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PubMed2005

Cyclooxygenase-2 (COX-2) is frequently expressed in multiple myeloma and is an independent predictor of poor outcome.

Cyclooxygenase 2 (COX-2) is an inflammation-associated enzyme involved in the pathogenesis of many solid tumors, but little is known about its presence and role in hematologic neoplasms. Multiple myeloma (MM) is known to involve a deregulated cytokine network with secretion of inflammatory mediators. We thus decided to investigate the involvement of COX-2 in this neoplasm. Western blotting (WB) was used to evaluate 142 bone marrow (BM) specimens, including MM and monoclonal gammopathy of undetermined significance (MGUS). Selected cases under-went further evaluation by WB on purified CD138(+) cells, immunohistochemistry (IC), and real-time polymerase chain reaction (PCR) for mRNA expression. COX-2 was expressed in 11% (2 of 18) of MGUS specimens, 31% (29 of 94) of MM at diagnosis, and 47% (14 of 30) of MM with relapsed/refractory disease. COX-2 positivity was associated with a poor outcome in terms of progression-free (18 vs 36 months; P < .001) and overall survival (28 vs 52 months; P < .05). Real-time PCR showed COX-2 mRNA overexpression. IC and cell separation studies demonstrated COX-2 expression to be restricted to malignant plasma cells. This is the first report of the presence and prognostic role of COX-2 expression in MM. Future studies will assess COX-2 involvement in other hematologic tumors and its potential use as a therapeutic or chemo-preventive target in onco-hematology.

Adult↗
PubMed2000

Prolonged complete remission of myelodysplastic syndrome treated with danazol, retinoic acid and low-dose prednisone.

Myelodysplastic syndrome (MDS) is a diverse group of clonal hematologic neoplasms. Different medications have been tried in MDS; however, no effective treatment has been yet established. We report a patient with MDS who achieved a complete remission in response to combination therapy of danazol, retinoic acid, and prednisone. A 53-year-old female presented with pancytopenia, macrocytosis, and hypercellular bone marrow with erythroid hyperplasia and dysplasia and 10% ringed sideroblasts. Cytogenetic studies revealed the presence of two abnormal clones. She was diagnosed as having MDS-refractory anemia and was given blood transfusions to maintain blood cell counts at acceptable levels. At the same time, she was started on a combination of danazol (600 mg/day), retinoic acid (100 mg/day), and prednisone (10 mg every other day). Fourteen months later, the patient was in complete hematologic remission; she had normal peripheral blood count, and the blood smear showed normal morphology. Bone marrow studies revealed normal trilineage hematopoiesis. She was continued on the same combination treatment for 86 months, and she remained in complete clinical remission. Eighty-eight months from diagnosis, she relapsed with acute myeloid leukemia. This is the first reported case of MDS-RA that sustained a complete hematologic remission for a prolonged period in response to this combination treatment. This report indicates that restoration of normal hematopoiesis, prolongation of disease-free survival, and delay in the transformation to acute leukemia may be achieved by this combination of treatment in a subset of patients with MDS, especially refractory anemia with severe thrombocytopenia.

Antineoplastic Agents↗
PubMed2004

Nodal and extranodal tumor-forming accumulation of plasmacytoid monocytes/interferon-producing cells associated with myeloid disorders.

