Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0027947 (neutropenia)
 17,527 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A large study of tumors of low malignant potential confirmed the favorable survival in this group of patients compared to invasive epithelial ovarian tumors. Only 8% of patients died with recurrent disease after surgery. Patients with stage IA borderline tumors with mucinous histology tended to recur later and carried a poorer prognosis than patients with serous histology and similar stage. The group at highest risk for relapse were age greater than 70, stage II or III tumors, and histology other than serous. Long-term survival in this group was less than 75%. This high-risk group of patients should be targeted for innovative adjuvant treatment strategies. This year several well-designed studies with large sample sizes showed DNA ploidy to be an important new independent prognostic factor in stage I ovarian carcinoma. In patients with well-differentiated early stage ovarian cancer, DNA flow cytometric analysis may indicate subgroups with less favorable prognostic characteristics. This method of analysis may be beneficial in determining the need for additional treatments after surgery for early stage ovarian carcinoma. Recommendations for the definitive management of early stage ovarian cancer awaits completion of current GOG and European randomized prospective studies. Paclitaxel given in combination with platinum-containing agents is an intense area of research for treatment of advanced stage disease. Early data from a prospective randomized trial of patients with advanced ovarian cancer showed a higher response rate and longer disease-free survival in patients treated with paclitaxel and cisplatin compared to a standard regimen of cyclophosphamide and cisplatin. The impact of this treatment on long-term survival awaits maturation of data. Preliminary results evaluating G-CSF in combination with paclitaxel and cisplatin for dose escalation was reported. Paclitaxel, 250 mg/m2, and cisplatin, 75 mg/m2, were the maximally tolerated doses, with peripheral neuropathy or myalgias the dose limiting toxicities. Further studies are now underway to test the effect of dose-response with escalation therapies and to determine the optimal dose and schedule for the management of patients with advanced ovarian cancer. IL-3 significantly ameliorated neutropenia but did not prevent cumulative platelet toxicity in a regimen utilizing high-dose carboplatin. This mild improvement in myelosuppression was obtained at the cost of significant toxicity. Nausea, vomiting, malaise, bone pain, headache, fever, chills and facial flushing were frequent. Intraperitoneal chemotherapy was tested as a means of consolidation treatment for patients after having a negative second-look laparotomy. These treatments were shown to be feasible; however, prospective randomized trials will be necessary to determine a benefit over operative therapy alone. Several studies addressed to problem of residual disease after primary surgery and adjuvant chemotherapy. A large phase II study conducted by the GOG confirmed the activity of salvage cisplatin-based intraperitoneal chemotherapy in patients with small-volume residual ovarian cancer with favorable pretreatment characteristics. Whether intraperitoneal platinum-based therapy represents an advantage over systemic platinum therapy is being addressed in a prospective SWOG study. The use of six additional cycles of CAP for treatment of residual disease after primary treatment of surgery and adjuvant chemotherapy did not significantly improve complete pathological response and survival. Prolonged duration of chemotherapy above six cycles is not likely to impact treatment for residual disease. A regimen of high dose carboplatin was compared to whole abdominal radiotherapy for treatment of residual disease after initial chemotherapy. There was no difference in survival or disease-free survival between treatments.(ABSTRACT TRUNCATED)
 ...
PMID:Gynecological malignancies. 863 1

