Biomedical subjects

M Talpaz

Publications and source records attributed to M Talpaz.

At least 91 records · Page 5Linked to original sources

PubMed1998

Local cutaneous necrotizing lesions associated with interferon injections.

Long-term i.m. or s.c. injections of interferon-alpha, beta, and gamma(IFN) in patients with chronic myelogenous leukemia (CML) can cause severe, long-lasting cutaneous complications consistent with necrotizing vasculitis. The purpose of this study was to describe the cutaneous lesions and the course of illness in 7 well-documented patients with Philadelphia chromosome-positive (Ph+) CML treated with IFN. We reviewed 7 patients diagnosed with Ph+ CML at M.D. Anderson Cancer Center between 1983 and 1994 who experienced cutaneous lesions at the injection site after treatment with i.m. or s.c. IFN (3 patients treated with IFN-alpha, 3 with combined IFN-alpha and IFN-gamma, and 1 with IFN-beta). According to pathology reports available for 3 patients, the cutaneous lesions seem to be consistent with necrotizing vasculitis. The skin reactions occurred independent of the IFN type, administration modality (i.m. or s.c.), duration of previously received IFN therapy (3-108 months), stage of disease, and cytogenetic response to IFN treatment. Of 7 patients, 4 developed low-grade fever during the occurrence of skin reactions, but all cultures taken from the abscesslike lesions were negative for bacterial or fungal infection. These lesions either did not resolve and required surgical debridement (5 patients) or resolved slowly with conservative management that included discontinuation of IFN at the specific, involved site. Independent of the IFN type or i.m. or s.c. injections, IFN can cause painful and long-lasting cutaneous lesions that frequently require surgical intervention. Whether this is a result of the high concentration of IFN at the injection site, the diluent, or an immunologic reaction remains unclear.

Adult↗

PubMed1998

Suppression of cytogenetic clonal evolution with interferon alfa therapy in patients with Philadelphia chromosome-positive chronic myelogenous leukemia.

PURPOSE: To investigate whether cytogenetic clonal evolution can be suppressed with interferon alfa (IFN-alpha) therapy in patients with chronic myelogenous leukemia (CML). PATIENTS AND METHODS: Ninety patients with CML and cytogenetic clonal evolution who received IFN-alpha-based regimens were analyzed. Clonal evolution was defined as the presence of karyotypic abnormalities in addition to the Philadelphia (Ph) chromosome. Patients were evaluated for the suppression of cytogenetic clonal evolution after therapy, the cytogenetic response, and survival. RESULTS: The median age of the population was 39 years (range, 15 to 70 years), median time from diagnosis to clonal evolution 14 months (range, 0 to 145 months), and median percentage of abnormal metaphases 18% (range, 4% to 100%). Fifty six patients (62%) achieved some suppression of cytogenetic clonal evolution; in 41 patients (46%), the suppression was complete. The overall median survival was 51 months, with 43% alive at 5 years. Patients who achieved a complete suppression of cytogenetic clonal evolution had a median survival of 66 months, with 51% alive at 5 years. Characteristics associated with a better response include a lower percentage of abnormal metaphases, time to cytogenetic clonal evolution of 24 months or less, and absence of other features of accelerated disease. A prognostic classification for cytogenetic clonal evolution defined three groups with complete response (CR) rates of 85%, 34%, and 0% (P < .0001) and median survival times of 58, 31, and 30 months, respectively (P=.02). CONCLUSION: Patients with cytogenetic clonal evolution can respond to IFN-alpha therapy, and this response is associated with longer survival. A previously described prognostic model separates patients into subsets with different probabilities of response to IFN-alpha and survival.

Adolescent↗

PubMed1998

Determinants of prognosis in late chronic-phase chronic myelogenous leukemia.

