Exploratory trial of a biepitopic CAR T-targeting B cell maturation antigen in relapsed/refractory multiple myeloma.

Relapsed and refractory (R/R) multiple myeloma (MM) patients have very poor prognosis. Chimeric antigen receptor modified T (CAR T) cells is an emerging approach in treating hematopoietic malignancies. Here we conducted the clinical trial of a biepitope-targeting CAR T against B cell maturation antigen (BCMA) (LCAR-B38M) in 17 R/R MM cases. CAR T cells were i.v. infused after lymphodepleting chemotherapy. Two delivery methods, three infusions versus one infusion of the total CAR T dose, were tested in, respectively, 8 and 9 cases. No response differences were noted among the two delivery subgroups. Together, after CAR T cell infusion, 10 cases experienced a mild cytokine release syndrome (CRS), 6 had severe but manageable CRS, and 1 died of a very severe toxic reaction. The abundance of BCMA and cytogenetic marker del(17p) and the elevation of IL-6 were the key indicators for severe CRS. Among 17 cases, the overall response rate was 88.2%, with 13 achieving stringent complete response (sCR) and 2 reaching very good partial response (VGPR), while 1 was a nonresponder. With a median follow-up of 417 days, 8 patients remained in sCR or VGPR, whereas 6 relapsed after sCR and 1 had progressive disease (PD) after VGPR. CAR T cells were high in most cases with stable response but low in 6 out of 7 relapse/PD cases. Notably, positive anti-CAR antibody constituted a high-risk factor for relapse/PD, and patients who received prior autologous hematopoietic stem cell transplantation had more durable response. Thus, biepitopic CAR T against BCMA represents a promising therapy for R/R MM, while most adverse effects are clinically manageable.

Matrix metalloproteinase-9 expression of GCTSC in peripheral tissue and central tissue of GCTB.

Giant cell tumor stromal cell (GCTSC) is the tumor cell of giant cell tumor of bone (GCTB). The biomarkers characterization of GCTSC is critical for the selection of GCTB targeting drugs. We believe the main functions of GCTSC in different part of tumor should be different for different environment. Then the biological behavior and molecular biomarkers of GCTSC should be different as well. Based on this idea, we focused on GCTSC which located in central tissue, peripheral tissue and took MMP-9 as the breakthrough point to carry out research. The results showed MMP-9 staining grade of GCTSC which located in central tissue was slight, whereas multinucleated giant cell staining grade was high. The peripheral tissue was consisted by almost GCTSC with high MMP-9 staining degree and mRNA expression. This study also provided clues and inspiration for reducing GCTB recurrence rate after intralesional curettage with MMP-9 targeted therapy which were aimed at the residual peripheral tissue.

[Expression of S100A8 and A100A9 in giant cell tumor of bone and its relation with CT and MR imaging findings].

OBJECTIVE: To investigate the mRNA and protein expression levels of S100A8 and S100A9 in giant cell tumor (GCT) of bone, and its relation with radiological findings and biological behavior. METHODS: Forty three patient with GCT of bone admitted in Ruijin Hospital Shanghai Jiaotong University School of Medicine from January 2009 to June 2012 were enrolled in the study. The expression levels of S100A8 and S100A9 mRNA and protein were detected by using semiquantitative RT-PCR and Western blotting in 43 specimens of GCT and 6 specimens of normal bone marrow. The CT and MRI findings of patients were retrospectively reviewed, its relation with tissue expression of S100A8 and S100A9 was analyzed. RESULTS: Among 43 GCT cases 40 showed positive expression of S100A8 and S100A9 mRNA and protein, and the expression levels were significantly higher than those in normal bone marrow P<0.05). The expression level of S100A8 protein was significantly different in bone GCT with different composition ratio on MRI (P<0.05).The expression level of S100A9 protein was significantly different in GCT with different degree of bone destruction on CT scan (P<0.05). CONCLUSION: The expression of S100A8 and S100A9 mRNA and protein is up-regulated in GCT of bone. The expression of S100A8 and S100A9 is associated with the real composition ratio and the degree of bone destruction, respectively, indicating that S100A8 and S100A9 may be involved in the biological behavior of bone GCT.

