Clinical results of total en bloc spondylectomy using a single posterior approach in spinal metastasis patients: Experiences from Thailand.

AIM: To demonstrate a single posterior approach, total en bloc spondylectomy (TES) could be performed safely without preoperative embolization in spinal metastasis patients. MATERIALS AND METHODS: Thirteen solitary spinal metastasis patients (five males) underwent single posterior approach TES at the thoracolumbar spine without preoperative embolization from January 2018 to January 2020. The primary sites were the breast (n = 4), hepatocellular carcinoma (n = 2), colon (n = 2), and others (n = 5). All patients underwent single posterior TES. The Eastern Cooperative Oncology Group, Frankel neurological status, operative time and blood loss, and any complications were all recorded. The patients were regularly followed-up with radiography, computed tomography, and magnetic resonance imaging to detect any local recurrences. RESULTS: The mean operative time was 354.6 min, and the mean operative blood loss was 2134.62 ml. None of the patients experienced any perioperative complications. Within the follow-up period (3-24 months), no local recurrences were detected. Two patients (15.38%) were found to have distant metastasis to adjacent and remote vertebrae. Three patients were lost to follow-up, and three patients died of disease. Six patients showed an improved ECOG functional status by at least one grade. Four of Frankel A patients improved their neurological status by at least one grade. CONCLUSION: Even without embolization, single posterior TES at the thoracolumbar spine is safe and effective for short-term local control in solitary spinal metastasis. However, TES cannot prevent distant metastasis. Longer-term follow-up studies will be able to further identify the benefits of TES for the long-term local control of diseases.

Short incision versus minimally invasive surgery with tool-kit for carpal tunnel syndrome release: a prospective randomized control trial to evaluate the anterior wrist pain and time to return to work or activities.

TRIAL DESIGN: The prospective randomized controlled trial. BACKGROUND: This study compares outcomes in terms of early postoperative anterior wrist pain and time to return to work or activities of daily living of patients who underwent carpal tunnel syndrome (CTS) release with short incision and those who had minimally invasive surgery (MIS) with CTS kits. METHODS: A total of 24 patients diagnosed with primary CTS confirmed with electrodiagnosis at an academic university hospital were randomly assigned into one of two groups of 12 patients each: a short incision group and an MIS with tool-kit group using computer-generated block randomization (block of four). Sequentially numbered, opaque, sealed envelopes were used in the allocation concealment process. In the short incision group, skin was incised longitudinally from Kaplan's line to the area distal to transverse wrist crease (2.5-4.0 cm) while in the tool-kit group, an incision of less than 2.5 cm. was made using special MIS-CTS kits. Primary outcomes evaluated include visual analogue scale (VAS) measurement of pain intensity in the anterior carpal area both while at rest and while conducting daily activities at the 2nd week postoperatively as well as the time to return to activities of daily living and work. Improvement in the Michigan hand questionnaire (MHQ) score, a secondary outcome, was also measured at the 2nd week postoperatively. Patients, allocator and outcome assessor were blinded. RESULTS: Demographic data, including preoperative electrodiagnostic severity and occupation, were similar in the two groups. There were no significant differences in terms of VAS of the early postoperative anterior carpal area at rest (p > 0.99), while conducting daily activities (p = 0.89) and time to return to activities of daily living (p = 0.46) and work (p = 0.24). The MHQ score improvement at the 2nd week postoperatively showed no significant difference between the groups (p = 0.95). The MIS wound length in the tool-kit group was significantly shorter than in the short incision group (1.95 vs 2.92 cm, p < 0.01). CONCLUSIONS: There is no difference in early postoperative anterior wrist pain, time to return to work or to activities of daily living between the surgical techniques. Short incision is recommended for benefit in term of cost-effectiveness, while MIS with tool-kit could be preferred in patients who concerned in cosmetic appearance between the surgical techniques. TRIAL REGISTRATION: www. CLINICALTRIALS: in.th (TCTR20200530003). Registered 30 May 2020.

Efficacy and safety of ultrasound-guided caudal epidural steroid injection in patients with low back pain and sciatica.

