IκB kinase inhibition as a potential treatment of osteoarthritis - results of a clinical proof-of-concept study.

OBJECTIVE: This publication summarizes the clinical development of the compound SAR113945, an IκB kinase inhibitor injected intra-articularly in a slow-release formulation to treat patients with symptomatic osteoarthritis (OA) of the knee. RESULTS: In vitro experiments demonstrated a specific inhibition of the IκB kinase complex. Profiling of SAR113945 on kinases, enzymes and ion channels supported the initiation of a clinical development. Cellular assay systems also revealed an inhibition in the synthesis of interleukin 1ß, tumor necrosis factor α (TNFα) and the prostaglandin E2 (PGE2). In vivo studies demonstrated positive effects of SAR113945 on thermal and mechanical hyperalgesia and even showed superiority in comparison with triamcinolone. Pharmacokinetic measurements showed a sustained release of dissolved SAR113945 locally supporting a comparably high exposure in the knee joint combined with a low systemic exposure. Three phase 1 studies with a dose-escalating design confirmed safety and tolerability of SAR113945. In those studies SAR113945 showed a positive trend on the WOMAC scores. The proof-of-concept or phase 2a study failed to show any effect in the overall group of recruited study participants for the primary endpoint, the WOMAC pain subscore at day 56, but showed a statistically significant difference in a subgroup of patients who had presented with effusion at baseline. CONCLUSION: Inhibiting the NFκB signaling pathway is an attractive method to treat patients with signs and symptoms of OA. The preclinical work and the results of the phase 1 studies appeared promising for a full clinical development, however, the proof-of-concept study failed to show efficacy in a larger patient sample size.

OARSI Clinical Trials Recommendations: Design and conduct of clinical trials for hip osteoarthritis.

The ability to assess the efficacy and effectiveness of an intervention for the treatment of hip osteoarthritis (OA) requires strong clinical trial methodology. This consensus paper provides recommendations based on a narrative literature review and best judgment of the members of the committee for clinical trials of hip OA. We provide recommendations on clinical trial design, outcome measures, including structural (radiography), and patient and physician global assessments, performance based measures, molecular markers and experimental endpoints including MRI imaging. This information can be utilized by sponsors of trials for new therapeutic agents for hip OA.

Change in knee osteoarthritis cartilage detected by delayed gadolinium enhanced magnetic resonance imaging following treatment with collagen hydrolysate: a pilot randomized controlled trial.

OBJECTIVE: To determine whether either of two magnetic resonance imaging approaches - delayed gadolinium enhanced magnetic resonance imaging of cartilage (dGEMRIC), or T2 mapping - can detect short-term changes in knee hyaline cartilage among individuals taking a formulation of collagen hydrolysate. DESIGN: Single center, prospective, randomized, placebo-controlled, double-blind, pilot trial of collagen hydrolysate for mild knee osteoarthritis (OA). Participants were allowed to continue the prior analgesic use. The primary outcome was change in dGEMRIC T1 relaxation time in the cartilage regions of interest at the 24-week timepoint. Secondary endpoints included the change in dGEMRIC T1 relaxation time between baseline and 48 weeks, the change in T2 relaxation time at 0, 24 and 48 weeks, the symptom and functional measures obtained at each of the visits, and overall analgesic use. RESULTS: Among a sample of 30 randomized subjects the dGEMRIC score increased in the medial and lateral tibial regions of interest (median increase of 29 and 41 ms respectively) in participants assigned to collagen hydrolysate but decreased (median decline 37 and 36 ms respectively) in the placebo arm with the changes between the two groups at 24 weeks reaching significance. No other significant changes between the two groups were seen in the other four regions, or in any of the T2 values or in the clinical outcomes. CONCLUSIONS: These preliminary results suggest that the dGEMRIC technique may be able to detect change in proteoglycan content in knee cartilage among individuals taking collagen hydrolysate after 24 weeks.

Peripheral primitive neuroectodermal tumor: challenge for multimodal treatment.

