Validation of a Diagnostic Model to Differentiate Multiple Myeloma from Bone Metastasis.

Purpose: A diagnostic model to differentiate multiple myeloma (MM) from bone metastasis (BM) in patients with destructive bone lesions (MM-BM DDx) was developed to promote timely and appropriate referral of patients with MM to hematologists. External validation has never been conducted. This study aims to externally validate the performance of the MM-BM DDx model. Patients and Methods: This multi-center external validation study was conducted using retrospective data of patients over 45 years old diagnosed with MM or BM at six university-affiliated hospitals in Thailand from 2016 to 2022. The MM-BM DDx development dataset, including patients from 2012 to 2015, was utilized during external validation. Diagnostic indicators for MM included in the MM-BM DDx model are serum creatinine, serum globulin, and serum alkaline phosphatase (ALP). MM and BM diagnosis was based on the documented International Classification of Diseases 10th Revision codes. Model performance was evaluated in terms of discrimination, calibration, and accuracy. Results: A total of 3018 patients were included in the validation dataset (586 with MM and 2432 with BM). Clinical characteristics were similar between the validation and development datasets. The MM-BM DDx model's predictions showed an AUC of 0.89 (95% CI, 0.87, 0.90). The predicted probabilities of MM from the model increased concordantly with the observed proportion of MM within the validation dataset. The estimated sensitivity, specificity, and LR for each odds class in the validation dataset were similar to those of the development dataset. Conclusion: The discriminative ability and calibration of the MM-BM DDx model were found to be preserved during external validation. These findings provide support for the practical use of the MM-BM DDx model to assist clinicians in identifying patients with destructive bone lesions who are likely to have MM and enable them to arrange timely referrals for further evaluation by hematologists.

Characterization of Cell-Free DNA Size Distribution in Osteosarcoma Patients.

PURPOSE: Cell-free DNA (cfDNA) analysis is a powerful tool for noninvasively predicting patient outcomes. We analyzed the size distribution of cfDNA and assessed its prognostic and diagnostic values in an osteosarcoma cohort. EXPERIMENTAL DESIGN: The fragment size distribution and level of cfDNA were analyzed in 15 healthy donors and 50 patients with osteosarcoma using automated capillary electrophoresis. The prognostic performance of cfDNA size analysis was assessed using univariate and multivariable analyses. By performing whole-genome sequencing of matched cfDNA and osteosarcoma tissue samples, we investigated the correlation between the size and mutation profiles of cfDNA and the mutation concordance between cfDNA and paired tissue tumors. RESULTS: The size of cfDNA fragments in patients with osteosarcoma was significantly shorter than in healthy donors, with the integrative analysis of size distribution and level of cfDNA achieving a high specificity and sensitivity of 100%. The short cfDNA fragment (150-bp cut-off) was an independent prognostic predictor in this osteosarcoma cohort [HR, 9.03; 95% confidence interval (CI), 1.13-72.20; P = 0.038]. Shortened cfDNA fragments were found to be a major source of mutations. Enrichment of cfDNA fragments with less than or equal to 150 bp by in silico size selection remarkedly improved the detection of copy-number variation signals up to 2.3-fold when compared with total cfDNA, with a higher concordance rate with matched osteosarcoma tissue. CONCLUSIONS: This finding demonstrated the potential of cfDNA size profiling in the stratification of poor prognostic patients with osteosarcoma. The short fragments of cfDNA are a promising source for boosting the detection of significant mutations in osteosarcoma. See related commentary by Weiser et al., p. 2017.

Performance of the Matsumiya scoring system in cervical cancer patients with bone metastasis: an external validation study.