PURPOSE: Since interferon alfa (IFN-A) became an established treatment in chronic myelogenous leukemia (CML), more patients are referred to tertiary centers in late chronic phase (ie, > 12 months after diagnosis). Trials conducted in this phase cannot be evaluated precisely unless the features that determine prognosis in late chronic-phase CML are identified. The purpose of this study is to define the prognostic determinants of late chronic-phase CML. PATIENTS AND METHODS: From 1980 to 1997,257 consecutive CML patients referred in late chronic phase were studied. Their clinical characteristics at the time of referral and their association with survival were investigated. A staging model was designed. RESULTS: The median survival from time of referral was 43 months. Pretreatment characteristics associated with worse outcome included older age, poor performance status, splenomegaly, low albumin level, high percentage of blasts or basophils in peripheral blood (PB) or bone marrow, longer duration of chronic phase, and poor-risk group as defined by the Synthesis model. Prior exposure to IFN-A was not associated with worse outcome. By multivariate analysis, characteristics associated with shorter survival were age of 60 years or older, time from diagnosis of 3 years or greater, performance status of 1 or greater, PB basophils of 7% or greater, spleen 10 cm or greater, PB blasts 3% or greater, and albumin level less than 4 g/dL. A model that included age, duration of chronic phase, performance status, and PB basophils was generated. Patients with no, one, two, or three or greater adverse factors had median survivals of 71, 49, 26, and 19 months, respectively. CONCLUSION: A staging model for late chronic-phase CML can stratify patients in four groups with significantly different outcomes. If confirmed in independent populations, such a model could be considered in the analysis of future trials of treatment strategies in late chronic-phase CML.

Adolescent↗

PubMed1998

Early treatment decisions with interferon-alfa therapy in early chronic-phase chronic myelogenous leukemia.

PURPOSE: To determine, in patients with Philadelphia chromosome (Ph)-positive chronic myelogenous leukemia (CML) on interferon alfa (IFNalpha), whether combining pretreatment characteristics and early response profiles would distinguish patients with differential benefits that would allow better decisions on subsequent therapy. PATIENTS AND METHODS: A total of 274 patients treated from 1982 through 1990 with IFNalpha regimens were analyzed. A second group of 137 patients treated with IFNalpha and low-dose cytarabine (ara-C) between 1990 and 1994 was later used to confirm the guidelines derived from the original study group analysis. Patients' pretreatment factors and response to IFNalpha therapy at 3, 6, and 12 months were analyzed in relation to subsequent achievement of major cytogenetic response. After univariate analysis of prognostic factors, a multivariate analysis selected, at 6 months, independent pretreatment factors that added to the response status in predicting subsequent outcome. The results were then applied at the 3- and 12-month periods and confirmed in the subsequent population. RESULTS: Response to IFNalpha therapy at 3, 6, and 12 months was a significant predictor of later major cytogenetic response. The presence of splenomegaly > or = 5 cm below the costal margin (BCM) or thrombocytosis > or = 700 x 10(9)/L pretreatment added significant independent prediction to response. At 6 months, patients with a partial hematologic response (PHR) or resistant disease had a less than 10% chance of achieving a later major cytogenetic response, as were those in complete hematologic response (CHR) and who had pretreatment splenomegaly and thrombocytosis. Applying the model at 3 months showed that only patients with < or = PHR and pretreatment splenomegaly or thrombocytosis at 3 months had such a low major cytogenetic response rate. Finally, at 12 months, patients with CHR still had a 15% to 25% chance of having a major cytogenetic response later if they did not have pretreatment splenomegaly and thrombocytosis. CONCLUSION: This analysis allows better selection of patients with Ph-positive CML on IFNalpha therapy for continuation of IFNalpha versus changing therapy early in the course of CML. For treatment programs that choose to change patients to other investigational therapies (eg, intensive chemotherapy and/or autologous stem-cell transplantation [SCT]), baseline outcome expectations are provided for patients continued on IFNalpha therapy, against which the results of new approaches can be compared.

Adolescent↗

PubMed1998

Conversion of interferon-induced, long-term cytogenetic remissions in chronic myelogenous leukemia to polymerase chain reaction negativity.

PURPOSE: Interferon alfa (IFN-alpha) induces complete cytogenetic remission in a significant minority of patients with chronic myelogenous leukemia (CML). To date, use of the polymerase chain reaction (PCR) has suggested that residual disease is present in virtually all these individuals at median follow-up intervals of approximately 1 year after initial achievement of cytogenetic remission. We sought to determine the PCR status of CML patients with very long continuous complete cytogenetic remissions on IFN-alpha. PATIENTS AND METHODS: Blood and/or bone marrow samples from 18 CML patients maintained in continuous cytogenetic remission by IFN-alpha for at least 1 year were studied for residual BCR-ABL mRNA by single-step reverse-transcriptase (RT)-PCR methodology, followed by detection of the amplification product by the hybridization protection assay (HPA). RESULTS: Ten of 18 patients showed RT-PCR negativity for BCR-ABL. The median duration of continuous complete cytogenetic remission at the time of sample collection for the negative patients was 42 months versus 21 months for the patients whose tests remained positive (P = .05). CONCLUSION: Very long-term follow-up of IFN-alpha-treated CML patients in continuous complete cytogenetic remission is associated with a decrease in the number of BCR-ABL transcripts to a level below that detectable by the RT-PCR assay used in this study.