In-depth analysis of local recurrence of giant cell tumour of bone with soft tissue extension after intralesional curettage.

PURPOSE: The aim of this study was to assess the local recurrence rate of giant cell tumour of bone (GCTB) with soft tissue extension, to identify characteristics of the soft tissue extension that can best indicate recurrence of GCTB after intralesional curettage. MATERIALS AND METHODS: A total of 48 cases of GCTB with soft tissue extension after intralesional curettage were recruited. Patients were divided into two groups based on various objective features of soft tissue extension including size, number, margins, involvement of adjacent tissues, signal intensity, static enhancement and Jaffe grade. The local recurrence rate was compared using the Chi-square test and Chi-square value correction for continuity. Risk factors were assessed by multivariate logistic regression analysis. RESULTS: The local recurrence rate was significantly different according to soft tissue extension size, number and margins (p < 0.05). There was no significant difference in the groups of adjacent tissue involvement and Jaffe grade (p > 0.05). Size, number and margins of the soft tissue extension were independent risk factors of local recurrence of GCTB after intralesional curettage (p < 0.05). CONCLUSIONS: The local recurrence rate of GCTB with soft tissue extension after intralesional curettage is higher if the soft tissue extension is large, multiple and lacking bone envelope integrity. For cases with the above-mentioned features, we suggest that the higher recurrence rate can be taken into full consideration when choosing appropriate surgical procedures.

Giant cell tumours of the mobile spine: characteristic imaging features and differential diagnosis.

PURPOSE: The aim of this study was to investigate the characteristic imaging features of giant cell tumours (GCTs) of the mobile spine. MATERIALS AND METHODS: Thirty pathologically proven GCTs of the mobile spine were reviewed. X-ray (n = 18), computed tomography (CT) (n = 24) and magnetic resonance (MR) (n = 21) images were retrospectively evaluated. RESULTS: Five tumours were located in the cervical spine, 15 tumours were located in the thoracic spine and 10 tumours in the lumbar spine. The characteristic X-ray findings included an osteolytic and expansile lesion with a "soap bubble" or purely lytic appearance. Cortical destruction was commonly seen. Margin sclerosis was seen in two lesions. No mineralised tumour matrix or periosteal reaction appeared. The CT findings were similar but outlined the cortical alterations in a more accurate way. The characteristic MR findings included a well-defined and expansile mass with heterogeneous low-to-iso signal intensity on T2-weighted images. Cystic areas were commonly seen in 17 cases. Five cases presented fluid-fluid levels, suggesting the development of aneurysmal bone cyst. The solid portions of the tumours were enhanced with a very heterogeneous signal pattern reflecting high blood supply after contrast-enhanced scan. Tumour involvement in the epidural space occurred in 12 cases, causing spinal cord and/or nerve root compression. Involvement of intervertebral discs and/or adjacent vertebrae appeared in two cases. CONCLUSIONS: Although rare, GCT can occur in the mobile spine as a kind of benign but locally aggressive tumour. Radiologists should be familiar with its characteristic imaging features in order to make a correct diagnosis and to help preoperative evaluations.

Identification of clinically relevant subsets CD39+PD-1+CD8+ T cells and CD39+ regulatory T cells in intrahepatic cholangiocarcinoma using single-cell CyTOF.

Intrahepatic cholangiocarcinoma (iCCA) is an aggressive liver malignancy with limited treatment options and a dismal prognosis. The tumor immune microenvironment (TIME) is crucial for iCCA progression, yet its comprehensive characterization remains incomplete. This study utilized mass cytometry by time of flight (CyTOF) to comprehensively analyze immune cell populations in fresh iCCA tumor samples and adjacent peritumor liver tissues. Notably, NK cell percentages significantly decreased in iCCA lesions compared to peritumor liver tissues. Conversely, an enrichment of immunosuppressive CD39+Foxp3+CD4+ regulatory T cells (CD39+T-regs) and exhausted-like CD8+T cells (with pronounced CD39 and PD-1 expression) within TIME was identified and confirmed by multiplex immunofluorescence staining in an independent patient cohort (n = 140). Crucially, tumor-infiltrating CD39+T-regs and CD39+PD-1+CD8+T cells emerged as independent prognostic indicators associated with an unfavorable prognosis in iCCA. These findings unveil the intricate immune landscape within iCCA, offering valuable insights for disease management and novel cancer immunotherapies.