BACKGROUND: Accurate prognostic prediction of survival in cervical cancer patients with bone metastasis is important for treatment planning. We aimed to externally validate the Matsumiya scoring system using external patient data. METHODS: We collected a retrospective cohort of patients with cervical cancer diagnosed with bone metastasis at Chiang Mai University Hospital from 1st January 2007 to 31st December 2016. The Matsumiya score was composed of 5 predictors, including the presence of extraskeletal metastasis, ECOG performance status, history of previous chemo- or radiotherapy, the presence of multiple bone metastasis, and bone metastasis-free interval < 12 months. Harrell's C-statistics and score calibration plots were used to evaluate the score performance. We also reconstructed the development study to estimate apparent performance values for comparison during external validation. RESULTS: A total of 124 cervical cancer patients with bone metastasis were included in this study. The 13-, 26-, and 52-week survival probabilities in the validation study were 70.1%, 50.5%, and 25.7%, respectively. Several differences were identified between development and validation studies regarding clinical characteristics, case-mix, and predictor-outcome associations. Harrell's C-statistics in the development and validation study were 0.714 and 0.567. The score showed poor agreement between the observed and the predicted survival probabilities in the validation study. Score reweighting and refitting showed only modest improvement in performance. CONCLUSION: A prognostic scoring system by Matsumiya et al. performed poorly in our cohort of Thai cervical cancer patients with bone metastasis. We suggested that the score should be sufficiently updated before being used.

A windows technique for sustentaculum tali screw fixation using the sinus tarsi approach for calcaneal fractures: a cadaveric study.

INTRODUCTION: The minimally invasive approach for displaced intra-articular calcaneal fractures is significantly reducing postoperative wound complications. One minimally invasive method, the sinus tarsi approach (STA) has been increasingly widely used. STA is, however, challenging due to its technical demands and the risk of injury to the sural nerve (SN). The purpose of this study was to identify the SN and its branches including their anatomical relationship to the STA as well as to describe an anatomical windows technique for STA including determination of the safe angle for screw insertion into the sustentaculum tali fragment. METHODS: Thirty-two adult cadaveric legs were disarticulated at the knee and unpaired. STA was performed on each specimen. The anatomy and distribution of the sural nerve and its branches were identified in relation to the incision. Three surgical windows were identified and selected. Kirshner wires were inserted in pairs via each of the windows towards the center of the sustentaculum tali. The safe angle for wire insertion in relation to the SN or its branches was then measured as well as the appropriate intraoperative drilling angle. RESULTS: The plantar branch presented in the distal window in none of the samples, while the dorsal branches presented in 37.5% and the main SN presented in only 6.25%. In the middle window, the dorsal branch presented most often (43.75%) followed by the plantar branch (25.00%) and the SN (21.88%). In the proximal window, the SN presented in 100% of the samples, while the dorsal branch presented in none and the plantar branch presented in about 15.63% of the specimens. All three windows had their own acceptable average angle for screw insertion towards the sustentaculum tali. CONCLUSIONS: The distal window is the safest for surgical approach and for calcaneal surgery screw fixation in terms of avoiding sural nerve injury. In addition, that window provides a wide working angle for screw fixation.

External Validation of the Individualized Prediction of Breast Cancer Survival (IPBS) Model for Estimating Survival after Surgery for Patients with Breast Cancer in Northern Thailand.

The individualized prediction of breast cancer survival (IPBS) model was recently developed. Although the model showed acceptable performance during derivation, its external performance remained unknown. This study aimed to validate the IPBS model using the data of breast cancer patients in Northern Thailand. An external validation study was conducted based on female patients with breast cancer who underwent surgery at Maharaj Nakorn Chiang Mai hospital from 2005 to 2015. Data on IPBS predictors were collected. The endpoints were 5-year overall survival (OS) and disease-free survival (DFS). The model performance was evaluated in terms of discrimination and calibration. Missing data were handled with multiple imputation. Of all 3581 eligible patients, 1868 were included. The 5-year OS and DFS were 85.2% and 81.9%. The IPBS model showed acceptable discrimination: C-statistics 0.706 to 0.728 for OS and 0.675 to 0.689 for DFS at 5 years. However, the IPBS model minimally overestimated both OS and DFS predictions. These overestimations were corrected after model recalibration. In this external validation study, the IPBS model exhibited good discriminative ability. Although it may provide minimal overestimation, recalibrating the model to the local context is a practical solution to improve the model calibration.