Adult↗

PubMed1998

Cellular pharmacodynamics and plasma pharmacokinetics of parenterally infused hydroxyurea during a phase I clinical trial in chronic myelogenous leukemia.

PURPOSE: To determine the maximum-tolerated dose (MTD), toxicities, and antileukemic activity of hydroxyurea (HU) administered intravenously to patients with advanced-phase chronic myelogenous leukemia (CML). Further objectives were to analyze pharmacodynamic effect on deoxynucleotides (dNTPs) and to seek relationships between the decrease in dNTP pools and inhibition of DNA synthesis in CML blasts. PATIENTS AND METHODS: HU (8, 12, 18, 27, and 40 g/m2) was administered intravenously by a 24-hour continuous infusion to 19 adults with CML in blastic or accelerated phase. Plasma levels of HU were analyzed in all patients. To determine the role of HU in inhibiting ribonucleotide reductase, dNTP pools in the leukemia cells were quantitated. Correlations were sought with these parameters and DNA synthesis inhibition measured ex vivo by [3H]thymidine incorporation. RESULTS: The MTD of HU given as a 24-hour infusion was 27 g/m2. The dose-limiting toxicity was mucositis. There was a significant but transient myelosuppression, with nadir counts generally seen 3 to 4 days after the dose. The steady-state concentration of HU in plasma was achieved by 6 hours, and was proportional to the dose. There was a median 57% decrease in the deoxyadenosine triphosphate (dATP) pool in circulating blasts. In contrast, deoxyguanosine triphosphate (dGTP) and pyrimidine dNTPs were not significantly affected. The extent of DNA synthesis inhibition was related to the residual concentrations of intracellular dATP. CONCLUSION: A 24-hour infusion of HU results in significant but transient myelosuppression in advanced-phase CML. The specific decrease of intracellular dATP correlated with the inhibition of DNA synthesis in CML blasts. This pharmacodynamic action of HU provides a rationale for combination with other chemotherapeutic agents, the effects of which could be augmented by the decline in dATP pools.

Adenosine Triphosphate↗

PubMed1998

Thrombopoietin stimulates myelodysplastic syndrome granulocyte-macrophage and erythroid progenitor proliferation.

Thrombopoietin (TPO) has been successfully used to stimulate megakaryocyte progenitor proliferation and platelet production both in vitro and in vivo. We and other investigators have found that TPO also stimulates normal marrow colony-forming unit granulocyte-macrophage (CFU-GM) and burst-forming unit-erythroid (BFU-E) growth. In contrast to its effect on normal marrow precursors, TPO stimulates acute myelogenous leukemia (AML) progenitor proliferation in only 25% of the cases. Because the hematopoietic cells in Myelodysplastic syndrome (MDS) originate from both the normal and leukemic clones, we hypothesized that TPO may be a useful therapeutic agent for MDS. To test this hypothesis, we used fresh marrow samples taken from 14 MDS patients. We found that in the presence of fetal calf serum (FCS) and erythropoietin (EPO) TPO (5 to 40 ng/ml) MDS CFU-GM and BFU-E colony-forming cell proliferation were stimulated in a dose-dependent fashion by up to 103% and 93% respectively. This effect was similar to the stimulation obtained with optimal concentrations of granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage CSF (GM-CSF), or interleukin-3 (IL-3). Furthermore, TPO increased the colony-stimulatory effects of G-CSF, GM-CSF, IL-3, and stem cell factor (SCF) on MDS marrow cells. However, depletion of either T lymphocytes or adherent cells abrogated the effect of TPO, suggesting that the effect is not a direct one but is mediated through interaction with cytokines produced by accessory cells. Taken together, our data suggest that the therapeutic role of TPO in the management of MDS warrants further investigation.

Aged↗

PubMed1998

High serum interleukin-6 levels correlate with a shorter failure-free survival in indolent lymphoma.