BACKGROUND: Fluoroscopy-guided caudal epidural steroid injection (EDSI) is an option for conservative treatment of low back pain and sciatica; however, repeated exposure to radiation is a concern. With the blind technique, the needle misplacement rate is 30%; hence, ultrasound-guided caudal EDSI is a favored option. OBJECTIVE: To determine the efficacy of ultrasound-guided EDSI for low back pain and sciatica. METHODS: One hundred and ten patients with low back pain and sciatica who were unresponsive to conservative treatment, were prospectively recruited. Ultrasound-guided caudal EDSI was administered at 0, 3, and 6 weeks. Visual Analog Scale (VAS) score was recorded at 0, 2, 4, 12, and 24 weeks. Patients completed the Roland-Morris Disability Questionnaire (RMDQ) at pre-injection and 24 weeks post-injection. RESULTS: VAS was significantly reduced at 2, 4, 12, and 24 weeks (p< 0.01). At 2, 4, 12, and 24 weeks after injection, 20%, 26%, 74%, and 83% of patients displayed > 50% VAS reduction, respectively. The mean pre-injection RMDQ score was 15 and that post-injection at 24 weeks was 7 (p< 0.01). The majority of patients had > 50% reduction in the RMDQ score. CONCLUSIONS: Ultrasound-guided EDSI was safe and efficacious for low back pain and sciatica treatment at the intermediate follow-up.

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.

Total en bloc spondylectomy is worth doing in complete paralysis spinal giant cell tumor, a minimum 1-year follow-up.

OBJECTIVE: To investigate the neurological recovery of Frankel A spinal giant cell tumor (GCT) patients after they had received a Total En Bloc Spondylectomy (TES). MATERIALS AND METHODS: We retrospectively recorded data of three patients (two females) with mobile spine GCT (T6, T10, and L2) Enneking stage III with complete paralysis before surgery, who had undergone TES in our institute from January 2018 to September 2020. The duration of neurologic recovery to Frankel E was the primary outcome. The intra-operative blood loss, operative time, operative-related complications, and the local recurrence were the secondary outcomes. RESULTS: The duration of suffering from Frankel A to TES surgery was 2 months for the T6 patient, 3 weeks for the T10 patient, and 1 month for the L2 patient. Three patients had achieved full neurological recovery to Frankel E within 6 months after TES (T6 for 5 months, T10 for 3 months, and L2 for 3 months). The average blood loss was 2833.33 ml and the mean operative time was 400 min. Up until the last follow-up (13-25 months), no evidence of local recurrences had been found in any of the three patients. CONCLUSION: Frankel A spinal GCT patients can achieve full neurological recovery after TES, if the procedure is performed within 3 months after complete paraplegia. TES can effectively control any local recurrences.

Safety and Neurologic Recovery of L2 Nerve Root Sacrificed in Total En Bloc Spondylectomy Involving the L2 Vertebra.

BACKGROUND: The L2 nerve root is considered part of the lumbar plexus that innervates the iliopsoas (IP) and quadricep muscles (Qd). Total en bloc spondylectomy (TES) at the L2 vertebra requires bilateral nerve root transection to facilitate surgical dissection and vertebral body removal. Information regarding neurological function recovery of the IP and Qd in patients with muscle weakness before TES is lacking. We aimed to report the neurological recovery of IP and Qd after TES involving the L2 vertebra in preoperative lower extremity weakness in spinal tumor patients. METHODS: We prospectively recorded all L2-involved spinal tumor patients undergoing TES between January 2018 and November 2020. As a primary outcome, we recorded the Manual Muscle Testing (MMT) grade of the IP and Qd preoperatively, immediately postoperatively, and at follow-up. Secondary outcomes included the Frankel neurological status, sensation impairment, and the Eastern Cooperative Oncology Group score. RESULTS: From 8 TES-involving L2 patients, 6 (4 males) met the inclusion criteria. One patient had first-grade deterioration of the Qd MMT immediately postoperatively. All patients could ambulate independently 6 months after surgery. Five patients required follow-up for more than 1 year and could walk without any gait aids. All patients had persistent anterior groin and bilateral thigh numbness until the final follow-up. CONCLUSION: Neurological recovery of the IP and Qd muscles as measured by MMT can occur within 6 months of bilateral L2 nerve root transection. Bilateral L2 nerve root sacrifice can have acceptable neurological outcomes and recovery, even in patients with preoperative IP and Qd weakness. LEVEL OF EVIDENCE: 4.

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.

Efficacy of vertebral cryoablation and immunotherapy in a patient with metastatic renal cell carcinoma: a case report.

