Monitoring the genotoxic effects of radiosynovectomy with Re-186 in paediatric age group undergoing therapy for haemophilic synovitis

PURPOSE: The aim of this study was to investigate the genotoxic effect on the peripheral blood lymphocytes potentially induced by Re-186 in paediatric age group undergoing radiosynovectomy for haemophilic synovitis, by using chromosomal aberration analysis (CA) and the micronuclei (MN) assay for detecting chromosomal aberrations, as well as the sister chromatid exchanges (SCE) technique for assessing DNA damage. METHODS: Cytogenetic analyses were evaluated in 20 boys (mean age: 13.8 +/- 2.7 years) before, and 2 and 90 days after radiosynovectomy from the peripheral lymphocytes of the patients. Joint retention and extra-articular spread of the radionuclides were evaluated by using quantitative gamma camera imaging. RESULTS: Imaging after radiosynovectomy revealed local lymph node visualization in 8 (40%) patients and hepatosplenic visualization in 3 (15%) patients due to extra-articular leakage of radioactive material. The mean frequency of chromosome aberrations (0.2 +/- 0.4/1000 cells) determined prior to the onset of therapy was not significantly increased in comparison with control values obtained 2 days (0.4 +/- 0.5/1000 cells) and 90 days (0.2 +/- 0.4/1000 cells) after therapy (P = 0.754 and P = 1.0). In the analysis of MN and SCE, when we compare the baseline levels, the mean MN and SCE frequencies were slightly higher in the control analyses performed 2 and 90 days after radiosynovectomy but there were no significant differences between baseline and control levels (chi(2) = 2.621, P = 0.270 and F = 0.573, P = 0.569, respectively). CONCLUSION: The major finding of this study with relatively small sample is that, radiosynovectomy with Re-186 does not seem to induce early genotoxic effects on the peripheral blood lymphocytes in paediatric age group.     

Opinions on radiosynovectomy for chronic haemophilic synovitis: point/counterpoint

Joint bleeding is the hallmark of severe haemophilia and the major cause of disability in patients with this coagulopathy. Repeated bleeding into the same joint can lead to chronic synovitis and progressive arthropathy. Radiosynovectomy is one option for the treatment of chronic haemophilic synovitis, but concerns about the risks of exposure to ionizing radiation have divided clinicians as to the safety and appropriate use of the procedure. This article presents two differing viewpoints, one from a pair of orthopaedic surgeons who collectively have performed more than 300 radiosynovectomies in patients with haemophilia. They maintain that radiosynovectomy is a simple, effective, safe and low‐cost technique children and adults with chronic haemophilic synovitis. The other perspective is from an experienced haemophilia treater who directs a major US haemophilia treatment centre. She believes that unresolved questions about the safety of radiation exposure in children argue against the use of radiosynovectomy in paediatric patients with haemophilia.     

Survival analysis of Y‐90 radiosynovectomy in the treatment of haemophilic synovitis of the knee: a 10‐year retrospective review

Despite recent advances including new therapeutic options and availability of primary prophylaxis in haemophiliacs, haemophilic synovitis is still the major clinical problem in significant patient population worldwide. We retrospectively reviewed our 10‐year experience with Y‐90 radiosynovectomy to determine the outcome in the knee joints of patients with haemophilic synovitis. Between 2002 and 2012, 82 knee joints of 67 patients with haemophilic synovitis were treated with Y‐90 radiosynovectomy. The mean age was 16.8 ± 7.8 years (range: 5–39 years). The mean follow‐up period was 39.6 ± 25.6 months (range: 12–95 months). Failure of therapy represented re‐bleeding after a radiosynovectomy was used as an end point in patient time to progression (TTP) analysis. The median TTP was calculated as 72.0 ± 3.6 months (95% CI 64.8–79.1 months) in Kaplan–Meier analysis. The 1, 3 and 5‐year survival rates were 89%, 73% and 63% respectively. Longer TTP (hazard ratio for progression, 2.5; P = 0.00) was evident in patients who have greater reduction in bleeding frequency within 6 months after radiosynovectomy. We did not find a relationship between the TTP and the following variables: age, type and severity of haemophilia, the presence or absence of inhibitor, the radiological score, range of motion status of joints and the pretreatment bleeding frequency. We concluded that Y‐90 radiosynovectomy in knee joint represents an important resource for the treatment of haemophilic synovitis, markedly reducing joint bleeding and long‐term durability, irrespective of the radiographic stage and inhibitor status.     