Interleukin-6 (IL-6) is a potent immunomodulatory cytokine that may have pathogenetic and prognostic significance in a number of disorders. The objective of this study was to examine the correlation between serum IL-6 levels and phenotypic characteristics, as well as failure-free survival of patients with low-grade non-Hodgkin's lymphomas (NHL). Using a sensitive enzyme-linked immunoabsorbent assay (ELISA), we measured IL-6 in frozen sera from 55 healthy controls and in the pre-treatment frozen sera from 100 low-grade lymphoma patients who were enrolled on protocols at MD Anderson Cancer Center. Serum IL-6 levels were correlated with clinical and laboratory features at diagnosis and with failure-free survival. The serum IL-6 levels were > or =2 pg/mL in 9% (median, <0.91 pg/mL; range, <0.91-4.31 pg/mL) of controls versus 25% of the indolent lymphoma patients (median, <0.91 pg/mL; range <0.91 to 225.97) (p = 0.0118). Serum IL-6 levels were higher in patients with B-symptoms (p = 0.02), an elevated P2-microglobulin level (> or =3.0 mg/L) (p = 0.00013), and unfavorable International Index (p = 0.03). Patients with elevated serum IL-6 levels had an inferior failure-free survival (log rank p = 0.008) compared with those with normal serum IL-6 levels (three-year-failure-free-survival = 55% versus 81%, respectively). In conclusion a minority (25%) of patients with indolent non-Hodgkin's lymphomas have elevated serum levels of IL-6 at diagnosis. In these individuals, high IL-6 levels are associated with adverse disease features, and predictive of a shorter failure-free survival.

Adult↗

PubMed1998

Serum cytokine levels in infectious mononucleosis at diagnosis and convalescence.

Infection with the Epstein-Barr virus (EBV) is common worldwide. A significant number of infected individuals develop infectious mononucleosis (IM). IM is manifested in most patients as a benign disease with mild symptoms. However, serious complications may develop in a subset of patients. Because EBV-infected B lymphocytes produce various cytokines that may provide the cells with a proliferative advantage, cytokine concentrations in serum samples taken from IM patients were measured in order to identify the cytokines responsible for the clinical manifestations of the disease. The concentrations of interleukin-1beta (IL-1beta), IL-2, IL-6, IL-8, IL-10, tumor necrosis factor-alpha (TNF-alpha), and lymphotoxin (LT) were measured using an enzyme-linked immunosorbent assay (ELISA) in serum obtained from 14 IM patients during the acute phase of the disease and during convalescence, 5 patients with identical clinical manifestations who did not have IM (sick controls), and 11 healthy volunteers. It was found that the serum levels of TNF-alpha and IL-6 were significantly high in patients with acute IM compared with the serum levels in healthy individuals (P = 0.008 and P < 0.001, respectively) but returned to normal at convalescence (P = 0.009 and P = 0.005 respectively). However, whereas TNF-alpha concentrations were significantly higher (P = 0.04) in patients with acute IM than in the sick controls, no significant difference in IL-6 concentrations was found between the two groups of patients. Changes in IL-10 concentration were not statistically significant, and IL-1beta, IL-2, IL-8, and LT were detected only sporadically. The data in this study suggest that TNF-alpha may have a specific role in causing the clinical manifestations of IM. Further studies should determine the clinical significance of TNF-alpha inhibition in IM.

Convalescence↗

PubMed1998

Philadelphia chromosome-positive myeloid cells in the peripheral blood of chronic myelogenous leukemia patients: comparison with the frequency detected in cycling cells of the bone marrow.

Monitoring the frequency of the Philadelphia (Ph) chromosome in chronic myelogenous leukemia (CML) is important in determining the effectiveness of treatment for patients during therapy. This can be done with high resolution by subjecting short-term bone marrow cultures (48 h) to 24 h of mitotic arrest before harvest and detecting Ph-positive (Ph+) metaphases by fluorescence in situ hybridization (FISH) in a procedure termed hypermetaphase FISH or HMF. Here, we compared procedures for detecting Ph+ interphase cells (interphase FISH or I-FISH) in peripheral blood polymorphonucleocytes (PMNs) with HMF results on the bone marrow of the same 26 CML patients in different stages of remission. The probes for I-FISH in these experiments were relatively large (200-300 kb) and sufficiently resolved in PMNs so that 97.5% of the cells were scorable. The correlation between the frequencies of Ph+ cells from the two different cell sources was excellent (r = 0.983, P < 0.0001); however, there was a consistently higher level of Ph+ cells observed in the cycling marrow cells than in the peripheral blood PMNs. This was discussed in terms of current theories of apoptosis in CML cells. The large number of PMNs analyzable by I-FISH (approximately 500/patient in this study) provided sufficiently narrow 99% confidence intervals to suggest the procedure as an effective and efficient method for monitoring the frequency of Ph+ cells in CML patients undergoing therapy. However, for detection and quantification of minimal residual disease, HMF is preferable to I-FISH because of the much lower frequency of false-positive readings with the former procedure.

