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Biomedical subjects

R Kurzrock

Publications and source records attributed to R Kurzrock.

At least 73 records · Page 4Linked to original sources
PubMed1996

Combined modality therapy for cutaneous T-cell lymphoma.

BACKGROUND: Cutaneous T-cell lymphoma (CTCL) may respond to many therapies, but long-term disease-free survival is uncommon. Patients with advanced disease have a median survival of approximately 3 years. OBJECTIVE: Our purpose was to combine known effective agents sequentially to determine whether we could achieve remission in more patients or for longer duration. METHODS: Patients with mycosis fungoides (n = 23) or Sézary syndrome (n = 5) were treated with 4 months of recombinant interferon alfa together with isotretinoin, followed by total skin electron beam therapy alone (for stage I to II disease) or preceded by chemotherapy (for stage III to IV disease). Maintenance therapy consisted of interferon for 1 year and topical nitrogen mustard for 2 years. RESULTS: Twenty-eight patients were treated. The overall response rate (complete and partial remissions) was 82%. Although the median duration of remission was 5 months in patients with stage III to IV disease, two patients remain in complete remission at 39 + and 46 + months. In patients with stage I to II disease the median duration of remission has not been reached at a median follow-up of 18 months. Five patients, all with stage III to IV disease, have died. Overall, the regimen was well tolerated with one treatment-related death from neutropenic sepsis. CONCLUSION: Combined modality therapy may be effective for the treatment of CTCL with similar response rates to other current therapies.

Administration, Cutaneous↗
PubMed1996

Molecular and biologic characterization of a newly established Philadelphia-positive acute lymphoblastic leukemia cell line (Z-33) with an autocrine response to GM-CSF.

We have recently established a new Philadelphia chromosome (Ph1)-positive acute lymphoblastic leukemia (ALL) cell line, designated Z-33. This line has L2 morphology, ultrastructural characteristics of lymphoblasts and typical B lineage surface markers identical to those observed in the Ph1-positive ALL patient from whom the line was derived. In addition, a rearranged immunoglobulin heavy-chain gene (JH) band was found in Z-33 cells by Southern blot analysis, confirming B cell clonality. Cytogenetic analysis of the cell line revealed t(9;22)(q34;q11.2). Polymerase chain reaction (PCR)-amplified cDNA from Z-33 cells demonstrated an e1-az BCR-ABL junction, and the p190BCR-ABL protein was detected in them by the immune complex kinase assay. Z-33 cells produce interleukin (IL)-1 beta, IL-6, granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage CSF (GM-CSF), tumor necrosis factor (TNF)-alpha, and transforming growth factor (TGF)-beta, Neither IL-1 beta, G-CSF, TNF-alpha, nor their corresponding antibodies affected the cell line's growth. In contrast, anti-GM-CSF neutralizing antibodies suppressed Z-33 colony formation, and GM-CSF stimulated it in a dose-dependent fashion. In addition, receptor studies with biotinylated GM-CSF demonstrated specific binding to Z-33 cells, indicating that the cells express GM-CSF receptors. Taken together, our data suggest that the Ph1-positive Z-33 ALL cells produce GM-CSF, express GM-CSF receptors, and show an autocrine proliferative response to this cytokine.

Antibodies↗
PubMed1995

Transformation of chronic lymphocytic leukemia to lymphoma of true histiocytic type.

BACKGROUND: Chronic lymphocytic leukemia (CLL) may evolve into large cell lymphoma (Richter's syndrome), prolymphocytic leukemia, acute lymphoblastic leukemia, and myeloma. METHODS: A patient with CLL that transformed into a lymphoma of true histiocytic type is described, and the literature on the association of these two disorders is reviewed. RESULTS: Lymphomas of true histiocytic type developing as an aggressive terminal phase of CLL previously have been reported in nine patients. Fever and rapidly increasing lymphadenopathy and splenomegaly were the most common signs and symptoms. As with de novo lymphoma of true histiocytic type, extranodal involvement of the soft tissue, gastrointestinal tract, kidneys, bone marrow, liver, and lungs was documented among the 10 patients with lymphoma of true histiocytic type transformed from CLL. The median interval between diagnosis of CLL and the evolution to lymphoma of true histiocytic type was 25.5 months. Patients with lymphomas of true histiocytic type after CLL were treated with fludarabine and various other combination chemotherapy regimens with only short-lived responses. The median time to death after transformation was only 33 days (range, 10 days to 5 months). CONCLUSION: Lymphomas of true histiocytic type appear to represent an additional, though uncommon, form of transformation in CLL. Although their presentation is reminiscent of other intermediate to high grade lymphomas, they can be distinguished based on their morphologic and immunophenotypic features. In the patients described in this study to date, transformation of CLL to lymphomas of true histiocytic type is a poor prognostic sign, with survival generally of only days to weeks.