Nodal tumor-forming accumulations of plasmacytoid monocytes/interferon-producing cells (PMs/IPCs) have been described in patients with myeloproliferative disorders. Here we report a series of 9 additional cases of such association. The patients were predominantly adult (median, 62 years), males (male/female ratio, 7:2), who presented with chronic myelomonocytic leukemia (4 cases), acute myeloid leukemia (1), acute monocytic leukemia (2), unclassifiable chronic myeloproliferative (1), or myeloproliferative/myelodysplastic disease (1). The prognosis was poor (median survival, 24 months) and related to progression of the underlying myeloid neoplasm. We found that in addition to lymph nodes, PMs/IPCs accumulated to bone marrow (8 cases) and skin (4 cases). Immunohistochemical markers typically expressed by PMs/IPCs (CD68, CLA/HECA452, CD123) were found in all cases and shown useful to identify cells with variations from classic morphology. In addition, PMs/IPCs expressed the interferon-alpha (IFN-alpha) inducible protein MxA, the B-cell oncogene TCL1, and granzyme B. The biologic and clinical significance of the association between PMs/IPCs and myeloid disorders remains not clarified. Using fluorescence in situ hybridization analysis in a case known to harbor monosomy 7 in the myeloid leukemia, we demonstrated that PMs/IPCs share the same chromosomal abnormality, thus indicating that they are clonal, neoplastic in nature, and closely related to the associated myeloid tumor. Recently, a novel CD56+ hematologic neoplasm has been reported and retained to stem from PMs/IPCs. The majority of PMs/IPCs in the present series failed to express CD56, thus indicating that variants of PMs/IPCs neoplasms exist, which might represent parts of a spectrum.

Adult↗
PubMed1989

[MR imaging of the bone marrow using short TI IR. Part 2--Normal and pathological intensity distribution of the bone marrow].

Bone marrow pathology of hematological neoplasms was evaluated using short TI IR sequences and T2 weighted STIR (IR 1500/100/40, IR 1500/100/80). Material consisted of 49 individuals including 10 leukemias, 5 myelofibroses and 30 multiple myelomas. On IR 1500/100/40, all cases revealed heterogenously or diffusely high intensity. On IR 1500/100/80, both of acute and chronic myelocytic leukemias revealed definite signal decrease, while chronic lymphocytic leukemia, myelofibrosis and multiple myeloma showed no obvious signal decrease.

Adolescent↗
PubMed2006

Biomarkers of exposure, effect, and susceptibility in workers exposed to nitrotoluenes.

Nitrotoluenes, such as 2-nitrotoluene, 2,4-dinitrotoluene (24DNT), and 26DNT, are carcinogenic in animal experiments. Humans are exposed to such chemicals in the workplace and in the environment. It is therefore important to develop methods to biomonitor people exposed to nitrotoluenes to prevent the potential harmful effects. For the present study, workers exposed to high levels of these chemicals were investigated. The external dose (air levels), the internal dose (urine metabolites), the biologically effective dose [hemoglobin (Hb) adducts and urine mutagenicity], and biological effects (chromosomal aberrations and health effects) were determined. Individual susceptibility was assessed by determining genetic polymorphisms of enzymes assumed to function in nitrotoluene metabolism, namely glutathione S-transferases (GSTM1, GSTT1, GSTP1), N-acetyltransferases (NAT1, NAT2), and sulfotransferases (SULT1A1, SULT1A2). The levels of urinary metabolites did not correlate with the air levels. The urinary mutagenicity levels determined in a subset of workers correlated with the levels of a benzylalcohol metabolite of DNT. The Hb-adducts correlated with the urine metabolites but not with the air levels. The frequency of chromosomal aberrations (gaps included) was increased (P < 0.05) in the exposed workers in comparison with a group of factory controls and correlated with the level of 24DNT Hb-adducts in young subjects (<31 years). The GSTM1-null genotype was significantly more prevalent in the controls than in the exposed group, which probably reflected an elevated susceptibility of the GSTM1-null genotype to adverse health effects of DNT exposure, such as nausea (odds ratio, 8.8; 95% confidence interval, 2.4-32.2). A statistically significant effect was seen for SULT1A2 genotype on a 24DNT Hb-adduct; GSTP1 genotype on a 2,4,6-trinitrotoluene Hb-adduct; and SULT1A1, SULT1A2, NAT1, GSTT1, and GSTP1 genotypes on chromosomal aberrations in the exposed workers.

Adult↗
PubMed1991

Decision making in critically ill patients with hematologic malignancy.