MicroRNA-126 inhibits osteosarcoma cells proliferation by targeting Sirt1.

Numerous studies have recently suggested that miRNAs contribute to the development of various types of human cancer as well as to their proliferation and metastasis. The aim of this study was to investigate the functional significance of miR-126 and to identify its possible target genes in osteosarcoma (OS) cells. Here, we found that expression level of miR-126 was reduced in osteosarcoma cells in comparison with the adjacent normal tissues. The enforced expression of miR-126 was able to inhibit cell proliferation in U2OS and MG63 cells, while miR-126 antisense oligonucleotides (antisense miR-126) promoted cell proliferation. At the molecular level, our results further revealed that expression of Sirt1, a member of histone deacetylase, was negatively regulated by miR-126. Therefore, the data reported here demonstrate that miR-126 is an important regulator in osteosarcoma, which will contribute to better understanding of the important misregulated miRNAs in osteosarcoma cells.

Giant cell-rich osteosarcoma in long bones: clinical, radiological and pathological features.

PURPOSE: The purpose of this study was to review the clinical presentation, imaging, pathology and outcome of patients with giant cell-rich osteosarcoma (GCRO) of long bones. MATERIALS AND METHODS: Radiography (n=9), magnetic resonance imaging (MRI) (n=6), computed tomography (CT) (n=3) and clinical course of nine patients (five males and four females; mean age, 26 years) with pathologically confirmed GCRO were retrospectively reviewed. Specific imaging findings, including size, eccentricity, ossification, lysis, cystic change, expansile growth, periosteal reaction, cortical destruction, soft tissue extension and joint involvement were documented. RESULTS: Presenting symptoms were pain in six patients and pain and palpable mass in three. An ill-defined margin surrounding a predominantly osteolytic lesion was detected at the proximal tibia (n=7) or femur (n=2) on imaging studies. Seven cases showed limited ossification. Three cases had tumours in the metaphysis and six in the metaepiphysis. The average maximum tumour dimension was 4.7 cm×5.2 cm×7.8 cm. Microscopically, tumours were composed of atypical cells with scanty osteoid formation and multinucleated giant cells. All patients received chemotherapy, and surgery was performed in eight patients. Three patients were dead and six were alive at the last follow-up. CONCLUSIONS: GCRO is a rarer variant that has very close resemblance to giant cell tumour. Patients usually present nonspecific symptoms of pain and palpable mass. It usually shows an osteolytic lesion with locally spared new bone formation in the metaphysis and/or metaepiphysis on imaging. Histologically, the atypical tumour cells with osteoid formation and multinucleated giant cells are the key factor in the diagnosis and differential diagnosis.

Recurrence in giant cell tumour of bone: imaging features and risk factors.

PURPOSE: This study was done to investigate X-ray, computed tomography (CT) and magnetic resonance (MR) imaging features of recurrence in giant cell tumour of bone (GCTB) and to evaluate risk factors. MATERIALS AND METHODS: Medical records and imaging data were reviewed for 55 cases of recurrent GCTB. All images were reviewed retrospectively and independently by two radiologists experienced in skeletal musculature. The common radiological findings; factors related to tumour recurrence such as gender, age, location; pathological fracture, Campanacci grading and surgical procedure were analysed by nonparametric test (Mann-Whitney U test for two independent samples test and Kruskal-Wallis H test for multiple independent samples test). p values <0.05 were considered to indicate a statistically significant difference. RESULTS: The imaging features of recurrent GCTB were as follows: osteolytic destruction or bone resorption of graft bone or around the polymethylmethacrylate (PMMA), soft tissue mass formation and expansile change. Tumour parenchyma showed markedly heterogeneous enhancement, except for necrotic cystic cavities, on contrast-enhanced MR images. Wide resection had a smaller (p=0.031) risk of local recurrence than did intralesional curettage. There was no statistical significance in gender, age, location, pathological fracture and Campanacci staging (p>0.05). CONCLUSIONS: The risk of recurrence in GCTB was influenced by the type of surgery and adjuvants. Bone transformaresorption, soft tissue mass formation and aggravated expansile change are reliable signs of recurrence on imaging.

