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1.  Variable CD52 Expression in Mature T Cell and NK Cell Malignancies: Implications for Alemtuzumab Therapy 
British journal of haematology  2009;145(2):173-179.
Summary
The anti-CD52 antibody alemtuzumab has been explored as a novel targeted therapy in T-cell malignancies. To assess the suitability of alemtuzumab therapy we carried out a comprehensive study of CD52 expression using flow cytometry (FC) in 78 untreated patients diagnosed with mature T/NK cell neoplasms, including 34 adult T-cell leukemia /lymphomas (ATLL), two anaplastic large cell lymphomas (ALCL), three angioimmunoblastic T-cell lymphomas (AITL), 16 cutaneous T-cell lymphomas (CTCL), four extra-nodal T/NK cell lymphomas (ENT/NKCL), four hepatosplenic T-cell lymphomas (HSTCL), 13 peripheral T-cell lymphomas, unspecified (PTCL-NOS), and two T-prolymphocytic leukemia (T-PLL). The level of CD52 expression was quantitated using QuantiBRITE standard beads. The level of CD52 expression varied widely within each diagnostic category. All AITL, HSTCL, and T-PLL cases were CD52 positive and the frequency of CD52 expression was high in PTCL-NOS (92.3%), ATLL (94.1%) and CTCL (87.5%), implying a rational role for alemtuzumab in the treatment of these diseases; however, CD52 expression was low in ALCL (50%) and ENT/NKCL (25%). FC testing for cell surface expression of CD52 is indicated in patients with T/NK cell malignancies being considered for alemtuzumab therapy. Further studies are necessary to determine if the level of CD52 expression correlates with response to therapy.
doi:10.1111/j.1365-2141.2009.07606.x
PMCID: PMC3487105  PMID: 19236377
Alemtuzumab; CD52; flow cytometry; NK cell lymphoma; T cell lymphoma
2.  Disseminated Strongyloides stercoralis Infection in HTLV-1-Associated Adult T-Cell Leukemia/Lymphoma 
Acta Haematologica  2011;126(2):63-67.
A 55-year-old woman with human T-cell lymphotropic virus type-1 (HTLV-1)-associated adult T-cell leukemia (ATL) and a history of previously treated Strongyloides stercoralis infection received anti-CD52 monoclonal antibody therapy with alemtuzumab on a clinical trial. After an initial response, she developed ocular involvement by ATL. Alemtuzumab was stopped and high-dose corticosteroid therapy was started to palliate her ocular symptoms. Ten days later, the patient developed diarrhea, vomiting, fever, cough, skin rash, and a deteriorating mental status. She was diagnosed with disseminated S. stercoralis. Corticosteroids were discontinued and the patient received anthelmintic therapy with ivermectin and albendazole with complete clinical recovery.
doi:10.1159/000324799
PMCID: PMC3080579  PMID: 21474923
Adult T-cell leukemia; Alemtuzumab; Corticosteroid; Disseminated Strongyloides; HTLV-1; Human T-cell lymphotropic virus type-1
3.  Vaccination With Patient-Specific Tumor-Derived Antigen in First Remission Improves Disease-Free Survival in Follicular Lymphoma 
Journal of Clinical Oncology  2011;29(20):2787-2794.
Purpose
Vaccination with hybridoma-derived autologous tumor immunoglobulin (Ig) idiotype (Id) conjugated to keyhole limpet hemocyanin (KLH) and administered with granulocyte-monocyte colony-stimulating factor (GM-CSF) induces follicular lymphoma (FL) –specific immune responses. To determine the clinical benefit of this vaccine, we conducted a double-blind multicenter controlled phase III trial.
Patients and Methods
Treatment-naive patients with advanced stage FL achieving complete response (CR) or CR unconfirmed (CRu) after chemotherapy were randomly assigned two to one to receive either Id vaccine (Id-KLH + GM-CSF) or control (KLH + GM-CSF). Primary efficacy end points were disease-free survival (DFS) for all randomly assigned patients and DFS for randomly assigned patients receiving at least one dose of Id vaccine or control.