Hematologic neoplasms that were previously considered fatal are now potentially curable with techniques such as bone marrow transplantation. Such therapies also carry significant morbidity and mortality. With the increasing application of these therapies, a growing number of physicians are using medical decision making regarding critical care for these patients. The process by which ethical decisions are reached for these critically ill patients may be baffling because of several factors: rapidly evolving treatments, uncertain probabilities of the cure of the malignant disorder, the relatively young age of many of these patients, and the poor prognosis with critical illness. I discuss a process to reach acceptable decisions, providing a case example of the application of the process. This process is derived from the ethical principles that drive decision making in general medicine and attempts to maximize patients' autonomy. It involves a consideration of accurate information regarding the disease process and the prognosis, a clear delineation of the goals of the medical care, and communication with patients. Appropriate, ethical, and consistent decisions regarding the critical care of patients with hematologic malignancy can be reached when these considerations are addressed.

Adult↗
PubMed1996

Expression of intercellular adhesion molecule-3 (ICAM-3/CD50) in malignant lymphoproliferative disorders and solid tumors.

ICAM-3/CD50 is a recently described LFA-1 counter receptor that seems to play an important role in the initiation of immune responses. In this study we have examined the expression of ICAM-3/CD50 in a large series of human neoplasms including 101 Non-Hodgkin's lymphomas (NHL), 26 Hodgkin's disease, and 38 solid tumors to define the distribution patterns of this molecule in malignant neoplasms and their possible correlation with clinical and pathological characteristics of the patients. In NHL, ICAM-3/CD50 was expressed in almost all the tumors with a tendency to be lost in high grade lymphomas. Reed-Sternberg cells and their variants in Hodgkin's disease were always negative independently of the histological subtype of the disease. No expression was observed in tumor epithelial cells of the 38 solid tumors examined. Strong endothelial cell staining was observed in 31% of the NHL and 31% of Hodgkin's disease. ICAM-3 expression in these cases was restricted to small tumor vessels. ICAM-3 expression in endothelial cells of NHL was significantly more frequent in high grade (40%) than in low grade lymphomas (14%) (p = 0.012). In addition, tumor vessels were also positive in 29% of solid tumors independently of the histological type. No correlation was observed between ICAM-3 expression in tumor or endothelial cells and other clinical and pathological characteristics of the patients. These findings indicate that ICAM-3 expression in human tumors is restricted to hematological neoplasms with a tendency to be lost in high grade lymphomas and Hodgkin's disease. ICAM-3 is also expressed by endothelial cells from tumor-associated neovascularization in both lymphoid and solid tumors.

Animals↗
PubMed1996

Differential efficacy of adenoviral mediated gene transfer into cells from hematological cell lines and fresh hematological malignancies.

As a first step to evaluate the possibility of gene therapy using adenoviral vectors in hematological malignancies in vivo, we tested the efficacy of gene transfer by a recombinant adenovirus in cell lines and fresh cells from various hematological neoplasms. Thirteen cell lines and samples from 27 patients were studied. Cells were infected by a recombinant adenovirus expressing beta galactosidase gene (Ad RSV betagal) and efficacy of transduction assessed by evaluating betagal expression in cells with a histochemical method. After infection of the cells at a multiplicity of infection (MOI) of 200 p.f.u./cell, the percentage of beta gal-positive cells after 48h was high in two cell lines. K562 (64%) and RPMI 8226 (a myeloma cell line, 65%), relatively large in the two myeloma cell lines tested (41% and 20%, respectively) and in MT4 (an adult T cell leukemia cell line, 38%) and low or absent in other cell lines. In fresh samples from AML, ALL, CLL, NHL, myeloma and MDS, no betagal positive cells were seen 48h and 72h after infection, except in one case of myeloma and one case of CLL (where 10% and 2% of betagal positive cells were seen after infection, respectively). Exposure of fresh malignant cells to GM-CSF before and during adenoviral infection, in three cases, did not increase the number of transfected cells. This suggests that adenoviral vectors, at least in their present form, cannot efficiently be used for direct gene transfer in hematological malignant cells.

Adenoviruses, Human↗
PubMed1987

Lymphoma 1987. An interim approach to diagnosis and classification.

