-
The New England Journal of Medicine Feb 2003Ewing's sarcoma and primitive neuroectodermal tumor of bone are closely related, highly malignant tumors of children, adolescents, and young adults. A new drug... (Clinical Trial)
Clinical Trial Randomized Controlled Trial
BACKGROUND
Ewing's sarcoma and primitive neuroectodermal tumor of bone are closely related, highly malignant tumors of children, adolescents, and young adults. A new drug combination, ifosfamide and etoposide, was highly effective in patients with Ewing's sarcoma or primitive neuroectodermal tumor of bone who had a relapse after standard therapy. We designed a study to test whether the addition of these drugs to a standard regimen would improve the survival of patients with newly diagnosed disease.
METHODS
Patients 30 years old or younger with Ewing's sarcoma, primitive neuroectodermal tumor of bone, or primitive sarcoma of bone were eligible. The patients were randomly assigned to receive 49 weeks of standard chemotherapy with doxorubicin, vincristine, cyclophosphamide, and dactinomycin or experimental therapy with these four drugs alternating with courses of ifosfamide and etoposide.
RESULTS
A total of 518 patients met the eligibility requirements. Of 120 patients with metastatic disease, 62 were randomly assigned to the standard-therapy group and 58 to the experimental-therapy group. There was no significant difference in five-year event-free survival between the treatment groups (P=0.81). Among the 398 patients with nonmetastatic disease, the mean (+/-SE) five-year event-free survival among the 198 patients in the experimental-therapy group was 69+/-3 percent, as compared with 54+/-4 percent among the 200 patients in the standard-therapy group (P=0.005). Overall survival was also significantly better among patients in the experimental-therapy group (72+/-3.4 percent vs. 61+/-3.6 percent in the standard-therapy group, P=0.01).
CONCLUSIONS
The addition of ifosfamide and etoposide to a standard regimen does not affect the outcome for patients with metastatic disease, but it significantly improves the outcome for patients with nonmetastatic Ewing's sarcoma, primitive neuroectodermal tumor of bone, or primitive sarcoma of bone.
Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Child; Cyclophosphamide; Dactinomycin; Disease Progression; Disease-Free Survival; Doxorubicin; Drug Administration Schedule; Etoposide; Female; Humans; Ifosfamide; Male; Neuroectodermal Tumors, Primitive; Prognosis; Sarcoma; Sarcoma, Ewing; Survival Rate; Treatment Failure; Vincristine
PubMed: 12594313
DOI: 10.1056/NEJMoa020890 -
Nature Methods Aug 2018Brain tumors are among the most lethal and devastating cancers. Their study is limited by genetic heterogeneity and the incompleteness of available laboratory models....
Brain tumors are among the most lethal and devastating cancers. Their study is limited by genetic heterogeneity and the incompleteness of available laboratory models. Three-dimensional organoid culture models offer innovative possibilities for the modeling of human disease. Here we establish a 3D in vitro model called a neoplastic cerebral organoid (neoCOR), in which we recapitulate brain tumorigenesis by introducing oncogenic mutations in cerebral organoids via transposon- and CRISPR-Cas9-mediated mutagenesis. By screening clinically relevant mutations identified in cancer genome projects, we defined mutation combinations that result in glioblastoma-like and central nervous system primitive neuroectodermal tumor (CNS-PNET)-like neoplasms. We demonstrate that neoCORs are suitable for use in investigations of aspects of tumor biology such as invasiveness, and for evaluation of drug effects in the context of specific DNA aberrations. NeoCORs will provide a valuable complement to the current basic and preclinical models used to study brain tumor biology.
Topics: Animals; Brain Neoplasms; Disease Models, Animal; Genes, myc; Genetic Engineering; Glioblastoma; Heterografts; Human Embryonic Stem Cells; Humans; Male; Mice; Mice, Nude; Mutation; Neuroectodermal Tumors, Primitive; Oncogenes; Organoids; Transcriptome; Xenograft Model Antitumor Assays
PubMed: 30038414
DOI: 10.1038/s41592-018-0070-7 -
Cell Feb 2016Primitive neuroectodermal tumors of the central nervous system (CNS-PNETs) are highly aggressive, poorly differentiated embryonal tumors occurring predominantly in young...
