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PubMed1991

Normal cytogenetic values for bone marrow based on studies of bone marrow transplant donors.

For individuals suspected of having hematologic neoplasms, interpretation of the clinical significance of sporadic cells with chromosome breakage, structural anomalies, aneuploidy, or polyploidy is often difficult. To help resolve this problem, we established normal cytogenetic values for bone marrow (BM) by investigating 219 BM transplant (BMT) donors using standard techniques for chromosome analysis. The donors ranged in age from 2 to 58 years and were studied for 7 years. The constitutional karyotype for two individuals was 47,XXY; one was mos45,X/46,XX, one was mos46,XX/47,XX, + mar, and 215 were normal. Among other statistics, the median and normal ranges (95th percentile) were determined for any kind of chromosome abnormality, autosomal loss, autosomal gain, sex chromosome loss, sex chromosome gain, chromosome breaks or gaps, major structural abnormalities, and polyploidy. The results suggest that random loss of chromosomes is common in cytogenetic preparations of BM, appears to be largely technical and is inversely proportional to chromosome size. Cells with extra chromosomes or with structural abnormalities are rare in normal BM. No specific sporadic structural abnormalities of chromosomes are associated with normal BM. The widely accepted cytogenetic definition for an abnormal clone appears to be valid, with the possible exception of occasional studies involving loss of smaller autosomes. There may be a correlation between loss of the Y chromosome and age of the patient.

Adolescent↗
PubMed1991

Trisomy 13 as a primary chromosome aberration in acute leukemia.

Four patients with acute leukemia displayed trisomy 13 as the primary chromosome abnormality. The two patients with acute nonlymphocytic leukemia FAB-type M1 (ANLL-M1) had the karyotypes 47,XY,+13/48,XY,+13,+13 and 47,XX,+13, a patient with the hypogranular form of ANLL M3 had 47,XX,+13, and the fourth patient, who had acute undifferentiated leukemia (AUL), had the karyotype 47,XY,+13/48,XY,+8,+13. Including these four cases, a total of 24 hematologic neoplasms with an extra chromosome 13 as the sole aberration have now been reported. Except for the AUL, all have been of myeloid origin--20 ANLL, one myelodysplastic syndrome, and two chronic myeloproliferative disorders. Trisomy 13 as the sole acquired karyotypic abnormality therefore seems to be strongly associated with myeloid differentiation of the neoplastic cells and with a differentiation block leading to acute leukemia.

Acute Disease↗
PubMed1992

Application of fluorescence in situ hybridization in hematological disorders.

In the present study, chromosome changes in bone marrow (BM) or peripheral blood (PB) cells from 13 patients with malignant hematologic disorders were analyzed by classical cytogenetic techniques (G-banding) and fluorescence in situ hybridization (FISH) procedures using centromere specific probes for chromosomes 1, 6, 7, 8, 9, 12, 18, 13/21, and X, and a DNA probe specific for the long arm of chromosome Y. The cytogenetic data obtained with G-banding were in accord with those obtained by FISH to metaphase chromosomes. Most significantly, FISH to interphase nuclei offered reliable results and in some cases provided important information concerning crucial chromosome anomalies which were not or could not be completely detected by analyzing metaphase chromosomes. Our results indicate that FISH could be clinically valuable in five major areas: 1) marker chromosome identification; 2) identification of trisomy consistent with certain specific hematological neoplasms; 3) clonal evaluation post observation of a single cell with trisomy; 4) clonal evaluation post-sex-mismatched bone marrow transplantation (BMT); and 5) residual disease detection following clinical remission.

Adolescent↗
PubMed1994

Telomere shortening in leukemic cells is related to their genetic alterations but not replicative capability.

We compared telomere length in donor leukemic cells and corresponding established cell lines from three patients with chronic myeloid leukemia (CML) and three with acute lymphoblastic leukemia (ALL) to study the relation between the immortalization capacity of hematologic neoplasms and telomere length. Six of the seven established leukemia cell lines (four CML and two ALL) carried additional chromosome changes and had shorter telomere repeats than those of the donor patients' leukemic cells; the remaining ALL line showed no significant difference in telomere length between fresh leukemic cells and the corresponding cell line. Thus, most established leukemic cells lose effective telomerase activity during the process of establishment, and reduction in telomere length of established leukemic cells appeared to be associated with the presence of additional chromosome changes.