When immunophenotyping is used for diagnosis, it is essential to use panels of antibodies, rather than a single marker for a specific tumor type. There is virtually no single marker that is absolutely diagnostic and completely reliable for any particular neoplasm. For the most important clinical differential diagnoses--reactive versus neoplastic lymphoid lesions and lymphoma versus nonlymphoid tumor--relatively simple panels of antibodies are usually sufficient. In the former situation, immunoglobulin heavy and light chains (G, M, kappa, lambda) and a pan-T-cell antibody (Leu-4) will usually provide the answer. For the latter circumstance, kappa and lambda, a pan-leukocyte antibody, a pan-B-cell (B1), and a pan-T-cell antibody (Leu-4) along with cytokeratin constitute the initial panel. Further subclassification of lymphomas and leukemias can proceed using other antibodies as indicated in the preceding specific sections on the lymphomas. The use of specific antibodies for nonlymphoid tumors will be dictated by the morphologic appearance of the tumor. These may be used as a second panel if the initial screening does not establish a diagnosis of lymphoma. Performing and interpreting immunohistologic studies requires experience, and probably should not be attempted by laboratories that do not encounter a large number of lymphomas. Frozen tissue can be obtained and stored at -20 degrees for a few days; if immunohistologic studies are deemed necessary, the frozen tissue can be sent on dry ice to a reference laboratory. In preparing biopsy specimens for immunohistologic studies, and in interpreting the results of these studies, it is necessary to bear in mind the fact that morphology remains the most important tool for the diagnosis and subclassification of hematologic neoplasms. Obtaining tissue for marker studies should not be permitted to interfere with adequate morphologic examination. Similarly, artifacts and technical problems can occasionally lead to misleading results; the immunohistologic studies must be interpreted in light of the case as a whole, and should never be allowed to contradict common sense.

Burkitt Lymphoma↗
PubMed2001

Primary effusion lymphoma: a liquid phase lymphoma of fluid-filled body cavities.

Primary effusion lymphoma (PEL) is a B-cell neoplasm characterized by infection of the tumor clone by human herpesvirus type-8/Kaposi's sarcoma-associated herpesvirus (HHV-8/KSHV) and by liquid growth in fluid-filled body spaces. During its entire clinical course, the lymphoma tends to remain localized to the serous body cavities with no formation of solid tumor masses. The epidemiology of PEL points to a close link with underlying immunodeficiency of the host, as most cases develop in individuals severely immunocompromised because of preexisting acquired immunodeficiency syndrome. The histogenesis and pathogenesis of PEL have been clarified to a sizeable extent by intensive investigations performed since the disease recognition in 1995. PEL is composed of postgerminal center B cells, which bridge immunoblastic and anaplastic features and typically display a non-B, non-T phenotype consistent with late stages of B-cell differentiation. HHV-8/KSHV is thought to play a major role in PEL pathogenesis via expression of several viral latent genes, which have the potential to affect B-cell growth. Other factors involved in PEL pathogenesis include deregulation of cytokine and growth factor autocrine loops, molecular alterations of the tumor DNA, cell cycle abnormalities, stimulation and selection by antigen, and infection by Epstein-Barr virus, which occurs in 70% of PEL cases. In the years since the disease discovery, the distinctiveness of the biological and clinicopathological features of PEL has prompted its recognition as an independent lymphoma category by the World Health Organization classification system of hematologic neoplasms.

Diagnosis, Differential↗
PubMed1991

Geographic heterogeneity of neoplasia-associated chromosome aberrations.

