Biomedical subjects

Carlos Bueso-Ramos

Publications and source records attributed to Carlos Bueso-Ramos.

At least 19 recordsLinked to original sources

PubMed2006

Resveratrol inhibits proliferation, induces apoptosis, and overcomes chemoresistance through down-regulation of STAT3 and nuclear factor-kappaB-regulated antiapoptotic and cell survival gene products in human multiple myeloma cells.

Whether resveratrol, a component of red grapes, berries, and peanuts, could suppress the proliferation of multiple myeloma (MM) cells by interfering with NF-kappaB and STAT3 pathways, was investigated. Resveratrol inhibited the proliferation of human multiple myeloma cell lines regardless of whether they were sensitive or resistant to the conventional chemotherapy agents. This stilbene also potentiated the apoptotic effects of bortezomib and thalidomide. Resveratrol induced apoptosis as indicated by accumulation of sub-G(1) population, increase in Bax release, and activation of caspase-3. This correlated with down-regulation of various proliferative and antiapoptotic gene products, including cyclin D1, cIAP-2, XIAP, survivin, Bcl-2, Bcl-xL, Bfl-1/A1, and TRAF2. In addition, resveratrol down-regulated the constitutive activation of AKT. These effects of resveratrol are mediated through suppression of constitutively active NF-kappaB through inhibition of IkappaBalpha kinase and the phosphorylation of IkappaBalpha and of p65. Resveratrol inhibited both the constitutive and the interleukin 6-induced activation of STAT3. When we examined CD138(+) plasma cells from patients with MM, resveratrol inhibited constitutive activation of both NF-kappaB and STAT3, leading to down-regulation of cell proliferation and potentiation of apoptosis induced by bortezomib and thalidomide. These mechanistic findings suggest that resveratrol may have a potential in the treatment of multiple myeloma.

Apoptosis↗

PubMed2006

Phase 1/2 study of the combination of 5-aza-2'-deoxycytidine with valproic acid in patients with leukemia.

We conducted a phase 1/2 study of the combination of 5-aza-2'-deoxycytidine (decitabine) and the histone deacetylase inhibitor valproic acid (VPA) in patients with advanced leukemia, including older untreated patients. A group of 54 patients were treated with a fixed dose of decitabine (15 mg/m(2) by IV daily for 10 days) administered concomitantly with escalating doses of VPA orally for 10 days. A 50 mg/kg daily dose of VPA was found to be safe. Twelve (22%) patients had objective response, including 10 (19%) complete remissions (CRs), and 2 (3%) CRs with incomplete platelet recovery (CRp). Among 10 elderly patients with acute myelogenous leukemia or myelodysplastic syndrome, 5 (50%) had a response (4CRs, 1CRp's). Induction mortality was observed in 1 (2%) patient. Major cytogenetic response was documented in 6 of 8 responders. Remission duration was 7.2 months (range, 1.3-12.6+ months). Overall survival was 15.3 months (range, 4.6-20.2+ months) in responders. Transient DNA hypomethylation and global histone H3 and H4 acetylation were induced, and were associated with p15 reactivation. Patients with lower pretreatment levels of p15 methylation had a significantly higher response rate. In summary, this combination of epigenetic therapy in leukemia was safe and active, and was associated with transient reversal of aberrant epigenetic marks.

Acetylation↗

PubMed2006

Results of a randomized study of 3 schedules of low-dose decitabine in higher-risk myelodysplastic syndrome and chronic myelomonocytic leukemia.