Glomus mosseae improved the adaptability of alfalfa (Medicago sativa L.) to the coexistence of cadmium-polluted soils and elevated air temperature.

The coexistence of heavy metal-polluted soils and global warming poses serious threats to plants. Many studies indicate that arbuscular mycorrhizal fungi (AMF) can enhance the resistance of plants to adverse environments such as heavy metals and high temperature. However, few studies are carried out to explore the regulation of AMF on the adaptability of plants to the coexistence of heavy metals and elevated temperature (ET). Here, we investigated the regulation of Glomus mosseae on the adaptability of alfalfa (Medicago sativa L.) to the coexistence of cadmium (Cd)-polluted soils and ET. G. mosseae significantly enhanced total chlorophyll and carbon (C) content in the shoots by 15.6% and 3.0%, respectively, and Cd, nitrogen (N), and phosphorus (P) uptake by the roots by 63.3%, 28.9%, and 85.2%, respectively, under Cd + ET. G. mosseae significantly increased ascorbate peroxidase activity, peroxidase (POD) gene expression, and soluble proteins content in the shoots by 13.4%, 130.3%, and 33.8%, respectively, and significantly decreased ascorbic acid (AsA), phytochelatins (PCs), and malondialdehyde (MDA) contents by 7.4%, 23.2%, and 6.5%, respectively, under ET + Cd. Additionally, G. mosseae colonization led to significant increases in POD (13.0%) and catalase (46.5%) activities, Cu/Zn-superoxide dismutase gene expression (33.5%), and MDA (6.6%), glutathione (22.2%), AsA (10.3%), cysteine (101.0%), PCs (13.8%), soluble sugars (17.5%), and proteins (43.4%) contents in the roots and carotenoids (23.2%) under ET + Cd. Cadmium, C, N, G. mosseae colonization rate, and chlorophyll significantly influenced shoots defenses and Cd, C, N, P, G. mosseae colonization rate, and sulfur significantly affected root defenses. In conclusion, G. mosseae obviously improved the defense capacity of alfalfa under ET + Cd. The results could improve our understanding of the regulation of AMF on the adaptability of plants to the coexistence of heavy metals and global warming and phytoremediation of heavy metal-polluted sites under global warming scenarios.

Multiple synostoses syndrome is due to a missense mutation in exon 2 of FGF9 gene.

Fibroblast growth factors (FGFs) play diverse roles in several developmental processes. Mutations leading to deregulated FGF signaling can cause human skeletal dysplasias and cancer.(1,2) Here we report a missense mutation (Ser99Asp) in exon 2 of FGF9 in 12 patients with multiple synostoses syndrome (SYNS) in a large Chinese family. In vitro studies demonstrate that FGF9(S99N) is expressed and secreted as efficiently as wild-type FGF9 in transfected cells. However, FGF9(S99N) induces compromised chondrocyte proliferation and differentiation, which is accompanied by enhanced osteogenic differentiation and matrix mineralization of bone marrow-derived mesenchymal stem cells (BMSCs). Biochemical analysis reveals that S99N mutation in FGF9 leads to significantly impaired FGF signaling, as evidenced by diminished activity of Erk1/2 pathway and decreased beta-catenin and c-Myc expression when compared with wild-type FGF9. Importantly, the binding of FGF9(S99N) to its receptor is severely impaired although the dimerization ability of mutant FGF9 itself or with wild-type FGF9 is not detectably affected, providing a basis for the defective FGFR signaling. Collectively, our data demonstrate a previously uncharacterized mutation in FGF9 as one of the causes of SYNS, implicating an important role of FGF9 in normal joint development.

OX40 agonist combined with irreversible electroporation synergistically eradicates established tumors and drives systemic antitumor immune response in a syngeneic pancreatic cancer model.

