Dosimetry of Bone Seeking Beta Emitters for Bone Pain Palliation Metastases.

Amongst cancer patients, bone pain due to skeletal metastases is a major cause of morbidity. A number of beta-emitting radiopharmaceuticals have been used to provide internal radiotherapy of bone metastases and provide palliative pain relief. In this article we describe the different physical characteristics of the various beta emitting radionuclides which have been used in this clinical setting and the potential impact of differences in dose-rate on radiobiological outcomes. A detailed review of the biodistribution of these treatments, based on both in-vivo clinical investigations and post mortem autoradiography assessments is provided. These treatments result in physiological delivery of radiation doses to the target disease as well as to critical healthy organs. Particular attention is paid to the radiation doses received by normal bone tissue, bone marrow as well as metastatic bone disease. The underlying models of radiation transport within bone and bone marrow are reviewed alongside the practical steps that must be taken to acquire and analyse the information require for clinical dosimetry assessments. The role of whole body measurements, blood and faecal assays as well as both planar and tomographic gamma camera imaging are considered. In addition we review the rationale for allocating measured bone uptake between trabecular and cortical bone tissue. The difference between bone volume and bone surface seeking radiopharmaceuticals are also discussed. This review also extends to the development of preclinical models of bone metastases which may inform future dosimetric calculations. Finally, we also present a comprehensive review of the dosimetry of the established treatments 89Strontium-chloride; 32Phosphorus; 188Rhenium-hydroxyethylidine disphosphonate; 186Rhenium-1,1-hydroxyethylidene disphosphonate (186Re-HEDP); 153Samarium-ethylenediaminetetramethylene phosphonate; as well as the emerging treatments 188Rhenium-zoledronic acid; 188Rhenium-ibedronat; 177Lutetium-zoledronic acid; and 177Lutetium ethylenediaminetetramethylene phosphonate. This review highlights not only the inter treatment differences in the radiation absorbed doses delivered to metastatic disease by different radiopharmaceuticals but also the intra treatment differences which result in a large range of observed doses between patients.

Radionuclide therapy for bone metastases by drugs based on Re-188.

The systemic radionuclide therapy with bone affinity substances is an effective therapy in bone palliative treatment. Studies with radiolabeled Bisphosphonate or strontium-89 show reduction of pain in 70-80% and about 20% of treated patients are pain-free. The generator product rhenium-188 represents an interesting radionuclide for bone pain palliation. It is readily available and with appropriate patient numbers is very cost-effective. Radiopharmaceuticals with Re-188 show a comparable effectiveness in bone pain palliation and bone marrow toxicity as the other known radioactive Bisphosphonate. Repeat courses of treatment with rhenium-188 HEDP even a slightly increased survival could be observed. Using therapy with alpha emitters Radium-223 in prostate cancer patients with bone metastases there was observed a prolongation of survival by 3,6 months compared with placebo. Two drugs are created in Russia on the basis of Re-188. Phosphoren is an analog of Re-188-HEDP. It showed properties similar to them in clinical studies. Complex Re-188-zoledronic acid (Zoleren) is a unique development that combines the therapeutic effect of zoledronic acid and Re-188.

Sensitivity of preparation with rhTSH or thyroid hormone withdrawal using ¹³¹I-whole body scans to identify metastases of differentiated thyroid cancer.

UNLABELLED: It has been reported that there is a higher sensitivity for Thyroid Hormone Withdrawal (THW) in detection of metastases of Differentiated Thyroid Cancer (DTC) when compared to Recombinant Human Thyroid-Stimulating Hormone (rhTSH). This study aims to confirm this reported difference in the sensitivity using radioiodine whole body scans (WBS). MATERIALS AND METHODS: In a retrospective study forty three patients with evidence or suspicion of metastatic differentiated thyroid cancer DTC (evaluated by thyroglobulin or abnormal findings in previous WBS) underwent WBS using of 24 h after oral administration of 370 MBq (131)I. The WBS was interpreted by two independent experienced observers categorizing their findings into a positive or negative for metastatic disease. The findings were controlled by stimulated thyroglobulin (TG) measurement and a two years follow-up. RESULTS: Of the evaluated patients, 14 patients were prepared with rhTSH and 29 with THW. No statistical differences in patient characteristics were documented between the two groups (age, sex, thyroglobulin level, TSH level, type of cancer). In this study, no differences in the sensitivity of WBS of patients prepared with rhTSH or THW were found. There were 11 of 14 patients (78%) that were positive after rhTSH and 19 of 29 patients (65%) after THW. Metastatic disease was confirmed by stimulated thyroglobulin value and follow-up. CONCLUSION: In contrast to previously published data, this study couldn't found any differences in the sensitivity of rhTSH or THW for the preparation of DTC patients undergoing (131)I imaging.