Blotting, Southern↗
PubMed1990

Effect of HLA incompatibility on graft-versus-host disease, relapse, and survival after marrow transplantation for patients with leukemia or lymphoma.

We analyzed the relevance of HLA incompatibility to acute graft-versus-host disease, relapse, and survival in 281 patients with hematologic neoplasms who underwent bone marrow transplantation. Each patient received marrow from a family member who shared one HLA haplotype with the patient but differed to a variable degree for the HLA-A, -B, and -D antigens of the haplotype not shared; 29 were phenotypically identical, 119 were incompatible for one locus, 104 for two loci, and 29 for three loci. These 281 patients were compared with 967 patients who received marrow from siblings with identical HLA genotypes. All patients were treated with cyclophosphamide and total-body irradiation followed by the infusion of unmodified donor marrow cells. Occurrence of severe acute graft-versus-host disease was evaluated in patients who achieved sustained engraftment. In recipients of haploidentical grafts occurrence of severe acute graft-versus-host disease was associated with (1) graft-versus-host disease prophylaxis containing the combination of methotrexate plus cyclosporine versus standard methotrexate, relative risk = 0.35; 95% confidence interval, 0.21-0.57, p less than 0.0001; and (2) the degree of recipient HLA incompatibility, relative risk = 1.95 for each locus incompatible; 95% confidence interval, 1.52-2.50, p less than 0.0001; (3) patient age, relative risk = 1.23 per decade; 95% confidence interval, 1.05-1.44, p = 0.0094. Acute graft-versus-host disease was associated with lower leukemic relapse after transplant in patients with acute lymphocytic leukemia, and chronic graft-versus-host disease was associated with lower relapse after transplant for acute nonlymphocytic leukemia in relapse or chronic myelogenous leukemia in blast crisis. After transplantation for acute nonlymphocytic leukemia in remission, the rate of leukemic relapse was 22% in 61 recipients of "one-locus" (A, B, or D)-incompatible grafts compared to 37% in 561 recipients of HLA-identical sibling grafts. Survival was decreased as the degree of HLA disparity increased. Survival of "one-locus"-incompatible transplant recipients, however, was equivalent to that of HLA-identical sibling transplant recipients.

Bone Marrow Transplantation↗
PubMed1993

Biology and treatment of multiple myeloma.

The uniformly fatal plasma cell malignancy, multiple myeloma (MM), currently represents 10-15% of hematologic neoplasms in the USA and has been steadily increasing in incidence for several decades. Therapeutic alternatives have lagged significantly behind insights into the biology and pathogenesis of this entity. Traditionally felt to be a neoplasm of fully differentiated plasma cells, evidence has been mounting that the self renewing population consist of cells derived from a much earlier compartment; perhaps prior to B-cell lineage commitment or even at the level of an earlier 'stem cell'. Bcl-2 protein overexpression has been almost uniformly seen in both clinical myeloma specimens as well as in myeloma cell lines. The failure to consistently identify the t(14;18) translocation, normally found in follicular lymphomas and characteristically associated with overexpression of bcl-2, implies a unique mechanism in MM. A number of cytokines, including TNF alpha, IL-1 and IL-6 have been found to play a central role not only in the biology of the malignant clone but also in the bony and other systemic manifestations of this disease. Since both IL-6 and bcl-2 protein have been shown to prevent programmed cell death, this may be the unifying event in MM. Standard therapy for MM has been an alkylating agent and corticosteroid. Combination chemotherapy provides more prompt palliation but no clear survival advantage. In advanced stages, adriamycin may offer some survival advantage. High dose chemotherapy with or without stem cell support offers a potentially curative therapeutic approach. New interventions directed at the complex cytokine networks pertinent to the pathogenesis of MM are an exciting new area of investigation. Identification of new prognostic parameters as well as new active agents remains the central theme in clinical myeloma research.

Adult↗
PubMed1986

Biphasic and differential effects of the cytostatic agents avarone and avarol on DNA metabolism of human and murine T and B lymphocytes.

