Potent, selective inhibitors of fibroblast growth factor receptor define fibroblast growth factor dependence in preclinical cancer models.

We describe here the identification and characterization of 2 novel inhibitors of the fibroblast growth factor receptor (FGFR) family of receptor tyrosine kinases. The compounds exhibit selective inhibition of FGFR over the closely related VEGFR2 receptor in cell lines and in vivo. The pharmacologic profile of these inhibitors was defined using a panel of human tumor cell lines characterized for specific mutations, amplifications, or translocations known to activate one of the four FGFR receptor isoforms. This pharmacology defines a profile for inhibitors that are likely to be of use in clinical settings in disease types where FGFR is shown to play an important role.

AT9283, a potent inhibitor of the Aurora kinases and Jak2, has therapeutic potential in myeloproliferative disorders.

Constitutive activation of Janus kinase (Jak) 2 is the most prevalent pathogenic event observed in the myeloproliferative disorders (MPD), suggesting that inhibitors of Jak2 may prove valuable in their management. Inhibition of the Aurora kinases has also proven to be an effective therapeutic strategy in a number of haematological malignancies. AT9283 is a multi-targeted kinase inhibitor with potent activity against Jak2 and Aurora kinases A and B, and is currently being evaluated in clinical trials. To investigate the therapeutic potential of AT9283 in the MPD we studied its activity in a number of Jak2-dependent systems. AT9283 potently inhibited proliferation and Jak2-related signalling in Jak2-dependent cell lines as well as inhibiting the formation of erythroid colonies from haematopoietic progenitors isolated from MPD patients with Jak2 mutations. The compound also demonstrated significant therapeutic potential in vivo in an ETV6-JAK2 (TEL-JAK2) murine leukaemia model. Inhibition of both Jak2 and Aurora B was observed in the model systems used, indicating a dual mechanism of action. Our results suggest that AT9283 may be a valuable therapy in patients with MPD and that the dual inhibition of Jak2 and the Aurora kinases may potentially offer combinatorial efficacy in the treatment of these diseases.

Treatment of carpal tunnel syndrome.

In September 2008, the Board of Directors of the American Academy of Orthopaedic Surgeons approved a clinical practice guideline on the treatment of carpal tunnel syndrome. This guideline was subsequently endorsed by the American Association of Neurological Surgeons and the Congress of Neurological Surgeons. The guideline makes nine specific recommendations: A course of nonsurgical treatment is an option in patients diagnosed with carpal tunnel syndrome. Early surgery is an option with clinical evidence of median nerve denervation or when the patient so elects. Another nonsurgical treatment or surgery is suggested when the current treatment fails to resolve symptoms within 2 to 7 weeks. Sufficient evidence is not available to provide specific treatment recommendations for carpal tunnel syndrome associated with such conditions as diabetes mellitus and coexistent cervical radiculopathy. Local steroid injection or splinting is suggested before considering surgery. Oral steroids or ultrasound are options. Carpal tunnel release is recommended as treatment. Heat therapy is not among the options to be used. Surgical treatment of carpal tunnel syndrome by complete division of the flexor retinaculum is recommended. Routine use of skin nerve preservation and epineurotomy is not suggested when carpal tunnel release is performed. Prescribing preoperative antibiotics for carpal tunnel surgery is an option. It is suggested that the wrist not be immobilized postoperatively after routine carpal tunnel surgery. It is suggested that instruments such as the Boston Carpal Tunnel Questionnaire and the Disabilities of the Arm, Shoulder, and Hand questionnaire be used to assess patient responses to carpal tunnel syndrome treatment for research.

A randomized controlled trial of calcium supplementation to increase bone mineral density in children with juvenile rheumatoid arthritis.

OBJECTIVE: To examine the effects of daily supplementation with calcium (Ca) in combination with vitamin D on total body and lumbar spine bone mineral density (BMD) in patients with juvenile rheumatoid arthritis (JRA) who had not taken corticosteroids for at least 3 months prior to the beginning of the study. METHODS: One hundred ninety-eight children and adolescents (141 girls and 57 boys) with JRA, ages 6 to 18 years, with a mean +/- SD age of 11.7 +/- 3.3 years and a mean +/- SD disease duration of 5.6 +/- 3.8 years at the beginning of the study, were enrolled in this randomized double-blind, placebo-controlled trial to receive either daily oral supplements of 1,000 mg of Ca and 400 IU of vitamin D (n = 103) or matched placebo tablets and 400 IU of vitamin D (n = 95) for 24 months. Total body BMD (TBBMD) was measured by dual x-ray absorptiometry at baseline and every 6 months for 24 months. RESULTS: At baseline, the mean +/- SD TBBMD was 0.89 +/- 0.14 gm/cm2 among patients randomized to the Ca group and 0.87 +/- 0.14 gm/cm2 among those randomized to placebo (P = 0.445). At 24 months, the mean +/- SD TBBMD among those receiving Ca was 0.95 +/- 0.13 gm/cm2, compared with 0.92 +/- 0.14 gm/cm2 among those receiving placebo. A longitudinal random-effects mixed model analysis that controlled for differences in the subject's initial BMD, sex, Tanner stage, adherence to the study medication regimen, and body composition revealed significantly higher TBBMD among patients who received Ca compared with patients who received placebo during the study period (P = 0.03). CONCLUSION: Ca supplementation resulted in a small, but statistically significant, increase in TBBMD compared with placebo in children with JRA.