The discovery of induced pluripotent stem cells(iPSCs) is a promising advancement in the field of regenerative medicine. Previous studies have indicated that the teratoma-forming propensity of iPSCs is variable; however, the relationship between tumorigenic potential and genomic instability in human iPSCs (HiPSCs) remains to be fully elucidated. Here, we evaluated the malignant potential of HiPSCs by using both colony formation assays and tumorigenicity tests. We demonstrated that HiPSCs formed tumorigenic colonies when grown in cancer cell culture medium and produced malignancies in immunodeficient mice. Furthermore, we analyzed genomic instability in HiPSCs using whole-genome copy number variation analysis and determined that the extent of genomic instability was related with both the cells' propensity to form colonies and their potential for tumorigenesis. These findings indicate a risk for potential malignancy of HiPSCs derived from genomic instability and suggest that quality control tests, including comprehensive tumorigenicity assays and genomic integrity validation, should be rigorously executed before the clinical application of HiPSCs. In addition, HiPSCs should be generated through the use of combined factors or other approaches that decrease the likelihood of genomic instability.
Animals ; Carcinogenesis ; Cells, Cultured ; DNA Copy Number Variations ; Genomic Instability ; Humans ; Induced Pluripotent Stem Cells ; cytology ; metabolism ; transplantation ; Mice ; Mice, SCID ; NIH 3T3 Cells ; Octamer Transcription Factor-3 ; metabolism ; Teratocarcinoma ; etiology ; Teratoma ; etiology ; Tumor Stem Cell Assay

Spatially and temporally programmed expression of the Hox genes along the antero-posterior (A-P) axis is essential for correct pattern formation during embryonic development. An accumulating body of evidence indicates the pivotal role of spatial chromatin organization for the coordination of gene regulation. Recently, chromosome conformation capture (3C) technique has been developed and opened a new way to study chromosomal interactions in the nucleus. In this study, we describe 3C method we applied in F9 embryonic teratocarcinoma cells and demonstrate that the chromosomal interactions at Hox loci are successfully detected. Interestingly, at Hoxc loci, the abundance of intrachromosomal interactions with neighboring fragments was drastically decreased when the genes are expressed. These results indicate the possibility of the dynamic pattern of chromosomal interaction in association with the transcriptional regulation of Hox genes.
Axis, Cervical Vertebra ; Chromatin ; Embryonic Development ; Female ; Gene Expression ; Genes, Homeobox ; Pregnancy ; Teratocarcinoma ; Transcriptional Activation

OBJECTIVETo study the clinical, radiologic and pathologic features, as well as differential diagnosis of teratocarcinosarcoma in nasal cavity and paranasal sinuses.

METHODSLight microscopic examination and immunohistochemical study was performed in 5 cases of sinonasal teratocarcinosarcoma. The clinical, radiologic and pathologic features were analyzed and the literature was reviewed.

RESULTSAll 5 patients were males and their age ranged from 34 to 43 years (mean age = 39 years). The clinical presentation was nasal obstruction, epistaxis and headache. Physical examination often revealed a polypoid mass with contact bleeding. Computed tomography showed a homogeneous nasal mass with obturation of sinuses. Cystic changes, calcification or ossification was not observed. Histologically, the tumor showed a heterogeneous admixture of components from the 3 germ cell layers, exhibiting various degrees of maturation. Squamous epithelium, smooth muscle cells, chondro-osseous tissue, intestinal or respiratory type epithelium, "fetal-type" clear cells and immature neuroepithelium were commonly seen. Immunohistochemical study demonstrated that the epithelial component expressed cytokeratin and epithelial membrane antigen, while the mesenchymal component variably expressed vimentin, smooth muscle actin and S-100 protein. On the other hand, the neuroepithelial component expressed neuron-specific enolase, synaptophysin and chromogranin, and the primitive component expressed CD99. The initial biopsy diagnosis included capillary hemangioma, olfactory neuroblastoma, craniopharyngioma and malignant mixed tumor. Follow-up information was available in all patients. Two of which had local recurrence and 1 had cervical lymph node metastasis.

CONCLUSIONSSinonasal teratocarcinosarcoma is a rare and highly malignant tumor occurring in sinonasal tract. It manifests mainly in adult males and is characterized by a complex admixture of teratomatous and carcinosarcomatous components. "Fetal-type" clear cells, squamous epithelium and immature neuroepithelium represent important histologic characteristics useful in diagnosis.