Using a database comprising 13,266 cytogenetically abnormal neoplasms, the geographic heterogeneity of neoplasia-associated chromosomal abnormalities was investigated by comparing the frequencies of characteristic aberrations in consecutive series of patients with the same diagnosis. Significant frequency differences between geographic areas were found for the aberrations +8, i(17q), +19, and an additional Ph1 chromosome in chronic myeloid leukemia (CML); -5, 5q-, and +8 in acute nonlymphocytic leukemia (ANLL); t(8;21) in ANLL-M2; t(15;17) in ANLL-M3; 5q- and -7 in myelodysplastic syndromes (MDS); t(9;22) and +21 in acute lymphocytic leukemia (ALL); t(14;18) in follicular lymphoma; -8 and -22/22q- in meningioma; and structural abnormalities of 12q in pleomorphic adenoma of the salivary glands (PAS). No geographic incidence variation was detected for -7 and +21 in ANLL; +8 in MDS; 6q- and +8 in ALL; +12 in chronic lymphocytic leukemia; 6q- in non-Hodgkin's lymphoma (NHL); t(8;14) in Burkitt's lymphoma; t(11;22) in Ewing's sarcoma; i(12p) in germ cell tumors; 1p- in neuroblastoma; structural abnormalities of 3q, 8q, and 9p in PAS; or 3p- in renal cell carcinoma. Intraregional frequency similarities between cytogenetically identical abnormalities in related tumor types were also analyzed. No significant correlations were found regarding the incidence of 5q- in ANLL and MDS, 6q- in ALL and NHL, -7 in ANLL and MDS, +8 in ANLL and CML, +8 in ANLL and MDS, +8 in ALL and ANLL, or +21 in ALL and ANLL. The findings indicate that some geographic heterogeneity of tumor-associated aberrations exists both in hematologic neoplasms and in solid tumors.(ABSTRACT TRUNCATED AT 250 WORDS)

Asia↗
PubMed2004

Hematological evaluation of splenomegaly.

OBJECTIVE: To find out the relative frequency of clinical conditions associated with splenomegaly that require hematological evaluation in our set up. DESIGN: Cross sectional study. PLACE AND DURATION OF STUDY: Combined Military Hospital, Quetta, Balochistan, from July 2000 to July 2003. SUBJECTS AND METHODS: Patients of either gender and all age groups with palpable spleen were included. Patients with splenomegaly due to liver disease, malarial parasites on thick or thin blood film, positive Widal test, or positive blood cultures were excluded from study. Patients were initially evaluated with clinical history, microscopic examination of blood smear, and blood counts. Depending upon provisional diagnosis bone marrow examination or investigations for hemolytic anemia were performed. RESULTS: One hundred patients were received. Seventy-eight patients were adults and 22 patients were of pediatric age group. In the adults, hematological malignancies were seen in 37%, malarial parasites in bone marrow in 20.5%, megaloblastic anemia in 13%, bacterial infections in 9%, hemolytic anemia in 9%, tropical splenomegaly in 5%, and positive bone marrow culture for salmonella in 6.5%. In children, hematological evaluation revealed hematological malignancies in 18%, beta thalassaemia in 55%, other hemolytic anemias in 13.5%, congenital sideroblastic anemia in 4.5%, and storage disorder in 9%. CONCLUSION: Hematological workup is informative in most of the cases. Bone marrow examination is the key investigation, hematological malignancies constituted 37% of the adult and 18% of pediatric age group patients. Hemolytic anemia constituted 68% of pediatric age group.

Adolescent↗
PubMed1998

The development of haematopathology laboratories: a possible model for other pathology services.

The diagnosis of haematological malignancies has undergone major conceptual changes in the past decade. Accurate diagnosis now depends on a combination of morphological examination, cell marker studies, and molecular biological techniques. Specialist haematopathology diagnostic services are best provided in an integrated laboratory, able to carry out the full range of techniques and staffed by pathologists and scientists with expertise in the investigation of leukaemia and lymphoma.

England↗
PubMed1999

Second primary cancers in patients with squamous cell carcinoma of the skin: a population-based study in Sweden.