[Non-Respectful Behavior and Violence in Romantic Relationships between Adolescents: Prevalence and Quality of Life among Hesse Pupils]. / Grenzüberschreitendes Verhalten und Gewalt in Liebesbeziehungen unter Jugendlichen: Prävalenz und Lebensqualität unter Hessischen Schülerinnen und Schülern.

BACKGROUND: International studies illustrate the high prevalence of non-respectful or violent behaviour in adolescents' romantic relationships (teen dating violence) and health implications being comparable to intimate partner violence between adults. For Germany, there have been only data on sexual aggressive acting. The study investigated the magnitude of teen dating violence among secondary school pupils between 14 and 18 years in Hesse. METHODS: Adolescents attending general education system and vocational schools in Hesse were standardised and anonymously surveyed with a modified paper-pencil version of the YPRQ and the KIDSCREEN-10. 462 questionnaires were included into the analysis. In a first step, weighted data have been analysed descriptively. RESULTS: 181 female students (78%) and 173 male students (75%) affirmed the question concerning first experiences with dates or relationships. About 65.7% of the girls [95% CI 58.8-72.6] and 60.1% of the boys [95% CI 52.8-67.4] at risk stated that they suffered from at least one form of non-respectful behaviour or violence. 61% of the girls and 57% of the boys reported on emotionally difficult situations, 26% of the girls and 13% of the boys experienced unwanted sexually behaviour as well as physical violence in 11% of the girls and 10% of the boys. Life quality was lower between victimised adolescents (female 45.25; SD 7.2 and males 50.19; SD 8.3) compared to non-victimised females (47.40; SD 7.06) or males (51.04; (SD 7.5). CONCLUSION: The high prevalence rates are comparable with results of existing studies and demonstrate the need for prevention. An underestimation of serious violence is assumed due to methodical reasons. Due to the cross-sectional design, the direction of a cause-and-effect association between victimisation and quality of life remains uncertain.

False-positive finding in FDG-PET in a patient with seminoma and sarcoidosis.

A 33-year-old white man with testicular cancer (seminoma) stage IIIa showed a response in mediastinal lymph node metastases after chemotherapy. However, the tumor markers increase slightly, and therefore an (18)F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography was performed. Multiple FDG avid lesions were found in lymph node, liver and bone. The standardized uptake value (SUV) was discrete increase with a value of 2·8 to 5·7, which is more typical for inflammatory disease than a malignancy. The histological findings in a mediastinal lymph node reported a sarcoidosis, and therefore all lesions were diagnosed as a sarcoidosis. The one-year follow-up showed no further increase in tumor markers and no evidence for metastases.

[Violence during pregnancy: prevalence studies in OECD countries]. / Gewalterfahrungen in der Schwangerschaft: Prävalenzstudien in OECD-Ländern.

Violence during pregnancy can be associated with health consequences for both the pregnant woman und the unborn child. The available data on prevalence are insufficient in Germany, an underestimation of the problem is probable. Therefore data from other OECD countries are considered. Searching in the databases EMBASE (incl. Medline), CINAHL, PsycINFO and SSCI in English or German language, primary and secondary studies from OECD countries published from 2004 to 2011 were identified. Studies without a valid instrument were excluded. 20 studies using 6 different, partially modified instruments were identified. In OECD countries the prevalence data vary, depending on the instrument applied and the design of the studies. The majority of the studies underestimate the prevalence of violence during pregnancy. Study results from OECD countries are in the analysed range of the reviews. The data collected in Germany are at the bottom of the spectrum. This suggests an underestimation of the problem in Germany. Further research is needed using more valid instruments and better study designs.

Internal radiotherapy of painful bone metastases.