Adult ; Carcinosarcoma ; diagnostic imaging ; metabolism ; pathology ; radiotherapy ; surgery ; Follow-Up Studies ; Humans ; Keratins ; metabolism ; Lymphatic Metastasis ; Male ; Mucin-1 ; metabolism ; Nasal Cavity ; Neck Dissection ; Neoplasm Recurrence, Local ; Nose Neoplasms ; diagnostic imaging ; metabolism ; pathology ; radiotherapy ; surgery ; Paranasal Sinus Neoplasms ; diagnostic imaging ; metabolism ; pathology ; radiotherapy ; surgery ; Radiography ; Teratocarcinoma ; diagnostic imaging ; metabolism ; pathology ; radiotherapy ; surgery

OBJECTIVES: Recent basic science studies continue to further our understanding of the fundamental mechanisms that likely underlie the therapeutic benefits of hyaluronan derivatives. The purpose of this study is to elucidate the effects of hyaluronan on ATDC5 proliferation and differentiation. METHODS: ATDC5 cells derived from mouse teratocarcinoma have the capacity to differentiate along a number of connective tissue pathways and are an attractive source of chondrocyte precursor cells. In this study, hyaluronan influencing ATDC5 chondrogenesis were investigated using an bone block culture system. The cell proliferation was analyzed by MTT assay. To validate ATDC5 differentiation we studied ALP activity, collagen content and western blot of Hsp40. RESULTS: In cell proliferation, ATDC5 cells didn't show significant difference between controls and hyaluronan-treated cultures. But hyaluronan induced ALP activity and increased collagen accumulation. Hyaluronantreated ATDC5 cells expressed Hsp40 mRNA and protein within 24 hours. CONCLUSIONS: Hyaluronan-induced chondrogenic differentiation was not associated with ATDC5 cell proliferation. Hyaluronan-induced Hsp40 in cells can protect the cell function from damaged protein. These data provide new insights into regulatory mechanism defining pharmacological effects of hyaluronan.
Animals ; Blotting, Western ; Cell Proliferation ; Chondrocytes* ; Chondrogenesis ; Collagen ; Connective Tissue ; Hyaluronic Acid* ; Mice ; RNA, Messenger ; Teratocarcinoma

Central diabetes insipidus is a rare disorder that can result as a consequence of diverse etiologies, including malformations, autoimmune, infiltrative(e.g. neoplastic or histiocytosis) or traumatic processes, as well as mutations in the gene encoding arginine vasopressin. Idiopathic central diabetes insipidus is a diagnosis of exclusion, one that has been made less frequently through the decades. Idiopathic central diabetes insipidus in children and adolescent requires a frequent follow-up regimen using serial brain MRI and CSF examinations especially if an isolated pituitary stalk thickening or loss of a hyperintense signal in the posterior lobe is observed. Also, so-called "idiopathic" central diabetes insipidus warrants close follow-up to determine the etiology, especially if anterior pituitary hormone deficiencies are detected. We report a case of idiopathic central diabetes insipidus with growth hormone deficiency and loss of a hyperintense signal in the posterior lobe of pituitary in the brain MRI. We followed up with serial contrast enhanced brain MRI and CSF evaluation for the early detection of an evolving occult hypothalamic-stalk lesion and finally detected a newly developed teratocarcinoma in the suprasellar region.
Adolescent ; Arginine Vasopressin ; Brain ; Child ; Diabetes Insipidus, Neurogenic* ; Diagnosis ; Follow-Up Studies ; Growth Hormone ; Humans ; Magnetic Resonance Imaging ; Pituitary Gland ; Pituitary Gland, Posterior ; Teratocarcinoma*

Sinonasal teratocarcinosarcoma is a very unusual malignant neoplasm. This neoplasm histologically consists of an epithelial elements and one or more mesenchymal components with immature and embryonal characteristics. These tumors, which is variously termed as malignant teratoma, blastoma, teratocarcinoma, or teratocarcinosarcoma, probably comprise a group of neoplasm by their similar characteristics of histology and biology. This is a case of teratocarcinosarcoma in a 67-year-old male, involving the right maxillary sinus and ethmoid sinus with invasion of hard palate. The tumor was totally resected via total maxillectomy, and the patient was given post-operative radiotherapy. A follow-up PNS CT after 7 months of the surgery showed no recurrence of the lesion or residual tumor. Extensive tumor necrosis, rapid growth and local destruction are the prominent features of this neoplasm. The clinical presentation, pathological features and clinical course of this unusuat malignancy are discussed with a reivew of the literature.
Aged ; Biology ; Ethmoid Sinus* ; Follow-Up Studies ; Humans ; Male ; Maxillary Sinus ; Necrosis ; Neoplasm, Residual ; Palate, Hard ; Paranasal Sinus Neoplasms ; Radiotherapy ; Recurrence ; Sarcoma ; Teratocarcinoma ; Teratoma