BACKGROUND: In metastatic renal cell carcinoma, immunotherapy is the only treatment modality associated with a complete and durable response, but severe toxicity limits its usefulness. If toxicity could be eliminated, immunotherapy might be an effective treatment for metastatic renal cell carcinoma. We present a case of a patient with spinal metastatic renal cell carcinoma treated with total en bloc spondylectomy and reconstruction using a cryo-treated tumor-bearing bone graft; the patient demonstrated an antitumor cryoimmunological response. CASE PRESENTATION: A 51-year-old Japanese man presented with back pain 4 years after undergoing a left-sided total nephrectomy for renal cell carcinoma. He was diagnosed with metastases in the T1-T3 vertebrae, right adrenal gland, sternum, left clavicle, and sacrum. Total en bloc spondylectomy and reconstruction using a cryo-treated tumor-bearing bone graft was performed to treat the vertebral metastases. Sunitinib and then everolimus were also administered. Serum interferon-γ and interleukin 12 levels were measured before surgery and at 1, 3, 6, and 12 months after surgery. Serum interferon-γ and interleukin 12 levels increased 3 months after surgery; this increase was sustained for 6 months. No local recurrence or other distant metastases occurred. The bone metastases remained stable, and the adrenal metastasis progressed slowly. The duration of progression-free survival during sunitinib and everolimus treatment was 24 and 40 months, respectively, and overall survival is currently 5.5 years. CONCLUSIONS: This report demonstrates that using cryo-treated tumor-bearing tissue in a patient with metastatic renal cell carcinoma stimulated an antitumor cryoimmunological response.

Lung metastases regression with increased CD8+ T lymphocyte infiltration following preoperative spinal embolization and total en bloc spondylectomy using tumor-bearing frozen autograft in a patient with spinal metastatic leiomyosarcoma.

PURPOSE: To report systemic immunological enhancement following preoperative spinal embolization and total en bloc spondylectomy (TES) using tumor-bearing frozen autograft in a patient with spinal metastatic leiomyosarcoma. METHODS: A 44-year-old woman with metastatic uterine leiomyosarcoma of the lung and L1 vertebra underwent TES following bilateral three-level preoperative segmental artery embolization. Resected tumor-bearing lamina was frozen using liquid nitrogen and used as tumor-bearing bone graft for spinal reconstruction. RESULTS: Tumor necrosis and obstructing material used in preoperative embolization were detected in the resected specimen of L1. Five days after TES, chest computed tomography scan demonstrated decreased solitary lung mass size without adjuvant treatment. Lobectomy was performed for the lung metastasis 42 days after TES. Infiltration of CD8+ T lymphocyte into tumor tissue significantly increased in shrunk lung metastasis. On the other hand, slight infiltration in both the resected L1 and primary uterine lesion was observed. Six months after TES, activities of daily living were normal with no evidence of local recurrence or distant metastasis. One year after TES, however, lung CT revealed occurrence of another lung metastasis, and molecular-targeting therapy (pazopanib) was initiated. CONCLUSIONS: There were no reports demonstrating metastasis regression with CD8+ T lymphocyte infiltration after TES. This case demonstrated that preoperative tumor embolization combined with TES using tumor-bearing autograft provided both a local radical cure and systemic antitumor immunological enhancement, although the long-term effect can be limited.

En bloc corpectomy for late gastrointestinal stromal tumor metastasis: a case report and review of the literature.

BACKGROUND: Spinal metastases of gastrointestinal stromal tumors are rare; however, the incidence has been increasing since the introduction of tyrosine kinase inhibitors, which have improved overall survival. Due to the rarity of cases, there are no treatment guidelines for spinal metastases of gastrointestinal stromal tumors. We describe a patient who underwent spinal metastasectomy for a rectal gastrointestinal stromal tumor; we further provide a review of all cases of gastrointestinal stromal tumors with spinal metastases. CASE PRESENTATION: A 51-year-old Japanese man who had undergone resection for a rectal gastrointestinal stromal tumor was diagnosed with L3 vertebral metastasis 10 years after surgery. As there were no metastases to vital organs, an en bloc corpectomy of the L3 vertebral body, using bilateral retroperitoneal approaches, was performed to achieve local cure and to prevent neural compression. A 3-year follow-up showed no local recurrence or new metastases; he had full neurological function. CONCLUSIONS: Spinal metastasectomy can be an effective treatment for solitary spinal metastases of gastrointestinal stromal tumors.

The most 5' truncating homozygous mutation of WNT1 in siblings with osteogenesis imperfecta with a variable degree of brain anomalies: a case report.