32P colloid radiosynovectomy in treatment of chronic haemophilic synovitis: Iran experience

Repeated intra-articular bleeding with subsequent development of chronic synovitis and cartilage changes, leading to haemophilic arthropathy, is one the most debilitating problems in haemophilic patients. Radiosynovectomy is a familiar therapeutic choice in management of chronic synovitis in haemophilia. We report the treatments results of synoviorthesis with (32)P chromic phosphate with emphasis on clinical aspects. Between 2002 and 2006 we performed 66 procedures in 53 patients. Seven patients were excluded. The remaining 46 patients were followed for an average of 31 months. The mean age of patients at the time of injection was 15.9 years (range: 6-28). There were three repeat injections. According to Fernandez-pallazi and Cavilgia clinical classification (Table 1) [23], nine joints were Stage II and 46 were Stage III. In latest follow-up, 77% of patients reported at least a 50% decrease in bleeding frequency after treatment (P < 0.0001). The need for antihaemophilic factor consumption dropped by about 74% postradiosynovectomy (P < 0.0001). In most of the injected joints, the range of motion remained stable or improved. A trend was found for the number of haemarthrosis to increase after a period of considerable improvement. Synoviorthesis using (32)P effectively reduces the intra-articular bleeding rate and factor concentrate use. Durability of the response seems to be unpredictable, perhaps attributable to the late intervention. An early radiosynovectomy might be more helpful in terms of stability of response to treatment.     

90Yttrium‐hydroxyapatite: a new therapeutic option for radioactive synovectomy in haemophilic synovitis

Summary. Recurrent haemarthroses often lead to chronic synovitis in patients with haemophilia and von Willebrand disease. Radioactive synovectomy with yttrium‐90 (⁹⁰Y) citrate is frequently used to treat this complication, usually with good results. Since 2006, the Nuclear Energy Research Institute (IPEN, Sao Paulo, Brazil) has produced hydroxyapatite particles labelled with ⁹⁰Y for radioactive synovectomy. The aim of this study was to compare the results achieved by both forms of ⁹⁰Y in the treatment of haemophilic synovitis. We included 221 joints from 136 patients (age range: 6–20 years), treated by one of the two radiopharmaceuticals, at the Hemocenter of Mato Grosso, Brazil. The outcomes analysed were the annual frequency of haemarthrosis, articular pain and joint range of motion before and 1 year after RS. Similar results were achieved regardless of whether ⁹⁰Y hydroxyapatite or ⁹⁰Y citrate was used, and results were independent of the joint type, age, gender, radiologic stage and presence of inhibitors. ⁹⁰Y hydroxyapatite appears to be equivalent to the reference product ⁹⁰Y citrate in the treatment of chronic synovitis associated with bleeding disorders.     

Agonistic anti‐human Fas monoclonal antibody induces fibroblast‐like synoviocyte apoptosis in haemophilic arthropathy: potential therapeutic implications