Results
Of 234 patients enrolled, 177 (81%) achieved CR/CRu after chemotherapy and were randomly assigned. For 177 randomly assigned patients, including 60 patients not vaccinated because of relapse (n = 55) or other reasons (n = 5), median DFS between Id-vaccine and control arms was 23.0 versus 20.6 months, respectively (hazard ratio [HR], 0.81; 95% CI, 0.56 to 1.16; P = .256). For 117 patients who received Id vaccine (n = 76) or control (n = 41), median DFS after randomization was 44.2 months for Id-vaccine arm versus 30.6 months for control arm (HR, 0.62; 95% CI, 0.39 to 0.99; P = .047) at median follow-up of 56.6 months (range, 12.6 to 89.3 months). In an unplanned subgroup analysis, median DFS was significantly prolonged for patients receiving IgM-Id (52.9 v 28.7 months; P = .001) but not IgG-Id vaccine (35.1 v 32.4 months; P = .807) compared with isotype-matched control-treated patients.
Conclusion
Vaccination with patient-specific hybridoma-derived Id vaccine after chemotherapy-induced CR/CRu may prolong DFS in patients with FL. Vaccine isotype may affect clinical outcome and explain differing results between this and other controlled Id-vaccine trials.
doi:10.1200/JCO.2010.33.3005
PMCID: PMC3139394  PMID: 21632504
4.  Adult T-cell leukemia/lymphoma with EBV-positive Hodgkin-like cells 
Human pathology  2011;42(7):1042-1046.
SUMMARY
Hodgkin-like cells (HLC) have been described in a variety of non-Hodgkin lymphomas (NHL) including chronic lymphocytic leukemia (CLL) and peripheral T-cell lymphoma (PTCL). There have been rare reports in the Japanese population of human T-cell lymphotrophic virus-1 (HTLV-1)-associated adult T-cell leukemia/lymphoma (ATLL) harboring HLC; however, no similar cases have been described in western patients. We report a 53-year-old African-American man that presented with progressive weakness and lethargy, and was found to have generalized lymphadenopathy and hypercalcemia. A lymph node biopsy showed involvement by ATLL with scattered Epstein-Barr virus (EBV)-positive cells, some of which resembled Hodgkin cells that had a B-cell phenotype, consistent with an Epstein-Barr virus-lymphoproliferative disorder (LPD). The patient had stage 4 disease with bone marrow involvement. In light of the associated B-cell lymphoproliferative process, the patient was treated with six cycles of intensive chemotherapy that targeted both the ATLL and the EBV-LPD that resulted in a complete response. An awareness of the association of EBV-LPD with Hodgkin-like cells in the context of ATLL is necessary to avoid potential misdiagnosis and to aid in therapeutic decisions.
doi:10.1016/j.humpath.2010.10.014
PMCID: PMC3118938  PMID: 21315416
Adult T-cell leukemia/lymphoma; Epstein-Barr virus; flow cytometry; Hodgkin-like; human T-cell lymphotrophic virus-1; immunohistochemistry
5.  New Strategies in Peripheral T-cell lymphoma: Understanding Tumor Biology and Developing Novel Therapies 
Peripheral T-cell lymphomas (PTCLs) constitute a group of heterogeneous diseases that are uncommon, representing, in Western countries, only approximately 10% of all non-Hodgkin lymphomas. They are typically associated with a poor prognosis compared to their B-cell counterparts and are much less well understood with respect to tumor biology, due to their rarity and biologic heterogeneity, and to the fact that characteristic cytogenetic abnormalities are few compared to B-cell lymphomas. While the outcome for patients with anaplastic large cell lymphoma (ALCL), particularly ALK-positive ALCL, is good, other types of peripheral T-cell lymphomas are associated with a poor prognosis even with aggressive anthracycline-based chemotherapy. In this respect, there is a need for new approaches in these diseases and this review focuses on and explores recent experience with novel therapies in PTCL.
doi:10.1158/1078-0432.CCR-09-1995
PMCID: PMC3058794  PMID: 21138864
6.  Visual Inspection Versus Quantitative Flow Cytometry to Detect Aberrant CD2 Expression in Malignant T Cells 
Background
Abnormal levels of T cell antigen expression occur in T cell neoplasia. We examined CD2 expression in malignant and normal T cells to determine if the level of CD2 expression differed significantly and if quantitation assisted in detecting this difference.
