Inactivation of Lkb1 in postnatal chondrocytes leads to epiphyseal growth-plate abnormalities and promotes enchondroma-like formation.

Liver serine-threonine kinase B1 (LKB1) is a tumor suppressor that has been linked to many types of tumors. However, the role of LKB1 in cartilaginous tumorigenesis is still poorly understood. In this study, we find that cartilage-specific, tamoxifen-inducible Lkb1 knockout results in multiple enchondroma-like lesions adjacent to the disorganized growth plates. We showed that chondrocytes retain an immature status caused by loss of Lkb1, which may lead to the dramatic expansion of growth-plate cartilage and the formation of enchondroma-like lesions. Additionally, increased mammalian target of rapamycin complex 1 (mTORC1) activity is observed in the Lkb1 conditional knockout (cKO) chondrocytes, and rapamycin (mTORC1 inhibitor) treatment significantly alleviates the expansion of growth-plate cartilage and eliminates the enchondroma-like lesions in Lkb1 cKO mice. Thus, our findings indicate that loss of Lkb1 leads to the expansion of chondrocytes and the formation of enchondroma-like lesions during postnatal cartilage development, and that the up-regulated mTORC1-signaling pathway is implicated in this process. Our findings suggest that modulation of LKB1 and related signaling is a potential therapy in cartilaginous tumorigenesis.-Zhou, S., Li, Y., Qiao, L., Ge, Y., Huang, X., Gao, X., Ju, H., Wang, W., Zhang, J., Yan, J., Teng, H., Jiang, Q. Inactivation of Lkb1 in postnatal chondrocytes leads to epiphyseal growth-plate abnormalities and promotes enchondroma-like formation.

MTNR1B loss promotes chordoma recurrence by abrogating melatonin-mediated ß-catenin signaling repression.

Chordoma is an extremely rare malignant bone tumor with a high rate of relapse. While cancer stem cells (CSCs) are closely associated with tumor recurrence, which depend on its capacity to self-renew and induce chemo-/radioresistance, whether and how CSCs participate in chordoma recurrence remains unclear. The current study found that tumor cells in recurrent chordoma displayed more dedifferentiated CSC-like properties than those in corresponding primary tumor tissues. Meanwhile, MTNR1B deletion along with melatonin receptor 1B (MTNR1B) down-regulation was observed in recurrent chordoma. Further investigation revealed that activation of Gαi2 by MTNR1B upon melatonin stimulation could inhibit SRC kinase activity via recruiting CSK and SRC, increasing SRC Y530 phosphorylation, and decreasing SRC Y419 phosphorylation. This subsequently suppressed ß-catenin signaling and stemness via decreasing ß-catenin p-Y86/Y333/Y654. However, MTNR1B loss in chordoma mediated increased CSC properties, chemoresistance, and tumor progression by releasing melatonin's repression of ß-catenin signaling. Clinically, MTNR1B deletion was found to correlate with patients' survival. Together, our study establishes a novel convergence between melatonin and ß-catenin signaling pathways and reveals the significance of this cross talk in chordoma recurrence. Besides, we propose that MTNR1B is a potential biomarker for prediction of chordoma prognosis and selection of treatment options, and chordoma patients might benefit from targeting MTNR1B/Gαi2/SRC/ß-catenin axis.

Intracellular cholesterol biosynthesis in enchondroma and chondrosarcoma.

Enchondroma and chondrosarcoma are the most common benign and malignant cartilaginous neoplasms. Mutations in isocitrate dehydrogenase 1 and 2 (IDH1/2) are present in the majority of these tumors. We performed RNA-seq analysis on chondrocytes from Col2a1Cre;Idh1LSL/+ animals and found that genes implied in cholesterol synthesis pathway were significantly upregulated in the mutant chondrocytes. We examined the phenotypic effect of inhibiting intracellular cholesterol biosynthesis on enchondroma formation by conditionally deleting SCAP (sterol regulatory element-binding protein cleavage-activating protein), a protein activating intracellular cholesterol synthesis, in IDH1 mutant mice. We found fewer enchondromas in animals lacking SCAP. Furthermore, in chondrosarcomas, pharmacological inhibition of intracellular cholesterol synthesis significantly reduced chondrosarcoma cell viability in vitro and suppressed tumor growth in vivo. Taken together, these data suggest that intracellular cholesterol synthesis is a potential therapeutic target for enchondromas and chondrosarcomas.

