Phase III randomized study of second line ADI-PEG 20 plus best supportive care versus placebo plus best supportive care in patients with advanced hepatocellular carcinoma.

Background: Arginine depletion is a putative target in hepatocellular carcinoma (HCC). HCC often lacks argininosuccinate synthetase, a citrulline to arginine-repleting enzyme. ADI-PEG 20 is a cloned arginine degrading enzyme-arginine deiminase-conjugated with polyethylene glycol. The goal of this study was to evaluate this agent as a potential novel therapeutic for HCC after first line systemic therapy. Methods and patients: Patients with histologically proven advanced HCC and Child-Pugh up to B7 with prior systemic therapy, were randomized 2 : 1 to ADI-PEG 20 18 mg/m2 versus placebo intramuscular injection weekly. The primary end point was overall survival (OS), with 93% power to detect a 4-5.6 months increase in median OS (one-sided α = 0.025). Secondary end points included progression-free survival, safety, and arginine correlatives. Results: A total of 635 patients were enrolled: median age 61, 82% male, 60% Asian, 52% hepatitis B, 26% hepatitis C, 76% stage IV, 91% Child-Pugh A, 70% progressed on sorafenib and 16% were intolerant. Median OS was 7.8 months for ADI-PEG 20 versus 7.4 for placebo (P = 0.88, HR = 1.02) and median progression-free survival 2.6 months versus 2.6 (P = 0.07, HR = 1.17). Grade 3 fatigue and decreased appetite occurred in <5% of patients. Two patients on ADI-PEG 20 had ≥grade 3 anaphylactic reaction. Death rate within 30 days of end of treatment was 15.2% on ADI-PEG 20 versus 10.4% on placebo, none related to therapy. Post hoc analyses of arginine assessment at 4, 8, 12 and 16 weeks, demonstrated a trend of improved OS for those with more prolonged arginine depletion. Conclusion: ADI-PEG 20 monotherapy did not demonstrate an OS benefit in second line setting for HCC. It was well tolerated. Strategies to enhance prolonged arginine depletion and synergize the effect of ADI-PEG 20 are underway. Clinical Trial number: www.clinicaltrials.gov (NCT 01287585).

Intravenous colchicine for low-back pain: a double-blind study.

Colchicine, a drug used for centuries in the treatment of gout, has been reported to be effective for low-back pain due to disc disorders. A prospective, randomized, double-blind study evaluating the therapeutic effect of intravenous colchicine was conducted in a group of patients with low-back pain with symptoms originating less than 6 months previously. Each patient completed a questionnaire and a pain drawing. Laboratory studies including uric acid and sedimentation rate were performed, as was a detailed physical examination and lumbar thermography. All treatment parameters (including physical therapy, anti-inflammatory medications, and instructions) were constant except that each patient received either intravenous colchicine or intravenous saline. Results indicate a significant difference between the two groups, the intravenous colchicine group showing improvement in symptoms for a few hours or days over a 3-week course of treatment. However, the relief was often of short duration.

A microtensiometer for the analysis of bioadhesive microspheres.

Bioadhesive polymer microspheres are potential vehicles for the delivery of bioactive agents to mucosal tissues. Bioadhesive delivery devices could improve drug absorption, enhance bioavailability, and increase patient compliance by minimizing dosing regimens. Identification of bioadhesive materials is the first phase in developing bioadhesive drug delivery systems. Additionally, quantification and analysis of the bioadhesive event are essential to successful development of a new generation of adhesive delivery systems. A unique, microbalance-based instrument was developed to analyze bioadhesive forces between polymer microspheres and mucosal tissue segments. A contact angle analyzer, with a custom-made physiologic tissue chamber, was linked to a computer via the serial port. Software was used to modify the microbalance operation to behave as a microtensiometer with a sensitivity of 0.1 microN. After mounting a microsphere and tissue segment in the balance and adjusting the experimental settings, the instrument performs a tensile experiment and automatically determines the following parameters: compressive deformation, peak compressive load, compressive work, yield point, deformation to yield, returned work, peak tensile load, deformation to peak tensile load, fracture strength, deformation to failure, and tensile work. Using this device the authors identified several bioadhesive materials ideally suited for orally-delivered, controlled-release systems. GI-transit studies in rats showed strong correlation between increased GI-residence time and strong bioadhesive interactions.

Clinicopathologic correlation of argon-laser photocoagulation of an idiopathic choroidal neovascular membrane in the macula.

The clinicopathologic features of an idiopathic choroidal neovascular membrane treated by argon laser photocoagulation are presented. The area of treatment is characterized microscopically by a proliferation of fibrocytes and retinal pigment epithelial cells. No choroidal vascular membrane was identified. Capillaries were present in the scar but not internal to the level of Bruch's membrane.

Spinal cord injury without osseous spine fracture.

Sixteen patients with spinal cord injury without osseous spine fracture and 55 patients with spinal cord injury with osseous spine fracture aged from birth through 18 years were studied. Those without osseous fracture were younger (mean age 6 years) than were those with osseous fracture (mean age 16 years). Extravasation of myelographic dye from the spinal canal was a poor prognostic sign. All three in the group with this finding without osseous fracture had complete spinal cord lesions. Those without osseous fracture should be followed for the development of late spinal deformity that may require orthotic support or surgical stabilization.