BACKGROUND: WNT1 mutations cause bone fragility as well as brain anomalies. There are some reported cases of WNT1 mutations with normal cognition. Genotype and phenotype correlation of WNT1 mutations has not been established. CASE PRESENTATION: Here we present two female siblings with osteogenesis imperfecta (OI) born to a consanguineous couple. Both sustained severe bone deformities. However, only the younger had severe brain anomalies resulting in an early death from pneumonia, while the older had normal intellectual development. Next generation sequencing showed a homozygous mutation, c.6delG, p.Leu3Serfs*36 in WNT1. To our knowledge, it is the most 5' truncating mutation to date. CONCLUSION: This report emphasizes the intrafamilial variability of brain anomalies found in this OI type and suggests that WNT1 may not be necessary for normal human cognitive development.

Four-Year Survival of a Patient With Spinal Metastatic Acinic Cell Carcinoma After a Total En Bloc Spondylectomy and Reconstruction With a Frozen Tumor-Bearing Bone Graft.

Acinic cell carcinoma metastasizing to the spine is extremely rare. The authors present a case of acinic cell carcinoma of the parotid gland with subsequent lung and spinal metastases, treated with en bloc spondylectomy. A 41-year-old man presented with a left parotid mass. After being diagnosed with acinic cell carcinoma, he underwent a total parotidectomy. Imaging studies revealed a metastatic osteoblastic lesion in the T4 vertebral body and multiple lung metastases. Total en bloc spondylectomy and reconstruction with a frozen tumor-bearing bone graft were performed to treat the T4 metastasis. Lung metastases were treated with periodic radiofrequency ablation. At the 48-month follow-up, there was no local recurrence of the lesions, and the lung metastases were controlled. The bone graft had fused with the adjacent vertebrae, and the patient had full neurological function and normal daily activities. This report indicates satisfactory long-term outcomes of total en bloc spondylectomy and reconstruction with frozen tumor-bearing bone graft in a patient with acinic cell carcinoma with spinal metastasis. It also emphasizes the benefits of radical resection of spinal metastasis even in cases with multiple organ metastases. [Orthopedics. 2018; 41(5):e727-e730.].

Natural History and Prognostic Factors of Cholangiocarcinoma With Spinal Metastasis: A 10-Year Single Center Study.

STUDY DESIGN: This is a retrospective analysis. OBJECTIVE: The aim of this study was to determine the epidemiology, survival, and prognostic factors for cholangiocarcinoma (CCA) with spinal metastasis. SUMMARY OF BACKGROUND DATA: CCA is an epithelial cell malignancy of the bile duct, and a frequent site for its metastasis is the spine. Many areas of Asia are endemic for CCAs. To date, there is limited data on the epidemiology, natural history, and prognostic factors of CCA with spinal metastasis, which is crucial for better management and treatment of the disease. MATERIALS AND METHODS: Patients diagnosed with CCA were recruited to our study, in order to identify cases with spinal metastasis. The survival rate was estimated by the Kaplan-Meier method. The univariate and multivariate analyses of tumor-specific and spinal metastatic factors were performed to identify the independent factors that affect survival. RESULTS: From 2006 to 2015, 4585 CCA patients were identified and 182 of these patients had spinal metastasis. The overall median survival of patients with spinal metastasis was 88 days. Serum carcinoembryonic antigen <5 ng/mL, carbohydrate antigen 19-9 <39 U/mL, albumin ≥3.5 g/L, and Frankel score D-E were found to be independent factors that resulted in better survival in a multivariate Cox regression analysis. CCA resection or spinal surgery did not prolong the survival of patients with spinal metastasis. CONCLUSION: Spinal surgery should be considered for CCA patients with spinal metastasis, who have a favorable prognosis, and are likely to live long enough to benefit from surgery. The aim is to palliate the symptoms and not as much to improve the survival.

Surgical Technique of Vertebral Body Removal and Anterior Reconstruction in L5 Spondylectomy.

