37 results on '"Miettinen MM"'
Search Results
2. Polymorphous hemangioendothelioma in a child with acquired immunodeficiency syndrome (AIDS)
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Paul SR, Hurford MT, Miettinen MM, Aronoff SC, Delvecchio M, Grewal H, and Tuluc M
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- 2008
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3. Phase I trial of Ganitumab plus Dasatinib to Cotarget the Insulin-Like Growth Factor 1 Receptor and Src Family Kinase YES in Rhabdomyosarcoma.
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Akshintala S, Sundby RT, Bernstein D, Glod JW, Kaplan RN, Yohe ME, Gross AM, Derdak J, Lei H, Pan A, Dombi E, Palacio-Yance I, Herrera KR, Miettinen MM, Chen HX, Steinberg SM, Helman LJ, Mascarenhas L, Widemann BC, Navid F, Shern JF, and Heske CM
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- Humans, Animals, Mice, Child, Adolescent, Young Adult, Adult, Dasatinib adverse effects, Insulin-Like Growth Factor I, Receptor, IGF Type 1, Antineoplastic Combined Chemotherapy Protocols adverse effects, Maximum Tolerated Dose, src-Family Kinases, Rhabdomyosarcoma
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Purpose: Antibodies against insulin-like growth factor (IGF) type 1 receptor have shown meaningful but transient tumor responses in patients with rhabdomyosarcoma (RMS). The SRC family member YES has been shown to mediate IGF type 1 receptor (IGF-1R) antibody acquired resistance, and cotargeting IGF-1R and YES resulted in sustained responses in murine RMS models. We conducted a phase I trial of the anti-IGF-1R antibody ganitumab combined with dasatinib, a multi-kinase inhibitor targeting YES, in patients with RMS (NCT03041701)., Patients and Methods: Patients with relapsed/refractory alveolar or embryonal RMS and measurable disease were eligible. All patients received ganitumab 18 mg/kg intravenously every 2 weeks. Dasatinib dose was 60 mg/m2/dose (max 100 mg) oral once daily [dose level (DL)1] or 60 mg/m2/dose (max 70 mg) twice daily (DL2). A 3+3 dose escalation design was used, and maximum tolerated dose (MTD) was determined on the basis of cycle 1 dose-limiting toxicities (DLT)., Results: Thirteen eligible patients, median age 18 years (range 8-29) enrolled. Median number of prior systemic therapies was 3; all had received prior radiation. Of 11 toxicity-evaluable patients, 1/6 had a DLT at DL1 (diarrhea) and 2/5 had a DLT at DL2 (pneumonitis, hematuria) confirming DL1 as MTD. Of nine response-evaluable patients, one had a confirmed partial response for four cycles, and one had stable disease for six cycles. Genomic studies from cell-free DNA correlated with disease response., Conclusions: The combination of dasatinib 60 mg/m2/dose daily and ganitumab 18 mg/kg every 2 weeks was safe and tolerable. This combination had a disease control rate of 22% at 5 months., (©2023 American Association for Cancer Research.)
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- 2023
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4. Multi-spectral immunofluorescence evaluation of the myeloid, T cell, and natural killer cell tumor immune microenvironment in chordoma may guide immunotherapeutic strategies.
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Lopez DC, Robbins YL, Kowalczyk JT, Lassoued W, Gulley JL, Miettinen MM, Gallia GL, Allen CT, Hodge JW, and London NR Jr
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Background: Chordoma is a rare, invasive, and devastating bone malignancy of residual notochord tissue that arises at the skull base, sacrum, or spine. In order to maximize immunotherapeutic approaches as a potential treatment strategy in chordoma it is important to fully characterize the tumor immune microenvironment (TIME). Multispectral immunofluorescence (MIF) allows for comprehensive evaluation of tumor compartments, molecular co-expression, and immune cell spatial relationships. Here we implement MIF to define the myeloid, T cell, and natural killer (NK) cell compartments in an effort to guide rational design of immunotherapeutic strategies for chordoma., Methods: Chordoma tumor tissue from 57 patients was evaluated using MIF. Three panels were validated to assess myeloid cell, T cell, and NK cell populations. Slides were stained using an automated system and HALO software objective analysis was utilized for quantitative immune cell density and spatial comparisons between tumor and stroma compartments., Results: Chordoma TIME analysis revealed macrophage infiltration of the tumor parenchyma at a significantly higher density than stroma. In contrast, helper T cells, cytotoxic T cells, and T regulatory cells were significantly more abundant in stroma versus tumor. T cell compartment infiltration more commonly demonstrated a tumor parenchymal exclusion pattern, most markedly among cytotoxic T cells. NK cells were sparsely found within the chordoma TIME and few were in an activated state. No immune composition differences were seen in chordomas originating from diverse anatomic sites or between those resected at primary versus advanced disease stage., Conclusion: This is the first comprehensive evaluation of the chordoma TIME including myeloid, T cell, and NK cell appraisal using MIF. Our findings demonstrate that myeloid cells significantly infiltrate chordoma tumor parenchyma while T cells tend to be tumor parenchymal excluded with high stromal infiltration. On average, myeloid cells are found nearer to target tumor cells than T cells, potentially resulting in restriction of T effector cell function. This study suggests that future immunotherapy combinations for chordoma should be aimed at decreasing myeloid cell suppressive function while enhancing cytotoxic T cell and NK cell killing., Competing Interests: NL receives research funding from Merck Sharp & Dohme, LLC regarding HPV related sinonasal carcinomas, holds stock in Navigen Pharmaceuticals and was a consultant for Cooltech Inc., none of which are relevant to the present manuscript. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Lopez, Robbins, Kowalczyk, Lassoued, Gulley, Miettinen, Gallia, Allen, Hodge and London.)
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- 2022
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5. Molecular Subtypes of Primary SCLC Tumors and Their Associations With Neuroendocrine and Therapeutic Markers.
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Qu S, Fetsch P, Thomas A, Pommier Y, Schrump DS, Miettinen MM, and Chen H
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- Basic Helix-Loop-Helix Transcription Factors genetics, Basic Helix-Loop-Helix Transcription Factors metabolism, CD8-Positive T-Lymphocytes, Cell Line, Tumor, Gene Expression Regulation, Neoplastic, Humans, Nuclear Proteins, Octamer Transcription Factors, Synaptophysin, YAP-Signaling Proteins, Lung Neoplasms genetics, Neuroendocrine Tumors genetics, Small Cell Lung Carcinoma genetics
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Introduction: A new molecular subtype classification was recently proposed for SCLC. It is necessary to validate it in primary SCLC tumors by immunohistochemical (IHC) staining and define its clinical relevance., Methods: We used IHC to assess four subtype markers (ASCL1, NEUROD1, POU2F3, and YAP1) in 194 cores from 146 primary SCLC tumors. The profiles of tumor-associated CD3
+ and CD8+ T-cells, MYC paralogs, SLFN11, and SYP were compared among different subtypes. Validation was performed using publicly available RNA sequencing data of SCLC., Results: ASCL1, NEUROD1, POU2F3, and YAP1 were the dominant molecular subtypes in 78.2%, 5.6%, 7%, and 2.8% of the tumors, respectively; 6.3% of the tumors were negative for all four subtype markers. Notably, three cases were uniquely positive for YAP1. Substantial intratumoral heterogeneity was observed, with 17.6% and 2.8% of the tumors being positive for two and three subtype markers, respectively. The non-ASCL1/NEUROD1 tumors had more CD8+ T-cells and manifested more frequently an "inflamed" immunophenotype. L-MYC and MYC were more often associated with ASCL1/NEUROD1 subtypes and non-ASCL1/NEUROD1 subtypes, respectively. SLFN11 expression was absent in 40% of the tumors, especially those negative for the four subtype markers. SYP was often expressed in the ASCL1 and NEUROD1 subtypes and was associated with less tumor-associated CD8+ T-cells and a "desert" immunophenotype., Conclusions: We validated the new molecular subtype classification in primary SCLC tumors by IHC and identified several intriguing associations between subtypes and therapeutic markers. The new subtype classification may potentially assist treatment decisions in SCLC., (Published by Elsevier Inc.)- Published
- 2022
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6. Phase I Clinical Trial of an Autologous Dendritic Cell Vaccine Against HER2 Shows Safety and Preliminary Clinical Efficacy.
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Maeng HM, Moore BN, Bagheri H, Steinberg SM, Inglefield J, Dunham K, Wei WZ, Morris JC, Terabe M, England LC, Roberson B, Rosing D, Sachdev V, Pack SD, Miettinen MM, Barr FG, Weiner LM, Panch S, Stroncek DF, Wood LV, and Berzofsky JA
- Abstract
Background: Despite recent advances, there is an urgent need for agents targeting HER2-expressing cancers other than breast cancer. We report a phase I study (NCT01730118) of a dendritic cell (DC) vaccine targeting HER2 in patients with metastatic cancer or bladder cancer at high risk of relapse., Patients and Methods: Part 1 of the study enrolled patients with HER2-expressing metastatic cancer that had progressed after at least standard treatment and patients who underwent definitive treatment for invasive bladder cancer with no evidence of disease at the time of enrollment. Part 2 enrolled patients with HER2-expressing metastatic cancer who had progressed after anti-HER2 therapy. The DC vaccines were prepared from autologous monocytes and transduced with an adenoviral vector expressing the extracellular and transmembrane domains of HER2 (AdHER2). A total of five doses were planned, and adverse events were recorded in patients who received at least one dose. Objective response was evaluated by unidimensional immune-related response criteria every 8 weeks in patients who received at least two doses. Humoral and cellular immunogenicity were assessed in patients who received more than three doses., Results: A total of 33 patients were enrolled at four dose levels (5 × 10
6 , 10 × 106 , 20 × 106 , and 40 × 106 DCs). Median follow-up duration was 36 weeks (4-124); 10 patients completed five doses. The main reason for going off-study was disease progression. The main adverse events attributable to the vaccine were injection-site reactions. No cardiac toxicity was noted. Seven of 21 evaluable patients (33.3%) demonstrated clinical benefit (1 complete response, 1 partial response, and 5 stable disease). After ≥3 doses, an antibody response was detected in 3 of 13 patients (23.1%), including patients with complete and partial responses. Lymphocytes from 10 of 11 patients (90.9%) showed induction of anti-HER2 responses measured by the production of at least one of interferon-gamma, granzyme B, or tumor necrosis factor-alpha, and there were multifunctional responses in 8 of 11 patients (72.7%)., Conclusions: The AdHER2 DC vaccine showed evidence of immunogenicity and preliminary clinical benefit in patients with HER2-expressing cancers, along with an excellent safety profile. It shows promise for further clinical applications, especially in combination regimens., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Maeng, Moore, Bagheri, Steinberg, Inglefield, Dunham, Wei, Morris, Terabe, England, Roberson, Rosing, Sachdev, Pack, Miettinen, Barr, Weiner, Panch, Stroncek, Wood and Berzofsky.)- Published
- 2021
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7. Neuraxial dysraphism in EPAS1- associated syndrome due to improper mesenchymal transition.
