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Biomedical subjects

R Kurzrock

Publications and source records attributed to R Kurzrock.

At least 55 records · Page 3Linked to original sources
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

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

Response duration and recovery of CD4+ lymphocytes following deoxycoformycin in interferon-alpha-resistant hairy cell leukemia: 7-year follow-up.

The long-term outcome of patients with hairy cell leukemia resistant to interferon-alpha (IFN-alpha) following treatment with deoxycoformycin (DCF) was examined, and the kinetics of recovery of lymphocyte subsets and factors influencing the rate of recovery investigated. Between May 1986 and May 1989, 15 patients with histologically confirmed hairy cell leukemia resistant to IFN-alpha received DCF 4 mg/m2 every 2 weeks with 12 cycles planned. All 15 patients were evaluable for response and have been followed for a median of 88 months (range, 72 to 106 months) from the start of therapy. Fourteen patients responded to DCF, all attaining complete remission (CR) (response rate 93%; 95% confidence interval, 69% to 100%). Seven patients have developed recurrent disease after 45 to 74 months. Using the method of Kaplan and Meier, the median remission duration is 74 months and, at 8 years, 46% (95% confidence interval, 33% to 59%) of patients are projected to be in ongoing CR. The seven relapsing patients have responded to treatment with 2-chlorodeoxyadenosine (2-CdA) and all 15 patients remain alive. After DCF, nadir CD4+ and CD8+ lymphocyte counts were significantly lower than prior to therapy (P < 0.0001 and P = 0.05, respectively), but returned to baseline levels during follow-up. Median times to attainment of the lower limit of the normal range of CD4+ and CD8+ lymphocytes were 54 and 36 months, respectively. Those patients who had previously undergone splenectomy (n=7) had higher baseline CD4+ (P= 0.073) and CD8+ (P= 0.043) lymphocyte counts and more rapid recovery of both CD4+ (P= 0.027) and CD8+ lymphocyte counts (P = 0.016) than non-splenectomized patients. One elderly patient (age, 78 years) was diagnosed with subsequent malignancy. No late opportunistic infections were observed. Resistance to IFN-alpha does not impair subsequent responsiveness of patients with hairy cell leukemia to treatment with DCF. Responses are durable and without evidence of long-term sequelae. CD4+ and CD8+ lymphocyte subsets recover slowly without clinical manifestations of immunodeficiency. Splenectomized patients appear to have higher baseline lymphocyte counts and more rapid lymphocyte recovery following treatment with DCF.

Adult↗
PubMed1997

Paclitaxel activity for the treatment of non-Hodgkin's lymphoma: final report of a phase II trial.

In order to determine the activity of paclitaxel in patients with relapsed or refractory non-Hodgkin's lymphoma (NHL), we conducted a phase II clinical trial in which eligible patients received paclitaxel 200 mg/m2 intravenously over 3 h. Treatment was repeated every 3 weeks. Patients achieving complete or partial responses after two courses of paclitaxel continued to receive therapy for a maximum of eight courses, otherwise they were removed from the study. Of 96 evaluable patients, 45 (47%) had primary refractory disease, and 51 (53%) had relapsed lymphoma. The median number of prior treatment regimens was two (range one to 10 regimens). 45 patients had lowgrade, 44 had intermediate-grade, and seven had mantle cell lymphoma. 24/96 patients responded (10 complete and 14 partial remissions) for an overall response rate of 25% (95% CI 17-35%). Patients with relapsed lymphoma had a higher response rate than those with primary refractory disease (19/51 = 37% v 5/45 = 11%; P < 0.01), and patients with relapsed intermediate-grade lymphoma had a higher response than those with relapsed low-grade lymphoma (9/18 = 50% v 10/31 = 32%; P = 0.22). The treatment was very well tolerated with the most common side-effects being alopecia (100%), peripheral neuropathy (35% of > or = grade II), and arthralgia/myalgia (25% of > or = grade II). After the first course of paclitaxel, grade III/IV thrombocytopenia and neutropenia were observed in 21% and 23% of the patients respectively. 23 episodes of neutropenic fever developed after 250 courses of paclitaxel therapy (8%). We conclude that paclitaxel, at this dose and schedule, is an active new drug for the treatment of non-Hodgkin's lymphoma. The activity of paclitaxel combination programmes are currently under investigation.

Adult↗
PubMed1997

Second cancer risk in hairy cell leukemia: analysis of 350 patients.