Adult↗

PubMed1998

Selective inhibition of cell proliferation and BCR-ABL phosphorylation in acute lymphoblastic leukemia cells expressing Mr 190,000 BCR-ABL protein by a tyrosine kinase inhibitor (CGP-57148).

The excessive proliferation of the myeloid marrow compartment in Philadelphia chromosome (Ph)-positive acute and chronic leukemias has been largely attributed to a hyperactive and autonomously acting hybrid tyrosine kinase BCR-ABL, a product of the fusion between the second exon of the c-ABL proto-oncogene and 5' portions of the BCR gene on chromosome 22. This specific molecular event, amenable to attack with specifically designed inhibitors, has recently been successfully influenced by the drug CGP-57148 in mammalian cells transfected with full-length BCR-ABL gene and expressing full-length p210Bcr-Abl protein, as well as in primary human leukemic cells expressing p210Bcr-Abl fusion protein. In view of the heterogeneity of BCR-ABL transcripts associated with various phenotypes, we investigated the effect of CGP-57148 on p190Bcr-Abl- and p210Bcr-Abl-expressing, patient-derived cell lines and primary intact blast cells. In particular, we were interested in whether the variations in molecular events and/or the phenotype of Ph-positive cells would affect their susceptibility to the specific tyrosine kinase inhibitor CGP-57148. We have demonstrated that the sensitivity of human cells with lymphoblastic immunophenotype expressing p190Bcr-Abl protein is comparable to that for leukemic myeloid cells expressing p210Bcr-Abl protein. After documenting profound and phenotype-independent suppression of both autophosphorylation and cell growth, we explored the importance of time and dose of exposure on the manifestation and stability of the induced events. Although there were variations between target cells, in vitro exposure for 24-48 h induced extensive and apparently irreversible apoptosis in BCR-ABL-expressing but not other normal or BCR-ABL-negative leukemic cells. These findings support the potential use of CGP-57148 to purge Ph-positive cells from autologous bone marrow in vitro. Another important finding was the comparable suppressive effect of temporary CGP-57148 exposure on both clonogenic KBM-5 cells and the whole cell population. Exposure time and dose appeared to be important variables among various cell types. Moreover, effective doses appeared uniformly harmless to cells lacking BCR-ABL protein functioning as tyrosine kinase. Thus, the continuous exposure of target cells, at least during the initial period of 24-48 h, may prove to be an important variable in the design of in vitro and in vivo therapy using tyrosine kinase inhibitors.

Apoptosis↗

PubMed1997

1,25-Dihydroxyvitamin D3 and its analogues inhibit acute myelogenous leukemia progenitor proliferation by suppressing interleukin-1beta production.

We hypothesized that 1,25-dihydroxyvitamin D3 (1,25D3) and its analogues may inhibit acute myelogenous leukemia (AML) proliferation by interrupting IL-1beta-mediated growth-stimulatory signals. The incubation of the IL-1beta- responsive AML cell line OCIM2 with 10 nM 1,25D3 reduced growth 80% in liquid culture, and a 100-1000-fold lower concentration of 20-epi analogues (MC1288 and MC1301) was sufficient to achieve similar growth inhibition. The growth inhibition was associated with a rapid but transient downregulation of IL-1beta and IL-1beta-converting enzyme (ICE) mRNAs in 1,25D3- and 20-epi analogue- treated cells, and the 20-epi analogue was more effective than 1,25D3 in repressing ICE expression. An examination of long-term changes in the levels of mature IL-1beta and its precursor revealed that 24-h incubation of OCIM2 with either 1,25D3 or its 20-epi analogues abolished the production of mature IL-1beta. The effect of 1,25D3 and its analogues on growth of fresh bone marrow cells from seven AML patients was tested by a clonogenic assay. Growth inhibition of 60% was reached in only one of seven 1,25D3-treated samples, but all seven samples were inhibited 60-90% by the 20-epi analogue MC1301. Growth inhibition by 1,25D3 and the analogue was reversible by addition of IL-1beta. These results suggest that 1,25D3 and its 20-epi analogues interrupt IL-1beta autocrine growth regulation by inhibiting IL-1beta production and processing but not the response to IL-1beta.