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Rosenblum JS, Cappadona AJ, Argersinger DP, Pang Y, Wang H, Nazari MA, Munasinghe JP, Donahue DR, Jha A, Smirniotopoulos JG, Miettinen MM, Knutsen RH, Kozel BA, Zhuang Z, Pacak K, and Heiss JD
- Abstract
Objective: To investigate the effect of somatic, postzygotic, gain-of-function mutation of Endothelial Per-Arnt-Sim (PAS) domain protein 1 ( EPAS1 ) encoding hypoxia-inducible factor-2α (HIF-2α) on posterior fossa development and spinal dysraphism in EPAS1 gain-of-function syndrome, which consists of multiple paragangliomas, somatostatinoma, and polycythemia., Methods: Patients referred to our institution for evaluation of new, recurrent, and/or metastatic paragangliomas/pheochromocytoma were confirmed for EPAS1 gain-of-function syndrome by identification of the EPAS1 gain-of-function mutation in resected tumors and/or circulating leukocytes. The posterior fossa, its contents, and the spine were evaluated retrospectively on available MRI and CT images of the head and neck performed for tumor staging and restaging. The transgenic mouse model underwent Microfil vascular perfusion and subsequent intact ex vivo 14T MRI and micro-CT as well as gross dissection, histology, and immunohistochemistry to assess the role of EPAS1 in identified malformations., Results: All 8 patients with EPAS1 gain-of-function syndrome demonstrated incidental posterior fossa malformations-one Dandy-Walker variant and 7 Chiari malformations without syringomyelia. These findings were not associated with a small posterior fossa; rather, the posterior fossa volume exceeded that of its neural contents. Seven of 8 patients demonstrated spinal dysraphism; 4 of 8 demonstrated abnormal vertebral segmentation. The mouse model similarly demonstrated features of neuraxial dysraphism, including cervical myelomeningocele and spinal dysraphism, and cerebellar tonsil displacement through the foramen magnum. Histology and immunohistochemistry demonstrated incomplete mesenchymal transition in the mutant but not the control mouse., Conclusions: This study characterized posterior fossa and spinal malformations seen in EPAS1 gain-of-function syndrome and suggests that gain-of-function mutation in HIF-2α results in improper mesenchymal transition., (Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)
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- 2020
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8. Safe marginal resection of atypical neurofibromas in neurofibromatosis type 1.
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Nelson CN, Dombi E, Rosenblum JS, Miettinen MM, Lehky TJ, Whitcomb PO, Hayes C, Scott G, Benzo S, Widemann BC, and Chittiboina P
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Objective: Patients with neurofibromatosis type 1 (NF1) are predisposed to visceral neurofibromas, some of which can progress to premalignant atypical neurofibromas (ANFs) and malignant peripheral nerve sheath tumors (MPNSTs). Though subtotal resection of ANF may prevent malignant transformation and thus deaths with no neural complications, local recurrences require reoperation. The aim of this study was to assess the surgical morbidity associated with marginal resection of targeted ANF nodules identified via preoperative serial volumetric MRI and 18F-FDG-PET imaging., Methods: The authors analyzed clinical outcomes of 16 NF resections of 21 tumors in 11 NF1 patients treated at the NIH Clinical Center between 2008 and 2018. Preoperative volumetric growth rates and 18F-FDG-PET SUVMax (maximum standardized uptake value within the tumor) of the target lesions and any electromyographic or nerve conduction velocity abnormalities of the parent nerves were measured and assessed in tandem with postoperative complications, histopathological classification of the resected tumors, and surgical margins through Dunnett's multiple comparisons test and t-test. The surgical approach for safe marginal resection of ANF was also described., Results: Eleven consecutive NF1 patients (4 male, 7 female; median age 18.5 years) underwent 16 surgical procedures for marginal resections of 21 tumors. Preoperatively, 13 of the 14 (93%) sets of serial MRI studies and 10 of the 11 (91%) 18F-FDG-PET scans showed rapid growth (≥ 20% increase in volume per year) and avidity (SUVMax ≥ 3.5) of the identified tumor, respectively (median tumor size 48.7 cm3; median growth rate 92% per year; median SUVMax 6.45). Most surgeries (n = 14, 88%) resulted in no persistent postoperative parent nerve-related complications, and to date, none of the resected tumors have recurred. The median length of postoperative follow-up has been 2.45 years (range 0.00-10.39 years). Histopathological analysis confirmed significantly greater SUVMax among the ANFs (6.51 ± 0.83, p = 0.0042) and low-grade MPNSTs (13.8, p = 0.0001) than in benign neurofibromas (1.9)., Conclusions: This report evaluates the utility of serial imaging (MRI and 18F-FDG-PET SUVMax) to successfully detect ANF and demonstrates that safe, fascicle-sparing gross-total, extracapsular resection of ANF is possible with the use of intraoperative nerve stimulation and microdissection of nerve fascicles.
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- 2019
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9. Low mutation burden and frequent loss of CDKN2A/B and SMARCA2, but not PRC2, define premalignant neurofibromatosis type 1-associated atypical neurofibromas.
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Pemov A, Hansen NF, Sindiri S, Patidar R, Higham CS, Dombi E, Miettinen MM, Fetsch P, Brems H, Chandrasekharappa SC, Jones K, Zhu B, Wei JS, Mullikin JC, Wallace MR, Khan J, Legius E, Widemann BC, and Stewart DR
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- Cyclin-Dependent Kinase Inhibitor p15 genetics, Cyclin-Dependent Kinase Inhibitor p16 genetics, Humans, Mutation genetics, Transcription Factors, Nerve Sheath Neoplasms, Neurofibroma, Neurofibroma, Plexiform, Neurofibromatosis 1 genetics, Neurofibrosarcoma
- Abstract
Background: Neurofibromatosis type 1 (NF1) is a tumor-predisposition disorder caused by germline mutations in NF1. NF1 patients have an 8-16% lifetime risk of developing a malignant peripheral nerve sheath tumor (MPNST), a highly aggressive soft-tissue sarcoma, often arising from preexisting benign plexiform neurofibromas (PNs) and atypical neurofibromas (ANFs). ANFs are distinct from both PN and MPNST, representing an intermediate step in malignant transformation., Methods: In the first comprehensive genomic analysis of ANF originating from multiple patients, we performed tumor/normal whole-exome sequencing (WES) of 16 ANFs. In addition, we conducted WES of 3 MPNSTs, copy-number meta-analysis of 26 ANFs and 28 MPNSTs, and whole transcriptome sequencing analysis of 5 ANFs and 5 MPNSTs., Results: We identified a low number of mutations (median 1, range 0-5) in the exomes of ANFs (only NF1 somatic mutations were recurrent), and frequent deletions of CDKN2A/B (69%) and SMARCA2 (42%). We determined that polycomb repressor complex 2 (PRC2) genes EED and SUZ12 were frequently mutated, deleted, or downregulated in MPNSTs but not in ANFs. Our pilot gene expression study revealed upregulated NRAS, MDM2, CCND1/2/3, and CDK4/6 in ANFs and MPNSTs, and overexpression of EZH2 in MPNSTs only., Conclusions: The PN-ANF transition is primarily driven by the deletion of CDKN2A/B. Further progression from ANF to MPNST likely involves broad chromosomal rearrangements and frequent inactivation of the PRC2 genes, loss of the DNA repair genes, and copy-number increase of signal transduction and cell-cycle and pluripotency self-renewal genes., (Published by Oxford University Press on behalf of the Society for Neuro-Oncology 2019.)
- Published
- 2019
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10. Loss of the PTCH1 tumor suppressor defines a new subset of plexiform fibromyxoma.
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Banerjee S, Corless CL, Miettinen MM, Noh S, Ustoy R, Davis JL, Tang CM, Yebra M, Burgoyne AM, and Sicklick JK
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- Adolescent, Adult, Aged, Carrier Proteins genetics, Chromosome Deletion, Cyclin D1 genetics, Exons, Female, Hedgehog Proteins genetics, High-Throughput Nucleotide Sequencing, Humans, Male, Membrane Glycoproteins genetics, Middle Aged, Retrospective Studies, Smoothened Receptor genetics, Young Adult, Zinc Finger Protein GLI1 genetics, Fibroma genetics, Genes, Tumor Suppressor, Patched-1 Receptor genetics, RNA, Long Noncoding genetics
- Abstract
Background: Plexiform fibromyxoma (PF) is a rare gastric tumor often confused with gastrointestinal stromal tumor. These so-called "benign" tumors often present with upper GI bleeding and gastric outlet obstruction. It was recently demonstrated that approximately one-third of PF have activation of the GLI1 oncogene, a transcription factor in the hedgehog (Hh) pathway, via a MALAT1-GLI1 fusion protein or GLI1 up-regulation. Despite this discovery, the biology of most PFs remains unknown., Methods: Next generation sequencing (NGS) was performed on formalin-fixed paraffin-embedded (FFPE) samples of PF specimens collected from three institutions (UCSD, NCI and OHSU). Fresh frozen tissue from one tumor was utilized for in vitro assays, including quantitative RT-PCR and cell viability assays following drug treatment., Results: Eight patients with PF were identified and 5 patients' tumors were analyzed by NGS. An index case had a mono-allelic PTCH1 deletion of exons 15-24 and a second case, identified in a validation cohort, also had a PTCH1 gene loss associated with a suspected long-range chromosome 9 deletion. Building on the role of Hh signaling in PF, PTCH1, a tumor suppressor protein, functions upstream of GLI1. Loss of PTCH1 induces GLI1 activation and downstream gene transcription. Utilizing fresh tissue from the index PF case, RT-qPCR analysis demonstrated expression of Hh pathway components, SMO and GLI1, as well as GLI1 transcriptional targets, CCND1 and HHIP. In turn, short-term in vitro treatment with a Hh pathway inhibitor, sonidegib, resulted in dose-dependent cell killing., Conclusions: For the first time, we report a novel association between PTCH1 inactivation and the development of plexiform fibromyxoma. Hh pathway inhibition with SMO antagonists may represent a target to study for treating a subset of plexiform fibromyxomas.
