Unrelated allogeneic bone marrow-derived mesenchymal stem cells for steroid-refractory acute graft-versus-host disease: a phase I/II study

We conducted a multicenter phase I/II study using mesenchymal stem cells (MSCs) manufactured from the bone marrow of healthy unrelated volunteers to treat steroid-refractory acute graft-versus-host disease (aGVHD). Fourteen patients with hematological malignancies who suffered from grade II (9 patients) or III aGVHD (5) were treated. Affected organs were gut (10 patients), skin (9 patients), and liver (3 patients). Seven patients had two involved organs. The median age was 52. No other second-line agents were given. MSCs were given at a dose of 2 × 10⁶ cells/kg for each infusion twice a week for 4 weeks. If needed, patients were continuously given MSCs weekly for an additional 4 weeks. By week 4, 13 of 14 patients (92.9 %) had responded to MSC therapy with a complete response (CR; n = 8) or partial response (PR; n = 5). At 24 weeks, 11 patients (10 with CR and 1 with PR) were alive. At 96 weeks, 8 patients were alive in CR. A total of 6 patients died, attributable to the following: underlying disease relapse (2 patients), breast cancer relapse (1), veno-occlusive disease (1), ischemic cholangiopathy (1), and pneumonia (1). No clear adverse effects associated with MSC infusion were observed. Third party-derived bone marrow MSCs may be safe and effective for patients with steroid-refractory aGVHD.     

Exacerbation of Established Collagen-Induced Arthritis in Mice Treated with An Anti—T Cell Receptor Antibody

Objective. To investigate the effect of T cell depletion on established collagen-induced arthritis (CIA) in mice, using monoclonal antibodies (MAb) to T cell receptor α/β (TCRα/β). In addition, experiments using anti-CD3 MAb were performed for comparison. Methods. CIA was induced in male DBA/1 mice by immunizing them twice with bovine type II collagen (CII). The arthritis score and anti-CII antibody titers were examined serially. Proportions of T cells were determined by fluorescence-activated cell sorter (FACS) analysis on spleen cells or peripheral blood cells. Results. When anti-TCRα/β MAb was injected on the day of CII priming, no arthritis was detected in association with depressed anti-CII antibody titers. Unexpectedly, however, when MAb was given after arthritis was established, a rapid exacerbation of arthritis was observed, which resulted in ankylosis of most joints. Anti-CII antibody titers were not affected. The addition of anti-TCRγ/δ MAb had no effect on the augmented arthritis. T cell depletion by anti-CD3 MAb during established CIA also caused an enhancement of arthritis, which was, however, weak and only transient. FACS analysis revealed that the early improvement of arthritis after the transient augmentation seen in the mice treated with anti-CD3 MAb paralleled the early recovery of α/β T cells in the periphery. Conclusion. The present results support the concept that α/β T cells, in general, may play a regulatory role in the clinical course of murine CIA after disease onset. Therefore, caution is recommended when using intensive T cell—targeted therapy in patients with rheumatoid arthritis.     

Rituximab does not compromise the mobilization and engraftment of autologous peripheral blood stem cells in diffuse-large B-cell lymphoma

To investigate effects of the preautografting administration of rituximab on the mobilization and engraftment of peripheral blood stem cells (PBSC), we retrospectively analyzed the outcomes of 43 newly diagnosed diffuse-large B-cell lymphoma patients who received CHOP chemotherapy with or without rituximab as a first-line treatment before autologous PBSC transplantation (PBSCT). There was no difference in the number of CD34(+) cells among PBSC between the non-rituximab and the rituximab groups. Although B-cells were completely depleted from PBSC in the rituximab group, we found no difference in the expression of CXCR-4, VLA-4 and c-Kit on PBSC, indicating that rituximab did not affect the expression of these adhesion molecules, which might be involved in the mechanism of mobilization. There was no significant difference in the recovery of neutrophils and platelets, transplant-related toxicity and post-transplant complications between the two groups. Despite the short follow-up, there was no significant difference in progression-free survival between the two groups. These results indicated no adverse effect of rituximab on the mobilization and engraftment of PBSC. Larger studies are required to determine the impact of rituximab on the mobilization and function of PBSC as well as whether a survival advantage exists in patients who undergo auto-PBSCT with rituximab.     

Endoscopic ultrasound-guided transmural drainage for pancreatic fistula or pancreatic duct dilation after pancreatic surgery

Background

Endoscopic ultrasound (EUS)-guided drainage is widely used to manage pancreatic pseudocysts. Several studies have reported the use of EUS-guided drainage for pancreatic fistula and stasis of pancreatic juice caused by stricture of the pancreatic duct after pancreatic resection.

Methods

At the authors’ hospital, 262 patients underwent surgery involving pancreatic resection from April 2005 to March 2010. In 90 of these patients (34%), a grade B or C postoperative pancreatic fistula developed that required additional treatment. The authors performed EUS-guided transmural drainage (EUS-TD) for six patients (2.1%) with a pancreatic fistula or dilation of the main pancreatic duct visible by EUS. Percutaneous drainage was provided for 18 patients (6.8%). The success rates for EUS-TD and percutaneous drainage were compared in a retrospective analysis.