Bone Marrow↗
PubMed1995

Serum levels of interleukin-10 in patients with diffuse large cell lymphoma: lack of correlation with prognosis.

Interleukin-10 (IL-10), also known as cytokine synthesis inhibitory factor, has multiple effects on lymphoid development. In addition, it has been previously reported that serum levels of IL-10 correlate with failure-free and overall survival in patients with non-Hodgkin's lymphoma. In this study, we used a sensitive enzyme-linked immunosorbent assay specific for human IL-10 (lower limit of sensitivity, 5 pg/mL) to measure serum levels in 52 newly diagnosed patients with diffuse large cell lymphoma and at least one adverse prognostic feature who were subsequently treated in a uniform way. Lymphoma patients had significantly higher serum levels of IL-10 (median, 7.98 pg/mL; range, < or = 5 to 27,143 pg/mL) than healthy volunteers (N = 50; median, < or = 5 pg/mL; range, < or = 5 to 19.21 pg/mL) (P = .0000012). Individuals with B symptoms had significantly higher serum levels of IL-10 than those without them (P = .03), but there was no correlation between IL-10 levels and any of the other prognostic variables analyzed, including age, lactic dehydrogenase, beta 2-microglobulin levels, performance status, bulky disease, Ann Arbor stage, or International Index score. More importantly, we found no correlation between IL-10 levels and the achievement of complete remission, nor with failure-free survival or overall survival. We conclude that in a uniform population of untreated patients with diffuse large cell lymphoma, serum levels of IL-10 do not appear to have any prognostic value.

Adult↗
PubMed1995

Cell cycle-related shifts in subcellular localization of BCR: association with mitotic chromosomes and with heterochromatin.

The disruption of the BCR gene and its juxtaposition to and consequent activation of the ABL gene has been implicated as the critical molecular defect in Philadelphia chromosome-positive leukemias. The normal BCR protein is a multifunctional molecule with domains that suggest its participation in phosphokinase and GTP-binding pathways. Taken together with its localization to the cytoplasm of uncycled cells, it is therefore presumed to be involved in cytoplasmic signaling. By performing a double aphidicolin block for cell cycle synchronization, we currently demonstrate that the subcellular localization of BCR shifts from being largely cytoplasmic in interphase cells to being predominantly perichromosomal in mitosis. Furthermore, with the use of immunogold labeling and electron microscopy, association of BCR with DNA, in particular heterochromatin, can be demonstrated even in quiescent cells. Results were similar in cell lines of lymphoid or myeloid origin. These observations suggest a role for BCR in the phosphokinase interactions linked to condensed chromatin, a network previously implicated in cell cycle regulation.

Cell Compartmentation↗
PubMed1995

Abnormalities in the PRAD1 (CYCLIN D1/BCL-1) oncogene are frequent in cervical and vulvar squamous cell carcinoma cell lines.