Clinical Implication of Circulating Tumor Cells Expressing Epithelial Mesenchymal Transition (EMT) and Cancer Stem Cell (CSC) Markers and Their Perspective in HCC: A Systematic Review.

Circulating tumor cells (CTCs) play a key role in hematogenous metastasis and post-surgery recurrence. In hepatocellular carcinoma (HCC), CTCs have emerged as a valuable source of therapeutically relevant information. Certain subsets or phenotypes of CTCs can survive in the bloodstream and induce metastasis. Here, we performed a systematic review on the importance of epithelial-mesenchymal transition (EMT)-CTCs and circulating cancer stem cells (CCSCs) in metastatic processes and their prognostic power in HCC management. PubMed, Scopus, and Embase databases were searched for relevant publications. PRISMA criteria were used to review all studies. Twenty publications were eligible, of which 14, 5, and 1 study reported EMT-CTCs, CCSCs, and both phenotypes, respectively. Most studies evaluated that mesenchymal CTCs and CCSCs positivity were statistically associated with extensive clinicopathological features, including larger size and multiple numbers of tumors, advanced stages, micro/macrovascular invasion, and metastatic/recurrent disease. A preliminary meta-analysis showed that the presence of mesenchymal CTCs in pre- and postoperative blood significantly increased the risk of early recurrence. Mesenchymal-CTCs positivity was the most reported association with inferior outcomes based on the prognosis of HCC recurrence. Our finding could be a step forward, conveying additional prognostic values of CTC subtypes as promising biomarkers in HCC management.

Descriptive epidemiology of soft tissue sarcomas and gastrointestinal stromal tumors in Thailand.

This study aimed to analyze burden of STS and GIST in population and survival rate which represented the current situation of treatment in Thailand. The data was collected from five population-based cancer registries around the country for the period 2001 through 2015. The Segi world standard population was used to calculated age-standardized incidence rates (ASR). Standardized rate ratios (SRR) were used to compare populations. Joinpoint Trend Analysis was used to assess changes in incidence. STATA was used to examine patient survival rates. During the study period, 4080 cases of STS and 457 cases of GIST were reported. The ASR of STS and GIST was 2.14/100,000 person-years and 0.22/100,000 person-years, respectively. The most common histological types of STS were unspecified sarcoma (24.8%), leiomyosarcoma (19.0%) and liposarcoma (11.4%). The overall ASR of STS in Thailand was relatively low compared to Western countries. The five-year survival rate was 62.6% for STS and 63.4% for GIST, which was comparable to the rates reported in other countries. This is the first report of STS and GIST from PBCRs in Thailand. Based on current healthcare service, an overall survival rates of STS and GIST are comparable to those reported from others.

Osteosarcoma-Specific Genes as a Diagnostic Tool and Clinical Predictor of Tumor Progression.

A liquid biopsy is currently an interesting tool for measuring tumor material with the advantage of being non-invasive. The overexpression of vimentin and ezrin genes was associated with epithelial-mesenchymal transition (EMT), a key process in metastasis and progression in osteosarcoma (OS). In this study, we identified other OS-specific genes by calculating differential gene expression using the Gene Expression Omnibus (GEO) database, confirmed by using quantitative reverse transcription-PCR (qRT-PCR) to detect OS-specific genes, including VIM and ezrin in the buffy coat, which were obtained from the whole blood of OS patients and healthy donors. Furthermore, the diagnostic model for OS detection was generated by utilizing binary logistic regression with a multivariable fractional polynomial (MFP) algorithm. The model incorporating VIM, ezrin, and COL5A2 genes exhibited outstanding discriminative ability, as determined by the receiver operating characteristic curve (AUC = 0.9805, 95% CI 0.9603, 1.000). At the probability cut-off value of 0.3366, the sensitivity and the specificity of the model for detecting OS were 98.63% (95% CI 90.5, 99.7) and 94.94% (95% CI 87.5, 98.6), respectively. Bioinformatic analysis and qRT-PCR, in our study, identified three candidate genes that are potential diagnostic and prognostic genes for OS.