Results

In all six cases, EUS-TD was performed successfully without complications. Five of the six patients were successfully treated with only one trial of EUS-TD. The final technical success rate was 100% for both EUS-TD and percutaneous drainage. Both the short- and long-term clinical success rates for EUS-TD were 100% and those for percutaneous drainage were 61.1 and 83%, respectively. The differences in these rates were not significant (short-term success, P?=?0.091 vs. long-term success, P?=?0.403). However, the time to clinical success was significantly shorter with EUS-TD (5.8?days) than with percutaneous drainage (30.4?days; P?=?0.0013) in the current series.

Conclusions

The EUS-TD approach appears to be a safe and technically feasible alternative to percutaneous drainage and may be considered as first-line therapy for pancreatic fistulas visible by EUS.     

Cyclophosphamide-using nonmyeloablative allogeneic cell therapy against renal cancer with a reduced risk of graft-versus-host disease.

PURPOSE: Much attention has been paid to nonmyeloablative allogeneic stem cell transplantation for the treatment of renal cancer. We recently proposed a cyclophosphamide-using nonmyeloablative cell therapy in which donor lymphocyte infusion (DLI) was carried out after the tolerance induction to donor cells. In considering the clinical application of the cyclophosphamide-using cell therapy, attempts to reduce graft-versus-host disease (GVHD) are crucial. The aim of the present study was to modify the cyclophosphamide-using cell therapy to reduce the risk of GVHD while preserving the antitumor activity against renal cancer. EXPERIMENTAL DESIGN: We assessed whether a delay in performing DLI from day 1 to day 5 after the cyclophosphamide treatment could reduce the risk of GVHD while preserving antitumor activity against RENCA, a murine carcinogen-induced renal cell carcinoma, in the cyclophosphamide-using cell therapy. RESULTS: Regarding the in vivo antitumor effect, there was no difference between DLI on day 1 and day 5 after the cyclophosphamide treatment, whereas the histologic findings of the small intestine showed that the cyclophosphamide-using cell therapy with DLI on day 5 decreased the risk of GVHD. In addition, the acquired immunity against RENCA was also observed in the RENCA-rejected mice that had been treated with DLI on day 5. CONCLUSIONS: Our results show that a delay in DLI during cyclophosphamide-using nonmyeloablative cell therapy can dissociate graft-versus-tumor effects from GVHD by reducing the risk of GVHD.     

Comparison of the prophylactic usefulness of epirubicin and doxorubicin in the treatment of superficial bladder cancer by intravesical instillation: a multicenter randomized trial

A multicentric randomized trial was conducted for the purpose of investigating the prophylactic efficacy of intravesical epirubicin instillation following transurethral resection of superficial bladder cancer in comparison with the efficacy of doxorubicin. The patients were centrally randomized into 2 groups and received 19 intravesical instillations of epirubicin or doxorubicin at 30 mg/30 ml physiological saline twice a week for 4 weeks and then once monthly for 11 months. A total of 150 patients with Ta and T1 superficial bladder cancer were entered in the trial, and 114 were evaluable. The nonrecurrence rates determined for each group at 1 and 2 years by the Kaplan-Meier method were 92.8% and 88.6%, respectively, for the epirubicin group and 86.4% and 81.7%, respectively, for the doxorbicin group. The differences between the two groups were not statistically significant. The main side effects encountered in this study were symptoms of bladder irritation such as micturitional pain, pollakisuria, and hematuria. The respective frequencies of those symptoms were 10%, 15.0%, and 5.0% in the epirubicin group and 14,8%, 14.8%, and O in the doxorubicin group. These results suggest that epirubicin is a useful drug, comparable with doxorubicin, for intravesical instillation chemotherapy in the prophylactic treatment of superficial bladder cancer.Paper presented at the 5th International Conference on Treatment of Urinary Tract Tumors with Adriamycin/Farmorubicin, 24–25 September 1993, Hakone, Japan     

Prognostic variables in patients with upper urinary tract cancers

Background We conducted a retrospective analysis of patients with upper urinary tract cancers in order to examine the usefulness of some clinicopathological factors as prognostic predictors. Methods Between January 1985 and December 1994, 74 patients underwent surgical treatment for primary upper urinary tract cancers. Clinicopathological patient data were examined based on the criteria of The Japanese Urological Association. Results In this series, 40 tumors were located in the renal pelvis, 30 in the ureter, and 4 in both the renal pelvis and ureter. Associated bladder cancers were found in 27 patients. Histopathological examination revealed that the tumor grade was grade 1 or grade 2 in 45 patients and grade 3 in 29 patients; the pathological stage was Ta or T1 in 36 patients, and T2, T3 or T4 in 38 patients. Vascular invasion was found in 34 patients. The 5-year survival rates were 53% for all patients, 73% for patients with grade 1 and 2 tumors, and 28% for those with grade 3 tumors (P<0.0005) 70% for patients with stage Ta and T1 tumors, and 36% for those with stage T2, T3, and T4 tumors (P<0.005); 89% for patients without vascular invasion and 0% for those with vascular invasion (P<0.0001). Multivariate analysis revealed a strong independent correlation of vascular invasion with poor prognosis. Conclusions Tumor grade, pathological stage, and vascular invasion were significantly important prognostic parameters in patients with upper urinary tract cancers, and among them only vascular invasion was an independent predictor of poor prognosis.