BACKGROUND: CYCLIN D1, a cell-cycle control gene, recently has been shown to be identical to an oncogene alternatively known as BCL-1 and PRAD1 and implicated in centrocytic lymphomas and parathyroid adenomas, respectively. PRAD1 complexes to the product of the retinoblastoma (Rb) tumor suppressor gene, an event followed by Rb inactivation. Squamous cell carcinomas of the cervix and vulva are gynecologic tumors in which human papillomaviruses have been implicated as an initiating event, and proteins derived from these viruses also complex with an inactivate Rb. Because of the overlap in some of the molecular processes mediated by human papillomaviruses and by the PRAD1 oncogene, the authors analyzed the PRAD1 (CYCLIN D1/BCL-1) genomic structure and expression in vulvar and cervical squamous cell carcinoma cell lines. METHODS: PRAD1 DNA and PRAD1 mRNA expression were assessed by Southern and Northern blotting, respectively, in 13 squamous cell carcinoma cell lines of gynecologic origin (10, cervical cancer; 3, vulvar cancer). RESULTS: We found low baseline levels of a 4.5-kb PRAD1 transcript in a series of control cell lines, which were derived from normal fibroblasts, various hematologic malignancies, and a choriocarcinoma. PRAD1 mRNA overexpression (> or = 10-fold greater than that in control lines) was seen in all three vulvar carcinoma cell lines, two of which also showed amplification (5-fold and > 10-fold) of PRAD1 genomic sequences. Abnormalities of PRAD1 also were seen in 4 of the 10 cervical cancer cell lines and included overexpression of PRAD1 transcripts (3-9-fold) in 3 lines and rearrangement of PRAD1 DNA in an additional line that, however, did not shown any aberration in PRAD1 mRNA as discernible by Northern blotting. PRAD1 abnormalities were observed in three of the four cervical cell lines derived from metastatic sites and in one of the six cervical lines derived from primary tissue. CONCLUSIONS: Seven of 13 squamous cell lines of gynecologic origin showed abnormalities of PRAD1. These abnormalities included amplification and rearrangement of DNA and overexpression of mRNA. The role of PRAD1 as a cell-cycle regulatory gene and its interactions with the Rb tumor suppressor gene suggests that PRAD1 deregulation may be a significant molecular event in the evolution of these tumors.

Blotting, Northern↗
PubMed1995

Interleukin-1 and its inhibitors: implications for disease biology and therapy.

IL-1 alpha and IL-1 beta are polypeptide hormones that exhibit a broad spectrum of beneficial and harmful biologic activities. Clinical trials designed to benefit from its stimulatory effects on human hematopoiesis and from its role in improving host defenses, are being currently conducted. Other in vivo studies, using IL-1 inhibitors with an attempts to block the detrimental effects of IL-1, are underway. Because of the multifunctional effects of IL-1 in human physiology and its pathogenetic role in several diseases, the capability to control the effects of IL-1 may prove to be a useful tool in medical practice.

Animals↗
PubMed1995

Cytokine expression in adherent layers from patients with myelodysplastic syndrome and acute myelogenous leukemia.

We have previously shown that long-term cultures of adherent layers derived from patients with chronic myelogenous leukemia in blast crisis express high levels of interleukin (IL)-1 beta and that this cytokine may participate in disease progression. In this study, we analyzed cytokine expression in bone marrow adherent layers derived from patients with myelodysplastic syndrome (MDS) and acute myelogenous leukemia (AML). IL-6 messenger RNA (mRNA) was expressed in adherent layers established from four of nine MDS patients, and from 10 of 17 AML patients (including all four individuals in whom AML had evolved from an antecedent MDS state). Similarly, IL-1 beta mRNA was expressed in adherent layers derived from two of nine MDS patients and from three of 17 AML patients. Cultures from two of 10 AML patients who expressed IL-6 also expressed granulocyte (G) colony-stimulating factor (CSF) mRNA. In contrast, IL-1 beta, IL-6, and G-CSF mRNA were not discernible in adherent layers from any of 14 normal volunteers. Transforming growth factor-beta 1, macrophage (M) CSF, IL-7, and leukemia inhibitory factor mRNA as well as IL-6 protein were constitutively expressed in adherent layers derived from both MDS patients, AML patients, and normal bone marrows, whereas IL-1 alpha, tumor necrosis factor-alpha, and GM-CSF were not expressed in either the normal-, MDS- or AML-derived adherent layers. These results indicate that cultured stroma from a subset of MDS and AML patients produce IL-1 beta and/or IL-6. Although, exposure of adherent layers to exogenous IL-1 beta was able to induce IL-6 expression, in 9 of the 14 samples constitutively expressing cytokines, IL-6 transcript levels were elevated without a concomitant increase in IL-1 beta, suggesting that IL-6 transcription was independently dysregulated.