The two novel antimitotic and potent antileukemic agents avarone and avarol were determined to inhibit the [3H]-dThd incorporation rates of both murine spleen and human peripheral blood lymphocytes within the concentration range of 2-6 microM. The mitogens concanavalin A (ConA; for T lymphocytes), lipopolysaccharide (LPS; for murine B lymphocytes) and pokeweed mitogen (PWM; for human T and B lymphocytes) were used to stimulate DNA synthesis in the lymphocyte fractions. The ED50 concentrations, causing a 50% reduction of [3H]-dThd incorporation, were significantly lower in the experiments with avarone than in those with avarol. Moreover it was established that the DNA synthesis of ConA-activated lymphocytes was more sensitively inhibited by the compounds than that of LPS or PWM-activated cells, or non-activated cells. In addition it was elucidated that at low concentrations (1-2 microM) avarone and avarol caused a stimulation of dThd incorporation only in LPS or PWM-activated lymphocytes. Based on these results it is assumed that both antileukemic agents also affect differentially the different hematologic neoplasms.

Animals↗
PubMed1993

Pneumocystis carinii pneumonia in cancer patients.

Concern has been arisen about the recently reported increasing incidence of PCP in patients with cancer and the potential transmissibility of this infection. Whether or not there is an increase in the incidence of P. carinii infections, PCP should be considered in the differential diagnosis of pulmonary infiltrates in bone marrow transplant recipients, in patients with hematologic neoplasms and in patients with primary or metastatic brain neoplasms. Intensity of immunosuppression plays a crucial role, especially long-term (> 2 months) corticosteroid treatment. PCP is usually manifested clinically during augmentation or during tapering of corticosteroid dose. Thus, if the chest radiograph of a high-risk patient shows diffuse infiltrates, bronchoscopy and bronchoalveolar lavage should be done immediately. Treatment options are the same as for the AIDS population, except that TMP-SMX is tolerated better in non-AIDS patients. The role of supportive care, including mechanical ventilation in such patients should not be underestimated. Oral therapy with dapsone-trimethoprim or with atovaquone, can be as effective as conventional therapy in mild disease, permitting treatment on an outpatient basis. PCP is often preventable and our understanding has improved about when prophylaxis should be initiated. In the future, the emergence of new technologies for diagnosis and of new agents for treatment and prophylaxis, will bring us closer to the goal of controlling this serious infection.

AIDS-Related Opportunistic Infections↗
PubMed1992

The origin and spread of human leukemia.

The human leukemias are a group of hematologic neoplasms characterized by uncontrolled proliferation of cells concerned with blood cell production. The cause(s) of human leukemia remains unknown. Bone marrow (BM) is believed to be the site of origin of human leukemias, although the specific locus(i) and/or cell(s) from which it arises have not been definitively identified. Generally, human leukemias and related proliferative diseases are thought to be clonal in nature; affecting a single hematopoietic stem cell, which then proliferates and replaces the marrow of normal hematopoietic stem cell systems. The condition is believed to be malignant in nature. Results of our current morphologic studies on well-fixed, ideally-stained thin sections of plastic-embedded bone marrow biopsies (BMB) from a large number of acute (AML, ALL) and chronic (CGL, CLL) leukemia patients suggest that human leukemias may not be clonal diseases. Instead, a large population of other resident cells--'endosteal cells'--appears to become involved in the process and it is possible that all members of this group enter the activity simultaneously. This change (transformation) in the endosteal cell population might be due to an abnormality (qualitative or quantitative) of diffusable, humoral factors (yet to be identified) that are responsible for the growth and proliferation of these hematopoietic precursor cells. In this context, the human leukemias may be considered not as malignant, but rather the result of an aberration of factor(s) that control hematopoiesis. In this respect, the human leukemias, particularly AML, ALL and CML, might be analogous to pernicious anemia (megaloblastic anemia) as it was understood 40-50 years ago.(ABSTRACT TRUNCATED AT 250 WORDS)

Bone Marrow↗
PubMed1994

Recent developments in the radioimmunotherapy of cancer.

Recent trials using radiolabeled monoclonal antibodies, particularly for hematologic neoplasms, have demonstrated the ability of these agents to destroy tumor cells safely and specifically. Advances in molecular biology, immunology and radiochemistry will allow the continued development of strategies to overcome the remaining obstacles to effective therapy with radioimmunoconjugates.