Primitive neuroectodermal tumors of the central nervous system (CNS-PNETs) are highly aggressive, poorly differentiated embryonal tumors occurring predominantly in young children but also affecting adolescents and adults. Herein, we demonstrate that a significant proportion of institutionally diagnosed CNS-PNETs display molecular profiles indistinguishable from those of various other well-defined CNS tumor entities, facilitating diagnosis and appropriate therapy for patients with these tumors. From the remaining fraction of CNS-PNETs, we identify four new CNS tumor entities, each associated with a recurrent genetic alteration and distinct histopathological and clinical features. These new molecular entities, designated "CNS neuroblastoma with FOXR2 activation (CNS NB-FOXR2)," "CNS Ewing sarcoma family tumor with CIC alteration (CNS EFT-CIC)," "CNS high-grade neuroepithelial tumor with MN1 alteration (CNS HGNET-MN1)," and "CNS high-grade neuroepithelial tumor with BCOR alteration (CNS HGNET-BCOR)," will enable meaningful clinical trials and the development of therapeutic strategies for patients affected by poorly differentiated CNS tumors.
Topics: Amino Acid Sequence; Central Nervous System Neoplasms; Child; DNA Methylation; Forkhead Transcription Factors; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Humans; Molecular Sequence Data; Neuroectodermal Tumors; Proto-Oncogene Proteins; Repressor Proteins; Signal Transduction; Trans-Activators; Tumor Suppressor Proteins
PubMed: 26919435
DOI: 10.1016/j.cell.2016.01.015 -
FEBS Letters Nov 2020Aberrant expression of glycosphingolipids (GSLs) is a unique feature of cancer and stromal cells in tumor microenvironments. Although the impact of GSLs on tumor... (Review)
Review
Aberrant expression of glycosphingolipids (GSLs) is a unique feature of cancer and stromal cells in tumor microenvironments. Although the impact of GSLs on tumor progression remains largely unclear, anticancer immunotherapies directed against GSLs are attracting growing attention. Here, we focus on GD2, a disialoganglioside expressed in tumors of neuroectodermal origin, and Globo H ceramide (GHCer), the most prevalent cancer-associated GSL overexpressed in a variety of epithelial cancers. We first summarize recent advances on our understanding of GD2 and GHCer biology and then discuss the clinical development of the first immunotherapeutic agent targeting a glycolipid, the GD2-specific antibody dinutuximab, its approved indications, and new strategies to improve its efficacy for neuroblastoma. Next, we review ongoing clinical trials on Globo H-targeted immunotherapeutics. We end with highlighting how these studies provide sound scientific rationales for targeting GSLs in cancer and may facilitate a rational design of new GSL-targeted anticancer therapeutics.
Topics: Antibodies, Monoclonal; Antigens, Tumor-Associated, Carbohydrate; Antineoplastic Agents, Immunological; Clinical Trials as Topic; Gangliosides; Gene Expression Regulation, Neoplastic; Glycosphingolipids; Humans; Immunotherapy; Neoplasms, Glandular and Epithelial; Neuroectodermal Tumors; Tumor Microenvironment
PubMed: 32860713
DOI: 10.1002/1873-3468.13917 -
Archives of Pathology & Laboratory... Nov 2018Melanotic neuroectodermal tumor of infancy, albeit rare and generally regarded as benign, is an important tumor to recognize because of its rapid growth, potential for... (Review)
Review
CONTEXT.—
Melanotic neuroectodermal tumor of infancy, albeit rare and generally regarded as benign, is an important tumor to recognize because of its rapid growth, potential for local recurrence, and small round blue cell morphology, which can lead to misdiagnosis of a malignant neoplasm.
OBJECTIVE.—
To review its clinical presentation and immunomorphologic findings, and discuss common entities in the differential diagnosis.
DATA SOURCES.—
The study involved PubMed searches, including multiple review articles, case studies, retrospective studies, selected book chapters, and University of Michigan cases.
CONCLUSIONS.—
Melanotic neuroectodermal tumor of infancy most commonly occurs in the bones of the head and neck region during the first year of life, but it can also present in other locations, including the central nervous system, testes, ovaries, and subcutaneous soft tissues. Histologically, it is composed of a biphasic population of cells, consisting of epithelioid melanin-producing cells and primitive neurogenic cells in a fibrocollagenous stroma. These microscopic findings, especially in small biopsies, can lead to a broad differential diagnosis that includes malignant small round blue cell tumors and malignant melanoma. Melanotic neuroectodermal tumor of infancy commonly has an infiltrative growth pattern, and anatomic constraints often lead to incomplete resection and local recurrence, requiring multiple surgical operations. Because melanotic neuroectodermal tumor of infancy can mimic a more aggressive and aggressively treated malignancy, recognition of this rare tumor is very crucial for pathologists.
