CD169(+) macrophages mediate pathological formation of woven bone in skeletal lesions of prostate cancer.

Skeletal metastases present a major clinical challenge for prostate cancer patient care, inflicting distinctive mixed osteoblastic and osteolytic lesions that cause morbidity and refractory skeletal complications. Macrophages are abundant in bone and bone marrow and can influence both osteoblast and osteoclast function in physiology and pathology. Herein, we examined the role of macrophages in prostate cancer bone lesions, particularly the osteoblastic response. First, macrophage and lymphocyte distributions were qualitatively assessed in patient's prostate cancer skeletal lesions by immunohistochemistry. Second, macrophage functional contributions to prostate tumour growth in bone were explored using an immune-competent mouse model combined with two independent approaches to achieve in vivo macrophage depletion: liposome encapsulated clodronate that depletes phagocytic cells (including macrophages and osteoclasts); and targeted depletion of CD169(+) macrophages using a suicide gene knock-in model. Immunohistochemistry and histomorphometric analysis were performed to quantitatively assess cancer-induced bone changes. In human bone metastasis specimens, CD68(+) macrophages were consistently located within the tumour mass. Osteal macrophages (osteomacs) were associated with pathological woven bone within the metastatic lesions. In contrast, lymphocytes were inconsistently present in prostate cancer skeletal lesions and when detected, had varied distributions. In the immune-competent mouse model, CD169(+) macrophage ablation significantly inhibited prostate cancer-induced woven bone formation, suggesting that CD169(+) macrophages within pathological woven bone are integral to tumour-induced bone formation. In contrast, pan-phagocytic cell, but not targeted CD169(+) macrophage depletion resulted in increased tumour mass, indicating that CD169(-) macrophage subset(s) and/or osteoclasts influenced tumour growth. In summary, these observations indicate a prominent role for macrophages in prostate cancer bone metastasis that may be therapeutically targetable to reduce the negative skeletal impacts of this malignancy, including tumour-induced bone modelling. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

How to critically appraise a clinical practice guideline.

PURPOSE: Clinical practice guidelines play a critical role in guiding the evidence-based clinical practice of urology. We describe a systematic approach to critical appraisal of urology guidelines. MATERIALS AND METHODS: Based on a focused clinical question derived from a clinical scenario, we identified a relevant clinical practice guideline that we critically appraised using the Users' Guide to the Medical Literature framework as to whether the results are valid, what are the results, and can they be applied to the care of an individual patient. RESULTS: A clinical practice guideline by the National Institute for Clinical Excellence on the use of sunitinib as the first line treatment for patients with metastatic renal cell carcinoma was identified. The guideline development process was found to be appropriately rigorous and included an explicit rating of the quality of evidence. The recommendations were clearly stated and appeared applicable to the specific patient in the clinical scenario. CONCLUSIONS: Clinical practice guidelines should be developed using rigorous evidence-based methodology. Urologists should have the skills and knowledge to critically appraise a guideline before applying it to the care of their patients.