Studies were carried out to determine whether the combination of IL-1 + M-CSF, similar to the effect of these cytokines on neutropenia, was able to reduce the duration of thrombocytopenia in the 5-fluorouracil (5-FU)-myelosuppressed mouse. In addition, comparisons were made between the in vivo effects of IL-1 + M-CSF and other "thrombopoietic" cytokines (e.g., IL-3, IL-6, and GM-CSF) that demonstrate some form of megakaryocytopoietic activity in vitro. Of the five cytokines studied, only IL-1 and IL-6, by themselves, were able to effect thrombopoietic recovery in the myelosuppressed mouse. IL-1, either when acting alone or interacting synergistically with M-CSF, was able to reduce significantly the period of thrombocytopenia, but the effects of IL-6 were restricted to enhancing platelet production during the period of rebound thrombocytopenia without altering the kinetics of thrombopoietic recovery. Moreover, none of the cytokine combinations studied were found to interact to reduce further the duration of thrombocytopenia beyond that observed with IL-1 + M-CSF. Nonetheless, IL-3, IL-6, and, to a lesser extent, GM-CSF were each able to interact with IL-1 + M-CSF to extend further the period of enhanced platelet production in the animal. However, scheduling studies suggested that these thrombopoietic cytokines interacted in sequence, rather than in concert, with IL-1 + M-CSF to enhance platelet production during thrombopoietic recovery. Furthermore, the data presented are consistent with the hypothesis that IL-1 + M-CSF initially acts on a multilineage, 5-FU-resistant target cell and that IL-6 (and possibly IL-3 and GM-CSF) serves as a secondary cytokine further to enhance platelet production during rebound thrombopoiesis in the 5-FU-treated mouse.
 ...
PMID:Enhanced platelet recovery in myelosuppressed mice treated with interleukin-1 and macrophage colony-stimulating factor: potential interactions with cytokines having megakaryocyte colony-stimulating activity. 869 40

Recombinant human interleukin 3 (rhIL-3) has been suggested to be a useful agent for the treatment of chemotherapy-induced thrombocytopenia. For evaluation of this possibility, rhIL-3 was given subcutaneously for 10 days to patients with small-cell lung cancer (SCLC). Chemotherapy consisted of carboplatin (CBDCA) given at 400 mg/m2 to previously untreated patients or at 350 mg/m2 to previously treated patients on day 1 and etoposide (VP-16) given at 100 mg/m2 on days 1-3 every 4 weeks. If the platelet count nadir was < 75,000/microliters in the control cycle of chemotherapy, patients were randomly assigned for the next cycle to rhIL-3 given at 5 or 10 micrograms/kg per day on days 4-13. A total of 41 patients (32 previously untreated patients and 9 previously treated patients) were enrolled in the study. The platelet count nadir in the cycles including rhIL-3 was significantly higher at both dose levels (P < 0.01) than in the control cycle. The duration of thrombocytopenia (< 75,000/microliters) and the mean time from the 1st day of chemotherapy to thrombocyte recovery (> 100,000/microliters) in the rhIL-3 cycle were significantly shorter than those in the control cycle (P < 0.01). The neutrophil count nadir and the duration of neutropenia (<1,000/microliters) were also significantly improved in the rhIL-3 cycle (P < 0.05). The major side effects were fever (80.5%), headache (24.3%), and fatigue (14.6%). All side effects were tolerable and of less than grade II. There was no difference in the efficacy of the two dose levels, but the 5-micrograms/kg dose appeared to be better tolerated than the 10-micrograms/ kg dose. We conclude that rhIL-3 administration following chemotherapy consisting of CBDCA and VP-16 reduces the incidence and severity of chemotherapy-induced thrombocytopenia and neutropenia with an acceptable adverse-events profile.
 ...
PMID:Phase II study of recombinant human interleukin 3 administration following carboplatin and etoposide chemotherapy in small-cell lung cancer patients. SDZ ILE 964 (IL-3) Study. 876 25