Epigenetic therapy with hypomethylating drugs is now the standard of care in myelodysplastic syndrome (MDS). Response rates remain low, and mechanism-based dose optimization has not been reported. We investigated the clinical and pharmacodynamic results of different dose schedules of decitabine. Adults with advanced MDS or chronic myelomonocytic leukemia (CMML) were randomized to 1 of 3 decitabine schedules: (1) 20 mg/m2 intravenously daily for 5 days; (2) 20 mg/m2 subcutaneously daily for 5 days; and (3) 10 mg/m2 intravenously daily for 10 days. Randomization followed a Bayesian adaptive design. Ninety-five patients were treated (77 with MDS, and 18 with CMML). Overall, 32 patients (34%) achieved a complete response (CR), and 69 (73%) had an objective response by the new modified International Working Group criteria. The 5-day intravenous schedule, which had the highest dose-intensity, was selected as optimal; the CR rate in that arm was 39%, compared with 21% in the 5-day subcutaneous arm and 24% in the 10-day intravenous arm (P < .05). The high dose-intensity arm was also superior at inducing hypomethylation at day 5 and at activating P15 expression at days 12 or 28 after therapy. We conclude that a low-dose, dose-intensity schedule of decitabine optimizes epigenetic modulation and clinical responses in MDS.

Aged↗

PubMed2006

Antileukemia activity of the combination of an anthracycline with a histone deacetylase inhibitor.

We studied the cellular and molecular effects of the combination of an anthracycline with 2 different histone deacetylase inhibitors (HDACIs): vorinostat (suberoylanilide hydroxamic acid) and valproic acid (VPA). The 10% inhibitory concentration (IC(10)) of idarubicin was 0.5 nM in MOLT4 and 1.5 nM in HL60 cells. Concentrations above 0.675 microM of vorinostat resulted in at least 80% loss of cell viability in both cell lines. Concentrations of 1.5 to 3 mM of VPA induced 50% to 60% loss in viability in HL60 and 80% in MOLT4 cells. The combination of idarubicin with vorinostat at 0.075 microM or VPA at 0.25 mM resulted in at least an additive loss of cell viability in both lines. Vorinostat (0.35 microM) and VPA (0.25 mM) in combination with idarubicin (0.5 nM) resulted in a significant increase in apoptotic cells in MOLT4 cells. The combination resulted in an increase in histone H3 and H4 acetylation at 24 hours, phosphorylated H2AX, as well as in the induction of p21(CIP1) mRNA. No effect on cell cycle transition was observed. Of importance, the cellular and molecular effects observed were independent of the sequence used. In summary, the combination of an anthracycline with an HDACI should have significant clinical activity in patients with leukemia.

Acetylation↗

PubMed2006

Chemoimmunotherapy with hyper-CVAD plus rituximab for the treatment of adult Burkitt and Burkitt-type lymphoma or acute lymphoblastic leukemia.

BACKGROUND: Adult Burkitt-type lymphoma (BL) and acute lymphoblastic leukemia (B-ALL) are rare entities composing 1% to 5% of non-Hodgkin lymphomas NHL) or ALL. Prognosis of BL and B-ALL has been poor with conventional NHL or ALL regimens, but has improved with dose-intensive regimens. METHODS: To evaluate the addition of rituximab, a CD20 monoclonal antibody, to intensive chemotherapy in adults with BL or B-ALL, 31 patients with newly diagnosed BL or B-ALL received the hyper-fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (hyper-CVAD) regimen with rituximab. Their median age was 46 years; 29% were 60 years or older. Rituximab 375 mg/m(2) was given on Days 1 and 11 of hyper-CVAD courses and on Days 1 and 8 of methotrexate and cytarabine courses. RESULTS: Complete remission (complete response [CR]) was achieved in 24 of 28 (86%) evaluable patients; 3 had a partial response, and 1 had resistant disease. There were no induction deaths. The 3-year overall survival (OS), event-free survival, and disease-free survival rates were 89%, 80%, and 88%, respectively. Nine elderly patients achieved CR with all of them in continuous CR (except 1 death in CR from infection), with a 3-year OS rate of 89%. Multivariate analysis of current and historical (those treated with hyper-CVAD alone) groups identified age and treatment with rituximab as favorable factors. CONCLUSIONS: The addition of rituximab to hyper-CVAD may improve outcome in adult BL or B-ALL, particularly in elderly patients.

Antibodies, Monoclonal↗

PubMed2006

Aerosolized ribavirin-induced reversible hepatotoxicity in a hematopoietic stem cell transplant recipient with Hodgkin lymphoma.