Topics: Female; Humans; Infant; Infant, Newborn; Male; Neuroectodermal Tumor, Melanotic
PubMed: 30407852
DOI: 10.5858/arpa.2018-0241-RA -
Pediatric Blood & Cancer Aug 2021Approximately 30% of children with medulloblastoma (MB) experience recurrence, which is usually incurable. This study compared the overall survival (OS) of patients... (Randomized Controlled Trial)
Randomized Controlled Trial
Temozolomide with irinotecan versus temozolomide, irinotecan plus bevacizumab for recurrent medulloblastoma of childhood: Report of a COG randomized Phase II screening trial.
BACKGROUND
Approximately 30% of children with medulloblastoma (MB) experience recurrence, which is usually incurable. This study compared the overall survival (OS) of patients receiving temozolomide (TMZ) and irinotecan with that of patients receiving TMZ, irinotecan, and bevacizumab for recurrent MB/central nervous system (CNS) primitive neuroectodermal tumor (PNET).
METHODS
Patients with relapsed/refractory MB or CNS PNET were randomly assigned to receive TMZ (150 mg/m /day PO on days 1-5) and irinotecan (50 mg/m /day IV on days 1-5) with or without bevacizumab (10 mg/kg IV on days 1 and 15).
RESULTS
One hundred five patients were eligible and treated on study. Median OS was 13 months in the standard arm and 19 months with the addition of bevacizumab; median event-free survival (EFS) was 6 months in the standard arm and 9 months with the addition of bevacizumab. The hazard ratio for death from the stratified relative-risk regression model is 0.63. Overall, 23 patients completed 12 courses of planned protocol therapy, 23% (12/52) in the experimental arm with bevacizumab versus 21% (11/53) in the standard arm. Toxicity profiles were comparable in both treatment arms. The estimate of the incidence of feasibility events associated with the bevacizumab arm is three of 52 (5.8%) (95% CI 1.2-16%). Events included myelosuppression, electrolyte abnormalities, diarrhea, and elevated transaminases. One intracranial hemorrhage event was observed in each arm.
CONCLUSION
The addition of bevacizumab to TMZ/irinotecan significantly reduced the risk of death in children with recurrent MB. The combination was relatively well tolerated in this heavily pretreated cohort. The three-drug regimen demonstrated a sufficient risk reduction to warrant further investigation.
Topics: Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Brain Neoplasms; Child; Humans; Irinotecan; Medulloblastoma; Neuroectodermal Tumors, Primitive; Temozolomide
PubMed: 33844469
DOI: 10.1002/pbc.29031 -
Archives of Pathology & Laboratory... Jun 2012Primitive neuroectodermal tumors exist as a part of the Ewing sarcoma/primitive neuroectodermal tumor family. These tumors most commonly arise in the chest wall and... (Review)
Review
Primitive neuroectodermal tumors exist as a part of the Ewing sarcoma/primitive neuroectodermal tumor family. These tumors most commonly arise in the chest wall and paraspinal regions; cases with a renal origin are rare entities, but have become increasingly reported in recent years. Although such cases occur across a wide age distribution, the average age for a patient with a renal primitive neuroectodermal tumor is the mid- to late 20s, with both males and females susceptible. Histologically, these tumors are characterized by pseudorosettes. Immunohistochemically, CD99 is an important diagnostic marker. Clinically, these are aggressive tumors, with an average 5-year disease-free survival rate of only 45% to 55%. Given that renal primitive neuroectodermal tumor bears many similarities to other renal tumors, it is important to review the histologic features, immunostaining profile, and genetic abnormalities that can be used for its correct diagnosis.
Topics: Biomarkers, Tumor; Diagnosis, Differential; Humans; Kidney; Kidney Neoplasms; Neuroectodermal Tumors, Primitive
PubMed: 22646279
DOI: 10.5858/arpa.2011-0104-RS -
The American Journal of Surgical... Jan 2014GATA3 is a transcription factor important in the differentiation of breast epithelia, urothelia, and subsets of T lymphocytes. It has been suggested to be useful in the...