Method
Flow cytometric immunophenotypic (FCI) evaluation was performed on specimens from 36 patients with mature T cell neoplasia. Abnormal T cells were identified based upon abnormal FCI and morphology. Levels of CD2 expression were quantitated using 1:1 PE conjugates of anti-CD2 and QuantiBRITE bead standards to calculate the antibodies bound per cell (ABC). The efficacy of ABC measurement verses simple examination of dots plots was compared.
Results
Abnormal levels of CD2 expression were frequently observed in mature T cell malignancies. The CD2 ABC values were highly sensitive in detecting differences between malignant and normal T cells (p=0.0028). In most cases (24/32 specimens, 75%) CD2 ABCs differed by > 20%. CD2 ABCs had high variability in normal T cells.
Conclusions
CD2 expression by malignant T cells differed significantly from that of normal T-cells by CD2 ABC quantitation. The high variability in normal T cell CD2 ABCs limited the determination of normal reference ranges, and thus its utility in the diagnosis of T cell neoplasia. However, examination of CD2 can help in detection of tumor cells when residual normal T cells are present for comparison. Moreover, the increased sensitivity of CD2 quantitation is valuable in confirming FCI cases where abnormalities in CD2 expression are difficult to appreciate by visual inspection alone.
doi:10.1002/cyto.b.20507
PMCID: PMC2916169  PMID: 20020522
CD2; quantitation; ABC; lymphoma; normal T cells
7.  Impacting tumor cell-fate by targeting the inhibitor of apoptosis protein survivin 
Molecular Cancer  2011;10:35.
Survivin (BIRC5), a member of the inhibitor of apoptosis protein (IAP) family that inhibits caspases and blocks cell death is highly expressed in cancer and is associated with a poorer clinical outcome. Functioning simultaneously during cell division and apoptosis inhibition, survivin plays a pivotal role in determining cell survival. Survivin has consistently been identified by molecular profiling analysis to be associated with higher tumor grade, more advanced disease, abbreviated survival, accelerated rates of recurrence, and chemotherapy and radiation resistance. Survivin's differential expression in cancer compared to normal tissue and its role as a nodal protein in a number of cellular pathways make it a highly flexible therapeutic target, suitable for small-molecule inhibitiors, molecular antagonists, and vaccination-based therapies. By targeting survivin it is hoped that multiple tumor signaling circuitries may be simultaneously disabled. This effect may be applicable to many tumor histologies irrespective of specific genetic makeup. To date, survivin inhibitors have shown modest activity as single agents, but it is anticipated that when given in combination with cytotoxic chemotherapy or monoclonal antibodies they may exhibit enhanced efficacy. This review discusses the complex circuitry of survivin in human cancers and highlights clinical trials involving novel agents that target this important protein.
doi:10.1186/1476-4598-10-35
PMCID: PMC3083377  PMID: 21470426
8.  The Role of Chemotherapy in Hodgkin’s Lymphoma 
Cancer journal (Sudbury, Mass.)  2009;15(2):150-154.
The development of curative chemotherapy regimens for the treatment of Hodgkin’s lymphoma is one of the true success stories in oncology. Most patients diagnosed with Hodgkin’s lymphoma today can be cured. The major task remaining before us is curing as many patients as possible with their initial therapeutic approach while minimizing the acute toxicities and limiting the lifetime risks of important secondary events such as cardiovascular complications and secondary malignancies. In the 40 years since DeVita and colleagues developed the MOPP (Mechlorethamine, Vincristine, Procarbazine, Prednisone) chemotherapy regimen, we have learned a great deal about risk stratification to minimize treatment-related toxicity. Positron-emission tomography may further assist us in reducing radiation treatment without compromising cures. This review will discuss the development of the chemotherapy regimens used in the management of early and advanced stage Hodgkin’s lymphoma and the advantages and disadvantages of their use in combination with radiation therapy.