Adolescent↗
PubMed1995

Elevated plasma thrombopoietic activity in patients with metastatic cancer-related thrombocytosis.

BACKGROUND AND PURPOSE: High platelet counts are occasionally seen in patients suffering from progressive malignant disorders. While granulocyte colony-stimulating factor (G-CSF) has been implicated in paraneoplastic leukemoid reactions, the stimulus for thrombocytosis is unknown. Our purpose in this study was to determine if plasma from cancer patients with thrombocytosis contains a factor or factors with thrombopoietic activity. METHODS: We tested the effects of plasma obtained from 5 individuals with advanced tumors and high platelet counts and from 4 patients with advanced cancer and normal platelet counts on megakaryocytic differentiation of two megakaryoblastic cell lines (Dami and HEL). Differentiation was evaluated by assessing the expression of the platelet-specific cell-surface antigens CD41 (HUPL-mI) and glycoprotein IIb-IIIa using an immunocytochemical staining score. In addition, plasma samples from 7 of the 9 patients and from 5 additional cancer patients with thrombocytosis were assayed for the levels of interleukin (IL)-3, IL-6, granulocyte-macrophage colony-stimulating factor (GM-CSF), G-CSF, and IL-1 beta protein using an enzyme-linked immunosorbent assay (ELISA). RESULTS: Expression of platelet-specific cell-surface antigen was increased in HEL cells after exposure to plasma from all 5 of the cancer patients with thrombocytosis, and in Dami cells after exposure to plasma from 4 of the 5. Similar, but less significant, results were found when these cells were incubated with control combinations of recombinant GM-CSF plus IL-6 or of IL-3 plus IL-6. Platelet-specific cell-surface-antigen expression was not increased in HEL or Dami cells after exposure to the plasma from the 4 cancer patients with normal platelet counts or to normal control plasma. ELISA revealed elevated levels of IL-6 in the plasma from 4 patients with thrombocytosis (38, 40, 63, and 99 pg/mL). In addition, GM-CSF concentration was high in 3 of these 4 patients (33, 47, and 127 pg/mL), and the G-CSF level was elevated in 1 (543 pg/mL). IL-1 beta and IL-3 levels were undetectable. CONCLUSIONS: Our data suggest that the thrombocytosis observed in individuals with advanced malignant disease is mediated by a humoral mechanism. Levels of IL-6, GM-CSF, and G-CSF are elevated in some of these patients, but the plasma concentrations are generally lower than those required for in vitro induction of megakaryocytic differentiation. Plasma from patients with paraneoplastic thrombocytosis may therefore contain thrombopoietins that have not yet been identified, and which might have clinical usefulness.

Adult↗
PubMed1995

Mucocutaneous paraneoplastic manifestations of hematologic malignancies.

PURPOSE: To review the clinical manifestations, pathophysiology, and oncologic implications of the major mucocutaneous paraneoplastic syndromes that can appear in patients with hematologic malignancies. METHODS: A comprehensive search of the medical literature was conducted. RESULTS: In vesiculobullous conditions, although the primary lesions are blisters, observed abnormalities may include large, flaccid bullae (pemphigus vulgaris), superficial crusted erosions (pemphigus foliaceus), or erythema multiforme-like lesions (paraneoplastic pemphigus). Paraneoplastic neutrophilic dermatoses include Sweet's syndrome and pyoderma gangrenosum. In both of these conditions, the skin lesions are characterized by a dermal infiltrate of mature neutrophils. Vascular dermatoses include vasculitis and erythromelagia. Papulosquamous conditions are characterized by small (papules) or large (plaques) raised skin lesions and are usually associated with solid tumors. Amyloidosis is a malignancy-related condition that probably stems from immune dysregulation. RECOMMENDATIONS: Continued surveillance of patients with potential cutaneous paraneoplastic syndromes is necessary, since the malignancy may not be immediately detectable. Some of the cutaneous paraneoplastic syndromes will respond to specific measures, such as systemic corticosteroid therapy, but for the most part, successful resolution requires eradication of the underlying malignancy.