GATA3 is a transcription factor important in the differentiation of breast epithelia, urothelia, and subsets of T lymphocytes. It has been suggested to be useful in the evaluation of carcinomas of mammary or urothelial origin or metastatic carcinomas, but its distribution in normal and neoplastic tissues is incompletely mapped. In this study, we examined normal developing and adult tissues and 2040 epithelial and 460 mesenchymal or neuroectodermal neoplasms for GATA3 expression to explore its diagnostic value in surgical pathology, using monoclonal antibody (clone L50-823) and Leica Bond automated immunohistochemistry. GATA3 was expressed in trophoblast, fetal and adult epidermis, adult mammary and some salivary gland and sweat gland ductal epithelia, urothelia, distal nephron in developing and adult tissues, some prostatic basal cells, and subsets of T lymphocytes. It was expressed stronger in fetal than in adult mesothelia and was absent in respiratory and gastrointestinal epithelia. In epithelial neoplasms, GATA3 was expressed in >90% of primary and metastatic ductal and lobular carcinomas of the breast, urothelial, and cutaneous basal cell carcinomas and trophoblastic and endodermal sinus tumors. In metastatic breast carcinomas, it was more sensitive than GCDFP. Among squamous cell carcinomas, the expression was highest in the skin (81%) and lower in cervical (33%), laryngeal (16%), and pulmonary tumors (12%). Common positivity was found in skin adnexal tumors (100%), mesothelioma (58%), salivary gland (43%), and pancreatic (37%) ductal carcinomas, whereas frequency of expression in adenocarcinomas of lung, stomach, colon, endometrium, ovary, and prostate was <10%. Chromophobe renal cell carcinoma was a unique renal tumor with frequent positivity (51%), whereas oncocytomas were positive in 17% of cases but other types only rarely. Among mesenchymal and neuroectodermal tumors, paragangliomas were usually positive, which sets these tumors apart from epithelial neuroendocrine tumors. Mesenchymal tumors were only sporadically positive, except epithelia of biphasic synovial sarcomas. GATA3 is a useful marker in the characterization of not only mammary and urothelial but also renal and germ cell tumors, mesotheliomas, and paragangliomas. The multiple specificities of GATA3 should be taken into account when using this marker to detect metastatic mammary or urothelial carcinomas.
Topics: Biomarkers, Tumor; Biopsy; Carcinoma; Embryo, Mammalian; Female; GATA3 Transcription Factor; Gestational Age; Humans; Immunohistochemistry; Male; Neoplasms, Connective Tissue; Neuroectodermal Tumors; Predictive Value of Tests; Prognosis
PubMed: 24145643
DOI: 10.1097/PAS.0b013e3182a0218f -
Pediatric and Developmental Pathology :... 2012Ewing sarcoma/peripheral primitive neuroectodermal tumor (EWS/pPNET) and other tumors with EWS gene rearrangements encompass a malignant and intermediate neoplasm with a... (Review)
Review
Ewing sarcoma/peripheral primitive neuroectodermal tumor (EWS/pPNET) and other tumors with EWS gene rearrangements encompass a malignant and intermediate neoplasm with a broad anatomic distribution and a wide age range but a predilection for soft tissue in children, adolescents, and young adults. The overlapping histologic, immunohistochemical and cytogenetic and molecular genetic features create diagnostic challenges despite significant clinical and prognostic differences. Ewing sarcoma is the 3rd most common sarcoma in children and adolescents, and desmoplastic small round cell tumor is a rare neoplasm that occurs more often in older children, adolescents, and young adults. Pathologic examination is complemented by immunohistochemistry, cytogenetics, and molecular genetics. This article reviews the clinicopathologic features of EWS/pPNET and desmoplastic small round cell tumor in the spectrum of tumors with EWS gene rearrangements. Other tumors with different histopathologic features and an EWS gene rearrangement are discussed elsewhere in this volume.
Topics: Adolescent; Child; Desmoplastic Small Round Cell Tumor; Gene Rearrangement; Humans; Neuroectodermal Tumors, Primitive, Peripheral; RNA-Binding Protein EWS; Sarcoma, Ewing; Young Adult
PubMed: 22420726
DOI: 10.2350/11-08-1078-PB.1 -
Seminars in Cancer Biology Apr 2009Chemokines and chemokine receptors play an important role in immune homeostasis and surveillance. Altered or defective expression of chemokines and/or chemokine... (Review)
Review
Chemokines and chemokine receptors play an important role in immune homeostasis and surveillance. Altered or defective expression of chemokines and/or chemokine receptors could lead to a disease state including autoimmune disorder or cancer. Tumors from glioblastoma, melanoma, and neuroblastoma secrete high levels of chemokines that can promote tumor growth and progression or induce stromal cells present in the tumor microenvironment to produce cytokines or chemokines which, in turn, can regulate angiogenesis, tumor growth, and metastasis. On the other hand, chemokines secreted by tumor or stromal cells can also attract leukocytes such as dendritic cells, macrophages, neutrophils, and lymphocytes which may downmodulate tumor growth. New therapies that are aimed at limiting tumor growth and progression by attracting immune effector cells to the tumor site with chemokines may hold the key to the successful treatment of cancer, although this approach may be hampered by possible tumor growth-stimulating effects of chemokines.
Topics: Animals; Cell Movement; Chemokines; Humans; Leukocytes; Neuroectodermal Tumors; Receptors, Chemokine; Stromal Cells
PubMed: 19049876
DOI: 10.1016/j.semcancer.2008.11.002