The tolerability and efficacy of four courses of paclitaxel and ifosfamide plus cisplatin every 3 weeks was evaluated in patients with residual or refractory ovarian cancer. Additionally, supportive haematological effects of recombinant human interleukin 3 (rhIL-3) and recombinant human granulocyte colony-stimulating factor (G-CSF) were studied. Paclitaxel starting dose was 135 mg m(-2) (day 1), with ifosfamide dose 1.2 g m(-2) day(-1) (days 2-4) and cisplatin dose 30 mg m(-2) day(-1) (days 2-4). All 16 patients received 5.0 microg kg(-1) day(-1) G-CSF (days 7-16) and, in addition, eight patients were randomized to receive 10 microg kg(-1) day(-1) rhIL-3 (days 5-9). Paclitaxel and ifosfamide doses were reduced when grade IV haematological toxicity occurred. In the absence of grade IV haematological toxicity and normal recovery of haematopoiesis, paclitaxel dose was escalated. Toxicity was evaluable in 56 courses, with haematological effects in 52. Despite antiemetic treatment, nausea and vomiting (> or = grade I) occurred in 50 courses. Five patients had persisting peripheral neuropathy. Renal and liver function were not affected. Grade IV neutropenia occurred in 12 out of 52 courses, with neutropenic fever in two patients, both of whom died from fatal septicaemia. Grade IV thrombocytopenia without bleeding was observed in 15 courses. Grade IV haematological toxicity was associated with hepatic metastases and concurrent increases in alkaline phosphatase (P <0.001) and gamma-glutamyltransferase (P=0.007). No relation was found between haematological toxicity and pharmacokinetic parameters of paclitaxel. Patients treated with rhIL-3 showed a tendency to a faster platelet recovery (not affecting platelet nadir), and the cisplatin dose intensity was higher (P=0.025). Six of the nine evaluable patients had a tumour response. The overall median progression-free survival was 7 months and the overall mean survival was 13 months. In conclusion, this potentially interesting combination as second-line treatment showed a low tolerability with unexpected mortality, while rhIL-3 administration tended to induce a more rapid platelet recovery.
 ...
PMID:Paclitaxel, ifosfamide and cisplatin with granulocyte colony-stimulating factor or recombinant human interleukin 3 and granulocyte colony-stimulating factor in ovarian cancer: a feasibility study. 904 28

The goal of our study was to identify cytokine combinations that would result in simultaneous ex vivo expansion of both the megakaryocyte (Mk) and granulocyte lineages, since these cell types have the potential to reduce the periods of thrombocytopenia and neutropenia following chemotherapy. We investigated the effects of cytokine combinations on expansion of the Mk (CD41a+ cells and colony forming unit [CFU]-Mk) and granulocyte (CD15+ cells and CFU-granulocyte/monocyte [GM]) lineages. Peripheral blood CD34+ cells were cultured in serum-free medium with interleukin 3 (IL-3), stem cell factor (SCF), and various combinations of thrombopoietin (TPO), IL-6, GM-CSF, and/or G-CSF. The Mk lineage was primarily influenced by TPO in our cultures, although Mk and CFU-Mk numbers were increased when TPO was combined with IL-6. The primary stimulator of the granulocyte lineage was G-CSF, although many synergistic and additive effects were observed with addition of other factors. Expansion of CFU-GM increased upon addition of more cytokines. The cytokine combination of IL-3, SCF, TPO, IL-6, GM-CSF and G-CSF produced the greatest number of granulocytes and CFU-GM. The minimum cytokines necessary for expansion of both the Mk and granulocyte lineages included TPO and G-CSF, since no other factors examined could increase Mk and granulocyte numbers to the same extent. The number of hematopoietic progenitors produced in our culture system should be sufficient for successful engraftment following myelosuppressive therapy if produced on a scale of about one liter.
 ...
PMID:Evaluation of cytokines for expansion of the megakaryocyte and granulocyte lineages. 917 Feb 11

A major potential application for ex vivo culture of hematopoietic progenitor cells is the treatment of cytopenia following high-dose chemotherapy and hematopoietic transplantation. We have previously postulated that infusion of a sufficient number of neutrophil postprogenitor cells generated by ex vivo culture of CD34+ cells may be able to abrogate neutropenia. In this article, we describe further development of an efficient stromal-free, cytokine-dependent, static culture system for generation of these cells. Our previous studies indicated that maximal production of nucleated cells and myeloid progenitor cells from PB CD34+ cells occurred with multiple hematopoietic growth factor (HGF), notably the 6-HGF combination of interleukin (IL)-1, IL-3, IL-6, granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage-CSF (GM-CSF), and stem cell factor (SCF). In the present study, we determine the contribution of each of these 6 HGF in generation of neutrophilic precursors. SCF, G-CSF, and IL-3 were found to be the most important HGF for production of neutrophilic cells. The 4-HGF combination of IL-3, IL-6, G-CSF, and SCF was optimized by performing dose-response experiments and shown to be as potent as 6 HGF for production of nascent CFU-GM and neutrophilic precursors.
 ...
PMID:Ex vivo culture of peripheral blood CD34+ cells: effects of hematopoietic growth factors on production of neutrophilic precursors. 936 84

