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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.

Summary:Twenty-one patients with relapsed or refractory germ cell tumors were treated with high-dose chemotherapy and marrow transplantation (HDC/BMT) from 1982-1993. Primary sites of disease were testis (17), ovary (three), and pineal gland (one). Pathology included dysgerminoma (one), choriocarcinoma with adenocarcinoma (one), seminoma (four), and nonseminoma or mixed germ cell tumor (15). Nineteen had at least two prior chemotherapy regimens and eight had cisplatinrefractory disease defined as progression within 4 weeks of a cycle of cisplatin-based chemotherapy. HDC regimens were mostly combinations of cyclophosphamide with etoposide and cisplatin or carboplatin. There were only two treatment-related deaths (aspergillosis and interstitial pneumonitis). Times to engraftment of granulocytes (21 ± 8.3 days) and platelets (32 ± 20.2 days) were reasonable with only the last nine patients receiving growth factors. At a minimum of 4 years follow-up, eight patients have died of disease, six of whom were cisplatin-refractory prior to transplant. Eleven patients (52% overall) are alive and continuously free of disease after 4-10 years including one of three with refractory ovarian germ cell tumor. HDC/BMT provides significant long-term disease-free survival as salvage therapy for both male and female relapsed germ cell tumor patients who are not refractory to cisplatin. Keywords: germ cell tumors; bone marrow transplantation; relapsed; cisplatin-refractory Metastatic germ cell tumors in both male and female patients are potentially curable with cisplatin-based combination chemotherapy with or without additional surgery. 1 Patients who relapse or fail first-line therapy, however, only have a 15-25% successful salvage rate with second-line conventional chemotherapy (cisplatin and ifosfamide combinations). 2,3 Initial experience with high-dose chemotherapy using carboplatin-and etoposide-containing regimens showed that 10-15% of heavily pretreated (two or more salvage chemotherapy regimens) patients could still obtain long-term remissions. [4][5][6][7][8][9] Recently, data on 283 heavCorrespondence: RA Mandanas, 920 SL Young Blvd WP2010, Oklahoma City, OK 73104, USA Received 23 June 1997; accepted 2 October 1997 ily pretreated patients with disseminated germ cell tumors from four large centers in the USA and Europe have been analyzed retrospectively for prognostic variables that predict a poor outcome with high-dose chemotherapy and hematopoietic stem cell support. 10 The resulting model categorized patients into three groups based on the number of prognostic factors present and allows the separation of poor (3-5 risk factors) risk patients from good (0 risk factors) and intermediate (1 or 2 risk factors) risk patients who might still have a beneficial outcome (27-51% 2-year failure-free survival) following high-dose chemotherapy and autologous stem cell support. Female patients with ovarian germ cell neoplasms were excluded from this analysis and although published data on high-dose chemotherapy with stem cell support f...

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Forty-two cytomegalovirus (CMV)-seropositive allogeneic marrow transplant patients or recipients of CMV-seropositive marrow allografts were entered into a surveillance program to detect and treat CMV infection during the first 120 days posttransplant. CMV infection was detected at a mean time of day 50 in 21/37 (58%) patients who had surveillance cultures. Twelve of 42 (28%) received preemptive ganciclovir treatment for virus isolated from blood (9 patients) or from bronchoalveolar lavage fluid (3 patients), and all had no CMV-associated sequelae. CMV disease was diagnosed in 5 patients (4 with pneumonia), 1 with gastroenteritis) who did not have positive cultures until the onset of their disease. CMV-related mortality was 4/42 (10%). Patients who earlier manifested lung injury or diffuse alveolar hemorrhage (DAH) were significantly predisposed to subsequent CMV pneumonia (P = 0.0013, Fisher's exact test) at a median onset of day 42. Restricted prophylactic use of ganciclovir in such patients may be indicated. Fifty percent of all patients never required ganciclovir during the surveillance period. When compared to a universal prophylaxis program of ganciclovir for the prevention of CMV disease, the use of ganciclovir in a preemptive strategy could avoid unnecessary therapy for a substantial number of patients and earn significant cost-savings.