Animals↗
PubMed2004

Aberrations involving 13q12 approximately q14 are frequent secondary events in childhood acute lymphoblastic leukemia.

Chromosome 13 aberrations, particularly in the region 13q12 approximately q14, are common events in hematological neoplasms that have a clinical significance in many cases. However, although chromosome 13 aberrations are a nonrandom event in childhood acute lymphoblastic leukemia (ALL), their biological and clinical associations are limited. We have studied a consecutive series of 277 cases of childhood ALL, including 33 initially at relapse, by conventional cytogenetic analysis. In 20 cases, a chromosome 13 aberration that involved the region 13q12 approximately q14 was detected at some point during the disease. An aberration was identified in 15 of 244 (6.1%) presentation cases and 7 of 54 (13%) relapsed cases, of which in 11 cases it was shown that the abnormality arose as a secondary karyotypic event. To further characterize the cases, fluorescence in situ hybridization (FISH) using the commercially available probes LSI 13 (RB1) and D13S25 (both 13q14) was undertaken. These analyses provided additional evidence for the secondary nature of many events and suggested that 13q14 deletions may confer a growth advantage in culture because the percentage of cells containing 13q14 deletions detected by FISH was often lower than that detected by G-banding. Since 13q12 approximately q14 aberrations in childhood ALL frequently occur as secondary events, these results imply that the abnormality has implications for disease progression.

Adolescent↗
PubMed2006

Induction of aberrant crypt foci in DNA mismatch repair-deficient mice by the food-borne carcinogen 2-amino-1-methyl-6-phenylimidazo [4,5-b] pyridine (PhIP).

Disruption of the DNA mismatch repair (MMR) pathway results in elevated mutation rates, inappropriate survival of cells bearing DNA damage, and increased cancer risk. Relatively little is known about the impact of environmentally relevant carcinogens on cancer risk in individuals with MMR-deficiency. We evaluated the effect of MMR status (Mlh1(+/+) versus Mlh1(-/-)) on the carcinogenic potential of the cooked-meat mutagen, 2-amino-1-methyl-6-phenylimidazo [4,5-b] pyridine (PhIP) in mice. PhIP exposure did not obviously increase lymphoma or small intestinal tumorigenesis in either Mlh1-deficient or -proficient mice. In contrast, the frequency of aberrant crypt foci (ACF), a preneoplastic biomarker for colon tumorigenesis, was increased by PhIP, and the increase due to PhIP was significantly greater in Mlh1(-/-) versus wild-type littermates. This apparent heightened susceptibility to induction of ACF parallels the previously reported hypermutability of Mlh1-deficient mice to PhIP and is consistent with the hypothesis that MMR-deficiency would increase the likelihood of PhIP-induced carcinogenic mutations. Further evaluation of the risk that consumption of heterocyclic amines may impart to MMR-deficient individuals therefore is warranted.

Adaptor Proteins, Signal Transducing↗
PubMed2004

Procarbazine in haematology: an old drug with a new life?

Procarbazine (PCB) was developed in the 1960s and was rapidly recognised as an active agent in lymphoid malignancies. PCB was one of the four drugs combined in mechlorethamine, vincristine, PCB, prednisolone (MOPP), one of the first combination chemotherapy regimens to show that advanced-stage disease could be cured in humans. During the last few decades, comprehensive studies have clarified cellular pathways involved in the modes of action of PCB and its drug resistance mechanisms. However, late toxicities, especially secondary leukaemias and sterility, led to its withdrawal from combination regimens used to treat Hodgkin's lymphomas (HLs). PCB was recently reintroduced in dose-intensified regimens and yielded impressive results. These new regimens (bleomycin, etoposide, doxorubicin, vincristine, PCB, and prednisone (BEACOPP) or escalated BEACOPP) are now being investigated versus the classic ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) or ABVD-like combination chemotherapy regimens in the treatment of HLs.

Antineoplastic Agents↗
PubMed2006

Release of MICB molecules by tumor cells: mechanism and soluble MICB in sera of cancer patients.