An analysis of the incidence and survival rates of bone sarcoma patients in thailand: reports from population-based cancer registries 2001-2015.

BACKGROUND: Epidemiology data from population-based cancer registries (PBCR) can be very valuable in the development of health policy and for improving the quality of cancer control strategies. METHODS: This study analyzed the incidence of bone sarcomas in Thailand during 2001 - 2015 by analyzing data obtained from 5 PBCRs across country. Incidence rates per million person-years by sex, histological subtype, primary site and 5-year age group were calculated. Age-standardized incidence rates (ASR) were adjusted using the WHO's World Standard Population and comparisons between populations were done using standardized rate ratios (SRR). Incidence trends were evaluated using Joinpoint Trend Analysis. Survival rates were analyzed using STATA. RESULTS: The ASR of bone sarcomas in Thailand was 5.1/106 person-years, with an estimated 328 newly diagnosed bone sarcomas per year for the country overall. Osteosarcoma (52.5%), chondrosarcoma (18%), Ewing's sarcoma (11.6%), giant cell tumor (4.8%) and chordoma (4.7%) were the most common malignant bone tumors, representing 91.5% of all bone sarcomas. Bone sarcoma has a predilection for males (1.29:1) and an age-specific bimodal rate pattern closely related to the major histological subtypes, osteosarcoma. One- and five-year survival rates of Thai patients with bone sarcoma were 74% and 52%, respectively. Survival rates of bone sarcomas, particularly osteosarcoma, were lower than the rates reported from the United States, Europe and Japan. CONCLUSION: The lower overall survival rate of bone sarcoma represented the gap of bone sarcoma control program in Thailand. That indicates the need for improvement in health promotion, treatment process and chemotherapy for bone sarcoma patients in the future.

Adjunctive Topical Tranexamic Acid for Blood Salvage Does Not Reduce Postoperative Blood Loss Compared with Placebo in Patients Who Undergo Palliative Decompressive Spinal Metastasis Surgery: A Randomized Controlled Trial.

STUDY DESIGN: Randomized controlled trial. OBJECTIVE: To evaluate the efficacy of adjunctive topical tranexamic acid (tTXA) in reducing postoperative blood loss and packed red cell (PRC) transfusion in patients who underwent palliative decompressive spinal metastasis surgery for malignant epidural spinal cord compression. SUMMARY OF BACKGROUND DATA: Palliative decompressive spinal metastasis surgery is associated with massive postoperative blood loss and increased transfusion rate. tTXA reduces blood loss in traumatic or degenerative spinal surgery; however, the role of topical TXA in decompressive spinal metastasis surgery remains controversial. METHOD: A total of 65 patients who underwent palliative decompressive thoracolumbar spinal metastasis surgery were included in this study. In 33 patients, 1 g of tTXA (20 mL) was soaked in an absorbable gelatin sponge and placed lateral to the decompressive site. The remaining 32 patients in the control group received the same procedures with normal saline at the same volume, instead of TXA. All of the patients received standard 1 g intravenous TXA, just before initiating the operation. The primary outcome was postoperative blood loss, and the secondary outcomes were postoperative PRC transfusion and complications. RESULTS: No differences were found in postoperative blood loss between tTXA and placebo group (P50 778 mL [IQR 347, 1,122 mL] versus P50 490 mL [IQR 295, 920 mL]; P = 0.238). The number of patients requiring postoperative PRC transfusion were quite similar in tTXA and placebo groups (PRC transfusion in 15 patients [45.45%] versus 16 patients [50%]; P = 0.585). No complications related to TXA and absorbable gelatin sponge were observed. CONCLUSION: We do not recommend tTXA as an adjunctive treatment for patients undergoing decompressive spinal metastasis surgery since it does not provide additional benefit to prophylactic intravenous TXA in postoperative blood loss and transfusion rate.Level of Evidence: 2.