INTRODUCTION: L5 spondylectomy for the treatment of spinal tumor is a technically demanding surgery because of the complex anatomy of major vessels, the obscurity of the posterior exposure from the iliac wings, and the increased comparative size of the L5 vertebral body. In this study, we present a surgical technique of L5 spondylectomy, vertebral body removal, and anterior reconstruction for a case with solitary spinal metastatic renal cell carcinoma (RCC). TECHNICAL NOTE: A 54-year-old man underwent right total nephrectomy for RCC one year ago. At the one-year postoperative follow-up, CT scan and MRI revealed a solitary L5 spinal metastasis. A two-stage posteroanterior approach was performed. To facilitate vertebral body removal, transverse processes were separated from the vertebral body by using the posterior approach. On the basis of the anterior approach, the vertebral body was removed via the interval space between the left common iliac vessels. Reconstruction was performed by using a liquid-nitrogen-frozen, tumor-bearing bone mixed with an autogenous bone graft in an expandable titanium cage. RESULTS: No intraoperative complications were observed. Postoperatively, the patient exhibited muscle weakness in the tibialis anterior and extensor hallucis longus bilaterally but improved with time. Seven months after the operation, the patient was able to walk independently. At the recent 2.5-year follow-up, the local recurrence of lesions was nonexistent. The bone graft had fused with the adjacent vertebrae. CONCLUSION: This report described a novel technique for L5 spondylectomy that can facilitate safe L5 vertebral body removal and demonstrated the effectiveness of liquid-nitrogen-frozen, tumor-bearing bone mixed with autogenous bone graft in anterior reconstruction both in terms of oncologic safety and biological healing.

A novel de novo COL1A1 mutation in a Thai boy with osteogenesis imperfecta born to consanguineous parents

Abstract Osteogenesis imperfecta (OI) is genetically heterogeneous. Mutations in COL1A1 and COL1A2 are responsible for at least 90% of the cases, which are transmitted in an autosomal dominant manner or are de novo events. We identified a Thai boy with OI whose parents were first cousins. Because the proband was the product of a consanguineous marriage, we hypothesized that he might be homozygous for a mutation in a known gene causing a recessive form of OI. Using whole exome sequencing (WES), we did not find any pathogenic mutations in any known gene responsible for an autosomal recessive form of OI. Instead, we identified a COL1A1 frameshift mutation, c.1290delG (p.Gly431Valfs*110) in heterozygosis. By Sanger sequencing, the mutation was confirmed in the proband, and not detected in his parents, indicating that it was a de novo mutation. These findings had implication for genetic counseling. In conclusion, we expanded the mutational spectrum of COL1A1 and provided another example of a de novo pathogenic mutation in heterozygosis in a patient born to consanguineous parents.

Massive parallel sequencing as a new diagnostic approach for phenylketonuria and tetrahydrobiopterin-deficiency in Thailand.

BACKGROUND: Hyperphenylalaninemia (HPA) can be classified into phenylketonuria (PKU) which is caused by mutations in the phenylalanine hydroxylase (PAH) gene, and BH4 deficiency caused by alterations in genes involved in tetrahydrobiopterin (BH4) biosynthesis pathway. Dietary restriction of phenylalanine is considered to be the main treatment of PKU to prevent irreversible intellectual disability. However, the same dietary intervention in BH4 deficiency patients is not as effective, as BH4 is also a cofactor in many neurotransmitter syntheses. METHOD: We utilized next generation sequencing (NGS) technique to investigate four unrelated Thai patients with hyperphenylalaninemia. RESULT: We successfully identified all eight mutant alleles in PKU or BH4-deficiency associated genes including three novel mutations, one in PAH and two in PTS, thus giving a definite diagnosis to these patients. Appropriate management can then be provided. CONCLUSION: This study identified three novel mutations in either the PAH or PTS gene and supported the use of NGS as an alternative molecular genetic approach for definite diagnosis of hyperphenylalaninemia, thus leading to proper management of these patients in Thailand.

A novel de novo COL1A1 mutation in a Thai boy with osteogenesis imperfecta born to consanguineous parents.

Osteogenesis imperfecta (OI) is genetically heterogeneous. Mutations in COL1A1 and COL1A2 are responsible for at least 90% of the cases, which are transmitted in an autosomal dominant manner or are de novo events. We identified a Thai boy with OI whose parents were first cousins. Because the proband was the product of a consanguineous marriage, we hypothesized that he might be homozygous for a mutation in a known gene causing a recessive form of OI. Using whole exome sequencing (WES), we did not find any pathogenic mutations in any known gene responsible for an autosomal recessive form of OI. Instead, we identified a COL1A1 frameshift mutation, c.1290delG (p.Gly431Valfs*110) in heterozygosis. By Sanger sequencing, the mutation was confirmed in the proband, and not detected in his parents, indicating that it was a de novo mutation. These findings had implication for genetic counseling. In conclusion, we expanded the mutational spectrum of COL1A1 and provided another example of a de novo pathogenic mutation in heterozygosis in a patient born to consanguineous parents.