MICA, a ligand of the activating immunoreceptor NKG2D, is released by tumor cells in a soluble form and can be detected in sera of tumor patients at significant levels. Soluble MICA has been proposed to counteract NKG2D-mediated immunosurveillance of tumors. Here, we report that MICB, the second member of the human MIC protein family, is likewise shed by metalloproteases from tumor cells and is present in sera of patients with gastrointestinal tumors. While cell-bound MICB causes downregulation of surface NKG2D, soluble MICB did not alter NKG2D expression on NK cells in vitro. Thus, proteolytic shedding of MICB by tumor cells may impair immunogenicity of tumors primarily by reducing NKG2D-ligand densities on malignant cells.

Cell Line, Tumor↗
PubMed2003

Outcomes of active operation during intensive followup for second primary malignancy after esophagectomy for thoracic squamous cell esophageal carcinoma.

BACKGROUND: Recent advances in the treatment of thoracic esophageal cancer have afforded it a better prognosis. As a consequence, increasing attention is being paid to the outcomes with postoperative monitoring for second primary malignancies after esophagectomy, but no recent study has focused on the longterm followup and outcomes in these patients. STUDY DESIGN: In 1989, we began intensive prospective screening and surveillance designed to detect cancers of the head and neck, lung, stomach, residual esophagus, and colon/rectum after esophagectomy. Between 1989 and 2001, 365 patients underwent esophagectomy for thoracic squamous cell esophageal carcinoma in our department. Of those, 200 were followed up as part of this program. Excluded were patients in whom esophageal cancer recurred, patients with other prior or simultaneous malignancies, and patients who died within a year of operation. Clinicopathologic profiles and treatment outcomes were determined for 33 patients who developed a second primary malignancy after esophagectomy. RESULTS: The interval between the primary esophageal cancer and the secondary carcinoma was 49 +/- 40 months (median, 48 months). The second primary malignancies were located in the stomach (30%), head and neck (24%), lung (24%), colon/rectum (9%), liver (6%), pancreas (3%), and blood (6%). Twenty-one patients (64%) were classified as stage 0, I, or II; 10 (30%) were stage III or IV. Overall, the 2-year, 3-year, and 5-year survival rates following diagnosis of a second primary malignancy were 58.0%, 58.0%, and 48.6%, respectively. Of the 19 patients (58%) in whom second primary malignancies were detected before symptoms developed, the 5-year survival rate was 70.7%, which was significantly greater than that among patients whose secondary malignancies were discovered after symptoms developed (17.1%). CONCLUSIONS: Good outcomes in the treatment of second primary malignancies after esophagectomy for thoracic squamous cell esophageal carcinoma can be obtained with longterm, intensive followup and active surgical intervention for detected malignancies.

Aged↗
PubMed2006

Neoplastic mast cells in systemic mastocytosis associated with t(8;21) acute myeloid leukemia are derived from the leukemic clone.

In systemic mastocytosis with associated clonal, hematological non-mast cell lineage disease (SM-AHNMD), mast cell infiltration of the bone marrow coexists with a hematologic neoplasm, usually of myeloid origin. Activating KIT gene mutations are universally present in these neoplastic mast cells. When SM is associated with AML, the leukemic cells commonly carry the t(8;21)(q22;q22) core binding factor translocation. The precise relationship between neoplastic mast cells and the leukemic clone has remained unclear. By target FISH analysis, we demonstrate t(8;21) in the bone marrow mast cells of a patient with systemic mastocytosis associated with t(8;21) AML, thus, proving the origin of these neoplastic mast cells from the leukemic clone. We also show that after successful allogeneic hematopoietic stem cell transplantation, these neoplastic bone marrow mast cells can persist without adverse consequences and gradually decline with time.

Acute Disease↗
PubMed2005

Rudhira is a cytoplasmic WD40 protein expressed in mouse embryonic stem cells and during embryonic erythropoiesis.

We describe a novel murine gene rudhira that is expressed at high levels in embryonic stem cells and is restricted to blood islands and the erythroid lineage during embryonic development. Rudhira is expressed in angiogenic precursors but is excluded from the differentiated endothelium. Rudhira-expressing cells are seen in close proximity to endothelial cells in angiogenic blood vessels. Rudhira encodes a predicted cytoplasmic WD40 protein that is 98% identical to human BCAS3. The gene encoding BCAS3 maps to a breakpoint of hematological neoplasms on human chromosome 17q23, but its expression and function remain to be determined. We demonstrate that mouse Rudhira is a novel marker for analysis of the erythroid lineage.

Alternative Splicing↗