doi:10.1097/PPO.0b013e3181a27018
PMCID: PMC2847426  PMID: 19390311
Hodgkin’s lymphoma; Antineoplastic Agents; Combined Modality Therapy; Positron-Emission Tomography
9.  Definition, Prognostic Factors, Treatment, and Response Criteria of Adult T-Cell Leukemia-Lymphoma: A Proposal From an International Consensus Meeting 
Journal of Clinical Oncology  2009;27(3):453-459.
Adult T-cell leukemia-lymphoma (ATL) is a distinct peripheral T-lymphocytic malignancy associated with a retrovirus designated human T-cell lymphotropic virus type I (HTLV-1). The diversity in clinical features and prognosis of patients with this disease has led to its subclassification into the following four categories: acute, lymphoma, chronic, and smoldering types. The chronic and smoldering subtypes are considered indolent and are usually managed with watchful waiting until disease progression, analogous to the management of some patients with chronic lymphoid leukemia (CLL) or other indolent histology lymphomas. Patients with aggressive ATL generally have a poor prognosis because of multidrug resistance of malignant cells, a large tumor burden with multiorgan failure, hypercalcemia, and/or frequent infectious complications as a result of a profound T-cell immunodeficiency. Under the sponsorship of the 13th International Conference on Human Retrovirology: HTLV, a group of ATL researchers joined to form a consensus statement based on established data to define prognostic factors, clinical subclassifications, and treatment strategies. A set of response criteria specific for ATL reflecting a combination of those for lymphoma and CLL was proposed. Clinical subclassification is useful but is limited because of the diverse prognosis among each subtype. Molecular abnormalities within the host genome, such as tumor suppressor genes, may account for these diversities. A treatment strategy based on the clinical subclassification and prognostic factors is suggested, including watchful waiting approach, chemotherapy, antiviral therapy, allogeneic hematopoietic stem-cell transplantation (alloHSCT), and targeted therapies.
doi:10.1200/JCO.2008.18.2428
PMCID: PMC2737379  PMID: 19064971
10.  Anti-HTLV antibody profiling reveals an antibody signature for HTLV-I-Associated Myelopathy/Tropical Spastic Paraparesis (HAM/TSP) 
Retrovirology  2008;5:96.
Background
HTLV-I is the causal agent of adult T cell leukemia (ATLL) and HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Biomarkers are needed to diagnose and/or predict patients who are at risk for HAM/TSP or ATLL. Therefore, we investigated using luciferase immunoprecipitation technology (LIPS) antibody responses to seven HTLV-I proteins in non-infected controls, asymptomatic HTLV-I-carriers, ATLL and HAM/TSP sera samples. Antibody profiles were correlated with viral load and examined in longitudinal samples.
Results
Anti-GAG antibody titers detected by LIPS differentiated HTLV-infected subjects from uninfected controls with 100% sensitivity and 100% specificity, but did not differ between HTLV-I infected subgroups. However, anti-Env antibody titers were over 4-fold higher in HAM/TSP compared to both asymptomatic HTLV-I (P < 0.0001) and ATLL patients (P < 0.0005). Anti-Env antibody titers above 100,000 LU had 75% positive predictive value and 79% negative predictive value for identifying the HAM/TSP sub-type. Anti-Tax antibody titers were also higher (P < 0.0005) in the HAM/TSP compared to the asymptomatic HTLV-I carriers. Proviral load correlated with anti-Env antibodies in asymptomatic carriers (R = 0.76), but not in HAM/TSP.