We describe a case of acute hepatic toxicity associated with aerosolized ribavirin in a bone marrow transplant recipient with documented respiratory syncytial virus infection. The temporal relationship with drug administration and the liver biopsy results suggested drug-induced hepatic injury. As the use of aerosolized ribavirin to treat respiratory syncytial virus infections continues, it is imperative that careful attention be paid to possible adverse effects of therapy in the high-risk population of immunosuppressed patients.

Adrenal Cortex Hormones↗

PubMed2005

Outcome of patients with acute myelogenous leukemia after second salvage therapy.

BACKGROUND: Although the prognosis is poor for patients with acute myelogenous leukemia (AML) who have disease recurrence after frontline therapy, this is a general reflection of first salvage therapies. The outcome of patients undergoing second salvage therapy in relation to complete response (CR) rates and survival has not been documented. The authors analyzed the outcome of patients with AML undergoing second salvage therapy, and identified prognostic factors associated with response and survival. METHODS: The records of 594 patients with AML undergoing second salvage therapy from 1980 until 2004 were reviewed. The patient median age was 50 years. Salvage therapy included allogeneic stem cell transplantation (SCT) in 74 patients, standard-dose cytosine arabinoside (ara-C) combinations in 30 patients, high-dose ara-C combinations in 171 patients, non-ara-C combinations in 73 patients, and Phase I-II single agents in 246 patients. RESULTS: Overall, 76 patients (13%) achieved CR. The median CR duration was 7 months. The median survival was 1.5 months, and the 1-year survival rate was 8%. A multivariate analysis of prognostic factors for CR identified the following 6 independent adverse factors: first CR duration < 6 months; second CR duration < 6 months; salvage therapy not including allogeneic SCT; non-inversion 16 AML; platelet counts < 50 x 10(9)/L, and leukocytosis > 50 x 10(9)/L. Patients were divided into low-risk (1-2 adverse factors; 8%), intermediate 1 (3 factors; 20%), intermediate 2 (4 factors; 38%), and high-risk groups (5-6 factors; 33%) with respective CR rates of 54%, 26%, 8%, and 0%. The respective 1-year survival rates were 36%, 21%, 6%, and 1%. A multivariate analysis for survival identified the following 7 independent adverse factors: first CR duration < 12 months; second CR duration < 6 months; bilirubin level > or = 1 mg/dL; albumin level < 3 g/dL; age > 60 years; bone marrow blasts > or = 50%; and year of therapy before 1991. Patients were divided into low-risk (0-2 adverse factors; 39%), intermediate (3 factors; 27%), and high-risk groups (> or = 4 factors; 34%) with estimated 1-year survival rates of 22%, 6%, and 0%, respectively. The respective CR rates were 26%, 8%, and 2%. CONCLUSIONS: The current analysis established the outcome and prognostic factors associated with second salvage therapy in AML. It also proposed risk models and groups that could be used for comparison of results of present and future investigational strategies.

Adolescent↗

PubMed2005

JAK2 mutation 1849G>T is rare in acute leukemias but can be found in CMML, Philadelphia chromosome-negative CML, and megakaryocytic leukemia.

An activating 1849G>T mutation of JAK2 (Janus kinase 2) tyrosine kinase was recently described in chronic myeloproliferative disorders (MPDs). Its role in other hematologic neoplasms is unclear. We developed a quantitative pyrosequencing assay and analyzed 374 samples of hematologic neoplasms. The mutation was frequent in polycythemia vera (PV) (86%) and myelofibrosis (95%) but less prevalent in acute myeloid leukemia (AML) with an antecedent PV or myelofibrosis (5 [36%] of 14 patients). JAK2 mutation was also detected in 3 (19%) of 16 patients with Philadelphia-chromosome (Ph)-negative chronic myelogenous leukemia (CML), 2 (18%) of 11 patients with megakaryocytic AML, 7 (13%) of 52 patients with chronic myelomonocytic leukemia, and 1 (1%) of 68 patients with myelodysplastic syndromes. No mutation was found in Ph(+)CML (99 patients), AML M0-M6 (28 patients), or acute lymphoblastic leukemia (20 patients). We conclude that the JAK2 1849G>T mutation is common in Ph(-) MPD but not critical for transformation to the acute phase of these diseases and that it is generally rare in aggressive leukemias.