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- 2019
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11. NUTM1-rearranged neoplasia: a multi-institution experience yields novel fusion partners and expands the histologic spectrum.
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Stevens TM, Morlote D, Xiu J, Swensen J, Brandwein-Weber M, Miettinen MM, Gatalica Z, and Bridge JA
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- Adolescent, Adult, Aged, Child, Female, Humans, Male, Middle Aged, Oncogene Fusion, Carcinoma genetics, Neoplasm Proteins genetics, Nuclear Proteins genetics, Oncogene Proteins, Fusion genetics, Sarcoma genetics
- Abstract
Poorly differentiated neoplasms lacking characteristic histopathologic features represent a significant challenge to the pathologist for diagnostic classification. Classically, NUT carcinoma (previously NUT midline carcinoma) is poorly differentiated but typically exhibits variable degrees of squamous differentiation. Diagnosis is genetically defined by NUTM1 rearrangement, usually with BRD4 as the fusion partner. In this multi-institutional next-generation sequencing and fluorescence in situ hybridization study, 26 new NUTM1-rearranged neoplasms are reported, including 20 NUT carcinomas, 4 sarcomas, and 2 tumors of an uncertain lineage. NUTM1 fusion partners were available in 24 of 26 cases. BRD4 was the fusion partner in 18/24 (75%) cases, NSD3 in 2/24 cases (8.3%), and BRD3 in 1/24 (4.2%) cases. Two novel fusion partners were identified: MGA in two sarcomas (myxoid spindle cell sarcoma and undifferentiated sarcoma) (2/24 cases 8.3%) and MXD4 in a round cell sarcoma in the cecum (1/24 cases 4.2%). Eleven cases tested for NUT immunoexpression were all positive, including the MGA and MXD4-rearranged tumors. Our results confirm that NUTM1 gene rearrangements are found outside the classic clinicopathological setting of NUT carcinoma. In addition, as novel fusion partners like MGA and MXD4 may not be susceptible to targeted therapy with bromodomain inhibitors, detecting the NUTM1 rearrangement may not be enough, and identifying the specific fusion partner may become necessary. Studies to elucidate the mechanism of tumorigenesis of novel fusion partners are needed.
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- 2019
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12. Associations of CDH1 germline variant location and cancer phenotype in families with hereditary diffuse gastric cancer (HDGC).
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Lo W, Zhu B, Sabesan A, Wu HH, Powers A, Sorber RA, Ravichandran S, Chen I, McDuffie LA, Quadri HS, Beane JD, Calzone K, Miettinen MM, Hewitt SM, Koh C, Heller T, Wacholder S, and Rudloff U
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- Alleles, Alternative Splicing, Antigens, CD chemistry, Antigens, CD metabolism, Cadherins chemistry, Cadherins metabolism, Exons, Family, Humans, Immunohistochemistry, Mutation, Missense, Odds Ratio, Pedigree, Signal Transduction, Stomach Neoplasms metabolism, Antigens, CD genetics, Cadherins genetics, Genetic Association Studies, Genetic Predisposition to Disease, Germ-Line Mutation, Phenotype, Stomach Neoplasms diagnosis, Stomach Neoplasms genetics
- Abstract
Introduction: Hereditary diffuse gastric cancer (HDGC) is a cancer syndrome associated with variants in E-cadherin (CDH1), diffuse gastric cancer and lobular breast cancer. There is considerable heterogeneity in its clinical manifestations. This study aimed to determine associations between CDH1 germline variant status and clinical phenotypes of HDGC., Methods: One hundred and fifty-two HDGC families, including six previously unreported families, were identified. CDH1 gene-specific guidelines released by the Clinical Genome Resource (ClinGen) CDH1 Variant Curation Expert Panel were applied for pathogenicity classification of truncating, missense and splice site CDH1 germline variants. We evaluated ORs between location of truncating variants of CDH1 and incidence of colorectal cancer, breast cancer and cancer at young age (gastric cancer at <40 or breast cancer <50 years of age)., Results: Frequency of truncating germline CDH1 variants varied across functional domains of the E-cadherin receptor gene and was highest in linker (0.05785 counts/base pair; p=0.0111) and PRE regions (0.10000; p=0.0059). Families with truncating CDH1 germline variants located in the PRE-PRO region were six times more likely to have family members affected by colorectal cancer (OR 6.20, 95% CI 1.79 to 21.48; p=0.004) compared with germline variants in other regions. Variants in the intracellular E-cadherin region were protective for cancer at young age (OR 0.2, 95% CI 0.06 to 0.64; p=0.0071) and in the linker regions for breast cancer (OR 0.35, 95% CI 0.12 to 0.99; p=0.0493). Different CDH1 genotypes were associated with different intracellular signalling activation levels including different p-ERK, p-mTOR and β-catenin levels in early submucosal T1a lesions of HDGC families with different CDH1 variants., Conclusion: Type and location of CDH1 germline variants may help to identify families at increased risk for concomitant cancers that might benefit from individualised surveillance and intervention strategies., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)
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- 2019
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13. ASXL3 Is a Novel Pluripotency Factor in Human Respiratory Epithelial Cells and a Potential Therapeutic Target in Small Cell Lung Cancer.
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Shukla V, Rao M, Zhang H, Beers J, Wangsa D, Wangsa D, Buishand FO, Wang Y, Yu Z, Stevenson HS, Reardon ES, McLoughlin KC, Kaufman AS, Payabyab EC, Hong JA, Zhang M, Davis S, Edelman D, Chen G, Miettinen MM, Restifo NP, Ried T, Meltzer PA, and Schrump DS
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- Animals, Cell Line, Tumor, Cells, Cultured, Cellular Reprogramming, Epigenesis, Genetic, Gene Expression Profiling methods, Humans, Induced Pluripotent Stem Cells transplantation, Lung Neoplasms metabolism, Lung Neoplasms pathology, Mice, Inbred NOD, Mice, Knockout, Mice, SCID, Respiratory Mucosa cytology, Small Cell Lung Carcinoma metabolism, Small Cell Lung Carcinoma pathology, Teratoma genetics, Teratoma metabolism, Transcription Factors metabolism, Transplantation, Heterologous, Epithelial Cells metabolism, Induced Pluripotent Stem Cells metabolism, Lung Neoplasms genetics, Small Cell Lung Carcinoma genetics, Transcription Factors genetics
- Abstract
In this study, we generated induced pluripotent stem cells (iPSC) from normal human small airway epithelial cells (SAEC) to investigate epigenetic mechanisms of stemness and pluripotency in lung cancers. We documented key hallmarks of reprogramming in lung iPSCs (Lu-iPSC) that coincided with modulation of more than 15,000 genes relative to parental SAECs. Of particular novelty, we identified the PRC2-associated protein, ASXL3, which was markedly upregulated in Lu-iPSCs and small cell lung cancer (SCLC) lines and clinical specimens. ASXL3 overexpression correlated with increased genomic copy number in SCLC lines. ASXL3 silencing inhibited proliferation, clonogenicity, and teratoma formation by Lu-iPSCs, and diminished clonogenicity and malignant growth of SCLC cells in vivo Collectively, our studies validate the utility of the Lu-iPSC model for elucidating epigenetic mechanisms contributing to pulmonary carcinogenesis and highlight ASXL3 as a novel candidate target for SCLC therapy. Cancer Res; 77(22); 6267-81. ©2017 AACR ., (©2017 American Association for Cancer Research.)
- Published
- 2017
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14. N-Glycomic Profiling of Pheochromocytomas and Paragangliomas Separates Metastatic and Nonmetastatic Disease.
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Leijon H, Kaprio T, Heiskanen A, Satomaa T, Hiltunen JO, Miettinen MM, Arola J, and Haglund C
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- Adrenal Gland Neoplasms diagnosis, Adrenal Gland Neoplasms pathology, Adult, Aged, Diagnosis, Differential, Female, Glycosylation, Humans, Male, Middle Aged, Neoplasm Metastasis, Paraganglioma diagnosis, Paraganglioma pathology, Pheochromocytoma diagnosis, Pheochromocytoma pathology, Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization, Young Adult, Adrenal Gland Neoplasms metabolism, Glycomics, Neoplasm Staging methods, Paraganglioma metabolism, Pheochromocytoma metabolism, Polysaccharides metabolism
- Abstract
Context: No effective methods for separating primary pheochromocytomas and paragangliomas with metastatic potential are currently available. The identification of specific asparagine-linked glycan (N-glycan) structures, which are associated with metastasized pheochromocytomas and paragangliomas, may serve as a diagnostic tool., Objective: To identify differences in N-glycomic profiles of primary metastasized and nonmetastasized pheochromocytomas and paragangliomas., Setting: This study was conducted at Helsinki University Hospital, University of Helsinki, and Glykos Finland Ltd. and included 16 pheochromocytomas and paragangliomas: 8 primary metastasized pheochromocytomas or paragangliomas and 8 nonmetastasized tumors., Methods: N-glycan structures were analyzed with matrix-assisted laser desorption-ionization time-of-flight (MALDI-TOF) mass spectrometry (MS) profiling of formalin-fixed, paraffin-embedded tissue samples., Main Outcome Measure: N-glycan profile of tumor tissue., Results: Four groups of neutral N-glycan signals were more abundant in metastasized tumors than in nonmetastasized tumors: complex-type N-glycan signals of cancer-associated terminal N-acetylglucosamine, multifucosylated glycans (complex fucosylation), hybrid-type N-glycans, and fucosylated pauci-mannose-type N-glycans. Three groups of acidic N-glycans were more abundant in metastasized tumors: multifucosylated glycans, acid ester-modified (sulfated or phosphorylated) glycans, and hybrid-type/monoantennary N-glycans. Fucosylation and complex fucosylation were significantly more abundant in metastasized paragangliomas and pheochromocytomas than in nonmetastasized tumors for individual tests but were over the false positivity critical rate, when adjusted for multiplicity testing., Conclusions: MALDI-TOF MS profiling of primary pheochromocytomas and paragangliomas can identify diseases with metastatic potential based on their different N-glycan profiles. Thus, malignancy-linked N-glycan structures may serve as potential diagnostic tools for pheochromocytomas and paragangliomas., (Copyright © 2017 Endocrine Society)
- Published
- 2017
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15. KLF4-dependent perivascular cell plasticity mediates pre-metastatic niche formation and metastasis.