Haemophilic arthropathy (HA) is characterized by chronic proliferative synovitis leading to cartilage destruction and shares some pathological features with rheumatoid arthritis (RA). Apoptosis has been implicated in RA pathogenesis, and an agonistic anti‐Fas monoclonal antibody (mAb) was found to induce RA fibroblast‐like synoviocyte (FLS) apoptosis and suppress synovial hyperplasia in animal models of RA. The aim of this study was to evaluate the effect of anti‐Fas mAb on HA‐FLS. FLS were isolated from knee synovial biopsies from six HA patients, six RA patients and six healthy subjects. The expression of Fas in synovial biopsies was investigated by immunohistochemistry. FLS were stimulated with anti‐Fas mAb at different concentrations, alone or in combination with tumour necrosis factor‐α (TNF‐α) and basic fibroblast growth factor (bFGF). Fas expression in FLS was assessed by Western blot. Cell viability was studied with the WST‐1 assay. Active caspase‐3 levels were measured using ELISA and Western blot. A strong Fas‐immunoreactivity was observed in different cells of HA synovium, including FLS, inflammatory cells and endothelial cells. Fas antigen was constitutively overexpressed in cultured HA‐FLS. Anti‐Fas mAb had a significant cytotoxicity on HA‐FLS in a dose‐dependent manner, either alone or in combination with TNF‐α and bFGF. These cytotoxic effects were due to the ability of anti‐Fas to induce HA‐FLS apoptosis, as shown by the increased active caspase‐3 levels. Anti‐Fas mAb exhibited a more pronounced pro‐apoptotic effect on HA‐FLS than RA‐FLS. Fas antigen is highly expressed on HA‐FLS and its stimulation by anti‐Fas mAb may be an effective strategy to induce HA‐FLS apoptosis.     

Renal nerve ablation reduces blood pressure in resistant hypertension: Long‐term clinical outcomes in a single‐center experience

Approximately 10% of patients with hypertension have resistant hypertension, even if adequate pharmacological therapy is established. In this regard, renal nerve ablation (RNA) could represent a valid alternative treatment option. In a retrospective analysis with a follow‐up of 6, 12, and 24 months, the authors investigated the efficacy and safety of catheter‐based renal artery ablation in 57 patients undergoing RNA with multiple renal nerve ablation in both renal arteries. In addition to medical antihypertensive therapy (4.2 ± 1.4 drugs per patient), RNA using three different ablation systems was performed in patients with confirmed resistant hypertension (systolic blood pressure >140 mm Hg in spite of three drugs including a diuretic). The primary end point was the change in office ambulatory systolic blood pressure from baseline to 6, 12, and 24 months of follow‐up after RNA. The primary safety end point was the change in plasma creatinine levels after 12 and 24 months compared with baseline. The mean office systolic blood pressure at baseline was 167.6 ± 22.4 and after 6, 12, and 24 months averaged 143.5 ± 21.1 (P < .05), 141.1 ± 21.1 (P < .05), and 139.4 ± 19.6 mm Hg (P < .05) respectively, with an average of 15.1 ± 5.3 nerve ablations performed. No significant changes in plasma creatinine levels were observed at 12 months (P = .421) and at 24 months (P = .217). There were no complications after RNA nor any relevant adverse vascular, renal, or cardiovascular events observed except in one patient in whom a covered stent had to be placed at the femoral puncture site. In this study, in all patients with resistant hypertension, RNA, if performed adequately in the number of ablations and energy delivery, is an efficient and safe treatment option to lower office and 24‐hour blood pressure. Whether these blood pressure–lowering effects will lead to a reduction of cardiovascular morbidity and mortality will require further studies.     

Long‐term symptomatic outcomes after Collis gastroplasty with fundoplication

Collis gastroplasty with fundoplication is an accepted treatment for gastroesophageal reflux disease (GERD) complicated by short esophagus. The procedure can be done either via left thoracotomy or using minimally invasive laparoscopic techniques. Few centers have reported long‐term follow‐up for patients undergoing a Collis gastroplasty using both the open and minimal access techniques. Retrospective review of prospectively collected data at Creighton University was done to identify patients who underwent Collis gastroplasty with fundoplication for GERD. After approval from the institutional review board, the patients were contacted and administered a questionnaire regarding symptoms and satisfaction. Data were entered in a dataset and analyzed from the patient's perspective. Eighty‐five patients underwent a Collis gastroplasty procedure over a period of 13 years. Forty‐eight percent (41 cases) were performed laparoscopically, and a transthoracic open repair was performed in the rest. Long‐term data (more than 9 months) was available on 52 patients. Surgery resulted in complete resolution of heartburn, chest pain, regurgitation, and dysphagia in 52, 22, 54, and 29% of patients, respectively. More than 75% of the patients were satisfied with the outcome of surgery, and more than 85% would recommend the procedure to another patient. Collis gastroplasty with fundoplication results in good long‐term patient satisfaction and symptom control.