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Radiation Synovectomy Using 165Dy Ferric-Hydroxide and Oxidative DNA Damage in Patients with Different Types of Arthritis

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Radiation Synovectomy Using 165Dy Ferric-Hydroxide and Oxidative DNA Damage in Patients with Different Types of Arthritis Radiation Synovectomy Using 165Dy Ferric-Hydroxide and Oxidative DNA Damage in Patients with Different Types of Arthritis Christian Pinch, Alexander Pilger, Eva Schwameis, Dietmar Germadnik, Ulrike Prufert, Ernst Havilk, Susanna Lang, Herbert Kvaternik, Juan A. Flores, Peter Angelberger, Axel Wanivenhaus, Hugo W. RUdiger, and Helmut Sinzinger Departments ofNuclear Medicine, Orthopedics, Occupational Medicine, and Pathology, University of Vienna, Vienna; and University Hospital of Vienna, Research Center Seibersdorf Vienna, Austria KeyWords:radiationsynovectomy;cytogeneticdamage;can Radiation synovectomy is an effective treatment for chronic cer;biomarker synovitisrefractorytopharmacologicaltreatmentinpatientswith J NucIMed2000;41:250-256 rheumatoidor seronegativearthritis.Concernspersistabout possible radiation-inducedcytogenetic damage after radiation synovectomyleadingto recommendationsto usethistechnique onlyintheelderly.Micronucleus(MN) frequencyinlymphocytes andurinaryexcretionof8-hydroxy-2'-deoxyguanosine(8OHdG) adiation synovectomy is an alternate, locally acting as an indicatorof cellularoxidativeDNA base damage are treatment for chronic synovitis refractory to the repetitive, biomarkersof radiation-inducedcytogeneticdamage.The course intraarticular application of glucocorticoids and systemic ofbothbiomarkerswasstudiedinpatientswithdifferenttypesof pharmacological treatment in patients with rheumatoid or chronicsynovitisundergoingradiationsynovectomywith very seronegative arthritis (RA or SA, respectively). A few case short-lived leaDy_ferric@hydroxide(DFH). Methods: Radiation synovectomyof the knee was performedin 13 men and 12 reports exist in the literature about malignancies after women(meanage,44 ±15 y) usinga meanactivityof9.48± radiation synovectomy (1). Therefore, concerns have per 1.65 GBq @Dy-DFHin 27 consecutivetreatments.MN fre sistedaboutpossibleradiation-inducedcytogeneticdamage quencyin lymphocytesand urinaryexcretionof 8OHdG, mea after radiation synovectomy (2). Chromosomal studies of sured by high-performanceliquidchromatography,were as circulating lymphocytes revealed an increased incidence of sessed before and 4 (MN only) and 20 h after radiation radiation-induced aberrations in patients undergoing radia synovectomy.Results: Urinaryexcretionof 8OHdG in patients (in pmol/molcreatinine; pretreatmentmean, 3.1 ±3.4; median, tion synovectomy with ‘98Auor @°Y(3—9).The immobiliza 2.27) was not significantlydifferentfromthat in healthyvolun tion of the treated joint after intraarticular injection (10) and teers(mean,2.0 ±1.2; median,1.87) and not alteredby the introductionof new preparationsof @°Y(6) or new radionu radiationsynovectomy(post-treatmentmean,2.5 ±1.5;median, cides with short half-lives and relatively large particulate carriers 2.04, NS). An increase in 8OHdG levels after radiation synovec (11—13)have significantly reduced the frequency and degree of tomy of more than 1 SD was found in only 1 patient, who leakage from the treatedjoint decreasing the irradiationof local experienced leakage to the lymph nodes but who already had elevatedurinary8OHdGlevelsbeforetreatment.The frequency lymph nodes and lymphocytes. The micronucleus (MN) assay ofMN/500binucleatedcells(BNCs)wasslightlylowerinpatients that measures the frequency of MN in lymphocytes is an (pretreatmentmean, 4.3 ±2.6; median,4.25) than in healthy accepted method of analysis for radiation-induced chromosomal volunteers(mean,5.4 ±2.3; median,5.3) and did not signifi aberrations. MN result from failure of chmmosomal fragments cantlychangeafter therapy,either (4-h post-treatmentmean, or of whole chromosomes to incorporate into daughter nuclei 3.9 ±2.1, median, 3.8; 20-h post-treatment mean, 4.1 ±2, during mitosis (14). The relation between the degree and site of median3.8 MN/500BNC).In22 of27 treatments,noleakageto nontarget organs could be monitored, whereas leakage to the leakage and the frequency of MN is not consistent (15). local lymph nodes and the liver was detectedafter 5 treatments. Furthermore, levels of biomarkers of cytogenetic damage were Conclusion:Radiationsynovectomyusing165Dy-DFHcauses analyzed at extended time intervals after radiation synovectomy, no significantradiationburdento mostpatientsas indicatedby with a possible influence of confounding factors, particularly the absence of adverse changes in levels of biomarkers of when using a very short-lived radionuclide such as cytogeneticdamageanda lowincidenceofleakage.Thesedata (16,17). suggestthattheriskofmalignancymaynotbeelevated. Urinary excretion of 8-hydroxy-2'-desoxyguanosine (8OHdG) has