Use of topical misoprostol to reduce radiation‐induced mucositis: Results of a randomized,double‐blind,placebo‐controlled trial

Radiation‐induced mucositis is an acute reaction of the mucosa of patients undergoing head and neck radiotherapy. It can have debilitating and dose‐limiting consequences. There is no consensus on an accepted intervention that significantly reduces its severity. Misoprostol is a synthetic prostaglandin E₁ analogue, with properties of a mucosal cytoprotectant. We designed a randomized, double‐blind, placebo‐controlled trial of misoprostol in patients with head and neck cancer. The aim of this study was to determine if topical misoprostol was effective in reducing the severity of radiation‐induced mucositis in patients receiving radical dose radiotherapy. The effect of this intervention on a patient’s general well‐being was also investigated. The primary end‐point of the study was the incidence of Radiation Therapy Oncology Group grade 3 mucositis. Between 1999 and 2002, 83 patients were recruited into the study at Westmead and Nepean Hospitals, Sydney. Forty‐two patients were randomized to receive misoprostol and 41 to receive a placebo. Most patients received radiotherapy in the adjuvant setting (52 of the 83) and had either an oral cavity (42 of the 83) or an oropharyngeal (16 of the 83) cancer. We could not identify any significant difference in the incidence of severe mucositis based on whether patients were allocated to receive misoprostol or placebo. There was no significant difference in the mean area under the mucositis curve (13.2 vs 16.6; P = 0.1). Patients allocated to misoprostol did report slightly increased soreness (7.6 vs 6.9; P = 0.04) and a greater use of analgesics. However, this difference did not translate into a worse feeling of general well‐being as measured by a simple visual analogue scale (5.8 vs 5.2; P = 0.3). In conclusion, we were unable to identify a reduction in radiation‐induced mucositis in patients receiving misoprostol. There is a paucity of high‐level evidence on potentially useful interventions and a continued need for new and innovative research, incorporating quality‐of‐life measurements, in patients experiencing radiation‐induced mucositis.     

Therapeutic efficacy by recombinant human granulocyte/monocyte-colony stimulating factor on mucositis occurring in patients with oral and oropharynx tumors treated with curative radiotherapy

BACKGROUND: Previous studies suggested granulocyte-macrophage-colony stimulating factor (GM-CSF) might be beneficial for radiotherapy-induced mucositis. This trial examined the efficacy of GM-CSF in reducing mucositis of the oral cavity and/or oropharynx compared with conventional treatment. METHODS: Mucositis, documented by a five-grade scale, was defined in patients with tumors of the head-neck. Centers were allowed to use their own preferred fractionation regimen. Randomization to treatment was decided before radiotherapy. Treatment with GM-CSF 4 microg/kg/d subcutaneous, started when patients displayed a mucositis score > or = 1.5. RESULTS: Ninety-two patients entered the study according to intention-to-treat principle. Twenty did not reach a mucositis index of 1.5. Sixty-one patients were included in the statistical analysis. Forty-five percent of the patients randomized to receive GM-CSF had a significant reduction of the mucositis more than one grade compared to 9% of the conventional treated. CONCLUSIONS: In severe mucositis, GM-CSF is more effective than conventional treatment.     

Systemic administration of cholera toxin B subunit conjugated to horseradish peroxidase in the adult rat labels preganglionic autonomic neurons, motoneurons, and select primary afferents for light and electron microscopic studies

Retrograde and transganglionic labeling techniques are commonly used to visualize subsets of neurons and sensory afferent projections in the nervous system. These methods commonly require anesthesia and surgical methods. However, some tracers can also be administered systemically in awake animals, thus reducing risks associated with anesthesia and surgery and allowing for labeling of neuronal populations that are difficult to label with local tracer injections. Here, we demonstrate in the adult rat that intraperitoneal administration of cholera toxin subunit B conjugated to horseradish peroxidase labels preganglionic autonomic neurons, motoneurons, and the terminal projections of select primary afferents for both light and electron microscopic studies. We demonstrate also that this method can be combined with post-embedding immunogold labeling to detect amino acid transmitters in synaptic boutons.     

Anti-Interleukin-6 Therapy Decreases Hip Synovitis and Bone Resorption and Increases Bone Formation Following Ischemic Osteonecrosis of the Femoral Head

Legg-Calvé-Perthes disease (LCPD) is a juvenile form of ischemic femoral head osteonecrosis, which produces chronic hip synovitis, permanent femoral head deformity, and premature osteoarthritis. Currently, there is no medical therapy for LCPD. Interleukin-6 (IL-6) is significantly elevated in the synovial fluid of patients with LCPD. We hypothesize that IL-6 elevation promotes chronic hip synovitis and impairs bone healing after ischemic osteonecrosis. We set out to test if anti-IL-6 therapy using tocilizumab can decrease hip synovitis and improve bone healing in the piglet model of LCPD. Fourteen piglets were surgically induced with ischemic osteonecrosis and assigned to two groups: the no treatment group (n = 7) and the tocilizumab group (15 to 20 mg/kg, biweekly intravenous injection, n = 7). All animals were euthanized 8 weeks after the induction of osteonecrosis. Hip synovium and femoral heads were assessed for hip synovitis and bone healing using histology, micro-CT, and histomorphometry. The mean hip synovitis score and the number of synovial macrophages and vessels were significantly lower in the tocilizumab group compared with the no treatment group (p < .0001, p = .01, and p < .01, respectively). Micro-CT analysis of the femoral heads showed a significantly higher bone volume in the tocilizumab group compared with the no treatment group (p = .02). The histologic assessment revealed a significantly lower number of osteoclasts per bone surface (p < .001) in the tocilizumab group compared with the no treatment group. Moreover, fluorochrome labeling showed a significantly higher percent of mineralizing bone surface (p < .01), bone formation rate per bone surface (p < .01), and mineral apposition rate (p = .04) in the tocilizumab group. Taken together, tocilizumab therapy decreased hip synovitis and osteoclastic bone resorption and increased new bone formation after ischemic osteonecrosis. This study provides preclinical evidence that tocilizumab decreases synovitis and improves bone healing in a large animal model of LCPD. © 2020 American Society for Bone and Mineral Research (ASBMR).