Humans↗

PubMed2005

Protein expression of a triad of frequently methylated genes, p73, p57Kip2, and p15, has prognostic value in adult acute lymphocytic leukemia independently of its methylation status.

PURPOSE: To study the relationship between protein expression and DNA methylation of a triad of cell-cycle regulatory genes known to be frequently methylated in adult acute lymphocytic leukemia (ALL). PATIENTS AND METHODS: Protein expression of p73, p15, and p57Kip2 was analyzed by immunohistochemistry using a tissue microarray (TMA) platform. The TMA was constructed using pretreatment bone marrow biopsy specimens from 64 adult patients with ALL. Protein expression was then correlated with DNA methylation and relevant clinical biologic characteristics. RESULTS: p73 protein expression was observed in 19 (30%) patients, cytoplasmic p15 in 19 (31%), and p57 in 40 (70%). Three patients (5%) had expression of all three proteins, 16 (29%) of two proteins, 31 (55%) of one protein, and six (11%) of zero proteins. An inverse association was observed between p73 DNA methylation and protein expression (P = .003). This effect was not observed for either p15 or p57Kip2. Expression of any of the proteins studied was not associated with any distinct biologic characteristic. By multivariate analysis, expression of p57Kip2, cytoplasmic p15, or a combination of p57Kip2 with either p15 or p73 was associated with a better overall survival (P < .001, .04, and .03 respectively). CONCLUSION: Expression of a triad of cell cycle regulatory proteins that includes p73, p15, and p57Kip2 has prognostic value in adult patients with ALL independently of the methylation status of each gene.

Adolescent↗

PubMed2005

Flow cytometry and fluorescence in situ hybridization to detect residual neuroblastoma cells in bone marrow.

BACKGROUND: In patients with neuroblastoma morphological assessment of BM for residual NB cells is not precise, particularly when the number of tumor cells is small. PROCEDURE: To develop a sensitive and rapid method of detecting NB cells in BM, we assessed the efficiency of flow cytometry (FCM) using markers CD9, CD56, and CD45. The percent of CD9+/CD56+/CD45- (NB phenotype) cells was determined by FCM in 41 samples (16 patients) at various time points. For confirmation fluorescence in situ hybridization (FISH) for 17q gain was performed. RESULTS: Nineteen of the 22 (86%) samples that were negative by morphology were positive by FCM (>0.006% CD9+/CD56+/CD45- cells). The longest time to complete the FCM study was 3 hr. In six FISH experiments the sorted CD9+/CD56+/CD45- population had a higher percentage of cells with 17q gain (11.5-95%) compared to a CD56-/CD45+ internal control population (2-8%). CONCLUSIONS: Our preliminary results suggest that FCM determination of the percent of CD9+/CD56+/CD45- cells is an effective method of rapidly detecting NB cells in BM.

Adolescent↗

PubMed2005

Thrombopoietic growth factors and cytokines.

Chemotherapy-induced thrombocytopenia is largely managed with platelet transfusions and reductions of chemotherapy doses. In the last decade, several thrombopoietic cytokines have been investigated without much success. Thrombopoietin (TPO), a key physiologic regulator of platelet production, is found to be the most potent thrombopoietic cytokine studied so far. Unfortunately, the clinical development of recombinant human thrombopietin has met challenges related to the biology of TPO with a delayed peak platelet response and the findings of neutralizing antibodies to the pegylated molecule. Recent clinical studies showed the importance of TPO schedule in relation to chemotherapy. Also, recombinant TPO facilitated collection of platelets in normal donors and patients for transfusions. The initial trials in leukemia or transplant settings did not impact the need for platelet transfusions. Future developments of TPO and mimetics will require carefully designed clinical trials with the consideration of unique biology of TPO and the time lag for a peak platelet response.