PURPOSE: The discovery of effective therapy for hairy cell leukemia (HCL) has increased the relevance of long-term outcome. We have therefore examined the incidence of second cancers. PATIENTS AND METHODS: Data on 350 HCL patients was obtained from the M.D. Anderson Cancer Center Cancer Registry's computerized data base and from chart review. Standardized incidence ratios (SIRs) and standardized mortality ratios (SMRs) (observed/expected [O/E]) were calculated with the expected number determined using age, sex, and calendar-year-specific rates from the Connecticut Tumor Registry and from national mortality data, respectively. RESULTS: The median age of the patients was 50 years and the median follow-up duration was 6 years. Twenty-six patients developed a second cancer at least 6 months after the HCL diagnosis (O/E ratio, 1.34; P = .08). There was no excess of malignancy among patients treated with interferon alfa (IFN-alpha; P = .27), 2-chlorodeoxyadenosine (2CDA; P = .37), or deoxycoformycin (DCF; P = .7). However, an excess of myeloma-related neoplasms (O/E, 13.04; P < .001) and lymphomas (O/E, 8.7; P = .03) was observed. Survival from the advent of systemic therapy for HCL was better than before this time (P = .0009). Nevertheless, mortality remained excessive (O/E, 6.17; P < .001), mainly because of HCL-related infections and secondary malignancy. CONCLUSION: Among 350 patients with HCL, there was an increase in the number of second cancers; however, it did not reach statistical significance and was not associated with therapy. The incidence of lymphoid neoplasms was significantly higher than expected. Survival since the advent of effective systemic therapy was excellent, although excess mortality was still observed.

Adult↗
PubMed1997

Apoptosis in chronic myelogenous leukemia: studies of stage-specific differences.

In this study we compared rates of apoptosis, survival and metabolic activity from CML peripheral blood neutrophils with peripheral blood and bone marrow neutrophils from healthy volunteer donors and studied the influence of the disease stage and of cytokines including G-CSF, GM-CSF and IL-1beta on these parameters. Quantification of apoptosis by morphology, diphenylamine DNA fragmentation assay and by gel electrophoresis showed similar rates of apoptosis in chronic phase CML and normal peripheral blood neutrophils when the cells were incubated in RPMI + FCS or in serum-free medium. However, there were lower rates of apoptosis in accelerated and blast phase CML neutrophils (p < .001) and in normal bone marrow neutrophils (p < .001) compared to normal peripheral blood neutrophils (incubated in RPMI + FCS). Survival among neutrophils from chronic phase or accelerated/blast phase CML patients was significantly longer (p < 0.002 and p < 0.001, respectively) than among normal peripheral blood neutrophils but neutrophils purified from normal bone marrow had a survival rate which fell between that of normal peripheral blood and chronic phase CML patients. When the cells were incubated in RPMI + autologous sera, neutrophils from chronic phase CML patients showed markedly lower rates of apoptosis (p < 0.001) and maintained higher metabolic activities (p < 0.002) compared to normal neutrophils. G-CSF and GM-CSF were found to considerably decrease the rate of apoptosis in chronic phase CML neutrophils (p < 0.001 and p = 0.008 respectively) while IL-1beta did not show any antiapoptotic effect. It is suggested that the endogenous production of growth factors may therefore participate in delaying apoptotic cell death, during the progression of CML.

Adult↗
PubMed1997

Interleukin-10 in non-Hodgkin's lymphoma.

Interleukin-10 (IL-10) is a pleiotropic cytokine produced by type 2 helper cells (Th2), as well as by monocytes and macrophages, and normal and neoplastic B lymphocytes. It is highly homologous to an open reading frame of Epstein-Barr virus (EBV) called BCRF1, and EBV infection of B-cells up-regulates IL-10. IL-10 production has strong immunosuppressive effects via inhibition of Th1 type cytokines, including interferon gamma and interleukin-2. On B-cells, IL-10 has a potent stimulating effect, inducing proliferation and differentiation. Interestingly, in cell lines derived from B-cell lymphomas, IL-10 production has been found to be up-regulated, and it serves as an autocrine growth factor. In patients with non-Hodgkin's lymphoma (NHL), serum IL-10 levels are significantly increased when compared to normal individuals and NHL patients in remission. The prognostic significance of these increased levels vary according to the assay used. Both human IL-10 and viral IL-10 are increased, and when specific assays for human IL-10 are used, there seems to be no prognostic significance, whereas when the assay cross-reacts with viral IL-10, high levels correlate with poor prognosis. These results suggest that viral IL-10 might have some pathogenic role in NHL.

Animals↗
PubMed1997

Chronic myelogenous leukemia--progress at the M. D. Anderson Cancer Center over the past two decades and future directions: first Emil J Freireich Award Lecture.