Internal radiotherapy is effective in the treatment of metastatic bone pain and can improve quality of life. A number of controlled studies using various agents have shown a mean response rate in pain relief of 70-80% of treated patients. Some investigators prefer radionuclides which emit low beta particles for the treatment of bone pain, because the assumption of lower bone marrow toxicity of this agents. However, neither dosimetric data for radiation absorbed dose to the bone marrow nor clinical blood count depression have shown any significant differences between these agents. Other researchers suggest enhanced antitumoral effects using high-energy beta emitters and propose aggressive first-line treatment in the early disease stage instead of using these radiopharmaceuticals only in end-stage patients suffering intractable bone pain. Another approach consists of including other treatment modalities such as autologous stem cell rescue or in combination with chemo or bisphosphonate therapy to a radionuclide treatment scheme. Future research should focus more on the curative effects of combination with radiosensitizer, for example, chemotherapy, or repeated treatments with bone seeking agents.

New model for the induction of osteoblastic bone metastases in rat.

BACKGROUND: We have investigated different models for osteoblastic lesions. Currently, there are two models using MatLyLu R-3327prostate cancer cells: tumor cell application in the left heart ventricle and intravenous application with concomitant transient surgical clamping of the lower caval vein. MATERIALS AND METHODS: Thirty male Copenhagen rats (age 9+/-2 months, mean weight 323+/-21 g) were each injected with 200,000 R-3327 prostate cancer cells. In 10 rats the left ventricle route was used (group 1), in an other 10 rats the intravenous route (group 2), while in the third group of 10 rats a new model of a direct intra-osseous route was applied (group 3). Additionally, a control group of 5 rats underwent the same procedure as in group 3, but only saline without tumor cells was administered. A 99mTc-HMDP bone scan and histological examination of bone and lung were performed for follow-up. RESULTS: In the bone scan, bone lesions could be not visualized in groups 1 and 2, but in group 3 osteoblastic lesions were observed in both femora in 9 out of 10 rats. Upon histological examination, there were lung metastases in animals from groups 1 and 2, but not in group 3. Clinical signs for bone metastases in the lumbar spine (motor disablement of the hind legs) were found in groups 1 and 2. CONCLUSION: The intra-osseous administration of MatLyLu R-3327 prostate cancer cells represents a useful and effective model for osteoblastic bone lesion, and allows further autoradiographic evaluation of bone uptake using bone-seeking radiopharmaceuticals.

Therapeutic efficiency of rhenium-188-HEDP in human prostate cancer skeletal metastases.

Rhenium-188-HEDP ((188)Re-HEDP) is a new and attractive radiopharmaceutical for the treatment of metastatic bone pain. As a product of (188)W/(188)Re generator, it is convenient for clinical therapeutic use with a short physical half-life of 16.9 h and a maximal beta-energy of 2.1 MeV. We investigated the effect of (188)Re-HEDP on pain relief, analgesic intake and impairment of bone marrow function in 27 patients with bone metastases induced from prostate cancer. All patients were interviewed using a standardised set of questions before, and after therapy for 12 weeks. The patients were treated with 2700-3459 MBq of (188)Re-HEDP. Blood samples were taken weekly for 12 weeks, and a blood count was performed. Patients described an improvement on the Karnofsky performance scale from 74+/-7 to 85+/-9% 12 weeks after therapy (P=0.001). The pain score showed a maximum decrease from 44+/-18 to 27+/-20% in the third to the eight week after therapy (P=0.009). Seventy-six percent of the patients described a pain relief without increase of analgesic intake. Twenty percent of the patients could discontinue their analgesics and were pain free. Mean platelet count decreased from (286+/-75)*10(3) microl(-1) to (215+/-92)*10(3) microl(-1), and mean leucocyte count from (7.7+/-1.5)*10(3) microl(-1) to (6.0+/-1.9)*10(3) microl(-1) in the second to the fourth week after therapy. The maximal differences between the values of platelets and leucocytes before and after therapy were not statistically significant (P=0.021 and 0.094). In conclusion, (188)Re-HEDP is an effective radiopharmaceutical used in the palliative treatment of metastatic bone pain in prostate cancer and shows minimal bone marrow toxicity.

[Beta-radiation exposure at the finger tips during the radionuclide synovectomy]. / Beta-Ortsdosimetrie der Fingerkuppen bei der Radiosynoviorthese.