Ten pediatric patients with solid tumors and chemotherapy-induced neutropenia were given recombinant human granulocyte-macrophage colony-stimulating factor (rHuGM CSF). The duration of the neutropenic phase was then compared with the results obtained from eight patients also with solid tumors, but not treated with rHuGM-CSF. It was found that rHuGM-CSF treatment significantly decreased the duration of the neutropenic phase. Endogenous plasma GM-CSF, IL-3, and IL-4 levels were also measured in the study group and in healthy children. No significant correlation has been found between plasma GM-CSF concentrations and absolute neutrophil counts. However, IL-3 levels of the neutropenic patients positively correlated with platelet counts. Furthermore, IL-4 concentrations were positively correlated with the GM-CSF level in the same individual. Plasma GM-CSF, IL-3, and IL-4 levels in the neutropenic solid tumor group were found to be significantly higher than those in healthy children. Plasma IL-4 levels were significantly elevated in patients with osteosarcoma as compared to patients with other solid tumors. Although rHuGM-CSF has a half-life of only two to three hours, one day after rHuGM-CSF therapy, plasma GM-CSF levels were found to be higher than initial values. In contrast, plasma IL-4 values decreased significantly after administration of rHuGM-CSF. The probable mechanisms for the changes in cytokine levels are discussed.
 ...
PMID:Recombinant human granulocyte-macrophage colony-stimulating factor therapy and endogenous plasma GM-CSF, IL-3, IL-4 concentrations in pediatric patients with solid tumors. 943 49

Ex vivo expanded CD34+ progenitor cells from fresh or cryopreserved primate bone marrow, induced to granulocytic differentiation with growth factors, were investigated to determine whether myeloid cells produced in liquid cultures have the normal biologic functions needed for the treatment of patients with neutropenia following high-dose chemotherapy or therapeutic or accidental radiation exposure. Human and simian (baboons or macaques) CD34+ cells were cultured with granulocyte-colony stimulating factor (G-CSF), stem cell factor (SCF), interleukin-1 (IL-1), IL-3, and IL-6, and assessed at 14 days of culture for their capacity to respond to different functional tests. Immunostaining revealed that human ex vivo expanded cells contained myeloperoxydase (MPO, 82% +/- 8%) and lactoferrin (LF, 30% +/- 6%) in their granules. Maturation of cultured cells was associated with stimulated chemotactic responsiveness and respiratory burst activity (superoxide anion and hydrogen peroxide production) in expansions from human, baboon, and macaque CD34+ progenitor cells. Mature cells obtained from ex vivo expansion of selected cryopreserved human bone marrow CD34+ cells presented reduced but significant functional activities (chemotactic responsiveness and hydrogen peroxide production) when compared with human peripheral blood neutrophils. The validation of nonhuman primate ex vivo expansion systems may permit their use as models of irradiation. The feasibility of ex vivo expansion from cryopreserved bone marrow cell samples may offer considerable opportunity for banking bone marrow for autologous transfusion.
 ...
PMID:Functional studies of maturing myeloid cells during ex vivo expansion for treatment of aplasia: feasibility of ex vivo expansion from cryopreserved bone marrow cell samples. 950 83