PURPOSE: We reviewed clinical features and survival rates of nonseminomatous germ cell testicular tumors(NSGCTs) and analyzed pathological risk factors of relapse in stage I group under surveillance program. MATERIALS AND METHODS: Forty one patients were treated for primary NSGCTs from February 1983 to April 1998. 20(48.8%) patients were stage I and 19 of them were followed up under surveillance program after orchiectomy and 1 underwent orchiectomy and adjuvant therapy(RPLND and PVB chemotherapy). 11(26.8%) were stage II and 10(24.4%) stage III and all stage II and III patients underwent orchiectomy and adjuvant therapy. Statistical analysis with Fisher`s exact test was performed to identify that pathological risk factors affected relapse rate. RESULTS: Mean age at diagnosis was 26 years(range 16-47) and mean follow-up period was 58 months(range 5-163). According to histopathological types, embryonal carcinoma, teratoma, teratocarcinoma and mixed type represented 19.5%, 26.8%, 7.3% and 46.3%, respectively. Among 41 patients, 33 showed significant elevation of tumor markers at diagnosis. The 5-year survival rates of stage I, II and III were 95%, 80% and 56%, respectively and overall 5-year survival rate was 82%. Among stage I patients under surveillance program, there was statistically significant increase of relapse rate in the patients with pathological risk factors(presence of embryonal elements, local stage T2 or higher, presence of lymphovascular invasion) as compared to those without. CONCLUSIONS: In stage I NSGCT patients, if there are pathological risk factors after orchiectomy, aggressive therapy such as early retroperitoneal lymph node dissection or chemotherapy is selectively needed.
Carcinoma, Embryonal ; Diagnosis ; Drug Therapy ; Follow-Up Studies ; Germ Cells* ; Humans ; Lymph Node Excision ; Orchiectomy ; Recurrence ; Risk Factors* ; Survival Rate* ; Teratocarcinoma ; Teratoma ; Biomarkers, Tumor

PURPOSE: The relative rarity of prepubertal testis tumors has resulted in poor understanding about incidence, histologic distribution and prognosis of germ cell tumors in children. We attempted to elucidate overall clinical features of testicular germ cell tumors in infants and children, to analyze risk factors for relapse in stage A yolk sac tumor(YST) and to find out possibility of testis-sparing surgery in prepubertal testicular teratoma. MATERIALS AND METHODS: Retrospectively, we reviewed 74 cases of primary testicular germ cell tumors of infants and children(under 15 years old) experienced in Seoul National University Hospital from January 1970 to November 1995. RESULTS: There were 38 YSTs(stage A, 34 cases, stage B; 3, stage C; 1), 32 teratomas(all stage A) and 4 teratocarcinomas(stage A, 3, stage C; 1). Median age of presentation was 2.0(range 0.4-15.0) years. Preoperative serum alpha-fetoprotein (alpha-FP) elevation was observed in 37 patients(100%) with YST, 2(7%) with teratoma, 3(100%) with teratocarcinoma and elevated serum beta human chorionic gonadotropin(beta-HCG) was observed in one patient(33%) with teratocarcinoma. Orchiectomy including 4 partial orchiectomy(all with teratoma) was done in all patients, chemotherapy in all patients with teratocarcinoma and stage B, C YST. Two-year survival rate was 92%(22 out of 24 patients who had been followed up) and 100%(19/19) with teratoma. Out of 4 patients with teratocarcinoma, 2 patients with stage A disease showed no evidence of disease, one patient progressed to death and follow-up was lost in the other one patient with stage C. In 9 patients with YST who had ultimately presented recurrence, initial symptoms and signs for recurrence were as follows; marker elevation(4), abdominal mass(3), inguinal mass(1) and scrotal mass(1). Their mean duration of relapse after surgery was 7.0 months. On pathologic review, 7 patients among total 34 patients with YST had at least one risk factors such as epididymal involvement(2), microangioinvasion(3) and focal embryonal component(2). Out of them(7), 5 patients proved to have relapse. There was statistically significant relationship between having risk factors and relapse(Fisher's exact test, p=0.0086). Complete remission rate after chemotherapy In all relapsed patients was 83%(5/6). Until now, there is no evidence of recurrence in 4 patients with teratoma who underwent partial orchiectomy CONCLUSIONS: YST is characterized as early presentation, high relapse rate and short relapse interval and had high response rate to chemotherapy and high survival rate. Therefore, careful surveillance is needed at least for 2 year in stage A patients with high risk group on pathology(microangioinvasion etc). Testis-sparing surgery may be considered as one of treatment options in prepubertal teratoma.
alpha-Fetoproteins ; Child* ; Chorion ; Drug Therapy ; Endodermal Sinus Tumor ; Follow-Up Studies ; Germ Cells* ; Humans ; Incidence ; Infant* ; Neoplasms, Germ Cell and Embryonal* ; Orchiectomy ; Prognosis ; Recurrence ; Retrospective Studies ; Risk Factors ; Seoul ; Survival Rate ; Teratocarcinoma ; Teratoma ; Testis ; Yolk Sac