Cytokines↗

PubMed2004

Expression of CD2 in acute promyelocytic leukemia correlates with short form of PML-RARalpha transcripts and poorer prognosis.

We studied the immunophenotype of 100 cases of acute promyelocytic leukemia (APL) with cytogenetic evidence of t(15;17)(q22;q21), 72 hypergranular (M3) and 28 microgranular (M3v), and correlated the results with molecular and clinical features. Most neoplasms (75/100 [75%]) had a typical immunophenotype: CD13+CD33+CD34-HLA-DR-. CD64, CD2, CD34, and HLA-DR were expressed in 27% (24/88), 23% (22/94), 21% (21/100), and 9% (9/98), respectively. CD34 expression was restricted to M3v; HLA-DR and CD2 were expressed more often in M3v than in M3 (P < .001). PML-RARalpha fusion transcripts were detected by reverse transcriptase-polymerase chain reaction in all 70 patients assessed. The short form of PML-RARalpha transcripts was found more frequently in M3v (P < .002) and CD2+ APL (P < .0001) than in M3 and CD2- APL, respectively. The median follow-up was 128 weeks. CD2+ APL was associated significantly with leukocytosis (P = .004), shorter complete remission duration (P = .03), and a trend toward shorter overall survival (P = .07) than CD2- APL. Overall survival for M3v vs M3 (P = .68) and short vs long transcripts (P = .21) was not significantly different. Immunophenotyping is useful for predicting the biologic and clinical behavior of APL.

Adolescent↗

PubMed2003

Importance of predosing of recombinant human thrombopoietin to reduce chemotherapy-induced early thrombocytopenia.

PURPOSE: Recombinant human thrombopoietin (rhTPO) increases platelets, and the peak response of rhTPO is delayed and is, therefore, not uniformly effective when administered after chemotherapy. The purpose of this study was to identify an effective schedule of rhTPO to best attenuate early thrombocytopenia. PATIENTS AND METHODS: Cohorts of six patients with sarcoma (66 assessable patients) were treated sequentially with doxorubicin and ifosfamide (AI), with rhTPO by a fixed dose and varying schedules being administered before and/or after chemotherapy in cycle 2 and subsequent cycles. Cycle 1 without rhTPO served as an internal control. RESULTS: AI causes cumulative thrombocytopenia. The platelet nadir in cycle 2 was higher than in cycle 1 (mean nadir +/- SEM, 119 +/- 12 x 10(3)/microL v 80 +/- 7 x 10(3)/microL, respectively; P <.001) in 24 (80%) of the 30 patients (P <.001) in whom rhTPO (1.2 microg/kg) was administered starting from 5 days before chemotherapy (pre/postdoses, three/one or one/one) compared with only four (17%) of 24 patients given rhTPO by other schedules (pre/postdoses, two/two, one/three, zero/four, or four/zero) and none of 15 historical control patients. The need for platelet transfusions in four cycles was significantly lower (13 [11%] of 114 cycles, P <.001) in patients who received rhTPO from day -5 (pre/post doses, three/one or one/one) compared with patients who received rhTPO at later time points (28 [47%] of 60 cycles). Bone marrow megakaryocytes increased markedly (four-fold) before chemotherapy with predosing rhTPO and remained elevated (two-fold) after chemotherapy, which may explain the possible mechanism for response. One patient developed subclavian vein thrombosis, and no patients developed neutralizing antibodies to rhTPO. CONCLUSION: These results demonstrate the importance of timing of rhTPO in relation to chemotherapy and indicate that, by optimizing the timing, only two doses of rhTPO (one before and one after chemotherapy) were required to significantly reduce the severity of chemotherapy-related early thrombocytopenia.

Adolescent↗

PubMed2003

Rituximab in relapsed or refractory hairy cell leukemia.