AIM: The radiation synovectomy is a widespread therapeutic option in rheumatoid arthritis. However, data for the beta-radiation exposure are rare. The aim of this study was to determine the personal dose equivalent H(P) (0.07) of the skin of the hands. METHODS: Thermo-luminescence detectors (TLDs) were attached at all fingertips of the therapist, the radiochemist and the nurse. In summary, the measurement of beta-exposure occurred in 155 joints at 6 days with different radio-nuclides ((169)Er, (186)Re, (90)Y). RESULTS: The greatest beta exposure were show at the forefinger (L-Ff) and thumb (L-Th) of the left hand, with which the therapist (right hander) fixed the injection needle. In 52 treated finger-joints (1204 MBq (169)Er), 29 treated large joints (2405 MBq (186)Re) and 15 treated knees (3100 MBq (90)Y) we found a cumulative beta exposure over all radionuclides of 190 mSv at L-Ff and 48 mSv at L-Th. The specific beta exposure for the individual radio-nuclides showed beta exposures of 0.56 mu Sv/MBq for (169)Er and 1.52 mu Sv/MBq for (186)Re-186 at the L-Ff. With using a manipulator the beta-exposure ((90)Y) could reduced from 22,09 to 0.42 mu Sv/MBq at the L-Ff. The greatest beta exposures for the radiochemist was 119 mSv at the L-Ff for all radionuclides. CONCLUSION: In usual techniques of radiation synovectomy the (90)Y produced the greatest part of radiation exposure. Especially at the L-Ff it might exceed the German limit for the official dosimetry service at the skin ( section sign 55 Strl-SchV). Using a holding forceps we can keep the legal rules and can reduce considerably the beta exposure.

Accuracy of the intra-operative radioguided localization of the sentinel lymph node (SLN) 24 hours after lymphoscintigraphy in patients with malignant melanoma.

AIM: For optimized logistics for the sentinel lymphadenectomy (SL) it might be helpful for the clinics involved if a longer time period between the lymphoscintigraphy (LS) and surgery is possible. Therefore, we investigated if a precise localization of the sentinel lymph node is possible 24 hours after LS. METHODS: 78 patients with primary malignant melanoma (MM; n = 44) or with MM pre-operated by excisional biopsy (n = 34) were investigated. In 40 cases the tumor was localized on the trunk and in 38 cases on the extremities. Mean MM thickness was 2.68 mm (range: 0.29 to 12 mm). In all patients a lymphoscintigraphy (LS) with an average of 85 MBq of Tc-99m nanocolloid was performed one day prior to surgery. Immediately after tracer application dynamic data acquisition was started at a LFOV gamma camera followed by a whole body scan. With a hand-held gamma detector (C-Trak) 2, 4, 6, 8, and 24 hours after tracer administration the SLN was identified and the counts registered. RESULTS: 94 SLNs were identified in 87 lymphatic basins from which 86 could be resected. Nine MM showed two draining channels. After 24 hours 15.5% (as an average) of the initial counts could be measured in the SLN. The uptake in the SLN in pre-operated versus patients with primary tumor was statistically not significant (p = 0.4). In 16 cases (20.5%) the SLN was tumor positive. Four of those patients developed distant metastases and two died within the first year. None of the patients with negative SLN developed distant metastases or died. CONCLUSION: The remaining activity in the SLN up to 24 hours after administration is sufficient for their intra operative localization. The method of lymphoscintigraphy and localization of the SLN by a hand-held gamma detector optimizes the intra operative identification of the SLN in patients with malignant melanoma.

Significant reduction of the mass of bone metastasis 1 year after rhenium-186 HEDP pain palliation therapy.

A 59-year-old man with prostate cancer and pain from multiple bone metastases was treated with 1,424 MBq (38.5 mCi) rhenium-186 hydroxyethylidene diphosphonate (Re-186 HEDP). In addition, he had nonsteroidal antiandrogen, progestagen, and an analog-luteinizing hormone. Neither chemotherapy nor external-beam radiotherapy was administered. Bisphosponate therapy was stopped 4 weeks before the administration of Re-186 HEDP. The Tc-99m HMDP whole-body scan obtained 6 weeks after therapy showed the same results as before therapy. However, 1 year after therapy, a significant reduction of the mass of the metastases was visible on bone scan. The bone scan index decreased from 34 before therapy to 10 after 1 year. The patient described significant pain relief and stopped his analgesic intake 3 weeks after therapy.

[Comparison of rhenium-188, rhenium-186-HEDP and strontium-89 in palliation of painful bone metastases]. / Vergleich von Rhenium-188-HEDP, Rhenium-186-HEDP und Strontium-89 für die palliative Schmerztherapie von Skelettmetastasen.

