ABSTRACT
CD123 is the α-subunit of the interleukin-3 receptor; it represents a potential therapeutic target in systemic mastocytosis (SM) given its absent expression on normal/reactive mast cells (MCs) and aberrant expression on neoplastic MCs. We studied 58 SM patients to define CD123 expression patterns by immunohistochemistry and its clinical significance. Two hematopathologists independently scored bone marrow slides using predefined histologic parameters. In all, 23 patients had indolent SM (ISM), 10 aggressive SM (ASM), 23 SM with associated hematological neoplasm (SM-AHN) and 2 had mast cell leukemia (MCL). MC_CD123 expression was demonstrable in 37 (64%) cases; expression rates were 100%, 61%, 57% and 0% in ASM, ISM, SM-AHN and MCL, respectively (P=0.02). Focal proliferation of plasmacytoid dendritic cells (PDCs) around MC aggregates, suggesting a tumor-promoting role for PDCs, was noted in 44 (76%) cases, and was significantly higher in CD123-positive versus -negative cases (87% versus 50%, P=0.005). CD123 expression and its staining intensity had prognostic value in SM-chronic myelomonocytic leukemia and nonindolent SM patients, respectively. These observations suggest that targeting CD123 in SM may have direct (via MCs) and indirect (via PDCs) antitumor effects and clinical trials to that effect require laboratory correlative studies to address the observed target expression heterogeneity.
Subject(s)
Biomarkers, Tumor/metabolism , Hematologic Neoplasms/metabolism , Interleukin-3 Receptor alpha Subunit/metabolism , Leukemia, Mast-Cell/metabolism , Mastocytosis, Systemic/metabolism , Adult , Aged , Aged, 80 and over , Female , Follow-Up Studies , Hematologic Neoplasms/pathology , Humans , Immunoenzyme Techniques , Leukemia, Mast-Cell/pathology , Male , Mastocytosis, Systemic/pathology , Middle Aged , Neoplasm Staging , Prognosis , Retrospective StudiesABSTRACT
PURPOSE: The objective of this study is to evaluate the feasibility of proton beam treatment verification using in-room PET. As of February 2012, four patients have been studied in a clinical trial. In addition, we suggest a new method comparing the distal surface of the measured and simulated PET activities to verify the location of the distal dose surface. METHODS: Patients were scanned for 20 minutes with an in-room PET positioned next to the proton treatment head in a gantry room for beam delivery using passive scattering. The time between end of treatment and the start of the scan was within about 2 minutes. The predicted distribution of the PET activities and the proton dose distributions in the patients were also calculated using Monte Carlo (MC). Along the beam direction, the 50% fall-off positions of the maximum PET activity at each line profile were compared with the MC simulated and the measured PET images, and then the differences were assessed with root-mean-square deviation (RMSD) and mapped in the beam's eye view. RESULTS: The measured PET images showed a good spatial correlation with the simulated PET images and the proton dose distributions even though the treated volumes and locations varied between patients. The RMSD values, representing the surface differences between the measured and simulated PET, were assessed to be 4.3-5.1 mm for four patients. Some region including the penumbra showed larger differences but was excluded. CONCLUSIONS: We have explored the potential of the in-room PET for proton therapy monitoring through a clinical trial. The PET image analysis method based on MC simulations showed that the distal dose surface could be determined within a few millimeters but not within the aimed accuracy of 2-3 mm. Improvements in PET-CT image registration and biological washout modeling will most likely increase the accuracy further. NIH/NCI P01 CA021239.
