Outcome with lenalidomide plus dexamethasone followed by early autologous stem cell transplantation in patients with newly diagnosed multiple myeloma on the ECOG-ACRIN E4A03 randomized clinical trial: long-term follow-up.

In Eastern Cooperative Oncology Group-ACRIN E4A03, on completion of four cycles of therapy, newly diagnosed multiple myeloma patients had the option of proceeding to autologous peripheral blood stem cell transplant (ASCT) or continuing on their assigned therapy lenalidomide plus low-dose dexamethasone (Ld) or lenalidomide plus high-dose dexamethasone (LD). This landmark analysis compared the outcome of 431 patients surviving their first four cycles of therapy pursuing early ASCT to those continuing on their assigned therapy. Survival distributions were estimated using the Kaplan-Meier method and compared with log-rank test. Ninety patients (21%) opted for early ASCT. The 1-, 2-, 3-, 4- and 5-year survival probability estimates were higher for early ASCT versus no early ASCT at 99, 93, 91, 85 and 80% versus 94, 84, 75, 65 and 57%, respectively. The median overall survival (OS) in the early versus no early ASCT group was not reached (NR) versus 5.78 years. In patients <65 years of age, median OS in the early versus no early ASCT groups was NR in both, hazard ratio 0.79, 95% confidence interval: (0.50, 0.25). In patients ⩾65 years of age, median OS in the early versus no early ASCT was NR versus 5.11 years. ASCT dropped out of statistical significance (P=0.080). Patients opting for ASCT after induction Ld/LD had a higher survival probability and improvement in OS regardless of dexamethasone dose density.

Contribution of chemotherapy mobilization to disease control in multiple myeloma treated with autologous hematopoietic cell transplantation.

In patients with multiple myeloma (MM) undergoing autologous hematopoietic cell transplantation (auto-HCT), peripheral blood progenitor cells may be collected following mobilization with growth factor alone (GF) or cytotoxic chemotherapy plus GF (CC+GF). It is uncertain whether the method of mobilization affects post-transplant outcomes. We compared these mobilization strategies in a retrospective analysis of 968 patients with MM from the Center for International Blood and Marrow Transplant Research database who received an auto-HCT in the US and Canada between 2007 and 2012. The kinetics of neutrophil engraftment (⩾0.5 × 10(9)/L) was similar between groups (13 vs 13 days, P=0.69) while platelet engraftment (⩾20 × 10(9)/L) was slightly faster with CC+GF (19 vs 18 days, P=0.006). Adjusted 3-year PFS was 43% (95% confidence interval (CI) 38-48) in GF and 40% (95% CI 35-45) in CC+GF, P=0.33. Adjusted 3-year OS was 82% (95% CI 78-86) vs 80% (95% CI 75-84), P=0.43 and adjusted 5-year OS was 62% (95% CI 54-68) vs 60% (95% CI 52-67), P=0.76, for GF and CC+GF, respectively. We conclude that MM patients undergoing auto-HCT have similar outcomes irrespective of the method of mobilization and found no evidence that the addition of chemotherapy to mobilization contributes to disease control.

Negative regulation of the tumor suppressor p53 gene by microRNAs.

The tumor suppressor p53, encoded by the TP53 gene, is recognized as the guardian of the human genome because it regulates many downstream genes to exercise its function in cell cycle and cell death. Recent studies have revealed that several microRNAs (miRNAs) are important components of the p53 tumor suppressor network with miR-125b and miR-504 directly targeting TP53. In this study, we use a screening method to identify that two miRNAs (miR-25 and miR-30d) directly target the 3'UTR of TP53 to downregulate p53 protein levels and reduce the expression of genes that are transcriptionally activated by p53. Correspondingly, both miR-25 and miR-30d adversely affect apoptotic cell death, cell cycle arrest and cellular senescence. Inhibition of either miR-25 or miR-30d expression increases endogenous p53 expression and elevates cellular apoptosis in several cell lines, including one from multiple myeloma that has little TP53 mutations. Thus, beyond miR-125b and miR-504, the human TP53 gene is negatively regulated by two more miRNAs: miR-25 and miR-30d.

Incidence of Clostridium difficile-associated diarrhea before and after autologous peripheral blood stem cell transplantation for lymphoma and multiple myeloma.