Periocular Manifestations of Afatinib Therapy.

Epidermal growth factor receptor tyrosine kinase inhibitor therapy has been increasingly employed in the treatment of a variety of tumors. The authors report the rarely documented side effect of trichiasis with the use of Afatinib in a patient with spinal chordoma and review-related literature. A 67-year-old lady was referred to the oculoplastic service with a 3-month history of ocular irritation and pain associated with blurred vision. She has a 4-year history of spinal chordoma treated with daily Afatinib 50 mg over the past 6 months. Clinical examination revealed trichomegaly and trichiasis affecting all 4 eyelids associated with blepharitis, conjunctival, and corneal abrasion on fluorescein staining. Hypertrichosis of the eyebrow bilaterally was also present. Afatinib and other epidermal growth factor receptor tyrosine kinase inhibitor-associated changes to eyelash and eyebrow hair is a result of epidermal growth factor receptor pathway activation in keratinocytes results in remodeling of the hair follicle. This results in the variation in the severity of clinical presentation of trichiasis.

Novel Unidirectional Porous ß-Tricalcium Phosphate Used as a Bone Substitute after Excision of Benign Bone Tumors of the Hand: A Case Series.

Unidirectional porous ß-tricalcium phosphate (UDPTCP; Affinos®, Kuraray, Tokyo, Japan) has been in clinical use since 2015. Animal studies have confirmed the excellent potential of UDPTCP with regard to bone formation and material absorption. We present the first three clinical cases using UDPTCP as a bone substitute after curettage of benign bone tumors of the hand. All three patients were males, 29-, 30- and 81-years-old, two having a diagnosis of enchondroma and the other, a bone ganglion, with a pathological fracture identified in one case. Over a mean follow-up of 10 months, all patients achieved satisfactory clinical result, with no adverse events of UDPTCP noted. Radiographic evidence of good bone formation and material absorption was observable over the postoperative course. UDPTCP provided satisfactory clinical results, with good biocompatibility and fast resorption characteristics. Therefore, UDPTCP could provide a safe and reliable filling substitute for bone defects following curettage of small bone tumors.

Treatment of hand enchondroma with injectable calcium phosphate cement: a series of eight cases.

The gold standard treatment for enchondroma in the hand is curettage and filling of the defect. The goal of this study was to evaluate the results when injectable calcium phosphate cement is used to fill the bone defect. Eight patients having a mean age of 44 years were operated through a minimally invasive skin incision. After a small bone window was made, curettage of the lesion was performed and verified by intraosseous endoscopy. The defect was filled with injectable calcium phosphate cement (JectOS/AREX®BONE, Kasios, L'Union France). The mean pain score (out of 10) decreased from 4.1 preoperatively to 1.6 postoperatively. The mean QuickDASH (out of 100) improved from 37.66 to 24.14. At the last follow-up (mean of 16 months), the range of motion in the operated hand had reached 89.3% of the contralateral hand. Based on radiographs, a mean of 69.3% calcium phosphate cement remained in the bone. There were two cases of extraosseous cement leakage, one of which required revision and resulted in a poor outcome. Overall, these results show that curettage of a hand enchondroma followed by filling of the defect with injectable calcium phosphate cement is a simple, reliable technique with no donor site morbidity, as long as cement does not leak out.

Receptor-Activator of Nuclear KappaB Ligand Expression as a New Therapeutic Target in Primary Bone Tumors.