been described as a sensitive marker of Received Nov. 30, 1998; revision accepted Jun. 21, 1999. oxidative DNA damage by ionizing radiation linked to the Forcorrespondenceorreprintscontact:ChristianPinch,MD,Departmentof Nuclear Medicine, Universityof Vienna, Wahringer GOrtel 18—20,Vienna, responsetoradiotherapyandchemotherapyinlungcancer Austria. patients (18). The levels of 8OHdG have not been assessed 250 Tm@JOURNALOF NUCLEARMEDICINE•Vol. 41 •No. 2 •February 2000 in patients undergoing radionuclide therapy. Measurement ([ReAJ n = 2), osteoarthritis ([OA] n = 3), pigmented villonodular of urinary excretion of 8OHdG as a marker of oxidative synovitis ([PVNS] n = 4), and SA (n = 5). Of the remaining 3 DNA damage by radiation is a highly sensitive method (19). patients, 1 had adult-onset Still's disease, another had arthritis 8OHdG might be more suitable for biological dosimetry associated with inflammatory bowel disease (IBD), and another had ankylosing spondylitis. Patients were eligible for radiation than the MN assay, the latter showing in some cases a low synovectomy if suffering from persistent synovitis of the knee proliferation response of lymphocytes isolated from patients refractory to systemic and local pharmacological treatment, but with chronic inflammatory disease (9, 14). 8OHdG reflects withoutanyevidence ofinfection, trauma,orjoint instability.Local total radiation energy absorbed by different cells, whereas management involved glucocorticoids that were injected intraarticu MN relate to the DNA damage in lymphocytes. This larly. Systemic pharmacotherapy was defined as the use of nonste difference might be of importance since it is not known roidal anti-inflammatory drugs (NSAIDs), glucocorticoids, and whether any suggested increase in malignancy risk already disease-modifying antirheumatoid drugs for at least 3 mo. The derives from irradiation of the highly vascular inflamed latter were taken by patients with autoimmune disease (RA, Still's synovium or, in the case of leakage of circulating lympho disease, IBD). NSAIDs were taken by all patients. All patients had cytes,throughthelymphnodes(3,4). undergone multiple arthrocenteses of the affected knee with We postulated that the urinary excretion of 8OHdG might cytological analysis for confirmationof diagnosedchronicsynovi tis. Patients with SA, RcA, and OA were treated when arthritis provide a useful index of total DNA damage (i.e., that which scintigraphy with @Tc-humanimmunoglobulin (HIG) had mdi has occurred but has been repaired) in patients undergoing cated synovitis. HIG scintigraphy was used as the imaging radiation synovectomy. Therefore, this study aimed to modality, because this method yields high accuracy in detecting investigate the course of biomarkers and their relevance in andgradinginflammatoryjoint disease (20). patients with different types of chronic synovitis of the knee 1\welve patients (including all patients with PVNS) had under treated with radiation synovectomy with 165Dy—ferric gone diagnostic arthroscopy at least 6 wk before radiation synovec hydroxide (FDH). tomy. Patients with RA were included after excluding a state of acutepolyarticularexacerbationof the disease. Radiographstaken MATERIALSAND METhODS before inclusion were classified according to Larsen et al. (21). The use of any accepted form of contraceptionwas obligatory @Dy-DFHPreparation for any fertile women treated with ‘65Dy-DFH.Exclusion criteria @Dy-DFHis aprecipitateof @Dy-hydmxideon Fe(II)Fe(ffl)hy fortreatmentwith ‘65Dy-DFHwerepregnancy,any life-threatening dioxide used as carrier. The improved preparation of the carrier was orinfectiousdisease,orthepresenceof a majorBakercystof the previously described in detail (13). respective joint. The carrier was prepared as follows: 90 mg FeSO4 X 7 H20 and Each patient was admitted to the application room at calibration 14 mg Fe(N03)3 X 9H20 were dissolved in 0.5 mL 0.1 moIIL time. Arthrocentesis was performed in this room, under strictly H2S04 and diluted with 7.5 mL H20. Two mL 0.5 mollL NaOH aseptical conditions, with the patient in a supine position. ‘65Dy were slowly added while shaking the vial. The lO-mL vial was DFH was injected into the joint space using a 1.2-mm gauge sealed and heated for 30 mm at 90°C.The color of the suspension needle. The knee was then moved once or twice through a changed from green to deep black duringheating.The suspension flexion/extension arc and immobilized in extension. The patient was filtered through an 8-jim Nuclepore polycarbonate membrane was confined to rest for 5—6h to minimize movement. Both knee (Millipore Inc., Bedford, MA) before use. joints were treated with an interval of at least 2 mo in 2 patients. A 3-mg sample of naturalDy203 (Aldrich 20.318—1; Aldrich, Vienna, Austria) was dissolved in concentrated HNO3 and evapo EstimationofActivftyforTherapy rated in a quartz ampoule. The resulting Dy(N03)3
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