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Murgai M, Ju W, Eason M, Kline J, Beury DW, Kaczanowska S, Miettinen MM, Kruhlak M, Lei H, Shern JF, Cherepanova OA, Owens GK, and Kaplan RN
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- Animals, Blotting, Western, Cell Line, Tumor, Enzyme-Linked Immunosorbent Assay, Extracellular Matrix metabolism, Flow Cytometry, Fluorescent Antibody Technique, Gene Knockdown Techniques, In Vitro Techniques, Kruppel-Like Factor 4, Melanoma, Experimental, Mice, Muscle, Smooth, Vascular cytology, Neovascularization, Pathologic genetics, Neovascularization, Pathologic metabolism, Real-Time Polymerase Chain Reaction, Tumor Microenvironment, Cell Plasticity genetics, Kruppel-Like Transcription Factors genetics, Myocytes, Smooth Muscle metabolism, Neoplasm Metastasis genetics, Pericytes metabolism
- Abstract
A deeper understanding of the metastatic process is required for the development of new therapies that improve patient survival. Metastatic tumor cell growth and survival in distant organs is facilitated by the formation of a pre-metastatic niche that is composed of hematopoietic cells, stromal cells and extracellular matrix (ECM). Perivascular cells, including vascular smooth muscle cells (vSMCs) and pericytes, are involved in new vessel formation and in promoting stem cell maintenance and proliferation. Given the well-described plasticity of perivascular cells, we hypothesized that perivascular cells similarly regulate tumor cell fate at metastatic sites. We used perivascular-cell-specific and pericyte-specific lineage-tracing models to trace the fate of perivascular cells in the pre-metastatic and metastatic microenvironments. We show that perivascular cells lose the expression of traditional vSMC and pericyte markers in response to tumor-secreted factors and exhibit increased proliferation, migration and ECM synthesis. Increased expression of the pluripotency gene Klf4 in these phenotypically switched perivascular cells promoted a less differentiated state, characterized by enhanced ECM production, that established a pro-metastatic fibronectin-rich environment. Genetic inactivation of Klf4 in perivascular cells decreased formation of a pre-metastatic niche and metastasis. Our data revealed a previously unidentified role for perivascular cells in pre-metastatic niche formation and uncovered novel strategies for limiting metastasis.
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- 2017
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16. Histopathologic evaluation of atypical neurofibromatous tumors and their transformation into malignant peripheral nerve sheath tumor in patients with neurofibromatosis 1-a consensus overview.
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Miettinen MM, Antonescu CR, Fletcher CDM, Kim A, Lazar AJ, Quezado MM, Reilly KM, Stemmer-Rachamimov A, Stewart DR, Viskochil D, Widemann B, and Perry A
- Subjects
- Biomarkers, Tumor analysis, Biopsy, Cell Nucleus pathology, Consensus, Disease Progression, Humans, Immunohistochemistry, Mitosis, Neoplasm Grading, Neurilemmoma chemistry, Neurilemmoma classification, Neurofibromatosis 1 classification, Neurofibromatosis 1 metabolism, Predictive Value of Tests, Terminology as Topic, Neurilemmoma pathology, Neurofibromatosis 1 pathology
- Abstract
Patients with neurofibromatosis 1 (NF1) develop multiple neurofibromas, with 8% to 15% of patients experiencing malignant peripheral nerve sheath tumor (MPNST) during their lifetime. Prediction of transformation, typically from plexiform neurofibroma, is clinically and histologically challenging. In this overview, after a consensus meeting in October 2016, we outline the histopathologic features and molecular mechanisms involved in the malignant transformation of neurofibromas. Nuclear atypia alone is generally insignificant. However, with atypia, loss of neurofibroma architecture, high cellularity, and/or mitotic activity >1/50 but <3/10 high-power fields, the findings are worrisome for malignancy. We propose the term "atypical neurofibromatous neoplasms of uncertain biologic potential (ANNUBP)" for lesions displaying at least 2 of these features. This diagnosis should prompt additional sampling, clinical correlation, and possibly, expert pathology consultation. Currently, such tumors are diagnosed inconsistently as atypical neurofibroma or low-grade MPNST. Most MPNSTs arising from neurofibromas are high-grade sarcomas and pose little diagnostic difficulty, although rare nonnecrotic tumors with 3-9 mitoses/10 high-power fields can be recognized as low-grade variants. Although neurofibromas contain numerous S100 protein/SOX10-positive Schwann cells and CD34-positive fibroblasts, both components are reduced or absent in MPNST. Loss of p16/CDKN2A expression, elevated Ki67 labeling, and extensive nuclear p53 positivity are also features of MPNST that can to some degree already occur in atypical neurofibromatous neoplasms of uncertain biologic potential. Complete loss of trimethylated histone 3 lysine 27 expression is potentially more reliable, being immunohistochemically detectable in about half of MPNSTs. Correlated clinicopathological, radiologic, and genetic studies should increase our understanding of malignant transformation in neurofibromas, hopefully improving diagnosis and treatment soon., (Published by Elsevier Inc.)
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- 2017
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17. Neurofibromatosis Type 1-Associated MPNST State of the Science: Outlining a Research Agenda for the Future.
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Reilly KM, Kim A, Blakely J, Ferner RE, Gutmann DH, Legius E, Miettinen MM, Randall RL, Ratner N, Jumbé NL, Bakker A, Viskochil D, Widemann BC, and Stewart DR
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- Consensus, Humans, Nerve Sheath Neoplasms complications, Nerve Sheath Neoplasms diagnosis, Neurilemmoma complications, Neurilemmoma diagnosis, Neurofibromatosis 1 complications, Neurofibromatosis 1 diagnosis, Practice Guidelines as Topic standards, Therapies, Investigational methods, Biomedical Research trends, Nerve Sheath Neoplasms therapy, Neurilemmoma therapy, Neurofibromatosis 1 therapy, Therapies, Investigational trends
- Abstract
Malignant peripheral nerve sheath tumor (MPNST) is an aggressive soft tissue sarcoma for which the only effective therapy is surgery. In 2016, an international meeting entitled "MPNST State of the Science: Outlining a Research Agenda for the Future" was convened to establish short- and long-term research priorities. Key recommendations included the: 1) development of standardized, cost-efficient fluorodeoxyglucose positron emission tomography and whole-body magnetic resonance imaging guidelines to evaluate masses concerning for MPNST; 2) development of better understanding and histologic criteria for the transformation of a plexiform neurofibroma to MPNST; 3) establishment of a centralized database to collect genetic, genomic, histologic, immunohistochemical, molecular, radiographic, treatment, and related clinical data from MPNST subspecialty centers in a standardized manner; 4) creation of accurate mouse models to study the plexiform neurofibroma-to-MPNST transition, MPNST metastasis, and drug resistance; 5) use of trial designs that minimize regulatory requirements, maximize availability to patients, consider novel secondary end points, and study patients with newly diagnosed disease. Lastly, in order to minimize delays in developing novel therapies and promote the most efficient use of research resources and patient samples, data sharing should be incentivized., (© The Author 2017. Published by Oxford University Press.)
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- 2017
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18. Expression of the scaffold connector enhancer of kinase suppressor of Ras 1 (CNKSR1) is correlated with clinical outcome in pancreatic cancer.
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Quadri HS, Aiken TJ, Allgaeuer M, Moravec R, Altekruse S, Hussain SP, Miettinen MM, Hewitt SM, and Rudloff U
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- Adenocarcinoma diagnosis, Aged, Female, Humans, Male, Middle Aged, Pancreatic Neoplasms diagnosis, Prognosis, Proportional Hazards Models, Adenocarcinoma metabolism, Gene Expression Regulation, Neoplastic, Intracellular Signaling Peptides and Proteins genetics, Pancreatic Neoplasms metabolism
- Abstract
Background: Despite the near universal occurrence of activating codon 12 KRAS somatic variants in pancreatic cancer, there is considerable heterogeneity in the molecular make-up, MAPK/ERK pathway activation states, and clinical outcome in this disease. We analyzed the expression levels of CNKSR1, a scaffold that influences MAPK/ERK pathway activity, in clinical pancreas cancer specimens and their impact on survival of patients with pancreatic cancer., Methods: Immunohistochemical staining for CNKSR1 expression was performed on 120 specimens from three independent pancreatic cancer tissue registries, phospho-ERK levels were measured in 86 samples. Expression was divided into CNKSR1 low and CNKSR1 high and correlated with clinicopathological variables including overall survival using multivariate Cox proportional hazard ratio models., Results: CNKSR1 expression was increased in tumors compared to matched normal uninvolved resection specimens (p = 0.004). 28.3% (34/120) of patient specimens stained as CNKSR1 low compared to 71.7% (86/120) of specimens which stained as CNKSR1 high. High CNKSR1 expression was more prevalent in low grade tumors (p = 0.04). In multivariate analysis, low CNKSR1 expression status was independently correlated with decreased overall survival (HR = 2.146; 95% CI 1.34 to 3.43). When stratifying primary, non-metastatic tumor biopsies by CNKSR1 expression, resection was associated with improved survival in patients with high CNKSR1 expression (p < 0.0001) but not low CNKSR1 expression (p = 0.3666). Pancreatic tumors with nuclear in addition to cytoplasmic CNKSR1 staining (32/107) showed increased nuclear phospho-ERK expression compared to tumor with cytoplasmic CNKSR1 staining only (p = 0.017)., Conclusion: CNKSR1 expression is increased in pancreatic tissue specimens and was found to be an independent prognostic marker of overall survival. CNKSR1 may help to identify patient subgroups with unfavorable tumor biology in order to improve risk stratification and treatment selection. Cellular distribution of CNKSR1 was correlated with nuclear pERK expression.