Reducible Nonunited Type II Odontoid Fracture with Atlantoaxial Instability: Outcomes of Two Different Fixation Techniques.

Displaced nonunited type II odontoid fracture can result in atlantoaxial instability, causing delayed cervical myelopathy. Both Magerl's C1-C2 transarticular screw fixation technique and Harms-Goel C1-C2 screw-rod segmental fixation technique are effective techniques to provide stability. This study aimed to demonstrate the results of two surgical fixation techniques for the treatment of reducible nonunited type II odontoid fracture with atlantoaxial instability. Medical records of patients with reducible nonunited type II odontoid fracture hospitalized for spinal fusion between April 2007 and April 2018 were reviewed. For each patient, specific surgical fixation, either Magerl's C1-C2 transarticular screw fixation technique augmented with supplemental wiring or Harms-Goel C1-C2 screw-rod fixation technique, was performed according to our management protocol. We reported the fusion rate, fusion period, and complications for each technique. Of 21 patients, 10 patients were treated with Magerl's C1-C2 transarticular screw fixation technique augmented with supplemental wiring, and 11 were treated with Harms-Goel C1-C2 screw-rod fixation technique. The bony fusion rate was 100% in both groups. The mean time to fusion was 69.7 (95%CI 53.1, 86.3) days in Magerl's C1-C2 transarticular screw fixation technique and 75.2 (95%CI 51.8, 98.6) days in Harms-Goel C1-C2 screw-rod fixation technique. No severe complications were observed in either group. Displaced reducible, nonunited type II odontoid fracture with cervical myelopathy should be treated by surgery. Both fixation techniques promote bony fusion and provide substantial construct stability.

IMPDH2 and HPRT expression and a prognostic significance in preoperative and postoperative patients with osteosarcoma.

Osteosarcoma is one of the most aggressive bone tumors in children and adolescents. Development of effective therapeutic options is still lacking due to the complexity of the genomic background. In previous work, we applied a proteomics-guided drug repurposing to explore potential treatments for osteosarcoma. Our follow-up study revealed an FDA-approved immunosuppressant drug, mycophenolate mofetil (MMF) targeting inosine-5'-phosphate dehydrogenase (IMPDH) enzymes, has an anti-tumor effect that appeared promising for further investigation and clinical trials. Profiling of IMPDH2 and hypoxanthine-guanine phosphoribosyltransferase (HPRT), key purine-metabolizing enzymes, could deepen understanding of the importance of purine metabolism in osteosarcoma and provide evidence for expanded use of MMF in the clinic. In the present study, we investigated levels of IMPDH2, and HPRT in biopsy of 127 cases and post-chemotherapy tissues in 20 cases of high-grade osteosarcoma patients using immunohistochemical (IHC) analysis. Cox regression analyses were performed to determine prognostic significance of all enzymes. The results indicated that low levels of HPRT were significantly associated with a high Enneking stage (P = 0.023) and metastatic status (P = 0.024). Univariate and multivariate analyses revealed that patients with low HPRT expression have shorter overall survival times [HR 1.70 (1.01-2.84), P = 0.044]. Furthermore, high IMPDH2/HPRT ratios were similarly associated with shorter overall survival times [HR 1.67 (1.02-2.72), P = 0.039]. Levels of the enzymes were also examined in post-chemotherapy tissues. The results showed that high IMPDH2 expression was associated with shorter metastasis-free survival [HR 7.42 (1.22-45.06), P = 0.030]. These results suggest a prognostic value of expression patterns of purine-metabolizing enzymes for the pre- and post-chemotherapy period of osteosarcoma treatment.

Development of a clinical diagnostic tool to differentiate multiple myeloma from bone metastasis in patients with destructive bone lesions (MM-BM DDx).