ABSTRACT
Oncogenes involved in recurrent chromosomal translocations serve as diagnostic markers and therapeutic targets in hematopoietic tumors. In contrast to myeloid and B-cell neoplasms, translocations in peripheral T-cell lymphomas (PTCLs) are poorly understood. Here, we identified recurrent translocations involving the multiple myeloma oncogene-1/interferon regulatory factor-4 (IRF4) locus in PTCLs. IRF4 translocations exist in myeloma and some B-cell lymphomas, but have not been reported earlier in PTCLs. We studied 169 PTCLs using fluorescence in situ hybridization and identified 12 cases with IRF4 translocations. Two cases with t(6;14)(p25;q11.2) had translocations between IRF4 and the T-cell receptor-alpha (TCRA) locus. Both were cytotoxic PTCLs, unspecified (PTCL-Us) involving bone marrow and skin. In total, 8 of the remaining 10 cases were cutaneous anaplastic large-cell lymphomas (ALCLs) without TCRA rearrangements (57% of cutaneous ALCLs tested). These findings identified IRF4 translocations as a novel recurrent genetic abnormality in PTCLs. Cytotoxic PTCL-Us involving bone marrow and skin and containing IRF4/TCRA translocations might represent a distinct clinicopathologic entity. Translocations involving IRF4 but not TCRA appear to occur predominantly in cutaneous ALCLs. Detecting these translocations may be useful in lymphoma diagnosis. Further, due to its involvement in translocations, MUM1/IRF4 protein may play an important biologic role in some PTCLs, and might represent a possible therapeutic target.
Subject(s)
Interferon Regulatory Factors/genetics , Lymphoma, T-Cell, Cutaneous/genetics , Lymphoma, T-Cell, Peripheral/genetics , Oncogene Proteins, Fusion/genetics , Oncogenes , Skin Neoplasms/genetics , Translocation, Genetic , Adolescent , Adult , Aged , Aged, 80 and over , Bone Marrow Neoplasms/genetics , Child , Child, Preschool , Chromobox Protein Homolog 5 , Chromosomes, Human, Pair 14/genetics , Chromosomes, Human, Pair 14/ultrastructure , Chromosomes, Human, Pair 6/genetics , Chromosomes, Human, Pair 6/ultrastructure , Female , Humans , In Situ Hybridization, Fluorescence , Interferon Regulatory Factors/biosynthesis , Lymphoma, Primary Cutaneous Anaplastic Large Cell/genetics , Male , Middle Aged , Oncogene Proteins, Fusion/biosynthesis , Receptors, Antigen, T-Cell, alpha-beta/genetics , Young AdultABSTRACT
Peripheral T-cell lymphomas (PTCLs) are fatal in the majority of patients and novel treatments, such as protein tyrosine kinase (PTK) inhibition, are needed. The recent finding of SYK/ITK translocations in rare PTCLs led us to examine the expression of Syk PTK in 141 PTCLs. Syk was positive by immunohistochemistry (IHC) in 133 PTCLs (94%), whereas normal T cells were negative. Western blot on frozen tissue (n=6) and flow cytometry on cell suspensions (n=4) correlated with IHC results in paraffin. Additionally, western blot demonstrated that Syk-positive PTCLs show tyrosine (525/526) phosphorylation, known to be required for Syk activation. Fluorescence in situ hybridization showed no SYK/ITK translocation in 86 cases. Overexpression of Syk, phosphorylation of its Y525/526 residues and the availability of orally available Syk inhibitors suggest that Syk merits further evaluation as a candidate target for pharmacologic PTK inhibition in patients with PTCL.
Subject(s)
Intracellular Signaling Peptides and Proteins/metabolism , Lymphoma, T-Cell, Peripheral/enzymology , Protein-Tyrosine Kinases/metabolism , Adolescent , Adult , Aged , Aged, 80 and over , Blotting, Western , Child , Child, Preschool , Chromosomes, Human, Pair 5/genetics , Chromosomes, Human, Pair 9/genetics , Female , Flow Cytometry , Humans , Immunoenzyme Techniques , Immunophenotyping , In Situ Hybridization, Fluorescence , Intracellular Signaling Peptides and Proteins/genetics , Lymphoma, Extranodal NK-T-Cell/enzymology , Lymphoma, Extranodal NK-T-Cell/genetics , Lymphoma, Extranodal NK-T-Cell/pathology , Lymphoma, Large-Cell, Anaplastic/enzymology , Lymphoma, Large-Cell, Anaplastic/genetics , Lymphoma, Large-Cell, Anaplastic/pathology , Lymphoma, T-Cell, Cutaneous/enzymology , Lymphoma, T-Cell, Cutaneous/genetics , Lymphoma, T-Cell, Cutaneous/pathology , Lymphoma, T-Cell, Peripheral/genetics , Lymphoma, T-Cell, Peripheral/pathology , Male , Middle Aged , Phosphorylation , Protein-Tyrosine Kinases/genetics , Syk Kinase , Translocation, Genetic , Tyrosine/metabolismABSTRACT
The incidence of lymphoma in patients with HIV infection greatly exceeds that of the general population. The increased risk for lymphoma appears related to multiple factors, including the transforming properties of the retrovirus itself, the immunosuppression and cytokine dysregulation that results from the disease, and, most importantly, opportunistic infections with other lymphotrophic herpes viruses such as Epstein-Barr virus and human herpesvirus 8. Histologically lymphomas fall into three groups: (1) those also occurring in immunocompetent patients; (2) those occurring more specifically in HIV-positive patients; and (3) those also occurring in patients with other forms of immunosuppression. Aggressive lymphomas account for the vast majority cases. They frequently present with advanced stage, bulky disease with high tumour burden and, typically, involve extranodal sites. Clinical outcome appears to be worse than in similar aggressive lymphomas in the general population. However, following the introduction of highly active antiretroviral therapy, the risk for developing lymphoma in the context of HIV infection has decreased and the clinical outcome has improved.