The purpose of this study was to review the progress in clinical and translational research in chronic myelogenous leukemia (CML) over the past 20 years at M.D. Anderson Cancer Center. The CML database updating the clinical and basic research investigations was reviewed as the source of this report. Publications resulting from these investigations were summarized. The long-term results with intensive chemotherapy, IFN-alpha therapy alone or in combination, autologous stem cell transplantation, and new agents such as homoharringtonine and decitabine showed encouraging results. Biological studies related to the BCR-ABL molecular abnormality, other molecular events, and the detection of minimal residual disease were detailed. Future strategies with potential promise in CML were outlined. Significant progress in understanding CML biology and in treating patients afflicted with the disease has occurred. Several therapeutic and research tools are currently investigated, which should hopefully improve further the prognosis of patients with CML.

Antineoplastic Agents↗
PubMed1997

Mucocutaneous paraneoplastic syndromes.

Mucocutaneous paraneoplastic syndromes represent a group of dermatoses of variable morphology, pathology, and etiology that can occur as idiopathic conditions or in association with a visceral malignancy. These conditions can be categorized with respect to their predominant pathologic change: dermal "depositions," neutrophilic dermatoses, papulosquamous disorders, proliferative reactions, reactive erythemas, vacuolar degeneration of the basal layer, vasculitis, and vesiculobullous disorders. Some of these dermatoses occur more frequently in patients with hematologic malignancies whereas others are more prevalent in patients with solid tumors. The major clinical characteristics and commonly associated malignancies in patients with mucocutaneous paraneoplastic syndromes are reviewed. Suggested workups to evaluate for cancer in patients with these dermatoses are summarized. The appearance of a mucocutaneous paraneoplastic syndrome can either precede, occur concurrently with, or follow the detection of an associated neoplastic process. Therefore, the dermatosis can be the presenting feature of a previously unsuspected neoplasm or the earliest sign of recurrent cancer in an oncology patient. When the possibility of a mucocutaneous paraneoplastic syndrome is entertained, the diagnosis of the dermatosis should be confirmed either based on the clinical morphology of the lesions, the pathologic changes observed after lesional biopsy, or both. Once the diagnosis of a malignancy-associated dermatosis has been established, either an appropriate evaluation for an asymptomatic neoplasm in a cancer-free individual or an investigation for recurrence of malignancy in an oncology patient can be initiated.

Hematologic Neoplasms↗
PubMed1997

Cytokine deregulation in hematological malignancies: clinical and biological implications.

Endogenous cytokines are aberrantly produced in many cancers and serve as autocrine growth factors or indicators of immune response to the tumors. Hence, cytokine deregulation is likely to participate in the development or evolution of the malignant process. Over the last few years, we have performed a series of studies, with the objective of measuring cytokine levels in tumors and correlating endogenous levels with phenotypic manifestations of cancer and with prognosis. Here, we present our analysis of serum interleukin 6 (IL-6) levels in lymphomas. We demonstrate that IL-6 levels are elevated in both relapsed and newly diagnosed Hodgkin's and non-Hodgkin's lymphoma and that these levels correlate with established prognostic features. Furthermore, in diffuse large cell lymphoma, IL-6 is an independent prognostic variable for both complete remission and failure-free survival. The molecular mechanisms underlying cytokine deregulation are now being investigated, with preliminary data from our laboratory suggesting heterogeneous genetic driving forces. In some cases, oncogene aberrations, particularly in the RAS system, may be responsible.

Cytokines↗
PubMed1996

Leukemia-inhibitory factor stimulates breast, kidney and prostate cancer cell proliferation by paracrine and autocrine pathways.

Leukemia-inhibitory factor (LIF) is an inflammatory cytokine with pleiotropic activities. LIF was originally described as a differentiation factor of a murine leukemia cell line and was subsequently found to possess a broad spectrum of biological functions. Although LIF has been extensively studied in the hematopoietic system, little is known about its effects in solid tumors. We investigated the role of LIF in breast, kidney and prostate cancers. Using a clonogenic assay, we found that LIF significantly stimulated proliferation of 2 estrogen receptor-positive breast cancer cell lines (MCF-7 and T47-D) in a dose-dependent fashion at concentrations ranging from 10 to 200 ng/ml. This effect was observed both in the presence of FCS and under serum- and estrogen-free culture conditions, suggesting that the effect of LIF is direct and does not depend on estrogen or any other cytokine. Neither line produced LIF protein, as assessed by ELISA. In contrast, the estrogen receptor-negative breast cancer line MDA MB-231 produced LIF but did not respond to either LIF or its neutralizing antibodies. Similarly, increasing concentrations of LIF did not affect the growth of primary kidney (A-498), metastatic kidney (ACHN) and prostate (DU 145) cancer cell lines. These lines produce LIF, however, and antibodies to LIF significantly suppressed their proliferation, suggesting that they were maximally stimulated by the endogenously produced cytokine. Taken together, our data suggest that LIF acts as either a paracrine or an autocrine growth factor for breast, kidney and prostate cancers.