Conclusion
These studies indicate that anti-HTLV-I antibody responses detected by LIPS are useful for diagnosis and suggest that elevated anti-Env antibodies are a common feature found in HAM/TSP patients.
doi:10.1186/1742-4690-5-96
PMCID: PMC2580768  PMID: 18937847
11.  Phase II Study of Dose-Adjusted EPOCH-Rituximab in Untreated Diffuse Large B-cell Lymphoma with Analysis of Germinal Center and Post-Germinal Center Biomarkers 
Purpose
To assess the clinical outcome and the influence of biomarkers associated with apoptosis inhibition (Bcl-2), tumor proliferation (MIB-1) and cellular differentiation on the outcome with dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin and rituximab (DA-EPOCH-R) infusional therapy in diffuse large B-cell lymphoma and analysis of germinal center B-cell (GCB) and post-GCB subtypes by immunohistochemistry.
Patients and Methods
Phase II study of 72 patients with untreated de novo DLBCL who were at least 18 years of age and stage II or higher. Radiation consolidation was not permitted.
Results
Patients had a median age of 50 (range: 19-85) years and 40% had a high-intermediate or high International Prognostic Index (IPI). At five-years, progression-free (PFS) and overall survival (OS) were 79% and 80%, respectively, with a median potential follow-up of 54 months. PFS was 91%, 90%, 67% and 47%, and OS was 100%, 90%, 74% and 37%, for 0-1, 2, 3 and 4-5 IPI factors, respectively, at five-years. The Bcl-2 and MIB-1 biomarkers were not associated with PFS or OS. Based on DA-EPOCH historical controls, rituximab only benefited Bcl-2 positive tumors. Bcl-6 expression was associated with higher PFS whereas GCB exhibited a marginally significant higher PFS compared to post-GCB DLBCL.
Conclusion
DA-EPOCH-R outcome was not affected by tumor proliferation and rituximab appeared to overcome the adverse effect of Bcl-2. Bcl-6 may identify a biological program associated with a superior outcome. Overall, DA-EPOCH-R shows promising outcome in low and intermediate IPI groups. A molecular model of treatment outcome with rituximab and chemotherapy is presented.
doi:10.1200/JCO.2007.13.1391
PMCID: PMC2409217  PMID: 18378569
12.  Progress on new vaccine strategies for the immunotherapy and prevention of cancer 
Journal of Clinical Investigation  2004;113(11):1515-1525.
In recent years, great strides in understanding and regulating the immune system have led to new hope for harnessing its exquisite specificity to destroy cancer cells without affecting normal tissues. This review examines the fundamental immunologic advances and the novel vaccine strategies arising from these advances, as well as the early clinical trials studying new approaches to treat or prevent cancer.
doi:10.1172/JCI200421926
PMCID: PMC419494  PMID: 15173875
13.  Herpes Simplex Virus Types 1 and 2 Completely Help Adenovirus-Associated Virus Replication 
Journal of Virology  1981;40(1):241-247.
In addition to adenoviruses, which are capable of completely helping adenovirus-associated virus (AAV) multiplication, only herpesviruses are known to provide any AAV helper activity, but this activity has been thought to be partial (i.e., AAV DNA, RNA, and protein syntheses are induced, but infectious particles are not assembled). In this study, however, we show that herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) are in fact complete AAV helpers and that AAV type 2 (AAV2) infectivity yields can approach those obtained when coinfections are carried out with a helper adenovirus. AAV helper activity was demonstrated in KB cells with two HSV-1 strains (11124 and 17MP) and an HSV-2 strain (HG52). Each herpesvirus supported AAV2 multiplication with comparable efficiency. AAV2 multiplication was similarly efficient in HSV-1 coinfections of HeLa cells, whereas lower yields were obtained in HEp-2 and primary human embryonic kidney cells. HSV-1 also supported AAV1 multiplication in HeLa cells but, at corresponding multiplicities of infection, AAV1 grew less efficiently than AAV2. Comparisons of the time courses of AAV2 DNA, RNA, and protein syntheses after coinfection with either adenovirus type 5 or HSV-1 revealed that, in each case, the onset of synthesis and attainment of maximal synthesis rate occurred earlier in coinfections with HSV-1. These findings demonstrate the linkage of AAV macromolecular synthesis to an event(s) in the helper virus cycle. Aside from this temporal association, helper-related differences in AAV macromolecular synthesis were not apparent.
Images
PMCID: PMC256613  PMID: 6270377

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