The purpose of this study was to investigate the efficacy and safety of the monoclonal antibody, rituximab, in relapsed or refractory hairy cell leukemia (HCL). Fifteen patients with relapsed or primary refractory HCL after nucleoside analogs received rituximab 375 mg/m2 weekly for a total of 8 planned doses. An additional 4 doses could be administered to responders who had not achieved complete response (CR). The overall response rate was 80%. Eight patients (53%) achieved CR, 2 (13%) attained CR by hematologic parameters with residual marrow disease (1% to 5% marrow hairy cells), and 2 (13%) had a partial response. Of the 12 responders followed for a median of 32 months (range, 8 to 45+ months), 5 patients (42%) had progression of disease 8, 12, 18, 23, and 39 months from the start of therapy. Three patients failed to respond (after 4, 6, or 8 doses). Reductions in serum interleukin-2 receptor (sIL-2R) levels correlated with response. Toxicity was minimal, and no infectious episodes were observed. Rituximab has significant activity and minimal toxicity in HCL and warrants further study. Rituximab should be explored further in HCL with regard to eradication of minimal residual disease and in combination with nucleoside analogs.

Adult↗

PubMed2003

Calagualine inhibits nuclear transcription factors-kappaB activated by various inflammatory and tumor promoting agents.

Calagualine derived from the fern of the genus Polypodium, commonly called calaguala, has had clinically documented medicinal uses in South America and Spain and been shown to block tumor metastasis, proliferation, and inflammation, all known to require the activation of nuclear transcription factor-kappaB (NF-kappaB). Therefore, we investigated the effect of calagualine on NF-kappaB activation induced by various inflammatory and tumor promoting agents. Calagualine blocked tumor necrosis factor (TNF)-induced activation of NF-kappaB through inhibition of phosphorylation and degradation of IkappaBalpha, an inhibitor of NF-kappaB. The effects of calagualine were not cell type-specific, as it blocked TNF-induced NF-kappaB activation in a variety of cells. NF-kappaB-dependent reporter gene transcription activated by TNF was also suppressed by calagualine. The TNF-induced NF-kappaB activation cascade involving TNFR1-TNF receptor-associated death domain-TNF receptor-associated factor 2 (TRAF2)-NF-kappaB-inducing kinase (NIK)-IkappaBalpha kinase was interrupted at the TRAF2 and NIK sites by calagualine, which would account for its suppression of NF-kappaB reporter gene expression. Calagualine blocked NF-kappaB activation induced by phorbol ester and lipopolysaccharide. Overall our results indicate that calagualine inhibits activation of NF-kappaB and this may provide a molecular basis for calagualine's ability to suppress inflammation and tumorigenesis.

Ceramides↗

PubMed2003

Immunohistochemical analysis of Bin1/Amphiphysin II in human tissues: diverse sites of nuclear expression and losses in prostate cancer.

The Bin1/Amphiphysin II gene encodes at least seven alternately spliced adapter proteins that have been implicated in membrane dynamics and nuclear processes. Nuclear localized Bin1 polypeptides have tumor suppressor and proapoptotic activities, suggesting that Bin1 may suppress cancer in tissues where nuclear expression may occur. One question is the extent to which human tissues express nuclear Bin1 isoforms. A secondary issue has been the need for a specific antibody that can detect all the splice isoforms expressed by the human, mouse, and rat Bin1 genes. Using a novel mouse monoclonal antibody with these characteristics, we performed an immunohistochemical analysis of Bin1 expression in a panel of normal human tissues. We also compared the expression profile of Bin1 in normal or malignant tissues derived from human prostate, where Bin1 is a candidate tumor suppressor gene. In brain, a distinct nuclear staining pattern overlapped with a cytosolic staining pattern present in certain layers of the cerebral cortex and cerebellum. Bone marrow cells displayed mainly nuclear localization whereas peripheral lymphoid cells exhibited mainly cytosolic localization. In several epithelial tissues, nuclear or nucleocytosolic staining patterns were displayed by basal cells in skin, breast, or prostate, whereas cytosolic or plasma membrane-associated staining patterns were noted in gastrointestinal cells. Interestingly, a striking gradient of expression was observed in gastrointestinal epithelia, particularly in the large intestine, with the strongest staining displayed by cells destined to undergo apoptosis at the villus tip. In prostate, Bin1 staining was frequently absent in cases of primary prostate adenocarcinoma. This study used a novel reagent to document the extent of expression of nuclear Bin1 isoforms, which exhibit cancer suppression and proapoptotic activity in human cells.