In this study, we intended to explore a novel combination treatment scheme for pancreatic cancer, using irreversible electroporation (IRE) and OX40 agonist. We further aimed to investigate the capacity and mechanism of this combination treatment using an in vivo mouse aggressive pancreatic cancer model. To this end, mice subcutaneously injected with KPC1199 pancreatic tumor cells were treated with IRE, followed by intraperitoneal injection of OX40 agonist. Tumor growth and animal survival were observed. Flow cytometry analysis, immunohistochemistry, and immunofluorescence were used to evaluate the immune cell populations within the tumors. The tumor-specific immunity was assessed using ELISpot assay. Besides, the cytokine patterns both in serum and tumors were identified using Luminex assay. After combination therapy with IRE and OX40 agonist, 80% of the mice completely eradicated the established subcutaneous tumors, during the 120 days observation period. Rechallenging these tumor-free mice at day 120 with KPC1199 tumor cells leads to complete resistance to tumor growth, suggesting that the combination therapy generated long-term-specific antitumor immune memory. Moreover, combination therapy significantly delayed the growth of contralateral untreated tumors, and significantly prolonged animal survival, suggesting that a potent systematic anti-tumor immunity was induced by combination therapy. Mechanically, combination therapy amplified antitumor immune response induced by IRE, as manifested by the increased quality and quantity of CD8+ T cells trigged by IRE. Together, these results provide strong evidence for the clinical assessment of the combination of IRE and OX40 agonist in patients with pancreatic cancer.

Clinical Significance of MRI and Pathological Features of Giant Cell Tumor of Bone Boundary.

OBJECTIVE: To find new clues to reduce postoperative recurrence after intralesional curettage by studying MRI and pathological features of giant tumor of bone (GCTB) boundaries. METHODS: A retrospective study was performed in the departments of orthopaedic surgery and medical imaging at our hospitals from January 2006 to August 2016. A total of 16 GCTB patients confirmed by pathology were asked to participate in the present study. The age range was from 18 to 44 years (9 women and 7 men). All patients underwent MRI examination. All patients underwent en bloc resection and complete postoperative tumor segments were obtained. Five specimens were obtained randomly at the place of the segments where the GCTB boundary showed different types on MRI. Ordinary HE staining was used for all specimens and we measured the depth of local tumor cell infiltration (240 measurements). Results were expressed as means ± standard deviation. Statistical analyses were carried out with one-way ANOVA and the Student-Newman-Keuls test. P < 0.05 was considered statistically significant. The kappa test was used to analyze the degree of agreement of observers. RESULTS: A total of 16 patients (median age 30.56 years; range, 18-44 years) with GCTB (the number of distal femurs and proximal tibias was 9 and 7, respectively) were tested. The boundaries of all GCTB cases were composed of clear boundary, relatively clear boundary, and blurred boundary in different proportions on MRI. Based on continuous observation of all MRI, all boundaries were incomplete. The kappa value between two radiologists and two pathologists was 0.91 and 0.88, respectively. The average depth of local tumor cell infiltration in the clear boundary, relatively clear boundary, and blurred boundary groups was 0.42 ± 0.11 mm, 2.85 ± 0.21 mm, and 4.83 ± 0.12 mm, respectively. There was statistical difference among the three groups (F = 17.62, P < 0.05). There was also statistical difference between each of the two groups (q-value was 8.95, 14.28, and 5.21, respectively, P < 0.05). The depth of local tumor cell infiltration with blurred boundaries on MRI was the largest and the depth with clear boundaries was the smallest. CONCLUSION: The intralesional curettage boundaries need to be expanded on the basis of different types of boundaries provided by MRI.

Preliminary application of 3D-printed coplanar template for iodine-125 seed implantation therapy in patients with advanced pancreatic cancer.