We studied second primary cancer among 25,947 patients diagnosed with squamous cell carcinoma of the skin (SCC) in Sweden between 1958 and 1992. In total, 5,706 patients developed a second primary cancer at any site, compared with an expected number of 2,651 [standardized incidence ratio (SIR) = 2.15; 95% confidence interval (CI) = 2.10-2.21]. Men below 60 years of age at diagnosis of SCC had higher SIR (2.5; CI = 2.2-2.8) with the highest risk during the first year of follow-up (SIR = 9.2; CI = 6.9-12.2). If second primary SCC was excluded, the SIR was reduced to 1.30 (CI = 1.25-1.34); the relationships by sex, age and time since diagnosis remained similar. For skin cancer, the SIR for second SCC was markedly elevated (SIR = 15.6) and the risk of malignant melanoma was elevated 3-fold. Significantly increased risks were found for most second cancers in squamous cell epithelium: lip (SIR = 5.2), respiratory organs (SIR = 1.7), esophagus (SIR = 1.5), cervix uteri (SIR = 2.2), and vulva including vagina (SIR = 2.3). There was a generally increased risk of almost 2-fold for second cancer in hematopoietic or lymphoproliferative tissues. Slightly increased rates (SIR = 1.0-1.5) were seen for second tumors in digestive tissues. Finally, a high SIR (SIR = 5.5) was observed for second primary cancer in salivary glands. In conclusion, patients with SCC are at increased risk to develop new primary cancer, especially in skin, squamous cell epithelial and tobacco-related tissues. Common risk factors among the tumor types might explain our findings, however, an intrinsic susceptibility among SCC patients to develop cancer is also possible.

Age Distribution↗
PubMed1999

Spectrum of transforming sequences detected by tumorigenicity assay in a large series of human neoplasms.

We here summarize the analysis of 126 DNA samples from patients with hematopoietic neoplasias and solid tumors and from various tumor cell lines that were screened in the tumorigenicity assay. Thirty-eight samples were able to induce tumors after transfection in NIH/3T3 cells and injection into nude mice. Southern-blot analysis with a panel of oncogene probes revealed human ras genes in the vast majority of cases (25 N-ras, 2 K-ras, 1 H-ras) but also activated FGF4, dbl, ret and mas genes respectively. DNA samples from the 6 remaining transfectants were cloned into EMBL-3 phages and screened with a human specific repetitive Alu probe. Direct hybridization of a transfectant cDNA library allowed cloning of the ufo oncogene. Application of the exon-trapping technique to alu-positive phage DNA from the other transfectants enabled us to isolate tre, cot, B-raf, p85beta/HUMORF8 and a novel oncogene.

3T3 Cells↗
PubMed1980

Richter's syndrome with identification of marker chromosomes.

A case is presented of a man with Richter's syndrome with diffuse histiocytic lymphoma following a ten-year history of untreated chronic lymphatic leukemia. He did not respond to therapy. The lymphoma cells had 61 chromosomes with aneuploidy of 13 chromosomes and 11 structurally altered chromosomes. Only chromosomes 8, 9, 12, 14, and 18 were diploid and without abnormality. Significantly, part of chromsome 1q was duplicated as in the partial trisomy of 1q reported to characterize a number of hematologic neoplasms. A large marker chromosome with subterminal centromere was a tandem duplication of chromosome 4q.

Aneuploidy↗
PubMed1990

Acute lymphoblastic leukemia. An unusual case of primary relapse in the uterine cervix.

Female genital tract involvement by hematologic neoplasms is uncommon and is usually associated with disseminated disease. Lymphoid neoplasms, which involve the cervix and uterus primarily, are usually of either diffuse large cell or small cleaved cell type, and rarely Burkitt's (small non-cleaved) lymphoma or granulocytic sarcoma. In this report the authors describe young woman with acute stem cell leukemia which was terminal deoxyribonucleotidyl transferase positive, and involved the bone marrow and peripheral blood. After induction of remission and a 2-year disease-free interval, she relapsed with involvement localized to the uterus and cervix. At relapse the leukemic cells expressed CD1, CD2, CD5, CD7, and CD4 or CD8, antigens of the common thymocyte compartment. The authors postulate that the T-cell antigens, known extracellular matrix receptors, may have determined the tissue infiltration: an unusual pattern of relapse.

Adult↗