Breast Neoplasms↗
PubMed1996

Alterations in tretinoin pharmacokinetics following administration of liposomal all-trans retinoic acid.

We administered liposome-encapsulated all-trans retinoic acid (L-ATRA) to 48 patients with refractory hematologic malignancies using an every-other-day schedule for 28 days and doses of 15 to 175 mg/m2. In 19 patients, pharmacology studies were conducted after the first (day 1) and seventh (day 15) doses. In contrast to the decline in tretinoin concentration seen within 3 to 4 days of administration of daily oral ATRA, there were no differences between the area under the curve (AUC) of tretinoin concentration versus time on day 1 and day 15 (P = .98, Wilcoxon signed-rank test). Peak day 1 concentrations after 15 mg/m2 were higher than those reported after 45 mg/m2 oral ATRA. Six patients with relapsed acute promyelocytic leukemia (APL) were treated. Three, each in first relapse and at least year from the last exposure to oral ATRA, achieved a complete response (CR). Disease recurred in two (one at 3 months despite maintenance L-ATRA and similarity in tretinoin AUC on days 1 and 85, and the other at 5 months, 2 months after discontinuation of L-ATRA) and the third was transplanted 1 month into CR. The three nonresponders were in at least a second relapse and failed to respond to oral ATRA before or immediately after receiving L-ATRA. Severe toxicity developed in three of eight patients treated at 175 mg/m2 (joint pains in two, skin in one). The maximum tolerated dose (MTD) was determined to be 140 mg/m2, at which dose grade 2 toxicity (primarily headache and skin) occurred in eight of eight patients, but grade 3 to 4 toxicity in none. Compared with oral ATRA, L-ATRA apparently results in greater exposure to tretinoin and for a longer time.

Drug Carriers↗
PubMed1996

Role of granulocyte-macrophage colony-stimulating factor in Philadelphia (Ph1)-positive acute lymphoblastic leukemia: studies on two newly established Ph1-positive acute lymphoblastic leukemia cell lines (Z-119 and Z-181).

Philadelphia chromosome (Ph1)-positive acute lymphoblastic leukemia (ALL) is a malignant disorder characterized by a poor prognosis. In recent years hematopoietic growth factors have been used to recruit myeloid leukemia blasts into the proliferative phase of the cell cycle and as supportive agents, both with cytotoxic regimens and in the setting of bone marrow transplantation. This approach prompted us to investigate whether myeloid growth factors have a role in Ph1 positive ALL. To do this, we utilized two newly established Ph1-positive cell lines, Z-119 and Z-181. Both lines have L2 morphology, ultrastructural characteristics of lymphoblasts and typical B-lineage surface markers identical to those observed in the two Ph1-positive ALL patients from whom they were derived. In addition, a single rearranged immunoglobulin heavy-chain gene (JH) band was found in both cell lines by Southern blot analysis, confirming B-cell clonality. Cytogenetic analysis of the two lines revealed t(9;22). Polymerase chain reaction (PCR) amplified cDNA from both Z-119 and Z-181 cells revealed an e1--a2 BCR-ABL junction, and p190BCR-ABL protein was detected in them by the immune complex kinase assay. Both cell lines produce interleukin (IL)-1 beta, granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage CSF (GM-CSF), but neither IL-1 beta, G-CSF, their corresponding antibodies and inhibitory molecules, nor GM-CSF, affected the cell lines' growth. However, GM-CSF neutralizing antibodies inhibited Z-181 but not Z-119 colony formation in a dose-dependent fashion by up to 77% and addition of GM-SCF reversed this inhibitory effect. Receptor studies with radiolabeled GM-CSF demonstrated specific binding to Z-181 but not to Z-119 cells, and Scatchard analysis revealed that Z-181 cells express high-affinity GM-CSF receptors. Furthermore, PCR analysis showed that Z-181 but not Z-119 bears the transcript for the GM-CSF receptor. Finally, studies using PH1-positive ALL patients' marrow cells revealed similar data. In 3 of 8 samples we detected significant concentrations of GM-CSF (7.5-13 pg/2 x 10(7) cells) and in 2 of 3 cases GM-CSF significantly stimulated Ph1-positive ALL colony proliferation. These data suggest that Ph1-positive ALL cells may produce GM-CSF, express GM-CSF receptors and thus show a proliferative response to this cytokine.

Adult↗