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- 2017
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19. Soft-Tissue Sarcomas of the Abdomen and Pelvis: Radiologic-Pathologic Features, Part 2-Uncommon Sarcomas.
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Levy AD, Manning MA, and Miettinen MM
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- Diagnosis, Differential, Humans, Abdomen diagnostic imaging, Abdomen pathology, Pelvis diagnostic imaging, Pelvis pathology, Sarcoma diagnostic imaging, Sarcoma pathology
- Abstract
Soft-tissue sarcomas occurring in the abdomen and pelvis are an uncommon but important group of malignancies. Recent changes to the World Health Organization classification of soft-tissue tumors include the movement of gastrointestinal stromal tumors (GISTs) into the soft-tissue tumor classification. GIST is the most common intraperitoneal sarcoma. Liposarcoma is the most common retroperitoneal sarcoma, and leiomyosarcoma is the second most common. GIST, liposarcoma, and leiomyosarcoma account for the majority of sarcomas encountered in the abdomen and pelvis and are discussed in part 1 of this article. Undifferentiated pleomorphic sarcoma (previously called malignant fibrous histiocytoma), dermatofibrosarcoma protuberans, solitary fibrous tumor, malignant peripheral nerve sheath tumor, rhabdomyosarcoma, extraskeletal chondro-osseous sarcomas, vascular sarcomas, and sarcomas of uncertain differentiation uncommonly arise in the abdomen and pelvis and the abdominal wall. Although these lesions are rare sarcomas and their imaging features overlap, familiarity with the locations where they occur and their imaging features is important so they can be diagnosed accurately. The anatomic location and clinical history are important factors in the differential diagnosis of these lesions because metastasis, more-common sarcomas, borderline fibroblastic proliferations (such as desmoid tumors), and endometriosis have imaging findings that overlap with those of these uncommon sarcomas. In this article, the clinical, pathologic, and imaging findings of uncommon soft-tissue sarcomas of the abdomen and pelvis and the abdominal wall are reviewed, with an emphasis on their differential diagnosis.
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- 2017
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20. PAX3-FOXO1 is essential for tumour initiation and maintenance but not recurrence in a human myoblast model of rhabdomyosarcoma.
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Pandey PR, Chatterjee B, Olanich ME, Khan J, Miettinen MM, Hewitt SM, and Barr FG
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- Animals, Cell Death, Cell Differentiation, Cell Line, Tumor, Doxycycline administration & dosage, Female, Forkhead Box Protein O1 genetics, Forkhead Box Protein O1 metabolism, Gene Expression Regulation, Neoplastic, Humans, Mice, Mice, SCID, Muscle Development, Myoblasts metabolism, Myoblasts pathology, N-Myc Proto-Oncogene Protein genetics, N-Myc Proto-Oncogene Protein metabolism, Oncogene Proteins, Fusion metabolism, PAX3 Transcription Factor genetics, PAX3 Transcription Factor metabolism, Paired Box Transcription Factors metabolism, Rhabdomyosarcoma pathology, Carcinogenesis genetics, Neoplasm Recurrence, Local genetics, Oncogene Proteins, Fusion genetics, Paired Box Transcription Factors genetics, Rhabdomyosarcoma genetics, Translocation, Genetic genetics
- Abstract
The PAX3-FOXO1 fusion gene is generated by a 2;13 chromosomal translocation and is a characteristic feature of an aggressive subset of rhabdomyosarcoma (RMS). To dissect the mechanism of oncogene action during RMS tumourigenesis and progression, doxycycline-inducible PAX3-FOXO1 and constitutive MYCN expression constructs were introduced into immortalized human myoblasts. Although myoblasts expressing PAX3-FOXO1 or MYCN alone were not transformed in focus formation assays, combined PAX3-FOXO1 and MYCN expression resulted in transformation. Following intramuscular injection into immunodeficient mice, myoblasts expressing PAX3-FOXO1 and MYCN formed rapidly growing RMS tumours, whereas myoblasts expressing only PAX3-FOXO1 formed tumours after a longer latency period. Doxycycline withdrawal in myoblasts expressing inducible PAX3-FOXO1 and constitutive MYCN following tumour formation in vivo or focus formation in vitro resulted in tumour regression or smaller foci associated with myogenic differentiation and cell death. Following regression, most tumours recurred in the absence of doxycycline. Analysis of recurrent tumours revealed a subset without PAX3-FOXO1 expression, and cell lines derived from these recurrent tumours showed transformation in the absence of doxycycline. The doxycycline-independent oncogenicity in these recurrent tumour-derived lines persisted even after PAX3-FOXO1 was inactivated with a CRISPR/Cas9 editing strategy. Whereas cell lines derived from primary tumours were dependent on PAX3-FOXO1 and differentiated following doxycycline withdrawal, recurrent tumour-derived cells without PAX3-FOXO1 expression did not differentiate under these conditions. These findings indicate that PAX3-FOXO1 collaborates with MYCN during early RMS tumourigenesis to dysregulate proliferation and inhibit myogenic differentiation and cell death. Although most cells in the primary tumours are dependent on PAX3-FOXO1, recurrent tumours can develop by a PAX3-FOXO1-independent mechanism, in which rare cells are postulated to acquire secondary transforming events that were activated or selected by initial PAX3-FOXO1 expression. Published 2016. This article is a U.S. Government work and is in the public domain in the USA., (Published 2016. This article is a U.S. Government work and is in the public domain in the USA.)
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- 2017
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21. Soft-Tissue Sarcomas of the Abdomen and Pelvis: Radiologic-Pathologic Features, Part 1-Common Sarcomas: From the Radiologic Pathology Archives.
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Levy AD, Manning MA, Al-Refaie WB, and Miettinen MM
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- Diagnosis, Differential, Humans, Abdominal Cavity diagnostic imaging, Abdominal Cavity pathology, Pelvis diagnostic imaging, Pelvis pathology, Sarcoma diagnostic imaging, Sarcoma pathology, Soft Tissue Neoplasms diagnostic imaging, Soft Tissue Neoplasms pathology
- Abstract
Soft-tissue sarcomas are a diverse group of rare mesenchymal malignancies that can arise at any location in the body and affect all age groups. These sarcomas are most common in the extremities, trunk wall, retroperitoneum, and head and neck. In the adult population, soft-tissue sarcomas arising in the abdomen and pelvis are often large masses at the time of diagnosis because they are usually clinically silent or cause vague or mild symptoms until they invade or compress vital organs. In contrast, soft-tissue sarcomas arising from the abdominal wall come to clinical attention earlier in the course of disease because they cause a palpable mass, abdominal wall deformity, or pain that is more clinically apparent. The imaging features of abdominal and pelvic sarcomas and abdominal wall sarcomas can be nonspecific and overlap with more common pathologic conditions, making diagnosis difficult or, in some cases, delaying diagnosis. Liposarcoma (well-differentiated and dedifferentiated liposarcomas), leiomyosarcoma, and gastrointestinal stromal tumor (GIST) are the most common intra-abdominal primary sarcomas. Any soft-tissue sarcoma can arise in the abdominal wall. Knowledge of the classification and pathologic features of soft-tissue sarcomas, the anatomic locations where they occur, and their cross-sectional imaging features helps the radiologist establish the diagnosis or differential diagnosis so that patients with soft-tissue sarcomas can receive optimal treatment and management. In part 1 of this article, the most common soft-tissue sarcomas (liposarcoma, leiomyosarcoma, and GIST) are reviewed, with a discussion on anatomic locations, classification, clinical considerations, and differential diagnosis. Part 2 will focus on the remainder of the soft-tissue sarcomas occurring in the abdomen and pelvis.
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- 2017
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22. Malignant Peripheral Nerve Sheath Tumors State of the Science: Leveraging Clinical and Biological Insights into Effective Therapies.
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Kim A, Stewart DR, Reilly KM, Viskochil D, Miettinen MM, and Widemann BC
- Abstract
Malignant peripheral nerve sheath tumor (MPNST) is the leading cause of mortality in patients with neurofibromatosis type 1. In 2002, an MPNST consensus statement reviewed the current knowledge and provided guidance for the diagnosis and management of MPNST. Although the improvement in clinical outcome has not changed, substantial progress has been made in understanding the natural history and biology of MPNST through imaging and genomic advances since 2002. Genetically engineered mouse models that develop MPNST spontaneously have greatly facilitated preclinical evaluation of novel drugs for translation into clinical trials led by consortia efforts. Continued work in identifying alterations that contribute to the transformation, progression, and metastasis of MPNST coupled with longitudinal follow-up, biobanking, and data sharing is needed to develop prognostic biomarkers and effective prevention and therapeutic strategies for MPNST.
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- 2017
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23. Expression of neural cell adhesion molecule L1 (CD171) in neuroectodermal and other tumors: An immunohistochemical study of 5155 tumors and critical evaluation of CD171 prognostic value in gastrointestinal stromal tumors.
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Inaguma S, Wang Z, Lasota JP, and Miettinen MM
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- Adult, Aged, Aged, 80 and over, Female, Gastrointestinal Neoplasms mortality, Gastrointestinal Stromal Tumors mortality, Humans, Immunohistochemistry, Male, Middle Aged, Neuroectodermal Tumors mortality, Prognosis, Gastrointestinal Neoplasms chemistry, Gastrointestinal Stromal Tumors chemistry, Neural Cell Adhesion Molecule L1 analysis, Neuroectodermal Tumors chemistry
- Abstract
The neural cell adhesion molecule L1 (CD171) is a multidomain type 1 membrane glycoprotein of the immunoglobulin superfamily important in the nervous system development, kidney morphogenesis, and maintenance of the immune system. Recent studies reported CD171 expression being associated with adverse clinical outcome in different types of cancer and there has been a growing interest in targeting this cell membrane molecule on neoplastic cells by chimeric antigen receptor redirected T lymphocytes or specific antibodies. Nevertheless, conflicting results regarding the prognostic value of CD171 expression in renal cell carcinomas and gastrointestinal stromal tumors were published. In this study, CD171 expression was immunohistochemically analyzed in 5155 epithelial, mesenchymal, melanocytic, and lymphohematopoietic tumors to assess its utility in diagnostic pathology and to pinpoint potential targets for CD171-targeting therapy. A newly developed anti-CD171 rabbit monoclonal antibody, clone 014, was selected from the panel of commercially available CD171 antibodies. Immunohistochemistry was performed using Leica Bond Max automation and multitumor blocks containing up to 60 tumor samples. CD171 was constitutively and strongly expressed in neuroectodermal tumors such as schwannoma, neuroblastoma, and paraganglioma, whereas other mesenchymal tumors including schwannoma mimics showed only rarely CD171 positivity. Frequent CD171-expression was also detected in ovarian serous carcinoma, malignant mesothelioma, and testicular embryonal carcinoma. CD171 immunohistochemistry may have some role in immunophenotypic differential diagnosis of neurogenic tumors and pinpointing potential candidates for anti-CD171 therapy. Though, because of its rare expression and lack of predictive value, CD171 is neither a diagnostic nor prognostic marker for gastrointestinal stromal tumors.
