Prognostic variables for treatment response after HDCT can be identified. The proposed prognostic model might help to optimize the use of HDCT in germ cell tumors and warrants validation in future trials.
Immune thrombocytopenia (ITP) is an autoimmune disorder characterized by platelet destruction and insufficient platelet production. The resulting thrombocytopenia reduces patient health-related quality of life (HRQOL). In a randomized, open-label, 52-week study of nonsplenectomized ITP patients treated with romiplostim or medical standard of care (SOC), patients completed the 10-scale ITP-patient assessment questionnaire (PAQ) at the start of the study and after 12, 24, 36, 48, and 52 weeks of treatment. HRQOL changes were examined for all patients in both treatment groups and by responder status, splenectomy status, and after the use of rituximab. Patients in both groups showed marked increases in all HRQOL scales over 52 weeks of treatment. These change scores exceeded the minimally important difference values (a measure of clinical relevance) for most of these scales, especially in responders to treatment. Compared with baseline, patients receiving romiplostim showed statistically significant improvements compared to SOC over 52 weeks for the ITP-PAQ scales of Symptoms, Bother, Activity, Psychological Health, Fear, Overall QOL, and Social QOL. Overall, treatment of ITP was associated with improvement in HRQOL. Patients receiving romiplostim had greater HRQOL improvements than those receiving SOC, but the magnitude of the difference is of uncertain clinical benefit.Immune thrombocytopenia (ITP) is an autoimmune disorder characterized by persistent thrombocytopenia due to antibody binding to platelet antigen(s) causing their premature destruction by the reticuloendothelial system, particularly in the spleen [1]. In addition, recent evidence suggests that there is also insufficient platelet production, possibly immune-mediated [2]. The resulting thrombocytopenia places patients at risk for bruising and bleeding.Recent international practice guidelines recommend that initial ITP treatment include glucocorticoids, intravenous immunoglobulin (IVIg), or intravenous anti-D. Second-line treatment includes splenectomy or medical therapies such as azathioprine, danazol, rituximab, or the thrombopoietin (TPO) receptor agonists [3,4]. Many of these second-line treatments are associated with significant toxicities or cost [3,4].Romiplostim is a novel TPO receptor agonist that binds to and stimulates the TPO receptor. It has been shown to increase platelet counts with few adverse events [5]. In two randomized studies, an overall platelet response (weekly platelet counts 50 3 10 9 /L during 4 or more weeks of the 24-week study) was achieved by 83% of patients receiving romiplostim versus 7% of patients receiving placebo (P < 0.0001) [6]. In addition, 87% of romiplostim versus 38% of placebo patients were able to reduce or discontinue their concurrent ITP medication, including corticosteroids and IVIg [6]. Continuous long-term (up to 156 weeks) treatment with romiplostim produced a platelet response (platelet counts 50 3 10 9 /L) in 87% of 142 ITP patients [7]. Finally, romiplostim treatment led to fewer bleeding events, tran...
The p21 RAS product has been implicated as part of the downstream signaling of certain nonreceptor tyrosine kinase oncogenes and several growth factor receptor-ligand interactions. We have reported that the chronic myelogenous leukemia oncogene p210 bcr-abl transforms a growth- factor-dependent myeloid cell line NFS/N1.H7 to interleukin-3 (IL-3) independence. In these p210 bcr-abl-transformed cells (H7 bcr-abl.A54) and in two other murine myeloid cell lines transformed to IL-3 independence by p210 bcr-abl, endogenous p21 RAS is activated as determined by an elevated ratio of associated guanosine triphosphate (GTP)/guanosine diphosphate (GDP), assayed by thin-layer chromatography of the nucleotides eluted from p21 RAS after immunoprecipitation with the Y13–259 antibody. Treatment of p210 bcr-abl-transformed cells with a specific tyrosine kinase inhibitor herbimycin A resulted in diminished tyrosine phosphorylation of p210 bcr-abl and associated proteins, without major reduction in expression of the p210 bcr-abl protein itself. Inhibition of p210 bcr-abl-dependent tyrosine phosphorylation resulted in a reduction of active p21RAS-GTP complexes in the transformed cells, in diminished expression of the nuclear early response genes c-jun and c-fos, and in lower cellular proliferation rate. To further implicate p21 RAS in these functional events downstream of p210 bcr-abl tyrosine phosphorylation, we targeted G- protein function directly by limiting the availability of GTP with the inosine monophosphate dehydrogenase inhibitor, tiazofurin (TR). In p210 bcr-abl-transformed cells treated for 4 hours with TR, in which the levels of GTP were reduced by 50%, but GDP, guanosine monophosphate, and adenosine triphosphate (ATP) were unaffected, p210 bcr-abl tyrosine phosphorylation was at control levels. However, expression of c-fos and c-jun nuclear proto-oncogenes were strongly inhibited and p21 RAS activity was downregulated. These findings show that p210 bcr-abl transduces proliferative signals, in part, through downstream activation of p21 RAS. Furthermore, p21 RAS activity is linked to pathways that regulate c-jun and c-fos expression.
Transforming growth factor (TGF)-beta3 has been hypothesized to prevent or alleviate oral mucositis (OM) in cancer patients receiving high-dose chemotherapy (CT). Two double-blind, placebo-controlled, multicenter, phase II studies of TGF-beta3 were initiated in the United States, Europe, and Argentina in patients with lymphomas or solid tumors who were receiving highly stomatotoxic CT regimens. Patients were to apply 10-mL mouthwash applications of TGF-beta3 (25 microg/mL) or placebo four times daily (or twice daily) 1 day before and all days during CT. The patients were subsequently evaluated for OM incidence, severity, and duration using National Institute of Cancer Common Toxicity Criteria (NCI-CTC) criteria and an objective scoring system (1). After the start of the trials, negative results from new preclinical studies suggesting suboptimal formulation and/or dosing led to an interim analysis of the ongoing clinical trials. One hundred fifty-two patients from the combined studies were included in the interim analysis, with 116 patients on the TGF-beta3 four times daily and placebo arms. Most (72%) patients had breast cancer, 22% had lymphomas, and 6% had other solid tumors. Although 98% (149 of 152) of patients experienced adverse events, only 14% (22 of 152) experienced events that were judged as possibly or probably related to the study drug (primarily gastrointestinal symptoms). No clinically relevant differences were seen between the treatment and placebo arms regarding safety, nor was there evidence for systemic absorption of TGF-beta3. Finally, there was no advantage of TGF-beta3 treatment regarding the incidence (TGF-beta3 four times daily versus placebo [46% versus 47%]), onset, or duration of NCI-CTC grade 3 or 4 OM. For this dose, formulation, regimen. and patient population, TGF-beta3 was not effective in the prevention or alleviation of CT-induced OM.
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