CSF-CN contributes to cancer-induced bone pain via the MKP-1-mediated MAPK pathway.

Pain is a major complication of cancer and significantly affects the quality of life. Cerebrospinal fluid-contacting nucleus (CSF-CN) has been reported to be involved in the development of neuropathic pain and inflammatory pain. However, whether CSF-CN contributes to cancer-induced bone pain (CIBP) remains unknown. In this study, we aimed to illustrate the role of CSF-CN in the pathogenesis of CIBP and identify its potential mechanism via the MKP-1-mediated MAPK pathway. The Walker 256 cancer cells were injected into the tibia cavity of female Sprague-Dawley rats to induce CIBP models. Intracerebroventricular injection of cholera toxin subunit B- saporin (CB-SAP) was performed to "knockout" the CSF-CN. Morphine and LV-MKP-1 were applied. Mechanical and thermal hyperalgesia behaviors, double immunofluorescence staining and Western blot were conducted after CIBP induction. The results revealed that CIBP significantly reduced the mechanical withdrawal threshold and the thermal threshold. Double immunofluorescence staining revealed that c-Fos-positive neurons in CSF-CN were significantly higher in the CIBP group than that in the sham group. Targeted ablation of CSF-CN dramatically aggravated pain sensitivity. Moreover, MKP-1 was down-regulated in the CSF-CN after CIBP induction. Pharmacological intervention with morphine significantly ameliorated the mechanical and thermal hyperalgesia through reversing the down-expression of MKP-1 in the CSF-CN on day 14 after CIBP induction. Mechanically, overexpression of MKP-1 by LV-MKP-1 injection significantly relieved CIBP via inhibiting the expression of phosphorylated p38, which subsequently decreased the protein levels of Bax, cleaved caspase-3 and Iba-1, and reduced the mRNA levels of IL-1ß, TNF-α and IL-6 in CSF-CN. In conclusion, CSF-CN contributed to CIBP via regulating the MKP-1-mediated p38-MAPK pathway. Future therapy targeting the expression of MKP-1 in the CSF-CN may be a promising new choice.

Bone marrow aspirations and lumbar punctures in retinoblastoma at diagnosis: correlation with IRSS staging.

BACKGROUND: Few studies have suggested that routine bone marrow (BM) and cerebrospinal fluid (CSF) evaluation is not needed in all patients with retinoblastoma. Although the International Retinoblastoma Staging System was developed recently, there remain no clear stage-specific guidelines with regard to the need for BM and CSF evaluations as part of the metastatic workup for patients with retinoblastoma. METHODS: This is a retrospective study analyzing results of CSF cytology and BM evaluation at presentation/diagnosis in patients with retinoblastoma registered at our center from June, 2003 to June, 2009. Only cases with both BM biopsy and lumbar puncture were included. RESULTS: Of the 259 evaluable patients, 18 (7%) were positive for metastasis either in CSF and/or BM. Although 7 of these had overt metastasis at presentation (stage IV), 1 belonged to stage II and 10 to stage IIIa. No stage 0 or I patient tested positive despite presence of histopathologic high-risk factors. CONCLUSIONS: This is the largest study evaluating the role of metastatic workup in patients with retinoblastoma at presentation. We conclude that CSF and BM evaluation is not required in patients with stage 0 and I retinoblastoma at presentation. No definitive recommendation could be made for stage II patients; while stage III and IV patients must certainly be evaluated.