Quantitative ELISA-like Immunohistochemistry In The Diagnosis Of Tumor-induced Osteomalacia And Evidence-based Medicine Analysis Of Non-interventional Risk Factors

Part Ⅰ:Tumor-induced osteoaalacia and Quantitative ELISA-like immunohistocheaistry in the diagnosis of the diseaseObjective:Tumor-induced osteomalacia (TIO) is a rare acquired paraneoplastic disorder and fibroblast growth factor23(FGF-23) plays a key role in its pathogenesis. This study was conducted to comprehensively describe the clinical, laboratory and pathological manifestations of the disease, and also to document a novel FGF-23detecting and quantifying procedure.Methods:14cases of diagnosed TIO or cases with typical clinical manifestations of TIO were retrieved from our institution.26non-TIO tumors which TIO tumors always misdiagnosed of were also included. We simplified the quantitative ELISA-like immunohistochemistry procedure on the slide and FGF-23level was measured by the procedure using formalin-fixed and paraffin-embedded tissues. The results were also compared with a previously reported FGF-23RT-PCR assay.Results:Summarized by the14included TIO cases, the clinical manifestations of TIO were a long-standing history of osteomalacia, hypophosphatemia and urinary phosphate wasting. The associated tumors were mostly benign phosphaturic mesenchymal tumor mixed connective tissue variant (PMTMCT) that could be located anywhere of the body and most of which could be localized by conventional examinations and octreotide scanning. After complete tumor removal, serum phosphate would return to normal level within3.5±1.8days and clinical symptoms would be resolved within several months. By the quantitative ELISA-like immunohistochemistry,13/14cases were identified and quantified of high FGF-23level (0.99±0.56, compared with the26non-TIO tumors of0.08±0.04, p<0.001,95%CI0.48-1.14). The results were also confirmed and even had superiority over the FGF-23RT-PCR assay using paraffin-embedded tissues.Conclusion:Since TIO was often delay-diagnosed or misdiagnosed, clinicians and pathologists should be aware of the disease of TIO and PMTMCT, respectively. The quantitative ELISA-like immunohistochemistry was a feasible and reproducible procedure to detect and quantify the high FGF-23level using formalin-fixed and paraffin-embedded biopsies or specimens. Part II:Evidence-based medicine analysis of non-interventional risk factorsObjective:Hip fractures are always associated with a high postoperative mortality, the preoperative predictors for mortality have neither been well identified nor well summarized. Major lower extremity surgeries are associated with a high postoperative VTE (venous thromboembolism) incidence. It is all recommended that these patients should be assessed preoperatively for the increased VTE risks. However, the risk factors have not been well identified. The recommended risk factors differred from each other among these guidelines and they were also not specificly recommended for major lower extremity surgery patients either. This systematic review and meta-analysis was performed to identify the preoperative non-interventional predictors for mortality in hip fracture patients, and was also performed to identify the preoperative non-interventional predictors of VTE for THA, TKA and hip fracture patients.Methods:Non-interventional studies were searched in Pubmed, Embase, Cochrane central database (All to February26th,2011). Only prospective studies and retrospective studies with prospective collected data were included. Qualities of included studies were assessed by a standardized scale previous reported for observational studies. The effects of individual studies were combined with the study quality score using a previous reported model of best-evidence synthesis. The Hazard Ratios of strong evidence predictors were combined only by high quality studies in which risk factors were identified.Results:Preoperative risk factor analysis of mortality after hip fracture surgery:75studies involving64,316patients were included, the overall inpatient or one month mortality was13.3%,3-6months was15.8%,1year24.5%and2years34.5%; there were strong evidence for12mortality predictors, including advanced age, male gender, nursing home or facility residence, poor preoperative walking capacity, poor activities of daily living, higher ASA grading, poor mental state, multiple comorbidities, dementia or cognitive impairment, diabetes, cancer and cardiac disease; we also identified7moderate evidence and12limited evidence mortality predictors, and only the race was identified as the conflicting evidence predictor. VTE risk factor analysis for the major lower extremity surgery patients:of the47included studies involving97,082patients, the incidence of total VTE was25.8%, symptomatic DVT was1.7%and PE0.6%; by best-evidence, we had identified2strong evidence predictors including advanced age and TKA (versus THA) surgery, as well as5moderate evidence predictors including factor V Leiden mutation or APC resistance, history of previous thromboembolism,, impaired walking capacity, obesity and female gender; we also identified other12limited evidence predictors and2conflicting evidence predictors (including cardiovascular diseases and activated partial thromboplastin time).Conclusion:While there is no conclusive evidence of these preoperative predictors for mortality following hip fractures and preoperative predictors of VTE for patients undergoing THA, TKA and hip fracture surgery, special attention should be paid to the above strong and moderate evidence predictors. Further researches are still needed to evaluate these risk factors.