Diarrhea is a major cause of morbidity and discomfort for patients undergoing high-dose chemotherapy and autologous peripheral blood stem cell transplantation (APBSCT). There are multiple causes of diarrhea in patients undergoing transplantation including antineoplastic chemotherapy, antimicrobials and infection, including Clostridium difficile as the most common pathogen involved. The purpose of this study was to determine the incidence of C. difficile-associated diarrhea (CDAD) 1 week before and 30 days after APBSCT, and to identify risk factors for the development of CDAD including diagnosis. Two hundred and forty-two patients underwent APBSCT for multiple myeloma and lymphoma between October 1996 and October 2001 in two teaching hospitals. Diarrhea was reported in 157 (64.9%) subjects. One hundred and thirty-five out of the 157 subjects were tested for the presence of C. difficile toxin A. These subjects constitute the study group. The incidence of CDAD was 15%. Two thirds of the patients who developed CDAD had multiple myeloma and one third had lymphoma; this difference did not attain statistical significance. The use of cephalosporins (P = 0.03) and the use of intravenous vancomycin (P = 0.02) were the only identified risk factors associated with the development of CDAD. Patients treated with paclitaxel as part of the mobilization regimen had a lower incidence of CDAD than patients who received hematopoietic growth factor only (P = 0.01).

Performance of a hybrid central venous catheter utilized for both peripheral blood stem cell harvest and transplant support of patients undergoing autologous peripheral blood stem cell transplantation.

Patients undergoing autologous peripheral blood stem cell transplantation (PBSC) frequently require the sequential insertion of two central venous catheters, one for leukapheresis and one for transplant support. Hybrid catheters suitable for leukapheresis and long-term use have been increasingly used, but there is limited information regarding their performance and complication rate. The purpose of this study was to determine the performance of the Pheres-Flow hybrid catheter when utilized for both leukapheresis and transplant support, with particular emphasis on the incidence of infectious and occlusive complications. We prospectively analyzed the performance of 92 catheters in 82 consecutive patients who underwent autologous peripheral blood stem cell (PBSC) transplantation. Occlusion was the most frequent complication of this catheter with 29% of the patients experiencing difficulty drawing blood or infusing fluids. Infection was another frequent complication. Twenty-two percent of patients developed catheter-related bloodstream infections and 15 catheters had to be removed because of proven or suspected infection that did not respond to antibiotic therapy. Nevertheless, 77% of patients were able to complete leukapheresis and transplant support with only one catheter. We conclude that the utilization of the Pheres-Flow catheter for both leukapheresis and transplant support is feasible, but that new strategies need to be developed to decrease the incidence of occlusive and infectious complications of hybrid catheters.

Myeloma bone disease.

Bone destruction is a hallmark of myeloma, with 70% to 80% of patients manifesting bone involvement. Destruction is mediated through normal osteoclasts (OCLs), which respond to local osteoclast-activating factors (OAFs) produced by myeloma cells or by other cells in the local microenvironment. OAFs implicated in myeloma bone disease include tumor necrosis factor-beta (TNFbeta), RANK ligand (RANKL), interleukin-1 (IL-1), parathyroid hormone-related protein (PTHrP), hepatocyte growth factor (HGH), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNFalpha), and macrophage inflammatory protein-1-alpha (MIP-1alpha). To date, the leading candidates for OAFs are MIP-1alpha and RANKL. Adhesive interactions between marrow stromal cells and myeloma cells induce marrow stromal cells to secrete IL-6, a potent myeloma growth/survival factor that may contribute to the bone disease. Evaluation of myeloma bone disease includes plain radiographs, and newer methods, such as magnetic resonance imaging (MRI), positron emission tomography (PET) scans, technetium-99m-sestamibi (Mibi) scanning, and dual-energy x-ray absorptiometry (DEXA) scanning, may provide more complete information. In addition, biochemical markers of bone resorption are being evaluated, although the limited availability of these assays and lack of extensive testing in patients make their routine use premature. Treatment of myeloma bone disease includes radiation therapy, vertebroplasty, surgery, and bisphosphonates. New developments on the pathogenesis and treatment of myeloma bone disease present great opportunities to combat bone disease.

Treatment of oral chronic graft-versus-host disease with PUVA therapy: case report and literature review.

Chronic graft-versus-host disease commonly appears with oral manifestations subsequent to allogeneic bone marrow transplantation. These manifestations include leukoplakia, mucosal atrophy, erythema, ulcers, and xerostomia. Some lesions are resistant to treatment with immunosuppressive medications. Ultraviolet A irradiation therapy with oral psoralen has been shown to be effective in treating these resistant lesions. This article presents a review of the literature and a case report.

Pilot trial of prophylactic ursodiol to decrease the incidence of veno-occlusive disease of the liver in allogeneic bone marrow transplant patients.

