significantly by the combined treatment. These results highlight the potential benefit of alpha radiation-based radiotherapy in combination with chemotherapeutic drugs for anticancer treatment. Cancer 2009. © 2009 American Cancer Society.