AIM: Several radiopharmaceuticals were compared previously with regard to the efficiency in pain palliation of bone metastases. Furthermore, first results were reported on the suitability for such kind of therapy of the generator produced radionuclide rhenium-188. METHOD: Influence of Rhenium-188-HEDP (Re-188), Rhenium-186-HEDP (Re-186) and Strontium-89 (Sr-89) on pain symptoms and bone marrow function were obtained in 44 patients (pts). These were 16 pts. with Re-188 (2943 +/- 609 MBq), 13 pts. with Re-186 (1341 +/- 161 MBq) and 15 pts. with Sr-89 (152 +/- 18 MBq) (6 woman with breast cancer and 38 men with prostata cancer). RESULTS: 81 of pts. after Re-188, 77% after Re-186 and 80% after Sr-89 reported relief of pain. The Karnofsky-Index established by pts. increased from 74 +/- 9% to 85 +/- 11% after Re-188, from 70 +/- 11% to 76 +/- 11% after Re-186 and from 62 +/- 10% to 69 +/- 10% after Sr-89. However, the difference between the pre- and the post-therapeutic value is only statistically significant in the case of Re-188 therapy (p = 0.001). A decrease of platelets of 30 +/- 14% after 2.8 +/- 0.7 for pts. treated with Re-188, of 39 +/- 20% after 3.7 +/- 1.0 weeks for pts. treated with Re-186 and of 34 +/- 26% after 4.4 +/- 1.0 weeks for pts. treated with Sr-89 compared to the value before therapy was observed. The difference was not significant between the 3 groups of pts. (p = 0.125 to 0.862). CONCLUSION: All tried radiopharmaceuticals were effective in pain palliation. The various radionuclides had no significant difference in the pain relief or the bone marrow impairment. If only the Karnofsky-Index after Re-188 HEDP seems to be a little more increase.

Rhenium-188-HEDP in the palliative treatment of bone metastases.

INTRODUCTION: Rhenium-188-HEDP (188Re-HEDP) is a new and attractive radiopharmaceutical for the treatment of bone pain due to metastases. As a product of a 188W/188Re generator it is convenient for clinical use. With a short physical half life of 16.9 hours and a maximal beta-energy of 2.1 MeV, it is suitable for therapy. METHODS: We investigated the influence of 188Re-HEDP on pain relief, analgesic intake and impairment of bone marrow function in 15 patients. All patients were interviewed using standardized questions before, and 1, 2, 3, 4, 8, and 12 weeks after therapy. Blood samples were drawn weekly for 12 weeks, and a blood count was performed. Patients underwent gamma camera imaging to determine the radionuclide accumulation 4, 20, and 28 hours after therapy. The patients were treated with 1600 to 3459 MBq of 188Re-HEDP. RESULTS: Patients showed an improvement of the Karnofsky performance index from 74 +/- 8% to 84 +/- 11% 12 weeks after therapy. This improvement was statistically significant (p = 0.001). Eighty percent of the patients described pain relief and reduction of analgesics. Twenty percent of the patients could discontinue their analgesics. Mean platelet count decreased from (284 +/- 84)*10(3)/microliter to (205 +/- 62)*10(3)/microliter, and mean leukocyte count from (7.5 +/- 1.5)*10(3)/microliter to (5.9 +/- 2.1)*10(3)/microliter after therapy. The maximal differences between the values of platelets and leukocytes before and after therapy were not statistically significant (p = 0.021 and p = 0.094). Prostate specific antigen decreased from 95 +/- 83 ng/ml to 41 +/- 21 ng/ml, the difference was not statistically significant (p = 0.443). The bone accumulation 4, 20, and 28 hours after therapy was 1.3 +/- 0.5%, 0.6 +/- 0.3%, and 0.45 +/- 0.2% of the injected dose of a single metastasis, and 57 +/- 17%, 15.5 +/- 2% and 11 +/- 3% in the whole body, respectively. The effective half-life of 188Re-HEDP was 15.3 +/- 3.0 hours in the bone metastases, and 11.4 +/- 2.8 hours in the whole body. This corresponds to a residence time of 0.22 +/- 0.25 hours in the bone metastases, and of 10.54 +/- 2.59 hours in the whole body. CONCLUSION: In a small patient population, 188Re-HEDP therapy for bone pain palliation was effective and was associated with minimal toxicity.