Robert Feldman

BACKGROUND: Androgen-deprivation therapy is well-established for treating prostate cancer but is associated with bone loss and an increased risk of fracture. We investigated the effects of denosumab, a fully human monoclonal antibody against receptor activator of nuclear factor-kappaB ligand, on bone mineral density and fractures in men receiving androgen-deprivation therapy for nonmetastatic prostate cancer. METHODS: In this double-blind, multicenter study, we randomly assigned patients to receive denosumab at a dose of 60 mg subcutaneously every 6 months or placebo (734 patients in each group). The primary end point was percent change in bone mineral density at the lumbar spine at 24 months. Key secondary end points included percent change in bone mineral densities at the femoral neck and total hip at 24 months and at all three sites at 36 months, as well as incidence of new vertebral fractures. RESULTS: At 24 months, bone mineral density of the lumbar spine had increased by 5.6% in the denosumab group as compared with a loss of 1.0% in the placebo group (P<0.001); significant differences between the two groups were seen at as early as 1 month and sustained through 36 months. Denosumab therapy was also associated with significant increases in bone mineral density at the total hip, femoral neck, and distal third of the radius at all time points. Patients who received denosumab had a decreased incidence of new vertebral fractures at 36 months (1.5%, vs. 3.9% with placebo) (relative risk, 0.38; 95% confidence interval, 0.19 to 0.78; P=0.006). Rates of adverse events were similar between the two groups. CONCLUSIONS: Denosumab was associated with increased bone mineral density at all sites and a reduction in the incidence of new vertebral fractures among men receiving androgen-deprivation therapy for nonmetastatic prostate cancer. (ClinicalTrials.gov number, NCT00089674.)

Three hundred and seventy-six subjects with advanced Parkinson's disease participated in a prospective, double-blind placebo-controlled study of the dopamine agonist pergolide mesylate as an adjunct to Sinemet. At 6 months, patients randomized to pergolide had a statistically significant improvement in total Parkinson's score, scores of activities of daily living, motor function, number of "off" hours, Hoehn and Yahr stage, and numerous parameters of parkinsonian function including bradykinesia, rigidity, gait, and dexterity. This benefit was obtained with the addition of a mean dose of 2.94 mg of pergolide, which permitted a 24.7% reduction in dose of levodopa. Adverse reactions were, for the most part, mild, reversible, and not of major clinical significance. No significant cardiac or electrocardiographic abnormalities were detected. This study demonstrates that pergolide mesylate, as an adjunct to levodopa, is an effective antiparkinsonian agent that provides clinical improvement while permitting a reduction in levodopa dose.

Although irradiation for the treatment of acromegaly was introduced more than fifty years ago (1, 4), there is still lack of complete agreement on the selection of responsive cases and on optimal technic. Irradiation was first used for pituitary adenomas because of the high mortality and morbidity associated with surgical procedures on the hypophysis. Subsequently, its value was proved and it remains the procedure of choice except in patients with large tumors of long standing or with visual field defects sufficiently critical to require immediate decompression (2). In the latter group radiation is generally administered only after partial hypophysectomy for decompression. At present, external gamma or roentgen rays are commonly used, but surface applications or implants of radium (5), radioyttrium (8), colloidal chromic phosphate (10), and even the collimated proton beam from the synchrotron (7) have been employed. Over the years, two technics of radiation therapy for pituitary adenoma have evolved. The first was the “interval” technic, in which a pituitary dose varying from a few hundred to one or two thousand roentgens was given, and, after a period of observation of several weeks or months, the course of therapy was repeated if necessary. This approach was based on (a) the observation that certain patients do not require a larger dose, and (b) the concept that overfunction probably occurs cyclically and is logically treated by cyclic therapy. The alternate or “single-course” technic recognizes the uncertainty in dose necessary to control acromegaly in a particular patient and assumes that the disease will be more readily controlled by administration of an initial dose as high as is consistent with safety to the peripituitary structures (6). In addition to the loss of time entailed by the multipledose technic, the total dose with several courses of therapy frequently exceeds that of the larger single course and may, in the end, result in greater damage to surrounding normal structures. The available published data, summarized by Buschke (2), suggest that the single intense course produces the more satisfactory results. This paper presents the experiences gained between January 1942 and March 1959 at the University of California Hospitals, San Francisco, with radiation therapy for acromegaly in 37 patients. During this time the diagnosis of acromegaly was made in a total of 65 patients. Seven cases were discarded because of inadequate information. Of the remaining 58, 9 were considered quiescent and required only supportive or symptomatic treatment; 2 patients had hypophysectomy for marked visual impairment and 1 was treated by estrogen therapy alone.

Radiation therapy along with chemotherapy and surgery remain the main cancer treatments. Radiotherapy can be applied to patients externally (external beam radiotherapy) or internally (brachytherapy and radioisotope therapy). Previously, nanoencapsulation of radioactive crystals within carbon nanotubes, followed by end-closing, resulted in the formation of nanocapsules that allowed ultrasensitive imaging in healthy mice. Herein we report on the preparation of nanocapsules initially sealing “cold” isotopically enriched samarium (152Sm), which can then be activated on demand to their “hot” radioactive form (153Sm) by neutron irradiation. The use of “cold” isotopes avoids the need for radioactive facilities during the preparation of the nanocapsules, reduces radiation exposure to personnel, prevents the generation of nuclear waste, and evades the time constraints imposed by the decay of radionuclides. A very high specific radioactivity is achieved by neutron irradiation (up to 11.37 GBq/mg), making the “hot” nanocapsules useful not only for in vivo imaging but also therapeutically effective against lung cancer metastases after intravenous injection. The high in vivo stability of the radioactive payload, selective toxicity to cancerous tissues, and the elegant preparation method offer a paradigm for application of nanomaterials in radiotherapy.

To determine safe and effective placements of the arthroscope, 14 freshly amputated ankle joint specimens were used for experimental diagnostic and operative procedures. Preoperatively, chondral and osteochondral lesions, articular defects, and loose bodies were created within the ankle joint. The following arthroscopic portals were investigated: anteromedial, anterocentral, anterolateral, posteromedial, and posterolateral. Overlapping of vision fields was noted with the three anterior portals. Optimum visualization of a lesion was obtained when the arthroscope was placed on the same side as the lesion. Lesions on the posterior aspect of the talar dome and within the posterior talar pouch required the posterior placement of the arthroscope for optimum visualization. The use of the anterocentral approach, with a 2.7-mm arthroscope yields good visualization of the anterior aspect of the joint, and very often, of the posterior compartment. Anatomic guidelines for the avoidance of neurovascular structures and the exact placement of the arthroscope in both anterior and posterior portals are presented and were specifically defined in two additional fresh ankle specimens.