Two novel compound heterozygous BMP1 mutations in a patient with osteogenesis imperfecta: a case report.

BACKGROUND: Osteogenesis imperfecta (OI) is a collagen-related bone dysplasia leading to a susceptibility to fractures. OI can be caused by mutations in several genes including BMP1. It encodes two isoforms, bone morphogenetic protein 1 (BMP1) and mammalian tolloid (mTLD); both have proteolytic activity to remove the C-propeptide from procollagen. CASE PRESENTATION: We report a Thai OI patient who had his first fracture at the age of three months. Using next generation sequencing, we successfully identified two novel compound heterozygous BMP1 mutations. One mutation, c.796_797delTT (p.Phe266Argfs*25) affects both BMP1 and mTLD isoforms, while the other, c.2108-2A > G, affects only the BMP1 isoform. Preservation of the mTLD may explain the relatively less severe clinical phenotype in this patient. Intravenous bisphosphonate was given from the age of 8 months to 5 years. He was free from fractures for 9 months before discontinuation. CONCLUSION: This case expands the mutation spectrum of BMP1, strengthens the correlation between genotype and phenotype, and supports the benefits of bisphosphonate in OI patients with BMP1 mutations.

Exploring targeted therapy of osteosarcoma using proteomics data.

Despite multimodal therapeutic treatments of osteosarcoma (OS), some patients develop resistance to currently available regimens and eventually end up with recurrent or metastatic outcomes. Many attempts have been made to discover effective drugs for improving outcome; however, due to the heterogeneity of the disease, new therapeutic options have not yet been identified. This study aims to explore potential targeted therapy related to protein profiles of OS. In this review of proteomics studies, we extracted data on differentially expressed proteins (DEPs) from archived literature in PubMed and our in-house repository. The data were divided into three experimental groups, DEPs in 1) OS/OB: OS vs osteoblastic (OB) cells, 2) metastasis: metastatic vs non-metastatic sublines plus fresh tissues from primary OS with and without pulmonary metastasis, and 3) chemoresistance: spheroid (higher chemoresistance) vs monolayer cells plus fresh tissues from biopsies from good and poor responders. All up-regulated protein entities in the list of DEPs were sorted and cross-referenced with identifiers of targets of US Food and Drug Administration (FDA)-approved agents and chemical inhibitors. We found that many targets of FDA-approved antineoplastic agents, mainly a group of epigenetic regulators, kinases, and proteasomes, were highly expressed in OS cells. Additionally, some overexpressed proteins were targets of FDA-approved non-cancer drugs, including immunosuppressive and antiarrhythmic drugs. The resulting list of chemical agents showed that some transferase enzyme inhibitors might have anticancer activity. We also explored common targets of OS/OB and metastasis groups, including amidophosphoribosyltransferase (PPAT), l-lactate dehydrogenase B chain (LDHB), and pyruvate kinase M2 (PKM2) as well as the common target of all categories, cathepsin D (CTSD). This study demonstrates the benefits of a text mining approach to exploring therapeutic targets related to protein expression patterns. These results suggest possible repurposing of some FDA-approved medicines for the treatment of OS and using chemical inhibitors in drug screening tests.

Short stature, platyspondyly, hip dysplasia, and retinal detachment: an atypical type II collagenopathy caused by a novel mutation in the C-propeptide region of COL2A1: a case report.

BACKGROUND: Heterozygous mutations in COL2A1 create a spectrum of clinical entities called type II collagenopathies that range from in utero lethal to relatively mild conditions which become apparent only during adulthood. We aimed to characterize the clinical, radiological, and molecular features of a family with an atypical type II collagenopathy. CASE PRESENTATION: A family with three affected males in three generations was described. Prominent clinical findings included short stature with platyspondyly, flat midface and Pierre Robin sequence, severe dysplasia of the proximal femora, and severe retinopathy that could lead to blindness. By whole exome sequencing, a novel heterozygous deletion, c.4161_4165del, in COL2A1 was identified. The phenotype is atypical for those described for mutations in the C-propeptide region of COL2A1. CONCLUSIONS: We have described an atypical type II collagenopathy caused by a novel out-of-frame deletion in the C-propeptide region of COL2A1. Of all the reported truncating mutations in the C-propeptide region that result in short-stature type II collagenopathies, this mutation is the farthest from the C-terminal of COL2A1.