The Prognosis Of Patients With Tumor-induced Osteomalacia Treated With Surgeries

BackgroundTumor-induced osteomalacia(TIO)is a rare bone disease and the most common form of acquired osteomalacia with about 500 reported cases worldwide.The cause of the disease is that the tumor in one part of the body secretes too much Fibroblast growth factor 23(FGF23),which causes severe symptoms such as decreased blood phosphorus,bone pain,bone deformity and pathological fracture.However,with the increase of diagnosis and treatment cases,it was found that some of the patients could not alleviate or relapse after surgery.There is currently a lack of research on the prognosis of TIO patients undergoing surgical treatment.Objective1.Systematic describe the outcomes of surgeries in patients with TIO.2.Find risk factors related with refractory outcomes.3.Find potential biomarkers to predict the outcomes of surgeries.4.Looking for possible mechanisms for refractory outcomes in tumors.Methods1.Subjects:Patients who were suspected of having TIO and underwent tumor excision surgery at Peking Union Medical College Hospital between January 1,2004 and January 31,2018,were retrospectively studied.According to the outcomes of surgeries,these patients were divided into refractory group,which consist of nonremission patients and recurrent patients,and recovery group.2.Data collection:Clinical information such as general condition,clinical symptoms,signs,tumor distribution,surgical treatment data,postoperative blood phosphorus transformation and other clinical information of the patients were collected,as well as auxiliary examination results such as blood biochemistry,bone metabolism indicators,localization imaging methods and pathological results of the patients,and serum FGF23 level was determined by enzyme-linked immunosorbent assay.3.Metabonomics:Preoperative serum was analyzed by untargeted metabolomics and serum metabolites were determined by liquid chromatography-mass spectrometry(LC-MS).4.Statistical analysis:The clinical characteristics of the recovery group and the refractory group were compared,the correlation and regression analysis were used to analyze the relationship between each factor and the refractory outcome,and the Receiver operating characteristic curve(ROC curve)was used to find the indicators and pointcut used to predict the surgical outcome.Bioinformatics analysis includes principal component analysis,orthogonal partial least square method-mutiny analysis,hierarchical clustering analysis and metabolic pathway analysis.Results1.A total of 230 TIO patients were included in the study.After the initial operation,26(11.3%)patients had no remission,16(7.0%)had recurrence,and the remaining 188(81.7%)had complete recovery,with an overall refractory rate of 18.3%.After multiple operations,another 7 patients with refractory disease completely recovered,and the final recovery rate of surgical treatment was 88.3%.The median time of recurrence was 33 months.2.Refractory patients had a younger onset age(34.6±12.6 vs.38.9±12.0 years,p=0.041)and a higher proportion of female patients(female/male ratio:25/17 vs.77/111,p=0.029),the preoperative blood phosphorus level was lower(0.44±0.13 vs.0.50±0.11 mmol/L,p=0.002),and the preoperative FGF23 level was higher[1342.07(386.08,2030.73)vs.323.75(190.33,541.72)pg/ml,p<0.001].3.The Area under the ROC curve(AUC)of different indicators used to predict outcomes was 0.6465 for preoperative phosphate(95%confidence interval 0.5397?0.7534,p=0.003),0.7656 for preoperative FGF23(95%confidence interval 0.6298?0.9014,p=0.0003),0.7839 for FGF23/phosphate(95%confidence interval 0.6521?0.9156).P<0.0001),and 0.8643 for FGF23 on the first day after surgery(95%confidence interval 0.7361-0.9925,p<0.0001).4.About half of the TIO tumors were distributed in the lower limbs,the proportion of head and neck tumors in refractory TIO tumors was significantly lower than that in the recovery group(5/42,11.9%vs.62/188,33.0%,p<0.001),and the proportion of spinal tumors in refractory TIO tumors was significantly higher than that in the recovery group(7/42,16.7%vs.2/188,1.1%,p<0.001).The proportion of TIO tumors in the spine with refractory outcomes was significantly higher than that in the head and neck,upper limbs,trunk and viscera(p<0.001).5.The number of tumors involved bone tissue was similar to that bone tissue not involved,and the proportion of refractory outcomes in bone tissue involved tumors was significantly higher than that in bone tissue not involved tumors(32.7%vs,7.0%,p<0,001).There were 15 malignant tumors in total,and the proportion of refractory outcome of malignant tumors was significantly higher than that of benign tumors(46.3%vs.16.3%,p=0.006).6.In the multivariate regression analysis,female gender,spinal tumor,tumor involved bone tissue,malignant tumor,low preoperative blood phosphorus level and high preoperative FGF23 were risk factors for refractory outcome.7.The model established by OPLS-DA could not distinguish refractory TIO patients from the recovery group,but the serum L-Pipecolic acid,2-Dodecylbenzenesulfonic acid and 2-deoxypyranegalactose levels in refractory TIO patients were significantly lower than those in the recovery group,and patients with different surgical outcomes could be distinguished by these indicators.Conclusion1.We reported the largest TIO cohort to date and found that 80 percent of patients recovered with a single operation and nearly 90 percent recovered fully after multiple operations.2.Female gender,spinal tumor,tumor involved bone tissue,malignant tumor,low preoperative blood phosphorus level and high preoperative FGF23 were risk factors for refractory outcome.3.In clinical practice,the selection of appropriate FGF23 or FGF23/blood phosphorus ratio cut point to predict the outcome is expected to enable some refractory patients to obtain more appropriate treatment and more cautious follow-up strategies.4.L-Pipecolic acid,2-Dodecylbenzenesulfonic acid and 2-deoxypyranegalactose are expected to be more accurate indicators for predicting the outcome of surgery in the future.The reduction of 2-Dodecylbenzenesulfonic acid and 2-deoxypyranegalactose may enhance the growth and invasion ability of TIO tumor,leading to refractory outcome.