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- 2016
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24. Molecular Subtypes of KIT/PDGFRA Wild-Type Gastrointestinal Stromal Tumors: A Report From the National Institutes of Health Gastrointestinal Stromal Tumor Clinic.
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Boikos SA, Pappo AS, Killian JK, LaQuaglia MP, Weldon CB, George S, Trent JC, von Mehren M, Wright JA, Schiffman JD, Raygada M, Pacak K, Meltzer PS, Miettinen MM, Stratakis C, Janeway KA, and Helman LJ
- Subjects
- Adolescent, Adult, Aged, Child, DNA Methylation genetics, Female, Gastrointestinal Stromal Tumors classification, Gastrointestinal Stromal Tumors pathology, Germ-Line Mutation genetics, Humans, Male, Middle Aged, Prognosis, Promoter Regions, Genetic, Proto-Oncogene Proteins c-kit genetics, Receptor, Platelet-Derived Growth Factor alpha genetics, Electron Transport Complex II genetics, Gastrointestinal Stromal Tumors genetics, Membrane Proteins genetics, Succinate Dehydrogenase genetics
- Abstract
Importance: Wild-type (WT) gastrointestinal stromal tumors (GISTs), which lack KIT and PDGFRA gene mutations, are the primary form of GIST in children and occasionally occur in adults. They respond poorly to standard targeted therapy. Better molecular and clinical characterization could improve management., Objective: To evaluate the clinical and tumor genomic features of WT GIST., Design, Setting, and Participants: Patients enrolled in an observational study at the National Institutes of Health starting in 2008 and were evaluated in a GIST clinic held once or twice yearly. Patients provided access to existing medical records and tumor specimens. Self-referred or physician-referred patients younger than 19 years with GIST or 19 years or older with known WT GIST (no mutations in KIT or PDGFRA) were recruited; 116 patients with WT GIST were enrolled, and 95 had adequate tumor specimen available. Tumors were characterized by immunohistochemical analysis (IHC) for succinate dehydrogenase (SDH) subunit B, sequencing of SDH genes, and determination of SDHC promoter methylation. Testing of germline SDH genes was offered to consenting patients and families., Main Outcomes and Measures: For classification, tumors were characterized by SDHA, B, C, or D (SDHX) mutations and other genetic and epigenetic alterations, including presence of mutations in germline. Clinical characteristics were categorized., Results: Wild-type GIST specimens from 95 patients (median age, 23 [range, 7-78] years; 70% female) were classified into 3 molecular subtypes: SDH-competent (n = 11), defined by detection of SDHB by IHC; and 2 types of SDH-deficient GIST (n = 84). Of SDH-deficient tumors, 63 (67%) had SDH mutations, and in 31 of 38 (82%), the SDHX mutation was also present in germline. Twenty-one (22%) SDH-deficient tumors had methylation of the SDHC promoter leading to silencing of expression. Mutations in known cancer-associated pathways were identified in 9 of 11 SDH-competent tumors. Among patients with SDH-mutant tumors, 62% were female (39 of 63), median (range) age was 23 (7-58) years, and approximately 30% presented with metastases (liver [12 of 58], peritoneal [6 of 58], lymph node [15 of 23]). SDHC-epimutant tumors mostly affected young females (20 of 21; median [range] age, 15 [8-50] years), and approximately 40% presented with metastases (liver [7 of 19], peritoneal [1 of 19], lymph node [3 of 8]). SDH-deficient tumors occurred only in the stomach and had an indolent course., Conclusions and Relevance: An observational study of WT GIST permitted the evaluation of a large number of patients with this rare disease. Three molecular subtypes with implications for prognosis and clinical management were identified.
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- 2016
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25. MAGE-A is More Highly Expressed Than NY-ESO-1 in a Systematic Immunohistochemical Analysis of 3668 Cases.
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Kerkar SP, Wang ZF, Lasota J, Park T, Patel K, Groh E, Rosenberg SA, and Miettinen MM
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- Carcinoma, Squamous Cell pathology, Cohort Studies, Esophageal Neoplasms pathology, Female, Head and Neck Neoplasms pathology, Humans, Immunohistochemistry, Male, Neoplasm Metastasis, Neoplasms, Germ Cell and Embryonal pathology, Skin Neoplasms pathology, Tissue Array Analysis, Antigens, Neoplasm metabolism, Carcinoma, Squamous Cell metabolism, Esophageal Neoplasms metabolism, Head and Neck Neoplasms metabolism, Melanoma-Specific Antigens metabolism, Membrane Proteins metabolism, Neoplasms, Germ Cell and Embryonal metabolism, Skin Neoplasms metabolism
- Abstract
Two cancer testis antigens, the New York esophageal squamous cell carcinoma-1 (NY-ESO-1) and the melanoma-antigen family A (MAGE-A), represent promising immunotherapy targets due to the low expression of these antigens in nonmalignant tissue. To assess overexpression patterns in various cancers, we performed a systematic immunohistochemical analysis for NY-ESO-1 and MAGE-A on tissue array samples of 3668 common epithelial carcinomas (CA) and germ cell tumors of high prevalence and mortality. Here, we find significantly higher expression of MAGE-A (>50% on tumor cells) compared with NY-ESO-1 in several CAs including cutaneous squamous cell carcinomas (SCC) (52.8%/2.8%), esophageal SCC (50%/0%), head and neck SCC (41.1%/<1%), bladder urothelial CA (40.4%/8.3%), cervical/anal SCC (37.5%/0%), lung SCC (34%/3.8%), lung adenocarcinomas (27.6%/3.9%), ovarian CA (26.4%/3.6%), endometrial CA (26.3%/1.3%), lung small cell CA (24.4%/2.4%), gastric adenocarcinomas (20%/4%), breast mucinous CA (19.3%/0%), hepatocellular CA (18.8%/1.2%), breast infiltrating ductal CA (16.4%/1.8%), colorectal adenocarcinomas (10.7%/<1%), cholangiocarcinomas (9.8%/0%), thymic CA (9%/4.5%), and mesotheliomas (7.9%/<1%). Furthermore, high expression of MAGE-A, but not NY-ESO-1, was seen in whole slide evaluations of an independent cohort of metastatic SCC (45.5%/3.6%) and metastatic CA (13.5%/0%) of various primaries with significantly higher expression of MAGE-A in metastatic SCC compared with other metastatic CA. MAGE-A is also more highly expressed in germ cell tumors, seminomas (69%/3.5%) and nonseminomas (40.1%/4.7%). In summary, MAGE-A is more highly expressed than NY-ESO-1 in a majority of human malignancies, and targeting MAGE-A may benefit a large number of patients.
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- 2016
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26. Major cancer regressions in mesothelioma after treatment with an anti-mesothelin immunotoxin and immune suppression.
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Hassan R, Miller AC, Sharon E, Thomas A, Reynolds JC, Ling A, Kreitman RJ, Miettinen MM, Steinberg SM, Fowler DH, and Pastan I
- Subjects
- Adult, Aged, Antibodies, Monoclonal blood, Antibodies, Monoclonal immunology, Antibodies, Neutralizing pharmacology, Blood Cell Count, Female, Humans, Kaplan-Meier Estimate, Lymphocyte Subsets immunology, Lymphocyte Subsets metabolism, Male, Mesothelin, Mesothelioma diagnostic imaging, Mesothelioma pathology, Middle Aged, Peritoneal Neoplasms diagnostic imaging, Peritoneal Neoplasms pathology, Radiography, Remission Induction, Treatment Outcome, Antibodies, Monoclonal therapeutic use, GPI-Linked Proteins immunology, Immunosuppression Therapy, Mesothelioma immunology, Mesothelioma therapy, Peritoneal Neoplasms immunology, Peritoneal Neoplasms therapy
- Abstract
Immunotoxins are potent anticancer agents with an unusual mechanism of action: inhibition of protein synthesis resulting in apoptotic cell death. Immunotoxins have produced many durable complete responses in refractory hairy cell leukemia, where patients rarely form antibodies to the bacterial toxin component of the immunotoxin. Patients with mesothelioma, however, have normal immune systems and form antibodies after one cycle, and tumor responses to the immunotoxin have not been observed in this disease. We describe the results of a trial in which major antitumor responses were seen in patients with advanced mesothelioma who received the anti-mesothelin immunotoxin SS1P, together with pentostatin and cyclophosphamide, to deplete T and B cells. Of 10 patients with chemotherapy-refractory mesothelioma, 3 have had major tumor regressions with 2 ongoing at 15 months, and 2 others responded to chemotherapy after discontinuing immunotoxin therapy. Antibody formation was markedly delayed, allowing more SS1P cycles to be given, but this alone does not appear to account for the marked antitumor activity observed.
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- 2013
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27. When Benign Tumors Mimic Malignancies: A Case of Lymphangiomatosis Masquerading as Metastatic Disease.
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Spencer KR, Miettinen MM, Maki RG, and Mehnert JM
- Abstract
Lymphangiomatosis, a rare disorder of the lymphatic system characterized by the abnormal proliferation of lymphatic vessels, is a typically benign disorder that at times can exhibit invasive or malignant behavior. While generally considered a diagnosis of childhood, in adults the majority of cases are asymptomatic and found incidentally. Rarely, lymphatic overgrowth can occur, causing growth of lesions on imaging mimicking a metastatic process and occasionally, resulting in substantial morbidity and mortality. Here, we present such a case of lymphangiomatosis with multi-organ system involvement in liver, bone, and spleen. In addition to details of the clinical presentation and the pathologic review which led to the diagnosis, we describe our use of the tyrosine kinase inhibitor pazopanib, which may cause stabilization of lymphangiomatosis through blockade of vascular endothelial growth factor (VEGF) signaling, for systemic treatment in this unusual case.