Subject(s)
Lymphoma, AIDS-Related/pathology , Burkitt Lymphoma/immunology , Burkitt Lymphoma/pathology , Burkitt Lymphoma/virology , Hodgkin Disease/immunology , Hodgkin Disease/pathology , Hodgkin Disease/virology , Humans , Immunocompetence , Immunocompromised Host , Lymphoma, AIDS-Related/immunology , Lymphoma, B-Cell/immunology , Lymphoma, B-Cell/pathology , Lymphoma, B-Cell/virologyABSTRACT
OBJECTIVE: To gather clinicopathologic data on subcutaneous granuloma annulare (SGA), a subtype of granuloma annulare that occurs exclusively in children and is histologically similar to rheumatoid nodules. DESIGN: Retrospective record review. PATIENTS: Children <10 years old in whom SGA, deep granuloma annulare, or necrobiotic granuloma was diagnosed at the Mayo Clinic (Rochester, MN) from 1983 to 1998. RESULTS: Thirty-four patients (21 girls and 13 boys; average age at diagnosis: 4.6 years) were found to have SGA. The lesions predominantly occurred in the lower extremity, especially in a pretibial location. Local recurrence within 1 month to 7 years was documented in 38.2%; recurrence at other locations was documented in 14.7%. Average follow-up was 60 months; during follow-up, no patients developed signs or symptoms of rheumatologic disease. Insulin-dependent diabetes mellitus was diagnosed in 2 patients, 1 before the development of SGA and 1 after it by 1 month. CONCLUSIONS: SGA is a lesion that presents as subcutaneous nodules on the lower extremities, hands, or scalp in young children. Recurrence is common but usually does not warrant additional biopsy.
Subject(s)
Granuloma Annulare/diagnosis , Child , Child, Preschool , Diabetes Complications , Female , Granuloma Annulare/complications , Humans , Male , Recurrence , Retrospective StudiesABSTRACT
A 30-year-old woman died as a result of a large Candida parapsilosis septic thrombus located on the tip of a Groshong catheter. The catheter had been in place for 28 months for administration of a 27 month course of intravenous cefotaxime for an unsubstantiated diagnosis of chronic Lyme disease.
Subject(s)
Catheterization, Central Venous/adverse effects , Catheters, Indwelling/adverse effects , Lyme Disease/drug therapy , Adult , Candidiasis/etiology , Cefotaxime/administration & dosage , Cephalosporins/administration & dosage , Diagnostic Errors , Fatal Outcome , Female , Humans , Iatrogenic Disease , Lyme Disease/diagnosis , Thrombosis/etiologyABSTRACT
Hereditary haemorrhagic telangiectasia (HHT) is an autosomal dominant disorder characterized by multisystemic vascular dysplasia and recurrent haemorrhage. Linkage for some families has been established to chromosome 9q33-q34. In the present study, endoglin, a transforming growth factor beta (TGF-beta) binding protein, was analysed as a candidate gene for the disorder based on chromosomal location, expression pattern and function. We have identified mutations in three affected individuals: a C to G substitution converting a tyrosine to a termination codon, a 39 base pair deletion and a 2 basepair deletion which creates a premature termination codon. We have identified endoglin as the HHT gene mapping to 9q3 and have established HHT as the first human disease defined by a mutation in a member of the TGF-beta receptor complex.