AIM: To evaluate a 3D-printed coplanar template for iodine-125 seed implantation therapy in patients with pancreatic cancer. METHODS: A retrospective analysis of our database was performed, and a total of 25 patients with pancreatic cancer who underwent iodine-125 seed implantation between January 2014 and November 2017 were analyzed. Of these, 12 implantations were assisted by a 3D-printed coplanar template (group A), and 13 implantations performed freehand were selected as a control group (group B). A 3D coplanar template was designed and printed according to a preoperative CT scan and treatment planning system. The iodine-125 seeds were then implanted using the template as a guide. Dosimetric verification was performed after implantation. Pre- and postoperative D90, V100, and V150 were calculated. The success rate of iodine-125 seed implantation, dosimetric parameters, and complications were analyzed and compared between the two groups. RESULTS: Iodine-125 seed implantation was successfully performed in both groups. In group A, the median pre- and postoperative D90 values were 155.32 ± 8.05 Gy and 154.82 ± 16.43 Gy, respectively; the difference between these values was minimal and not statistically significant (P > 0.05). Postoperative V100 and V150 were 91.05% ± 4.06% and 64.54% ± 13.40%, respectively, which met the treatment requirement. A better dosimetric parameter was observed in group A than in group B, and the difference was statistically significant (V100: 91.05% ± 4.06% vs 72.91% ± 13.78%, P < 0.05). No major procedure-related complications were observed in either group. For group A, mild hemorrhage was observed in 1 patient with a peritoneal local hematoma due to mesenteric vein damage from the iodine-125 seed implantation needle. The hematoma resolved spontaneously without treatment. Postoperative blood amylase levels remained within the normal range for all patients. CONCLUSION: A 3D-printed coplanar template appears to be a safe and effective iodine-125 seed implantation guidance tool to improve implantation accuracy and optimize dosimetric distribution.

Novel impact of the DNMT3A R882H mutation on GSH metabolism in a K562 cell model established by TALENs.

DNA methyltransferase 3A (DNMT3A) mutations occurred in 18%~23% of acute myeloid leukemia (AML) patients, and were considered to be an adverse prognostic factor for adult de novo AML cases. However, the relevant molecular mechanism of the mutation in AML pathogenesis remains obscure. In this study, we established K562 and SKM1 cell model carrying the DNMT3A R882H mutation via transcription activator-like effector nuclease (TALEN) and Clustered regularly interspaced short palindromic repeats (CRISPR/Cas9) technology, and discovered that mutated DNMT3A could promote the proliferative capability of malignant cell clones. Further RNA microarray analysis revealed that some genes crucial for glutathione (GSH) synthesis, including CTH, PSPH, PSAT1 and especially SLC7A11 (the cysteine/glutamate transporter) were significantly up-regulated, which resulted in significant elevation of intracellular GSH levels. A subsequent experiment demonstrated that the mutant clones are resistant to chemotherapy as well as SLC7A11-inhibitorsBy shRNA induced SLC7A11 silencing, we discovered profoundly decreased cellular GSH and cell proliferative ability of DNMT3A mutated clones. Our results provided novel insight into the role of the DNMT3A R882H mutation in AML pathogenesis and suggested that targeting the cellular GSH synthetic pathway could enhance the current therapy for AML patients with the DNMT3A R882H mutation.

[CT-guided percutaneous removal of osteoid osteoma].

OBJECTIVE: To evaluate the methods of CT-guided percutaneous removal of osteoid osteoma. METHODS: From February 2003 to December 2003, there were 11 patients, at a mean age of 19.3 years old (from 14 to 32 years old). Seven cases were male, and 4 cases were female. Diagnosis was supported by the complete clinical and imaging file. Eleven cases with osteoid osteomas were treated with CT-guided percutaneous excision. The location involved were femoral neck (6 cases), acetabulum (4 cases), humeral neck (1 case). At first, CT scanning was done in the whole nidus with thin slices (2 mm thick), and the CT scan slice passing through the center of the nidus was selected. Then the whole nidus was removed by trephine along the guidewire which was inserted into the bone up to the nidus and was protected by the trocar. Finally complete lesion resection was checked with CT. RESULTS: Nine cases had a final pathological diagnosis of osteoid osteomas. Complete pain relief was obtained in these patients after the day of operation. There were no complications, no recurrence and patients remained symptom free at follow-up of 8-18 months (mean, 15.2 months). CONCLUSION: The methods of CT guided percutaneous removal of osteoid osteoma is a minimally invasive technique that represents the efficacy and safety.

