Dienogest 2 mg Daily in the Treatment of Adolescents with Clinically Suspected Endometriosis: The VISanne Study to Assess Safety in ADOlescents.

STUDY OBJECTIVE: To study the safety and efficacy of dienogest 2 mg in adolescents with suspected endometriosis. DESIGN: A 52-week, open-label, single-arm study. SETTING: In 21 study centers, in 6 European countries. PARTICIPANTS: Adolescents aged 12 to younger than 18 years with clinically suspected or laparoscopically confirmed endometriosis. INTERVENTIONS: Dienogest 2 mg once daily. MAIN OUTCOME MEASURES: The primary end point was relative change in lumbar spine (L2-L4) bone mineral density (BMD) measured using dual-energy x-ray absorptiometry. A key secondary end point was change in endometriosis-associated pain assessed using a visual analogue scale. RESULTS: Of 120 patients screened, 111 comprised the full-analysis set (ie, patients who took ≥1 dose of study drug and had ≥1 post-treatment observation) and 97 (87.4%) completed the study. Mean lumbar BMD at baseline was 1.1046 (SD, 0.1550) g/cm2. At the end of dienogest treatment (EOT; defined as at 52 weeks or premature study discontinuation), mean relative change in BMD from baseline was -1.2% (SD, 2.3%; n = 103). Follow-up measurement 6 months after EOT in the subgroup with decreased BMD at EOT (n = 60) showed partial recovery in lumbar BMD (mean change from baseline: -2.3% at EOT, -0.6% 6 months after EOT). Mean endometriosis-associated pain score was 64.3 (SD, 19.1) mm at baseline and decreased to 9.0 (SD, 13.9) mm by week 48. CONCLUSION: In adolescents with suspected endometriosis, dienogest 2 mg for 52 weeks was associated with a decrease in lumbar BMD, followed by partial recovery after treatment discontinuation. Endometriosis-associated pain was substantially reduced during treatment. Because bone accretion is critical during adolescence, results of the VISanne study to assess safety in ADOlescents (VISADO) study highlights the need for tailored treatment in this population, taking into account the expected efficacy on endometriosis-associated pain and an individual's risk factors for osteoporosis.

Cold ischemia does not interfere with tolerance induction.

BACKGROUND: Ischemia/reperfusion injury activates innate immunity, which in turn may prevent tolerance induction. We asked whether prolonged cold ischemia interferes with successful tolerance induction. METHODS: Kidneys from Dark Agouti donors were grafted into binephrectomized Lewis rats after short (20 min) or prolonged (6 hr) cold ischemia. Tolerance was induced by nondepleting anti-CD4 monoclonal antibody RIB 5/2 (10 mg/kg for 5 days). Binephrectomized untreated and cytotoxic T-lymphocyte antigen (CTLA)-4Ig treated recipients served as controls. Animals were followed for 100 days. Adoptive transfer experiments into sublethally irradiated naive Lewis were performed at day 100. Animals received kidneys from Dark Agouti rats subsequently without further immunosuppression and were followed for an additional 20 days. RESULTS: All RIB 5/2-treated recipients survived the first observation period independent of the cold ischemia time. Graft function, morphology, and transferred T-cell numbers were comparable in both groups. Twenty days after transfer amounts of intragraft and peripheral donor-derived cells were significantly reduced in recipients of the initially prolonged cold ischemia group associated with an attenuated immune response. CONCLUSIONS: Our results prove that an initially extended cold ischemia does not interfere with tolerance induced by RIB 5/2. Moreover, we conclude that a "tolerizing conditioning" achieved by prolonged cold ischemia during the tolerance-induction phase may reduce the immune response in recipients of an adoptive cell transfer.

Donor brain death significantly interferes with tolerance induction protocols.

Studies in rodents showed that antibodies are able to induce tolerance of allografts. As clinical results are unsatisfactory and deceased donors are still the main source of organ transplants, we investigated whether donor brain-death impacts on tolerance induction after experimental kidney transplantation. Anti-CD4 monoclonal antibodies (RIB 5/2; 2.5 mg/kg x 5 days) treated and untreated recipients of brain-dead donor grafts were compared with RIB 5/2 treated and untreated recipients of living donor grafts (F344-to-Lewis). All recipients received low-dose CsA (1.5 mg/kg x 10 days). Kidneys were recovered 4, 16 and 40 weeks after transplantation and examined by morphology, immunohistology and flow cytometry. Renal function was monitored monthly. RIB 5/2 treatment significantly decreased proteinuria in recipients of living donor allografts when compared with living donor controls. After 40 weeks, inflammatory cell infiltration and MHC class II expression were reduced while morphologic alterations were minimal. In contrast, treatment of brain-dead graft recipients had no impact on graft function. Structural changes and graft infiltration were comparable to brain-dead donor controls at all time points. RIB 5/2 treatment significantly improved graft function in recipients of living donor grafts; however, it was not effective in recipients of brain-dead donor organs.