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- 2013
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28. NY-ESO-1 expression in sarcomas: A diagnostic marker and immunotherapy target.
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Lai JP, Rosenberg AZ, Miettinen MM, and Lee CC
- Abstract
NY-ESO-1 (CTAG 1B) is highly expressed in the majority of synovial sarcomas and myxoid/round cell liposarcomas as well as in a subset of melanomas, but only rarely in other mesenchymal tumors. This points to a potential for using NY-ESO-1 in the differential diagnosis of these lesions. Furthermore, promising results have been obtained in clinical trials testing NY-ESO-1-targeted immunotherapy in subsets of melanoma and synovial sarcoma patients.
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- 2012
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29. NY-ESO-1 expression in synovial sarcoma and other mesenchymal tumors: significance for NY-ESO-1-based targeted therapy and differential diagnosis.
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Lai JP, Robbins PF, Raffeld M, Aung PP, Tsokos M, Rosenberg SA, Miettinen MM, and Lee CC
- Subjects
- Biomarkers, Tumor genetics, Diagnosis, Differential, Gene Rearrangement, Humans, Immunohistochemistry, Immunotherapy, Adoptive methods, Maryland, Neoplasm Staging, Oncogene Proteins, Fusion genetics, Patient Selection, Predictive Value of Tests, Prognosis, Sarcoma, Synovial classification, Sarcoma, Synovial genetics, Sarcoma, Synovial pathology, Sarcoma, Synovial therapy, T-Lymphocytes immunology, T-Lymphocytes transplantation, Antigens, Neoplasm analysis, Biomarkers, Tumor analysis, Membrane Proteins analysis, Sarcoma, Synovial immunology
- Abstract
A promising targeted therapy against NY-ESO-1 (CTAG 1B) using genetically modified T-cells in synovial sarcomas was recently demonstrated in a clinical trial at the NCI. To investigate the role of NY-ESO-1 immunohistochemistry in patient selection and gain better insight into the incidence of NY-ESO-1 expression in synovial sarcomas and other mesenchymal tumors, we evaluated NY-ESO-1 expression by immunohistochemistry in 417 tumors. This collection of samples included: 50 SS18/SSX1/2 fusion positive synovial sarcomas, 155 gastrointestinal stromal tumors (GIST), 135 other spindle cell sarcomas as well as 77 other sarcomas (chondrosarcoma, osteosarcoma, dedifferentiated liposarcoma, alveolar soft part sarcoma, rhabdomyosarcoma, angiosarcoma, malignant mesothelioma, and Ewing's sarcoma). We report that 76% of synovial sarcomas expressed NY-ESO-1 in a strong and diffuse pattern (2-3+, >50-70% of tumor cells). In contrast, only rare cases of other spindle cell mesenchymal tumor expressed NY-ESO-1 (GIST (2/155), malignant peripheral nerve sheath tumors (1/34), and dermatofibrosarcoma protuberans (2/20)). Individual cases of other sarcomas (angiosarcoma, malignant mesothelioma, chondrosarcoma, osteosarcoma, dedifferentiated liposarcoma, alveolar soft part sarcoma, and Ewing's sarcoma) were positive for NY-ESO-1. However, no positive cases were identified amongst our cohort of leiomyosarcomas (0/24), hemangiopericytoma/solitary fibrous tumors (0/40), and cellular schwannomas (0/17). In summary, we find that NY-ESO-1 is strongly and diffusely expressed in a majority of synovial sarcomas, but only rarely in other mesenchymal lesions. Beyond its role in patient selection for targeted therapy, immunohistochemistry for NY-ESO-1 may be diagnostically useful for the distinction of synovial sarcoma from other spindle cell neoplasms.
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- 2012
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30. Comparative genomic hybridization of postirradiation sarcomas.
- Author
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Tarkkanen M, Wiklund TA, Virolainen MJ, Larramendy ML, Mandahl N, Mertens F, Blomqvist CP, Tukiainen EJ, Miettinen MM, Elomaa AI, and Knuutila YS
- Subjects
- Adult, Aged, Aged, 80 and over, Base Sequence, Chromosomes, Human, Pair 7, Chromosomes, Human, Pair 8, Female, Humans, Male, Middle Aged, Neoplasms, Radiation-Induced pathology, Neoplasms, Second Primary pathology, Nucleic Acid Hybridization, Sarcoma etiology, Sarcoma pathology, Chromosome Aberrations, Neoplasms, Radiation-Induced genetics, Neoplasms, Second Primary genetics, Sarcoma genetics
- Abstract
Background: Radiotherapy is a known risk factor for sarcoma development. Postirradiation sarcomas arise within the radiation field after a latency period of several years and usually are highly malignant. Very little is yet known about their genetic changes., Methods: Twenty-seven postirradiation sarcomas were analyzed by comparative genomic hybridization, which allows genome-wide screening of DNA sequence copy number changes., Results: Copy-number aberrations were detected in 20 (74%) tumors. The mean number of aberrations per tumor was 5.3 with gains outnumbering losses. The most frequent gains affected the minimal common regions of 7q11.2-q21 and 7q22 in 30% and 7p15-pter in 26%. Gain of 8q23-qter was detected in 22%. The most frequent losses affected 11q23-qter and 13q22-q32 in 22%. In osteosarcomas, the most frequent aberration was loss of 1p21-p31, in malignant fibrous histiocytomas (MFH) gain of 7cen-q22, and in fibrosarcomas gain of 7q22. The findings in postirradiation osteosarcomas and MFHs were compared with findings in sporadic osteosarcomas and MFHs, reported previously by the authors. In sporadic osteosarcomas, gains outnumbered losses, but, in postirradiation osteosarcomas, losses were more frequent than gains. Loss at 1p was rare in sporadic osteosarcoma (3%) but frequent (57%) in postirradiation osteosarcomas. Gains at 7q were frequent both in postirradiation and sporadic MFH., Conclusions: According to previous studies on different types of sporadic sarcomas, gains at 7q or 8q are associated with poor prognosis or large tumor size. Thus, the frequent gains at 7q and 8q might have been responsible in part for the poor prognosis of postirradiation sarcomas. Also, however, some of their clinical features, i.e., high malignancy grade, late diagnosis, and central location, are associated with a poor prognosis., (Copyright 2001 American Cancer Society.)
- Published
- 2001
- Full Text
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31. Calponin and h-caldesmon in soft tissue tumors: consistent h-caldesmon immunoreactivity in gastrointestinal stromal tumors indicates traits of smooth muscle differentiation.
- Author
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Miettinen MM, Sarlomo-Rikala M, Kovatich AJ, and Lasota J
- Subjects
- Biomarkers, Tumor metabolism, Cell Differentiation, Humans, Immunohistochemistry, Microfilament Proteins, Neoplasms, Complex and Mixed metabolism, Neoplasms, Fibrous Tissue metabolism, Stromal Cells metabolism, Tissue Distribution, Calponins, Calcium-Binding Proteins metabolism, Calmodulin-Binding Proteins metabolism, Gastrointestinal Neoplasms metabolism, Neoplasms, Muscle Tissue metabolism, Soft Tissue Neoplasms metabolism
- Abstract
Currently, the immunohistochemical evaluation of smooth muscle differentiation is usually based on desmin, which also reacts with skeletal muscle and is not present in all smooth muscle tumors, and alpha-smooth muscle actin, which reacts with myoepithelial cells. Neither marker typically reacts with gastrointestinal stromal tumors (GISTs), previously classified as smooth muscle tumors or presently often classified as smooth muscle/stromal tumors. Two cytoskeleton-associated actin-binding proteins, calponin (CALP) and h-caldesmon (HCD), are putative smooth muscle markers that also react with myoepithelia. These markers are of particular interest in the immunohistochemical analysis of tumors; neither of them has been extensively documented in soft tissue tumors. In this study, we evaluated selected normal and reactive tissues and more than 250 mesenchymal tumors for CALP and HCD. Both markers were expressed in parenchymal and vascular smooth muscle cells in various organs and in myoepithelial cells. CALP also reacted with myofibroblasts of desmoplastic stroma. All of our 25 benign smooth muscle tumors from various locations were positive for CALP and HCD, as were most of the retroperitoneal and uterine leiomyosarcomas. HCD was more specific, because CALP also reacted with myofibroblastic lesions. The common reactivity of malignant fibrous histiocytomas with CALP and HCD suggests a combination of myofibroblastic and smooth muscle differentiation in these tumors. The GISTs (c-kit positive, usually actin negative) showed nearly consistent HCD reactivity, suggesting traits of smooth muscle differentiation. GISTs were usually CALP negative and showed a CALP expression pattern similar to that of alpha-smooth muscle actin. Although nonmuscle, nonmyofibroblastic tumors were negative for CALP and HCD, synovial sarcomas showed streaks of CALP-positive cells of unknown significance. CALP and HCD should be explored as markers to identify myofibroblastic and smooth muscle cell differentiation in mesenchymal tumors.