Hematologic Diseases↗
PubMed1995

Interferon-alpha therapy for chronic myelogenous leukemia.

PURPOSE: To provide a status report on the use of interferon (IFN)-alpha in patients with chronic myelogenous leukemia (CML). DATA SOURCES: Data on IFN-alpha therapy for CML collected from published articles identified in a MEDLINE computer search. RESULTS: Previously untreated patients with low-risk factors and early-stage disease consistently had the best results in clinical trials. A dose response was seen, with patients treated with dosages of 5 million units (MU)/m2 per day showing the greatest incidence of cytogenetic remissions. In addition, randomized trials showed a survival advantage for IFN-alpha-treated patients. In studies comparing IFN-alpha therapy to chemotherapy, IFN-alpha produced significantly more major and durable cytogenetic responses than chemotherapy did. In studies combining IFN-alpha and chemotherapy, patients had significantly more cytogenetic responses, although more patient accrual and follow-up data are needed to offer conclusive statements concerning durability of response. IFN-alpha also showed activity in maintaining remissions after both chemotherapy and bone marrow transplantation. CONCLUSIONS: IFN-alpha has significant activity in patients with CML, with best results at dosages of 5 MU/m2 per day. At these dosages, in patients with early-stage, Philadelphia+ CML, hematologic response rates of 70% to 80% and cytogenetic response rates of 50% (approximately 20% of which were complete) are seen. One randomized trial shows a survival advantage with cytogenetic response in IFN-alpha-treated patients, and this advantage appears to be unrelated to the degree of that response. These questions remain under study.

Antineoplastic Agents↗
PubMed1995

Cutaneous paraneoplastic syndromes in solid tumors.

OBJECTIVE: To provide an overview of the clinical manifestations, pathophysiology, and oncologic implications of the cutaneous paraneoplastic syndromes that occur predominantly in patients with solid tumors. METHODS: A review was performed of the literature identified by a comprehensive MEDLINE search. RESULTS: Diverse cutaneous paraneoplastic syndromes may be associated with underlying tumors. They include musculoskeletal disorders (clubbing, hypertrophic osteoarthropathy, dermatomyositis, and multicentric reticulohistiocytosis), reactive erythemas (erythema gyratum repens and necrolytic migratory erythema), vascular dermatoses (Trousseau's syndrome), papulosquamous disorders (acanthosis nigricans, tripe palms, palmar hyperkeratosis, acquired ichthyosis, pityriasis rotunda, Bazex's syndrome, florid cutaneous papillomatosis, the sign of Leser-Trélat, and extramammary Paget's disease), and disorders of hair growth (hypertrichosis lanuginosa acquisita). The clinical manifestations of these dermatoses may precede, coincide with, or follow the diagnosis of cancer. The presence of a cutaneous paraneoplastic syndrome is often associated with a poor prognosis. CONCLUSIONS: Cutaneous paraneoplastic syndromes are specific constellations of mucous membrane and/or skin abnormalities that are caused by an underlying tumor. Since they may be the presenting sign of an occult cancer, cognizance of their features and clinical implications are of considerable importance. Individuals with these syndromes should have a thorough workup for an associated malignancy.

Female↗
PubMed1995

Leukemia inhibitory factor binds to human breast cancer cells and stimulates their proliferation.

Leukemia inhibitory factor (LIF) is a cytokine that was originally described as a differentiation factor of a murine myeloid leukemia cell line and subsequently found to be an important mediator of embryonic development. Although extensively studied in the hematopoietic system, its effects on solid tumors are generally unknown. In the present study we investigated the role of LIF in human breast cancer cells. Using the reverse transcriptase-polymerase chain reaction, we found that the human breast carcinoma MCF-7 cell line expressed the message for both LIF receptor and its signal-transducing protein gp130, suggesting that these receptors might be biologically active. Binding studies with radiolabeled LIF demonstrated that MCF-7 cells interacted with this cytokine, and the ligand binding was specific and time, dose, and temperature dependent. In addition, a Scatchard analysis of the data revealed a single class of high-affinity (Kd 0.27 nM) receptors with a density of approximately 430 sites per cell. MCF-7 cells exposed to LIF internalized and degraded the ligand. LIF stimulated the growth of MCF-7 as well as other estrogen-dependent and independent breast cancer cell lines, but the effect on normal breast epithelial lines was less significant. Likewise, it stimulated colony formation by breast cancer cells obtained from five different breast cancer patients in a dose-dependent fashion. These results overall suggest that human breast tumor cells express functional LIF receptors that play a role in breast cancer cell proliferation.