BACKGROUND: Most patients with destructive bone lesions undergo a comprehensive diagnostic procedure to ensure that proper treatment decisions are pursued. For patients with multiple myeloma, this can lead to delays in diagnosis and treatment initiation. This study was conducted to develop a diagnostic rule that could serve as a tool for early identification of multiple myeloma and promote timely referral of patients to haematologists. METHODS: The clinical prediction rule was developed using a retrospective case-series of patients with multiple myeloma (MM) and those with bone metastasis (BM) at Chiang Mai University Hospital from 2012 to 2015. Multivariable fractional polynomial logistic regression was used to derive a diagnostic model to differentiate between MM and BM patients (MM-BM DDx). RESULTS: A total of 586 patients (136 MM patients and 450 BM patients) were included. Serum creatinine, serum globulin, and serum alkaline phosphatase were identified as significant indicators for the differentiation of MM and BM patients. The MM-BM DDx model showed excellent discriminative ability [AuROC of 0.90 (95%CI 0.86 to 0.93)] and good calibration. CONCLUSIONS: This MM-BM DDx model could potentially allow for early myeloma diagnosis and improvement of overall prognosis. A prospective validation study is needed to confirm the accuracy of the MM-BM DDx model prior to its application in clinical practice.

Expression profiling of DNA methyl transferase I (DNMT1) and efficacy of a DNA-hypomethylating agent (decitabine) in combination with chemotherapy in osteosarcoma.

BACKGROUND: Abnormality in the DNA methylation process is one of the hallmarks of cancer. Emerging evidence strongly supports the idea that defects in DNA methyl transferases (DNMTs) are involved in tumor development and progression. This alteration has major effects at the transcription level of various cancer-associated genes. METHODS: Expression profiles of DNMT1 were investigated in fresh frozen tissues, patient-derived cells, and formalin-fixed paraffin-embedded tissues using immunoblotting and immunohistochemistry analysis. We also examined an anti-tumor effect of single DNA-hypomethylating agent (decitabine) and a combination of decitabine and chemotherapy in osteosarcoma cell lines. RESULTS: The results showed an overexpression of DNMT1 in most cases compared to normal cells and tissue samples. DNMT1 was also expressed at the same levels in paired primary cells derived from biopsy and post-chemotherapy tissues. Expression patterns of DNMT1 were examined in 77 osteosarcoma patients of whom 82% had positive DNMT1 with an IRS score > 0. Most of the cases expressed low to moderate levels of DNMT1 (IRS range 1-8, median = 2.0). Furthermore, we found that a combination of decitabine and chemotherapy had a synergistic effect in most of the tested osteosarcoma cells at a low dose therapeutic range of decitabine. CONCLUSIONS: Our study revealed DNMT1 expression patterns that indicated potential roles of DNMT1 in osteosarcoma transformation and progression. This finding also suggests the efficacy of a combination therapy of decitabine with chemotherapy for osteosarcoma treatment.

In vitro drug sensitivity (IDS) of patient-derived primary osteosarcoma cells as an early predictor of the clinical outcomes of osteosarcoma patients.

PURPOSE: Early prediction of clinical response to conventional chemotherapy is a significant factor in determining an overall treatment strategy for osteosarcoma. METHODS: Cells were extracted from treatment-naïve biopsies from 16 osteosarcoma patients who received a doxorubicin and cisplatin-based neoadjuvant chemotherapy regimen and their sensitivities to doxorubicin and cisplatin were measured as IC50 values. Associations of in vitro drug sensitivity (IDS) levels and clinical outcomes were examined. RESULTS: Primary osteosarcoma cells responded to doxorubicin and cisplatin with IC50 values of 0.088 ± 0.032 µM and 16.7 ± 8.5 µM, respectively. The patients with a non-metastatic phenotype and surviving patients showed significantly lower IC50 values for both drugs. ROC analysis defined the optimal IC50 cut-off values for doxorubicin (IDSdox) and cisplatin (IDScpt) as 0.05 µM (AUC 0.82) and 14 µM (AUC 0.87), respectively. Survival analysis found significantly longer disease-free survival (DFS, n = 14) and overall survival (OS, n = 16) times in the patients with low IDSdox (p = 0.0064 for DFS and p = 0.0102 for OS) and low IDScpt (p = 0.0204 for DFS and p = 0.0021 for OS). Interestingly, when the patients with low IDScpt and those with low IDSdox were combined (Group 1), significant associations with prolonged DFS (p = 0.0042, C-statistic 0.78) and OS (p = 0.0010, C-statistic 0.79) were found. In this cohort, histological response to neoadjuvant chemotherapy could predict only OS. CONCLUSIONS: This study indicates that IDS analysis could potentially be a practical, rapid, and reliable technique for predicting clinical outcomes. It could also be used to identify patients for whom conventional chemotherapy is most appropriate and, in the future, help advance personalized therapy.