Recombinant human interleukin 3 (rhIL-3, expressed in Escherichia coli) is a hematopoietic growth factor with protean biological effects on bone marrow in animal models, including enhanced granulocyte and platelet production and the capacity to ameliorate chemotherapy-induced bone marrow toxicity. We, therefore, undertook a Phase I trial in patients with advanced solid tumors and normal bone marrow function. Cohorts of four to six patients each received daily s.c. doses of rhIL-3 (SDZ-ILE-964; Sandoz) at dose levels of 1. 0, 2.5, 5.0, and 10.0 microgram/kg according to the following schedule: cycle 1, rhIL-3 days 1-14; cycle 2, carboplatin (350 mg/m2) on day 1 and etoposide (100 mg/m2) on days 1-3; and cycle 3, carboplatin (350 mg/m2) on day 1, etoposide (100 mg/m2) on days 1-3, and rhIL-3 on days 4-17. Each cycle was a total of 28 days. An analysis of 20 patients entered into all four escalating dose levels revealed that, during cycle 1, absolute neutrophil count (ANC) increased from a median baseline of 6,643/mm3 to a median of 12,692/mm3, and platelets increased from a median baseline of 314,000/mm3 to a median of 465,000/mm3. When cycle 2 was compared with cycle 3, the median ANC nadir increased from 192/mm3 to 988/mm3, and the mean ANC nadir increased from 458/mm3 to 1,297/mm3. Median platelet count nadirs increased from 29,000/mm3 to 84,000/mm3, and the mean nadir platelet counts increased from 72,000/mm3 to 129,000/mm3. Total days on which platelets were <50,000/mm3 was 52 for cycle 2 and 19 for cycle 3. The maximum tolerated dose of rhIL-3 was 5.0 microgram/kg/day; dose-limiting toxicities included fatigue, chills, fever, and headache. These data suggest a clear but variable biological activity observed with IL-3, as measured by the reduction in the depth and duration of thrombocytopenia and/or neutropenia when cycle 2 was compared with cycle 3. rhIL-3 is a promising cytokine that may help to ameliorate the bone marrow toxicity observed with the use of chemotherapeutic agents.
 ...
PMID:Phase I trial of recombinant interleukin 3 before and after carboplatin/etoposide chemotherapy in patients with solid tumors: a southwest oncology group study. 981 5

Betafectin PGG-glucan is a novel beta-(1,3)glucan that has broad-spectrum anti-infective activities without cytokine induction. Here we report that PGG-glucan also has both in vitro and in vivo hematopoietic activities. In vitro studies with bone marrow target cells from the C3H/HeN mouse revealed that although PGG-glucan alone had no direct effect on hematopoietic colony-forming cell (CFC) growth, when combined with granulocyte colony-stimulating factor (CSF) or granulocyte-macrophage CSF, it increased CFC numbers 1.5- to 2.0-fold over those obtained with CSFs alone. Bone marrow cells cultured for high-proliferative-potential CFCs in the presence of interleukin (IL)-1, IL-3, macrophage CSF, and stem cell factor (SCF), or cultured for erythroid burst-forming units in the presence of IL-3, SCF, and erythropoietin, also exhibited enhanced growth in the presence of PGG-glucan. The synergistic effect of PGG-glucan was specific and could be abrogated by anti-PGG-glucan antibody. The ability of PGG-glucan to modulate hematopoiesis in vivo was evaluated in myelosuppressed rodents and primates. C3H/HeN female mice were intravenously administered saline solution or PGG-glucan (0.5 mg/kg) 24 hours before the intraperitoneal administration of cyclophosphamide (200 mg/kg), and the recovery of bone marrow cellularity and granulocyte-macrophage progenitor cells was evaluated on days 4 and 8 after cyclophosphamide treatment. At both time points, enhanced hematopoietic recovery was observed in PGG-glucan-treated mice compared with saline-treated control mice. In a final series of in vivo experiments, we evaluated the ability of therapeutically administered PGG-glucan to enhance hematopoietic recovery in cyclophosphamide-treated cynomolgus monkeys. Monkeys received intravenous infusions of cyclophosphamide (55 mg/kg) on days 1 and 2, followed on days 3 and 10 by intravenous infusion of PGG-glucan (0.5, 1.0, or 2.0 mg/kg). Compared with those in saline-treated monkeys, accelerated white blood cell recovery and a reduction in the median duration of neutropenia were observed in PGG-glucan-treated monkeys. These studies illustrate that PGG-glucan has both in vitro and in vivo hematopoietic activities and that this agent may be useful in the prevention and/or treatment of chemotherapy-associated myelosuppression.
 ...
PMID:In vitro and in vivo hematopoietic activities of Betafectin PGG-glucan. 984 81


<< Previous 1 2 3 4 5 6 Next >>