The receptor-activator of nuclear kappaB ligand (RANKL) signaling pathway plays an important role in the regulation of bone growth and mediates the formation and activation of osteoclasts. Osteoclasts are involved in significant bone resorption and destruction. Denosumab is a fully human monoclonal antibody against RANKL that specifically inhibits osteoclast differentiation and bone resorption. It has been approved for use for multiple myeloma and bone metastases, as well as for giant cell tumor of bone. However, there is no previous report quantitatively, comparing RANKL expression in histologically varied bone tumors. Therefore, we analyzed the mRNA level of various bone tumors and investigated the possibility of these tumors as a new therapeutic target for denosumab. We examined RANKL mRNA expression in 135 clinical specimens of primary and metastatic bone tumors using real-time PCR. The relative quantification of mRNA expression levels was performed via normalization with RPMI8226, a human multiple myeloma cell line that is recognized to express RANKL. Of 135 cases, 64 were also evaluated for RANKL expression by using immunohistochemistry. Among all of the tumors investigated, RANKL expression and the RANKL/osteoprotegerin ratio were highest in giant cell tumor of bone. High RANKL mRNA expression was observed in cases of aneurysmal bone cyst, fibrous dysplasia, osteosarcoma, chondrosarcoma, and enchondroma, as compared to cases of multiple myeloma and bone lesions from metastatic carcinoma. RANKL-positive stromal cells were detected in six cases: five cases of GCTB and one case of fibrous dysplasia. The current study findings indicate that some primary bone tumors present new therapeutic targets for denosumab, particularly those tumors expressing RANKL and those involving bone resorption by osteoclasts.

[Gastrointestinal stromal tumor (GIST): advances in 2013]. / Gastrointestinální stromální tumor (GIST): pokroky do roku 2013.

Gastrointestinal stromal tumors (GIST) are currently regarded as a heterogenous group of tumors sharing common histological appearance, KIT immunopositivity and supposed origin from tissue progenitor cells capable of differentiation into the phenotype of Cajal interstitial cells. GISTs can be divided according to immunoexpression of the beta subunit of mitochondrial enzyme succinate dehydrogenase (SDHB) to SDHB-positive (encompassing KIT, PDGFRA and NF1 mutated GISTs), and SDHB-deficient GISTs (including Carney-Stratakis syndrome, Carney triad, sporadic pediatric GISTs, and a small subset of sporadic adult GISTs). The individual molecular subtypes differ in biological behavior and in their response to systemic targeted therapy, which is indicated in metastatic GISTs or in tumors with high risk of recurrence. Although several risk-stratification classifications have been developed, strictly defined criteria to identify patients at risk are still lacking. Pharmacogenomics have been successful in designing drugs to overcome not only the primary resistance of GISTs to the action of imatinib (e.g. GISTs with a substitution of Asp842Val in exon 18 PDGFRA or SDHB-deficient GISTs), but also the secondary resistance caused by secondary mutation of a gene encoding either the receptor tyrosine kinase or other molecules involved in the respective signalling cascade. Future directions concentrate on rational molecular targeting for systemic therapy based on complex genetic investigation of the tumor. Peripheral blood is planned to be used as a source of information for genetic events responsible for the secondary resistance of metastatic tumors.

Zoledronic acid in metastatic chondrosarcoma and advanced sacrum chordoma: two case reports.

INTRODUCTION: Chondrosarcomas and chordomas are usually chemoresistant bone tumors and may have a poor prognosis when advanced. They are usually associated with worsening pain difficult to control. PATIENTS AND METHODS: Zoledronic acid was used in a 63-year-old man with metastatic chondrosarcoma and in a 66-year-old woman with a diagnosis of sacrum chordoma both reporting severe pain related to tumor. RESULTS: In the first case, zoledronic acid was able to maintain pain control despite disease progression following chemotherapy, in the other case, zoledronic acid only produced significant clinical benefit. CONCLUSION: Control of pain associated with bone tumors such as chondrosarcoma and chondroma may significantly improve from use of zoledronic acid, independently from tumor response to other treatments. Evaluation on larger series are needed to confirm the clinical effect of this bisphosphonate on such tumors.

Nuclear magnetic resonance studies on human bone and soft tissue tumors.

The relaxation times of water protons of 71 normal, benign and malignant specimens of human bone and soft tissue were studied by nuclear magnetic resonance (NMR) method. By combining T1 and T2 into a malignancy index, it was possible to discriminate malignant and nonmalignant (normal and benign) tissue in 41 out of 44 bone tissue specimens and all 27 soft tissue specimens. In chondrosarcoma, there appeared to be a correlation of the malignancy index with the degree of tissue differentiation. Furthermore, the relaxation times might have been influenced by chemotherapy before operation was carried out.