Natural disease progression and novel survival prediction model for hepatocellular carcinoma with spinal metastases: a 10-year single-center study.

BACKGROUND: Individual prediction of life expectancy in patients with spinal metastases from hepatocellular carcinoma (HCC) is key for optimal treatment selection, especially when identifying potential candidates for surgery. Most reported prognostic tools provide categorical predictions, and only a few include HCC-related factors. This study aimed to investigate the natural progression of the disease and develop a prognostic tool that is capable of providing individualized predictions. METHODS: Patients with HCC-derived metastatic spinal disease were identified from a retrospective cohort of patients with spinal metastases who were diagnosed at Chiang Mai University Hospital between 2006 and 2015. Kaplain-Meier methods and log-rank tests were used to statistically evaluate potential factors. Significant predictors from the univariable analysis were included in the flexible parametric survival regression for the development of a prognostic prediction model. RESULTS: Of the 1143 patients diagnosed with HCC, 69 (6%) had spinal metastases. The median survival time of patients with HCC after spinal metastases was 79 days. In the multivariable analysis, a total of 11 potential clinical predictors were included. After backward elimination, four final predictors remained: patients aged > 60 years, Karnofsky Performance Status, total bilirubin level, and multifocality of HCC. The model showed an acceptable discrimination at C-statistics 0.73 (95% confidence interval 0.68-0.79) and fair calibration. CONCLUSION: Four clinical parameters were used in the development of the individual survival prediction model for patients with HCC-derived spinal metastases of Chiang Mai University or HCC-SM CMU model. Prospective external validation studies in a larger population are required prior to the clinical implication of the model.

Mycophenolic acid is a drug with the potential to be repurposed for suppressing tumor growth and metastasis in osteosarcoma treatment.

Our previous review of proteomics data showed that in osteosarcoma, some overexpressed proteins were targets of FDA-approved immunosuppressive and anti-arrhythmic drugs, including mycophenolate mofetil (MMF), ribavirin, leflunomide, azathioprine and digoxin. Here, these drugs were screened for growth inhibitory effects in human osteosarcoma cell lines, including MNNG/HOS, U2OS, SaOS-2, MG-63 and 143B cells. Only mycophenolic acid (MPA), an active metabolite of MMF, efficiently inhibited osteosarcoma cell growth with IC50 values of 0.46-7.3 µM; these values are in the therapeutic range for organ transplant patients. At a therapeutic dose (10 µM), MPA significantly inhibited colony formation, caused cell cycle arrest in the S phase, and induced apoptosis. Moreover, the in vitro invasion of osteosarcoma cells was reduced by MPA by inhibiting cell migration capability. The in vivo antitumor effect of MMF was determined in nude mice harboring 143B cell xenografts. Daily oral administration of 200 mg/kg/day MMF for 2 weeks significantly suppressed tumor growth in treated mice, achieving 57.4 ± 11.1% tumor growth inhibition. Compared with the vehicle group, the MMF group treated with 50-200 mg/kg/day for 3 weeks had a significant reduction in the number of lung metastatic nodules in a tail vein-lung metastasis model of 143B cells. MMF doses of 50, 100 and 200 mg/kg/day are approximately equivalent to the non-toxic doses of 0.25, 0.5 and 1 g/day in humans, respectively. These findings indicate that MPA/MMF can effectively control osteosarcoma tumor growth and metastasis. Thus, the potential to repurpose MPA/MMF for use in osteosarcoma chemotherapy is of great interest.