Adenocarcinoma↗

PubMed2003

Systemic mastocytosis with associated clonal hematological non-mast-cell lineage disease: analysis of clinicopathologic features and activating c-kit mutations.

The majority of patients with systemic mastocytosis with associated clonal, hematological non-mast cell lineage disease (SM-AHNMD) have a myeloid stem cell malignancy including myelodysplastic syndromes (MDS), myelodysplastic/myeloproliferative disorders, acute myeloid leukemia (AML), or chronic myeloproliferative disease. The clinicopathologic features of SM-AHNMD have not been fully characterized. We describe seven cases of this entity: 3 with MDS, 3 with AML, and 1 with chronic myelomonocytic leukemia. In the majority of cases, SM was diagnosed concurrently with the myeloid malignancy and aberrant mast cell morphology was observed. The commonly described c-kit enzymatic site mutation Asp816Val was detected only in 2 cases, while 3 patients carried the Asp816His mutation. Among the 3 cases with AML, 2 patients carried the translocation t(8;21). On the basis of our results and other reported cases, there appears to be a specific association between SM and AML with t(8;21). Concurrent occurrence of SM may define a subset of patients with de novo AML and other myeloid malignancies who have an adverse prognosis. As clinically effective tyrosine kinase inhibitors that inhibit enzymatic-type c-kit mutations are being developed, detection of mast cell proliferation associated with myeloid malignancy may have important therapeutic implications.

Adult↗

PubMed2003

Waldenstrom macroglobulinemia involving extramedullary sites: morphologic and immunophenotypic findings in 44 patients.

Waldenstrom macroglobulinemia (WM) is a clinicopathologic syndrome in which a B-cell neoplasm involving the bone marrow, usually lymphoplasmacytic lymphoma (LPL), is associated with immunoglobulin M paraprotein in the serum. Extramedullary involvement occurs in a subset of patients and is infrequently examined histologically. The files of M.D. Anderson Cancer Center were searched for patients with WM who underwent biopsy of one or more extramedullary sites during the course of disease. Each biopsy specimen was classified using the criteria of the World Health Organization classification. The study group consisted of 44 patients (26 men and 18 women), with a total of 51 specimens obtained from lymph nodes (n = 36), soft tissue (n = 4), spleen (n = 3), skin (n = 2), lung (n = 2), tonsils (n = 1), colon (n = 1), liver (n = 1), and gallbladder (n = 1). Lymphoplasmacytic lymphoma was the most common histologic type, in 40 (78%) samples. This category was morphologically heterogeneous and was further subclassified as lymphoplasmacytic (n = 21), lymphoplasmacytoid (n = 18), and polymorphous (n = 1). Four of these LPL cases morphologically resembled marginal zone B-cell lymphoma. Four additional samples were involved by diffuse large B-cell lymphoma, probably transformed from LPL. Three more samples were involved by LPL with unusual features: two were CD5-positive and one was a composite tumor with classical Hodgkin's disease. Other categories of lymphoma in this group of patients with WM included small lymphocytic lymphoma/chronic lymphocytic leukemia (n = 2), mantle cell lymphoma (n = 1), and follicular lymphoma (n = 1). Waldenstrom macroglobulinemia is most commonly associated with LPL but can rarely occur with other types of B-cell lymphoma. Lymphoplasmacytic lymphoma in patients with WM is morphologically heterogeneous and can be indistinguishable from marginal zone B-cell lymphoma. CD5+ B-cell lymphomas with features otherwise typical of LPL are rare, and we think these tumors are part of the spectrum of LPL.

Adult↗