Ursodiol is a hydrophilic, non-hepatotoxic bile salt indicated for the medical treatment of cholesterol gallstones. This pilot study explored the use of prophylactic ursodiol in an attempt to decrease the incidence and severity of veno-occlusive disease (VOD) of the liver following allogeneic bone marrow transplantation (BMT). Between February 1991 and January 1992, 22 consecutive patients undergoing BMT for hematologic malignancies received the BU(4)/CY(2) preparative regimen and CSA/MTX for GVHD prophylaxis. Ursodiol, 600-900 mg daily by mouth was begun at least 1 day prior to beginning the preparative regimen. Results for this pilot group were compared to a control group of 28 consecutive patients transplanted between June 1989 and January 1991 with the same regimen without ursodiol. There were no significant differences in disease or clinical status between the groups pretransplant. However, mean baseline AST levels were significantly higher in the ursodiol group, 28.0 U/l vs 18.1 U/l in the control group (p = 0.001). The median maximum bilirubin observed post-transplant was 2.35 mg/dl (range 0.9-45) in the ursodiol group, and 5.05 mg/dl (range 0.7-29.4) in controls. The incidence of VOD was 2/22 (9.1%) in the ursodiol group and 18/28 (64.3%) in controls (p = 0.0001). Death due to VOD occurred in 1/22 patients (4.5%) in the ursodiol group and in 6/28 (21.4%) controls (p = 0.12). Our data suggest that ursodiol may decrease the incidence of VOD in allogeneic BMT patients.

Immunohistochemical identification of tissue factor in solid tumors.

Patients with cancer experience a much higher than expected incidence of thromboembolic disorders, commonly referred as Trousseau syndrome. Although this association has been well documented, the etiology of the hypercoagulable state is not known. The expression on tumor cells of tissue factor (TF), a membrane-bound lipoprotein that functions as a cofactor to factor VIIa in the initiation of the extrinsic pathway of blood coagulation, has been postulated as a possible mechanism. Whereas the distribution of TF in normal tissues is known, no large survey of TF expression in malignant tissues has been reported. In this study a polyclonal, monospecific rabbit anti-human TF IgG was used for immunohistochemical localization of TF antigen in 85 different tumor specimens. In general, cell types which normally express TF continued to do so after malignant transformation (41 of 60 epithelial tumor specimens were positive for TF). Tumors of nonepithelial origin frequently lacked TF, with only 3 of 19 specimens containing evidence of TF antigen. In addition five of six benign tumors did not express TF. Many tumor types commonly associated with Trousseau syndrome, for example lung, pancreatic, breast, colon and gastric carcinomas, stained positively for TF. Based on this survey, it appears that TF expression by tumors may be an important factor in the pathogenesis of a hypercoagulable state in some patients with cancer.

Mechanisms of binding of recombinant extrinsic pathway inhibitor (rEPI) to cultured cell surfaces. Evidence that rEPI can bind to and inhibit factor VIIa-tissue factor complexes in the absence of factor Xa.

Extrinsic pathway inhibitor plays a key role in modulating tissue factor-dependent blood coagulation. We have studied binding of radioiodinated recombinant extrinsic pathway inhibitor (rEPI) to cultured cell surfaces. rEPI in the absence of added reactants bound to a limited extent to three cell lines studied. Binding of rEPI to two cell lines possessing surface tissue factor, but not to a cell line lacking surface tissue factor, was markedly increased in the presence of both factor VIIa and factor Xa, and calcium ions. Moreover, some increased tissue factor-dependent binding was also demonstrated with factor VIIa alone. Binding isotherms of rEPI to factor VIIa-tissue factor obtained with an ovarian carcinoma cell line were hyperbolic. Scatchard plots indicated the following: a Kd value of 4.5 +/- 1.5 nM and 335,000 +/- 84,000 sites/cell when factor Xa was present; a Kd value of 11.9 +/- 3.5 nM and 236,000 +/- 68,000 sites/cell when factor Xa was absent. In functional studies, high concentrations of rEPI, e.g. 27-67.5 nM, were found to inhibit factor VIIa-tissue factor-catalyzed release of activation peptide from tritiated factor IX in the absence of factor Xa. Whereas factor Xa was thus shown not to be required for rEPI to inhibit factor VIIa-tissue factor catalytic activity, its presence markedly enhanced rEPI's inhibitory function. Since the local concentration of extrinsic pathway inhibitor achieved at a site of tissue injury is unknown, the physiologic significance of the observation of extrinsic pathway inhibitor-induced inhibition of factor VIIa-tissue factor activity in the absence of factor Xa is not clear. However, factor Xa-independent inhibition could play a significant role when large doses of rEPI are administered in experimental studies of thrombosis.