DNMT3A mutation analysis in adult patients with acute lymphoblastic leukemia.

DNA methyl-transferase 3A (DNMT3A) mutation has recently been identified as an independent risk factor for patients with acute myeloid leukemia (AML). However, reports are scanty on its rate and subsequent impact on patients with acute lymphoblastic leukemia (ALL), especially in Chinese population. In this study, we investigated the incidence and prognostic implication of DNMT3A mutation in 57 Chinese adult ALL patients. A total of 3 (5.3%) T-ALL cases were found to have the DNMT3A R882H mutation, which was significantly greater than that found in B-ALL subtype (P=0.048). The patients aged between 40 and 60 years old had higher mutation rate than other age groups (P=0.042). Patients with DNMT3A mutation had shorter overall survival (OS) than their wild-type counterparts. Our study demonstrated that Chinese ALL patients might develop DNMT3A mutation, which exerts a negative impact on their prognosis. These findings might help in risk stratification and treatment choice for Chinese ALL patients.

mTORC1 maintains the tumorigenicity of SSEA-4(+) high-grade osteosarcoma.

Inactivation of p53 and/or Rb pathways restrains osteoblasts from cell-cycle exit and terminal differentiation, which underpins osteosarcoma formation coupled with dedifferentiation. Recently, the level of p-S6K was shown to independently predict the prognosis for osteosarcomas, while the reason behind this is not understood. Here we show that in certain high-grade osteosarcomas, immature SSEA-4(+) tumor cells represent a subset of tumor-initiating cells (TICs) whose pool size is maintained by mTORC1 activity. mTORC1 supports not only SSEA-4(+) cell self-renewal through S6K but also the regeneration of SSEA-4(+) TICs by SSEA-4(-) osteosarcoma cell dedifferentiation. Mechanistically, active mTORC1 is required to prevent a likely upregulation of the cell-cycle inhibitor p27 independently of p53 or Rb activation, which otherwise effectively drives the terminal differentiation of SSEA-4(-) osteosarcoma cells at the expense of dedifferentiation. Thus, mTORC1 is shown to critically regulate the retention of tumorigenicity versus differentiation in discrete differentiation phases in SSEA-4(+) TICs and their progeny.

Triple-phase dynamic MRI: a new clue to predict malignant transformation of giant cell tumor of bone.

OBJECTIVE: Our purpose was, through the comparison of the characteristics of time-intensity curve on triple-phase dynamic contrast-enhanced MRI among groups of giant cell tumor of bone (GCTB), recurrent benign giant cell tumor of bone (RBGCTB), and secondary malignant giant cell tumor of bone (SMGCTB), to find clues to predict the malignant transformation of GCTB. SUBJECTS AND METHODS: 21 patients diagnosed as GCTB were included in this study. All cases took recurrence after intralesional curettage. 9 cases were confirmed as SMGCTB and 12 cases were confirmed as RBGCTB. Cases were divided into four groups: group A, GCTB (n=9); group B, SMGCTB (n=9); group C, GCTB (n=12); group D, RBGCTB (n=12). Enhancement index(EI) of lesions on DCEMRI was calculated using formula: EI(t)=[S(t)-S(0)]/S(0), where S(0) was signal intensity of lesion on non-contrast-enhanced T1-weighted images and S(t) was signal intensity of lesion on DCEMRI (t=30, 60, 180s). Enhancement index of each group in each phase was compared using One-Way ANOVA analysis. Slope values of time-intensity curve were compared by the same way. RESULTS: Time-intensity curve of SMGCTB was characterized by a steep upward slope followed by an early and rapid washout phase. Time-intensity curve of GCTB and RBGCTB was characterized by a steep slope followed by a relatively slow washout phase. No significant difference in enhancement index was found in the first phase (p>0.05). There was significant difference in the second and the third phase (p<0.05). Enhancement index of group B (SMGCTB) was smaller. There was no difference in rising slope value (p>0.05). CONCLUSIONS: Dynamic contrast-enhanced MRI appears a helpful method to find new clues to predict malignant transformation of GCTB.