The primitive neuroectodermal tumor (PNET) is an extremely aggressive soft tissue neoplasm that occurs in children and adolescents. We retrospectively reviewed our therapeutic experience with a multidisciplinary approach, combining surgery, chemotherapy, and radiation therapy. Treatment of PNET was carried out in compliance with the soft tissue protocol (CWS) from the German Society of Pediatric Oncology. Biopsy-proven diagnosis was followed by chemotherapy, which in all cases led to partial remission, allowing excision of the remainder of the tumor without mutilation. After excision, irradiation of the tumor site and two further sequences of chemotherapy were performed. When PNET of the paravertebral region caused symptoms of paralysis and immediate surgery was required, postoperative chemotherapy, a second-look operation, and irradiation were undertaken. Between 1986 and 1998 we treated 13 patients (median age 15 years). In five patients the PNET originated from the chest wall and in eight patients from the paravertebral and retroperitoneal region. Five patients died after 20 months on average, and the remaining eight patients are in full remission after 7, 16, 46, 55, 70, 74, 75, and 115 months, respectively. Close cooperation between surgeons and their pediatric and radiotherapy colleagues is obligatory when treating PNET. Chemotherapy as the first stage is mandatory to avoid a mutilating surgical procedure and intraoperative tumor cell dissemination.

[Value of locoregional chemotherapy in liver metastases of breast carcinoma]. / Der Stellenwert der lokoregionären Chemotherapie bei Lebermetastasen des Mammakarzinoms.

Between 1985 and 1997, we performed a locoregional chemotherapy in 59 patients suffering from non-resectable liver metastases of breast cancer. 36 of them only had liver metastases, in 23 patients liver metastases were combined with extrahepatic tumor spread. Furthermore, in 7 patients locoregional chemotherapy was used as a adjuvant regimen after metastasectomy. The average age of our patients was 52 (32-81) years. In most of our patients, a cytostatic scheme of mitoxantron, 5-fluorouracil and doxorubicin or a scheme of vincristin, mitomycin and mitoxantron was administered. The median survival of all patients was 11 months, in the patients with no additional extrahepatic tumor spread it was 16, in the patients with extrahepatic metastases 3 months, respectively.

[Persistent chylothorax after fracture of the 12th thoracic vertebrae]. / Persistierender Chylothorax nach Fraktur des 12. Brustwirbelkörpers.

We report on a patient who suffered chylothorax 2 months after she had undergone internal fixation of a fracture of her 12th thoracic vertebral body. The pleural effusion was treated by insertion of a chest tube. The chylothorax was managed conservatively. The patient received protein-rich nutrition supplemented with medium-chain triglycerides. As the volume of chylous fluid drained from the pleura had not decreased after 2 weeks, the patient received total parenteral nutrition without any oral intake of calories. Chest X-rays documented the disappearance of the chylothorax. Reexpansion of the lungs was noted, and the costophrenic sinuses could be clearly visualised.

Treatment of ruptures of the symphysis and iliosacral joint in pediatric patients.

The three osseous parts of the human pelvis form a continuous structure because of the symphysis and both iliosacral joints that-owing to their mobility-make possible a shock-absorption of vertical forces. The goal in the treatment of ruptures of the symphysis and/or of the sacroiliac joints is the restoration of functioning joints. Especially in the adolescent, a stiffening of these joints has to be avoided. Therefore, we treat ruptures of the pelvic joints with an overbridging banding that preserves the function of shock absorption. Due to utilisation of a banding, made up of polydioxanone, another operation to remove internal fixation material is not necessary. Rupture of the symphysis or iliosacral joint in the pediatric patient is very rare. Only three among the 67 patients whom we operated on because of a rupture of the symphysis or iliosacral joints between 1984 and 1990 were children. These were an eleven-year-old girl and a nine-year-old boy, who had suffered a rupture of the symphysis, and an eight-year-old boy with a disrupted iliosacral joint. In these children a banding with PDS suture was performed. At a follow-up examination, the children were free from pain and did not feel restricted in their daily routine or their physical activities.