Antineoplastic Agents↗

PubMed1997

Thiotepa for the treatment of thrombocythemia in patients with Philadelphia chromosome positive chronic myelogenous leukemia.

BACKGROUND: Patients with chronic myelogenous leukemia (CML) occasionally experience persistent thrombocythemia despite having adequate white blood cell (WBC) counts. Trimethylenethiophosphoramide (thiotepa) is an alkylating agent that significantly inhibits platelet production. METHODS: The authors studied the effects of thiotepa in eight patients with CML with persistent thrombocythemia. All patients had adequate WBC counts while receiving therapy for leukemia. The median age of the patients was 58 years, and all had received at least 2 prior therapy regimens for CML. Thiotepa was administered by intravenous infusion at a dose of 75 mg/m2 once every 2 to 3 weeks; doses were adjusted according to hematologic response. RESULTS: Seven patients were evaluable for response to thiotepa. Their pretreatment median platelet count was 1215 x 10(9)/L. After receiving the first dose, 6 patients (86%) had favorable responses as the median platelet count dropped to 348 x 10(9)/L (P = 0.02). However, all the patients' platelet counts returned to near baseline values after the first course. Patients required a median of three courses to achieve stable platelet counts near the normal range. In 4 patients (57%), administration of thiotepa was discontinued because of a stable normal platelet count after a median of 7.5 courses; 1 patient was still receiving treatment at last follow-up (18 courses) and 2 patients stopped receiving treatment after their disease progressed to the blastic phase. Toxicity was mostly hematologic, with neutropenia (< or = 1 x 10(9)/L) occurring during 5 of the 64 courses (8%) administered but only 1 patient's course was complicated by fever. CONCLUSIONS: The authors conclude that thiotepa is useful in controlling thrombocythemia in CML patients who have elevated platelet counts despite having adequate WBC counts.

Adult↗

PubMed1997

Prognostic value of serum interleukin-6 in diffuse large-cell lymphoma.

BACKGROUND: Interleukin-6 has important lymphoid bioregulatory effects, and serum levels of interleukin-6 are often elevated in patients with lymphoma. OBJECTIVE: To determine the relation between serum levels of interleukin-6 before treatment and outcome in patients with diffuse large-cell lymphoma. DESIGN: Retrospective cohort analysis with multivariate analysis. SETTING: Tertiary referral center. PARTICIPANTS: 118 untreated patients with diffuse large-cell lymphoma who were enrolled in frontline chemotherapy protocols and 45 healthy controls. MEASUREMENTS: Serum levels of interleukin-6 were measured by using a sensitive enzyme-linked immunosorbent assay. Levels below the upper limit of the range for controls were considered normal. Outcomes were complete response, failure-free survival, and overall survival. RESULTS: Serum levels of interleukin-6 were higher in patients with lymphoma (median, 4.6 pg/ml [range, undetectable to 224 pg/mL]) than in controls (median, undetectable [range, undetectable to 4.3 pg/mL]) (P = 0.009). The complete response rate was 95% for persons with normal interleukin-6 levels and 55% for persons with high interleukin-6 levels (P = 0.001). Patients with high interleukin-6 levels had inferior failure-free and overall survival rates (P < 0.001 for both comparisons). The actuarial 4-year failure-free and overall survival rates were 72% and 85%, respectively, for persons with normal interleukin-6 levels and 37% and 46%, respectively, for persons with high interleukin-6 levels. In multivariate analysis, interleukin-6 was selected as the most significant predictor of complete response and failure-free survival. Failure-free and overall survival of patients stratified according to International Prognostic Index score could be further stratified by interleukin-6 level (P < or = 0.03 for all comparisons). CONCLUSION: In patients with diffuse large-cell lymphoma, serum interleukin-6 levels are an independent prognostic factor for complete response and failure-free survival.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed1997

Clinical correlates of elevated serum levels of interleukin 6 in patients with untreated Hodgkin's disease.