- Published
- 1999
32. Tumor size-related DNA copy number changes occur in solitary fibrous tumors but not in hemangiopericytomas.
- Author
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Miettinen MM, el-Rifai W, Sarlomo-Rikala M, Andersson LC, and Knuutila S
- Subjects
- Adult, Aged, Aged, 80 and over, Female, Hemangiopericytoma chemistry, Hemangiopericytoma pathology, Humans, Image Processing, Computer-Assisted, Immunohistochemistry, Male, Middle Aged, Neoplasms, Fibrous Tissue chemistry, Neoplasms, Fibrous Tissue pathology, Chromosome Aberrations, Chromosome Disorders, Hemangiopericytoma genetics, Neoplasms, Fibrous Tissue genetics
- Abstract
Solitary fibrous tumor (SFT) presenting in the pleura and other soft tissue sites and hemangiopericytoma (HPC) presenting at various soft tissue sites are mesenchymal tumors that share many histologic and immunohistochemical features. This raises the questions of whether these tumors are related and whether they belong within the spectrum of a single biologic entity. The behavior of both SFTs and HPCs is difficult to predict histologically. The genetic background of both SFTs and HPCs is poorly known, but it could be helpful in the evaluation of malignancy and could give clues to their possible relationship. In this study, we analyzed 15 SFTs and 11 HPCs by comparative genomic hybridization (CGH), a powerful molecular cytogenetic tool that can be applied to DNA extracted from formaldehyde-fixed and paraffin-embedded tissue. All of these tumors were immunohistochemically similar and showed reactivity for CD34-antigen but not for keratins, desmin, or muscle actins. Only 1 SFT smaller than 10 cm showed DNA copy number changes (a single loss in chromosome 13), but 7 of 8 SFTs larger than 10 cm (including all 4 tumors with more than 4 mitoses per 10 high power fields) showed changes, mostly chromosomal gains in 5q 7, 8, 12, and 18. Four cases showed losses, two of them in chromosome 13 and two others in 20q. These findings suggest that CGH might be useful in the evaluation of malignant transformation in SFT. The most common change, gain of the entire chromosome 8, seen in two cases as the only change, suggests trisomy 8 and parallels a similar finding previously described in other fibrous tumors, such as subsets of desmoid fibromatosis and infantile fibrosarcoma. In contrast, HPCs, including large and mitotically active tumors, showed no DNA copy number changes on CGH. This suggests that HPC is genetically different from SFT.
- Published
- 1997
33. Coexistence of different B-cell clones in consecutive lesions of low-grade MALT lymphoma of the salivary gland in Sjögren's disease.
- Author
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Lasota J and Miettinen MM
- Subjects
- Adult, B-Lymphocytes physiology, Base Sequence, Biopsy, Clone Cells physiology, Cloning, Molecular, Female, Humans, Immunohistochemistry, Molecular Sequence Data, Polymerase Chain Reaction, Lymphoma, B-Cell, Marginal Zone genetics, Lymphoma, B-Cell, Marginal Zone pathology, Parotid Neoplasms genetics, Parotid Neoplasms pathology, Sjogren's Syndrome pathology
- Abstract
Low-grade mucosa-associated lymphoid tissue (MALT) lymphomas of the salivary gland are usually indolent diseases with a protracted clinical course. Recurrent multifocal disease has been shown to represent identical clones in some cases, and intraclonal variation resulting from continuing somatic hypermutation has been described, but emergence of novel, major clones upon recurrent disease has not been documented. We analyzed three consecutive biopsy specimens of parotid lymphoid infiltrates of a young woman with Sjögren's disease. The immunoglobulin heavy chain (IgH) gene rearrangements were first amplified using FR2/LJH-VLJH consensus primers. Then, the PCR products were cloned, sequenced, and compared. On the basis of the sequences of the complementarity determining region 3 (CDR3), clone-specific primers were designed and used to evaluate the presence of similar sequences in different biopsy specimens. Recurrent parotid lymphoid infiltrates during a span of 9 years showed histologically similar features consistent with low-grade MALT lymphoma. Polymerase chain reaction amplification showed a clonal pattern of IgH gene rearrangement in all of the lesions with similar product sizes, suggesting the identity of the clones, but two major clones with different CDR3 sequences were found. Intraclonal variation was seen among the sequences seen in the three lesions consistent with the occurrence of somatic hypermutations. Primers specific to the clone seen in the first two lesions failed to amplify products from the third lesion, but primers specific to the third clone showed similar products in the second clone in a small quantity, indicating that this clone persisted and expanded. Our results suggest that different B-cell clones might dominate during the course of low-grade MALT lymphoma of the salivary gland. This implies that in some cases, these processes can represent oligoclonal B-cell proliferations.
- Published
- 1997
34. Characterization of estrogen-dependent growth of cultured MCF-7 human breast-cancer cells expressing 17beta-hydroxysteroid dehydrogenase type 1.
- Author
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Miettinen MM, Poutanen MH, and Vihko RK
- Subjects
- Breast Neoplasms genetics, Breast Neoplasms pathology, Cell Division drug effects, Female, Gene Expression Regulation, Neoplastic drug effects, Gene Transfer Techniques, Humans, Hydroxysteroid Dehydrogenases genetics, Tumor Cells, Cultured, Breast Neoplasms metabolism, Estrogens pharmacology, Hydroxysteroid Dehydrogenases biosynthesis
- Abstract
17beta-hydroxysteroid dehydrogenase (17HSD) type I converts the weakly active estrogen, estrone, into highly active estradiol. In addition to being essential for gonadal estradiol biosynthesis, the enzyme is also expressed in a significant proportion of breast tumors. In order to study the role of the enzyme in estrogen-dependent growth of breast cancer, MCF-7 breast-cancer cells stably expressing human 17HSD type I were generated. In control MCF-7 cells a very low 17HSD activity was observed and, in line with its low estrogenic activity, estrone was devoid of the growth-enhancing effect of estradiol. The presence of the enzyme in the stably transfected MCF-7 cells resulted in a rapid conversion of estrone into estradiol but did not alter the estrogen-receptor concentration in the cells. However, in transfected cells, estrone had a growth-promoting effect practically identical to that of estradiol. The presence or absence of 17HSD type I in breast-cancer cells may therefore be decisive with regard to estrogen exposure and the estrogen-responsive growth of breast-cancer tissues.
- Published
- 1996
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35. Human 17 beta-hydroxysteroid dehydrogenase type 1 and type 2 isoenzymes have opposite activities in cultured cells and characteristic cell- and tissue-specific expression.
- Author
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Miettinen MM, Mustonen MV, Poutanen MH, Isomaa VV, and Vihko RK
- Subjects
- 17-Hydroxysteroid Dehydrogenases biosynthesis, Animals, Breast Neoplasms, Cell Line, Cell Membrane enzymology, Chlorocebus aethiops, Endometrial Neoplasms, Endometrium enzymology, Female, Humans, Isoenzymes biosynthesis, Kidney, Kinetics, Male, Ovarian Neoplasms, Prostatic Neoplasms, RNA, Messenger analysis, RNA, Messenger biosynthesis, Tumor Cells, Cultured, 17-Hydroxysteroid Dehydrogenases metabolism, Gene Expression, Isoenzymes metabolism
- Abstract
17 beta-Hydroxysteroid dehydrogenase (17HSD) isoenzymes catalyse the interconversion between highly active 17 beta-hydroxy- and low-activity 17-keto-steroids and thereby regulate the biological activity of sex steroids. The present study was carried out to characterize 17HSD activity and the expression of 17HSD type 1 and 2 isoenzymes in several human cell types and tissues. The data indicate that in cultured cells the direction of 17HSD activity is exclusively determined by the expression of these distinct isoenzymes. The intracellular environment could not modulate the direction of the enzyme activities in any of the cell types analysed. 17HSD type 1 acts as a reductase converting oestrone into oestradiol, whereas 17HSD type 2 possesses oxidative activity inactivating oestradiol by converting it into oestrone. The data, furthermore, suggest that of the two 17HSD type 1 mRNAs (1.3 and 2.3 kb), expression of the 1.3 kb mRNA is related to enzyme concentration in all the cell types studied. This mRNA is principally expressed in cells of placental and ovarian origin, but is also present in malignant breast epithelial cells. In contrast, 17HSD type 2 is more widely expressed. It is present in several oestradiol-metabolizing tissues as well as in some target cells of sex steroid action. The opposite reaction directions observed in the cultured cells, together with differences in the distribution of the isoenzymes, suggest that type 1 is involved in oestradiol production in females while type 2 plays a role in the inactivation of this sex steroid in peripheral tissues, both in females and in males. However, some examples exist of simultaneous expression of both enzymes in the same cell type or tissue.
- Published
- 1996
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36. Benign adrenocortical masses: diagnosis with chemical shift MR imaging.
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Mitchell DG, Crovello M, Matteucci T, Petersen RO, and Miettinen MM
- Subjects
- Adenoma diagnosis, Adrenal Gland Diseases diagnosis, Adrenal Gland Neoplasms chemistry, Adrenal Gland Neoplasms pathology, Adrenal Gland Neoplasms secondary, Adrenal Glands pathology, Biomarkers, Tumor analysis, Cysts diagnosis, Hemorrhage diagnosis, Humans, Image Enhancement, Lipids analysis, Lipoma diagnosis, Liver pathology, Muscles pathology, Retrospective Studies, Adrenal Gland Neoplasms diagnosis, Magnetic Resonance Imaging methods
- Abstract
Benign adrenocortical masses often contain lipid; metastases and pheochromocytomas do not. Standard and lipid-sensitive (chemical shift) magnetic resonance (MR) images of the adrenal glands in 31 patients with 45 adrenal masses were reviewed to determine if simple visual analysis of these images would increase diagnostic specificity. Lipid was considered present if signal intensity of the adrenal mass relative to other tissues decreased on chemical shift images relative to comparable standard images. Both myelolipomas and 26 of 27 benign cortical masses displayed a loss of signal intensity on at least one chemical shift image; all 12 metastases, the three hemorrhages, and a cyst did not. Opposed-phase images were slightly more sensitive than fat-suppressed images in depicting lipid within benign cortical masses. All masses had higher signal intensity than that of the liver on standard T2-weighted MR images. Chemical shift MR imaging can demonstrate lipid within benign adrenocortical masses and thus increase specificity, potentially obviating biopsy and aggressive follow-up.
- Published
- 1992
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37. MRI of pancreatic gastrinomas.
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Mitchell DG, Cruvella M, Eschelman DJ, Miettinen MM, and Vernick JJ
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- Adult, Female, Gastrinoma diagnostic imaging, Humans, Multiple Endocrine Neoplasia diagnosis, Pancreas diagnostic imaging, Pancreas pathology, Pancreatic Neoplasms diagnostic imaging, Tomography, X-Ray Computed, Gastrinoma diagnosis, Magnetic Resonance Imaging, Pancreatic Neoplasms diagnosis
- Abstract
Pancreatic islet cell tumors are often small and multiple, and preoperative diagnosis can be difficult. In a woman with hypergastrinemia, angiography and CT each depicted a solitary lesion. Magnetic resonance images, acquired using fat suppression, fast spin echo, and contrast material injection, depicted seven separate lesions, which were surgically confirmed.
- Published
- 1992
- Full Text
- View/download PDF
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