Endoplasmic reticulum protein 29 (ERp29) as a novel prognostic marker and tumor suppressor in osteosarcoma.

BACKGROUND: Diverse aberrancy in genetic background, protein profiling, and biological pathways have emerged as important factors hindering discovery of effective treatment of osteosarcoma. In a previous study, we used a proteomic approach to identify some osteosarcoma-related proteins by analysis of protein profiling in individual patients through primary cell culture. Endoplasmic reticulum protein 29 (ERp29) emerged as a protein of interest for further study since accumulating evidence suggests it has broad functions in tumorigenesis of different types of cancer. Importantly, until now no report on examination of the expression patterns of ERp29 in osteosarcoma has been published. METHODS: In this study, an expression of ERp29 was examined in patient-derived osteosarcoma cells (7 cases) and normal bone graft-derived osteoblasts (7 cases) using western blotting. Expression profile of ERp29 in 94 osteosarcoma cases was investigated using immunohistochemically stained on formalin-fixed paraffin-embedded biopsied tissue. An association with clinicopathologic parameters and the patient survival was evaluated. The doubling time of five osteosarcoma cells lines expressing different levels of ERp29 was determined by a cell number along the exponential phase of the growth curve. RESULTS: The results substantiate the outcome from the proteomic study in which ERp29 expression was significantly higher in primary osteosarcoma cells compared to osteoblastic cells. Immunohistochemical analysis found that expression of ERp29 was low in 79% of the cases (immunoreactive score (IRS) <6). A significant correlation was observed between expression of ERp29 and patient survival. Lower expression of ERp29 (IRS<6) was statistically significantly associated with shorter overall survival of the patients (P = 0.041). In addition, we found that osteosarcoma cells with low ERp29 expression had a higher growth rate compared with high-ERp29-expressing cells. CONCLUSIONS: These findings suggest a tumor suppressive role of ERp29 in osteosarcoma. In addition, ERp29 might potentially be applied as a prognostic indicator in patients with osteosarcoma.

Surgical outcomes of extracorporeal irradiation and re-implantation in extremities for high grade osteosarcoma: A retrospective cohort study and a systematic review of the literature.

PURPOSE: To assess the failure rate and mode failure of high-grade osteosarcoma patients who received extracorporeal irradiation and re-implantation (ECIR) in extremities. PATIENTS AND METHODS: For the cohort study, patients who had received ECIR at a single institution between January 1996 and December 2014 were retrospectively evaluated. Characteristics of failure and time to failure were recorded and analyzed. In addition, a systematically search of published literatures regarding the use of ECIR for osteosarcoma was conducted. Failure rates and modes of failure were determined from the pooled data. RESULTS: In the cohort study, the overall reconstruction failure was 46% (23 of 50 cases) of which 6% were due to mechanical failure, and 40% were due to non-mechanical failure. In the systematic review, 164 cases reached the criteria for analysis (50 diaphysis, 97 osteochondral of lower extremity, 6 knee resection, and 11 proximal humerus resection). Among those cases, overall failure rate was 29.9% (49 of 164 cases) of which 7.9% were due to mechanical failure, and 22.0% to non-mechanical failure. Diaphyseal resection with intercalary re-implantation had a significantly lower failure rate than osteochondral reconstruction of lower extremity (OR: 2.7, p < 0.02), and knee extra-articular resection osteochondral re-implantation (OR: 10.5, p < 0.01). CONCLUSIONS: Diaphyseal resection and extracorporeal irradiation of intercalary re-implantation offer the most promising outcome among other type of reconstructions. Availability of graft, fewer structural complications, and biological permanence are advantages of this reconstruction method.