Base Sequence↗
PubMed1995

Serum interleukin-6 levels correlate with prognosis in diffuse large-cell lymphoma.

PURPOSE: 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 outcome of patients with diffuse large-cell lymphoma (DLCL). PATIENTS AND METHODS: Using an enzyme-linked immunosorbent assay (ELISA; lower limit of sensitivity, 0.35 pg/mL), we measured IL-6 levels in frozen sera from 33 healthy controls and 58 untreated patients with DLCL who were enrolled onto a single combination chemotherapy protocol. Serum IL-6 levels were correlated with clinical and laboratory features at diagnosis and with failure-free and overall survival. RESULTS: Serum IL-6 levels in the lymphoma patients (median, 4.37 pg/mL; range, < 0.35 to 110 pg/mL) were significantly higher than in the control group (median, < 0.35 pg/mL; range, < 0.35 to 1.87 pg/mL) (P < .0001). Serum IL-6 levels were higher in patients with B symptoms (P = .012), an elevated beta 2-microglobulin level (> or = 3.0 mg/L) (P = .017), and a poor performance status (P = .02). Direct linear correlations with the erythrocyte sedimentation rate (ESR), platelet count, and total WBC count, and an inverse linear correlation with the serum albumin level, were observed (all P < .02). Patients with elevated serum IL-6 levels had inferior failure-free (P = .042) and overall survival (P = .05) compared with those with normal serum IL-6 levels. CONCLUSION: In patients with DLCL, elevated serum levels of IL-6 at diagnosis are frequent, strongly associated with many adverse disease features, and predictive of a poor failure-free and overall survival.

Adult↗
PubMed1995

Miscellaneous genodermatoses: Beckwith-Wiedemann syndrome, Birt-Hogg-Dube syndrome, familial atypical multiple mole melanoma syndrome, hereditary tylosis, incontinentia pigmenti, and supernumerary nipples.

Beckwith-Wiedemann syndrome, familial atypical multiple mole melanoma syndrome, and hereditary tylosis are bona fide genodermatoses with malignant potential. Each of these conditions is associated with an increased incidence of certain tumors: Wilms' tumor, adrenocortical carcinomas, pancreatoblastomas, and hepatoblastomas in Beckwith-Wiedemann syndrome; intraocular malignant melanoma, pancreatic carcinoma, and noncolorectal gastrointestinal cancers in familial atypical multiple mole melanoma syndrome; and squamous cell carcinoma of the esophagus in hereditary tylosis. Other cancer-related genodermatoses are Birt-Hogg-Dube syndrome (associated with medullary carcinoma of the thyroid and renal cell carcinoma) and its variant, Hornstein-Knickenberg syndrome (associated with colon carcinoma). Kidney tumors (Wilms' tumor and malignant rhabdoid tumor), leukemias (acute myelogenous and acute myelomonocytic), retinoblastoma, and paratesticular rhabdomyosarcoma have been reported recently in children with another genodermatosis-incontinentia pigmenti. Supernumerary nipples (polythelia) may be sporadic or familial in occurrence; their presence has been associated with an increased incidence of renal adenocarcinoma, testicular cancer, prostate cancer, and urinary bladder carcinoma. The general characteristics, mucosal and skin manifestations, and noncutaneous features of all these conditions are reviewed. Also, the associated malignancies of these genodermatoses and other conditions that are characterized by dermatologic manifestations and may be either familial or secondary to an inherited gene defect are summarized.

Adult↗