Many drugs can result in a variety of pathologic reactions in the lung, especially the cytotoxic drugs. Amongcytotoxic drugs bleomycin is a prototype. Bleomycin-related pulmonary toxicity is usually known as dose-dependent and can be enhanced with concurrent oxygen therapy, irradiation, or other chemotherapeutic agents. The incidence of bleomycin-induced pulmonary toxicity has been reported as varying from 2 to 46%, and 1% of fatal lung disease. We describe the radiographic and HRCT findings of bleomycin-related pulmonary toxicity developed in two patients: one in ovarian teratocarcinoma, the other malignant lymphoma patient. Chest radiographs and HRCT of these patients showed ground-glass opacities, consolidation, linear and reticular opacities, and interlobular septal thickening. These abnormalities were bilateral, and symmetrical and were found predominantly in the area of mid-and lower-lung zone.
Bleomycin ; Humans ; Incidence ; Lung Diseases ; Lung* ; Lymphoma ; Oxygen ; Radiography, Thoracic ; Teratocarcinoma

BACKGROUND: Understanding the regulatory mechanisms of the smooth muscle cells differentiation is one of the central issues in researches of atherogenesis where smooth muscle cells undergo dedifferentiation and regain embryonic phenotype. Smooth muscle myosin heavy chain isoforms(SM1,SM2) are important molecular markers to define the stage of smooth muscle cell differentiation. METHODS: In order to establish an in vitro model of smooth muscle cell differentiation using a pluripotent murine embryonal teratocarcinoma cell line(P19 cell), we first isolated cDNA clone of mouse SM1 and then tried various chemicals to induce P19 cells to differentiate into smooth muscle cells, The expression of Sm1 and alpha-smooth muscle actin was examined using RNase protection assay, Western blotting and indirect immunofluorescence. RESULTS: In the presence of luM retinoic acid, a small proportion of P19 cells could be in duced to differentiate into smooth muscle cells expressing SM1 as well as alpha-smooth muscle actin since day 8 after treatment. By blocking the Brain-2 expression, thus inhibiting neuronal differentiation, we could obtain more abundant differentiated smooth muscle cells. Sequential immunofluorescencc demonstrated that it took weveral days for smooth muscle myosin heavy chain to organize completely in differentiation smooth muscle cells. On the other hand, 10nM retinoic acid, 1% dimethyl sulfoxide or 2mM hexamethylene bisacetamide could not indduce P19 cell to differentiate to smooth muscle cells. CONCLUSION: In conclusion, P19 cells can be induced to differentiate into smooth muscle cells and this in vitro system will be useful in understanding the regulation of SM1 gene expression as well as of angiogenesis.
Actins ; Animals ; Atherosclerosis ; Blotting, Western ; Clone Cells ; Dimethyl Sulfoxide ; DNA, Complementary ; Fluorescent Antibody Technique, Indirect ; Gene Expression ; Hand ; Mice ; Muscle, Smooth* ; Myocytes, Smooth Muscle* ; Myosin Heavy Chains ; Neurons ; Phenotype ; Ribonucleases ; Teratocarcinoma* ; Tretinoin