Giant cell tumor of bone (GCTB) is a rare primary bone tumor that primarily affects young adults, but can be seen in children. The primary modality of treatment is surgical resection; however, this is not always possible given the location and extent of the neoplasm. Recent developments in the understanding of the underlying molecular pathogenesis of disease have pointed to interactions between the stromal component producing receptor activator of nuclear factor-kappaB (RANK) and RANK-ligand (RANKL) causing the formation of osteoclast-like giant cells that drive bone destruction. The development of a monoclonal humanized antibody to RANKL, denosumab, has been shown to reduce skeletal-related events from osteoporosis and from bony metastases from solid tumors. Recent phase II clinical trials with denosumab in skeletally mature adolescents over age 12 years and adults with GCTB, have shown both safety and efficacy, leading to its accelerated US FDA approval on 13 June 2013. In children who are skeletally immature, safety and efficacy has not been established, and there has been only published anecdotal use.
Absidiosis was produced experimentally in rabbits by intravenous inoculation of 1.4 x 10(5) spores of Absidia corymbifera. Infected rabbits exhibited a rise in body temperature, anorexia, dullness, listlessness, diarrhoea, occasional blindness, convulsions and death in some cases. Mortality occurred mainly between 6 to 9 days post infection (DPI) and overall mortality was 50 per cent during the three week observation period. No significant difference was observed in erythrocytic indices viz., Hb, PCV, TEC in control and infected rabbits. However, erythrocyte sedimentation rate was considerably increased in the infected rabbits. A state of leucocytosis was observed in the infected rabbits, which was due to increase in the relative percentage of neutrophils and decrease in lymphocytes. There was a significant increase in blood urea nitrogen concentrations of infected rabbits from 3 to 14 DPI as compared to controls, but serum creatinine values were not significantly altered at any stage of infection. The cause of death was attributed to kidney failure and uraemia in infected rabbits. The rabbit was found to be a suitable model for the study of absidiosis.
2550 Background: Aldoxorubicin is a novel drug that covalently binds to albumin in the circulation with release in low pH environments. Preclinical studies in pancreatic and ovarian tumor xenograft models demonstrated that aldoxorubicin plus doxorubicin administered at 50% of their MTD provided complete and prolonged tumor remission in these models with less toxicity than each drug administered at their MTD. We evaluated the toxicity profile of a fixed dose of doxorubicin and escalating doses of aldoxorubicin in subjects with advanced solid tumors. Methods: Phase 1b open label, dose-escalation study of aldoxorubicin administered at either 175, 240 or 320 mg/m2 (130, 180, or 240 mg/m2 doxorubicin equivalents) iv + 35 mg/m2doxorubicin iv, both on Day 1 of 21 day cycles, for up to 8 cycles. The MTD is the dose level immediately below where 2/6 subjects experience a dose limiting toxicity (DLT) , or the maximum dose of 320 mg/m2aldoxorubicin. Additional subjects may be enrolled at the MTD to provide more safety data. Results: 10 subjects have been treated as of January 21, 2013. No DLT was observed and the MTD was defined as 320 mg/m2 aldoxorubicin and 35 mg/m2 doxorubicin iv administered on Day 1 of 21 day cycles. A median of 4.5 cycles have been received. 3/10 subjects were terminated due to either progressive disease (2) or death (1). No subject was terminated due to an adverse event. Grade 3 or 4 neutropenia was seen at all dose levels (8/10 subjects). 4/10 subjects exhibited grade 3 or 4 thrombocytopenia and 3/10 subjects had grade 3 or 4 anemia. Neutropenic fever occurred in 3/10 subjects. Other grade 3/4 adverse events seen in 2 or fewer subjects included fatigue, increased liver enzymes and dehydration. No significant mucositis or cardiotoxicity was observed. At this time the best response has been stable disease in 6/10 subjects and a partial response in 1 subject (malignant fibrous histiocytoma). Conclusions: The combination of aldoxorubicin (320 mg/m2)) + doxorubicin (35 mg/m2) can be safely administered to subjects with solid tumors. Hematologic toxicity is common and can be controlled with growth factors. The dose of aldoxorubicin is 90% of the MTD of aldoxorubicin administered as a single agent. Thus, doxorubicin does not appear to add to the toxicity of this combination. Clinical trial information: NCT01673438.
Intravenous inoculation of young rabbits with 1.4 x 10(5) spores ml-1 of Absidia corymbifera produced gross and microscopic changes principally in the kidneys. Grossly, there was congestion, haemorrhages and greyish-white necrotic foci giving a mottled appearance to the kidneys. Microscopically, besides congestion and haemorrhages, there was a granulomatous reaction characterized by a central necrotic mass containing mycelium surrounded by a reactive zone of neutrophils, lymphocytes, a few macrophages and giant cells. Fibrous tissue proliferation was also present. Characteristic dichotomously branched non-septate fungal hyphae could be demonstrated in the sections of kidneys up to 14 days of infection. In one rabbit, which had died on the 8th day, small granulomatous lesions with fungal hyphae were noticed in the liver's parenchyma.
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