BACKGROUND: Interleukin-6 (IL-6) is a potent immunomodulatory cytokine that may have pathogenetic significance in several malignancies. In addition, high IL-6 levels have been associated with a poor prognosis in multiple myeloma, nonHodgkin's lymphoma, ovarian cancer, and renal cancer, as well in advanced Hodgkin's lymphoma. In this study, we analyzed IL-6 levels in newly diagnosed Hodgkin's disease and determined clinical correlates of elevated levels. PATIENTS AND METHODS: Using a sensitive enzyme-linked immunosorbent assay (lower limit of sensitivity = 0.35 pg/mL) we measured IL-6 levels in sera from 33 healthy controls and 65 untreated patients with Hodgkin's disease. RESULTS: Interleukin-6 levels in the Hodgkin's patients (median 2.7 pg/mL; range < 0.35 to 38.4 pg/mL) were significantly higher than in the controls (median < 0.35 pg/mL; range < 0.35 to 1.87 pg/mL; P < 0.0001). Interleukin-6 levels were also higher in males (P = 0.03) and in patients with bulky disease (P = 0.026) or advanced Ann Arbor stage (P = 0.017). In addition, serum levels of IL-6 also showed direct linear correlations with the erythrocyte sedimentation rate (r = 0.64, P = 0.0007), platelet count (r = 0.53, P < 0.0001), leukocyte count (r = 0.36, P = 0.003), and beta (2)-microglobulin level (r = 0.4, P = 0.0012); and an inverse linear correlation with serum albumin level (r = -0.43, P = 0.0003). In the 10 patients tested who had elevated serum IL-6 levels pretherapy and who achieved complete remission, serum IL-6 values decreased at the time of remission to the range found in healthy controls. CONCLUSIONS: Our observations suggest that, in patients with Hodgkin's disease, serum levels of IL-6 are frequently elevated at diagnosis, normalize during remission, and are associated with specific disease characteristics including several adverse prognostic features.

Adolescent↗

PubMed1997

Physiology and pathophysiology of dendritic cells.

Dendritic cells are antigen-presenting cells derived from the hematopoietic stem cell. The dendritic cell family includes Langerhans' cells (CD1a-positive dendritic cells of the skin), and antigen-presenting cells that are found in the lymphoreticular system and throughout the organ parenchyme. Dendritic cells play a key role in both the primary and secondary immune responses. Several studies indicate that these cells participate in antitumor immunity, tumor surveillance, graft-versus-host disease, and in the pathogenesis of clinical syndromes of unknown origin or those induced by viruses, such as the human immunodeficiency virus. Different disorders are characterized by an abnormal proliferation and accumulation of dendritic cells; for example, the Langerhans' histiocytes, which accumulate in Langerhans' cell histiocytosis. In this review the immunophenotypic, morphological, and functional characteristics of the dendritic cell family is described. The clinical and laboratory studies suggesting a unique role for these cells in various syndromes and diseases are reviewed. The Langerhans' cell histiocytoses and the malignant disorders associated with transformation of cells belonging to the dendritic cell family, are discussed.

Dendritic Cells↗

PubMed1997

Suppressed formation of bone marrow adherent layers derived from acute myeloid leukemia patients after in vitro exposure to interleukin-4.

Long-term bone marrow cultures from ten acute myeloid leukemia (AML) patients exposed to recombinant human (rhu) interleukin (IL) 4 from culture initiation failed to develop adherent layers at 5 weeks as compared to controls. The adherent layers from two of our patients expressed IL-1 beta transcripts constitutively, and all produced IL-6 and leukemia inhibitory factor (LIF) proteins. Our results demonstrate that rhuIL-4 markedly inhibited AML-derived adherent layer formation in a time- and dose-dependent manner, and this effect was not mediated through enhanced apoptosis and did not correlate with IL-1 beta, IL-6 or LIF production.

Acute Disease↗

PubMed1997

Natural history and staging of chronic myelogenous leukaemia.

The natural history of chronic myelogenous leukaemia has changed in recent years, partly as a result of earlier diagnosis but mostly as a consequence of the availability of effective therapies that have the potential to eradicate the Philadelphia-positive clone. The prognostic models designed in the pre-interferon-alpha (IFN-alpha) era based on clinical characteristics of the disease are still useful in identifying different risk groups after treatment with IFN-alpha, but achieving a cytogenetic response with IFN-alpha is now the most important prognostic factor for survival. The significance of other molecular and biological variables remains to be determined.

Antineoplastic Agents↗