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Background: Inflammatory myofibroblastic tumors (IMTs) are a rare subgroup of soft tissue tumors. The outcome of patients with IMT has been reported as favorable when the tumor is completely resected. If surgical resection is not possible, systemic therapy has to be considered. However, the best systemic treatment and response rates are currently unclear., Methods: Thirty-eight patients under the age of 21, who were registered between 2000 and 2014 with a primary diagnosis of IMT, were analyzed., Results: IMT was typically localized intra-abdominally or in the pelvis. In 20 patients, the tumor was resected without further therapy; 17 patients were in complete remission at last evaluation and two patients were in partial remission. Eighteen patients received systemic therapy, 15 of whom had macroscopically incomplete resection. Systemic therapy most commonly consisted of regimens with dactinomycin, ifosfamide or cyclophosphamide, and vincristine, with or without doxorubicin, and it seemed to reduce tumor extension in individual cases. Five-year event-free survival was 74 ± 14% and 5-year overall survival was 91 ± 10% for all patients. The patients who died due to the disease were those with incomplete resection (n = 3)., Conclusions: Surgery without further systemic therapy was a feasible and acceptable therapeutic option for every second patient with IMT. Standard chemotherapy for pediatric soft tissue sarcoma produced favorable results in individual cases and was able to shrink the tumor enough to enable resection. Superior efficacy of new targeted therapies such as anaplastic lymphoma kinase-inhibitors compared to standard chemotherapy has to be proven in the future., (© 2018 Wiley Periodicals, Inc.)

Posttransplantation lymphoproliferative disorders (PTLDs) caused by uncontrolled expansion of Epstein-Barr virus (EBV)-infected B cells after hematopoietic stem cell transplantation (HSCT) can be predicted by an increase in EBV DNA in peripheral blood mononuclear cells. We used real-time quantitative polymerase chain reaction (RQ-PCR) analysis to determine whether frequent monitoring of EBV DNA to allow preemptive treatment is truly of value in patients after HSCT. More than 1300 samples from 85 recipients were analyzed. No patient with consistently low EBV DNA levels developed PTLD. Nine patients had a single episode with a high EBV load (more than 4000 EBV copies/microg peripheral blood mononuclear cell [PBMC] DNA), and 16 patients had high EBV loads detected on 2 or more occasions. Only 8 of these developed symptoms consistent with PTLD, and all were promptly and successfully treated with EBV-specific cytotoxic T cells or CD20 monoclonal antibody. Hence, quantitative measurement of EBV DNA may best be used to enable the prompt rather than the preemptive treatment of PTLD.

Viral diseases are a major cause of morbidity and mortality after hemopoietic stem cell transplantation. Because viral complications in these patients are clearly associated with the lack of recovery of virus-specific cellular immune responses, reconstitution of the host with in vitro expanded cytotoxic T lymphocytes is a potential approach to prevent and treat these diseases. Initial clinical studies of cytomegalovirus and Epstein-Barr virus in human stem cell transplant patients have shown that adoptively transferred donor-derived virus-specific T cells may restore protective immunity and control established infections. Preclinical studies are evaluating this approach for other viruses while strategies for generating T cells specific for multiple viruses to provide broader protection are being evaluated in clinical trials. The use of genetically modified T cells or the use of newer suicide genes may result in improved safety and efficacy.

Acute renal failure (ARF) with fluid overload (FO) occurs often in stem cell transplant (SCT) recipients. We have previously demonstrated that an increased percentage of FO prior to the initiation of continuous renal replacement therapy (CRRT) is associated with mortality in children with ARF. Based on these data, we devised a protocol for the prevention of FO in SCT patients with ARF. SCT patients with ARF and 5% FO were started on furosemide and low-dose dopamine. To allow for nutrition, medication, and blood product administration, RRT was initiated for patients with > or =10% FO. There were 272 patients who received allogeneic SCT from 1999 to 2002. Of these, medical records of 26 SCT patients with a first episode of oliguric ARF were reviewed. The mean patient age was 13+/-5 years (range 2-23.5 years). Mean days to ARF after SCT were 28+/-29 days (range 2-90 days). Of the 26 patients, 11 (42%) survived an initial ARF episode. All 11 survivors either maintained <10% FO during their course or re-attained <10% FO with RRT treatment. Of the 15 non-survivors, 6 had <10% FO at the time of death. Of 14 patients who received RRT, 4 (29%) survived. Mechanical ventilation and pediatric risk of mortality score > or =10 at the time of admission to the intensive care unit were associated with lower survival ( P<0.05). The use of one or more pressors, the presence of graft-versus-host disease, and septic shock were not correlated with survival. Our data demonstrate that maintenance of euvolemia ( <10% FO) is critical but not sufficient for survival in SCT patients with ARF, as all non-euvolemic patients died. We suggest that aggressive use of diuretics and early initiation of RRT to prevent worsening of FO may improve the survival of SCT patients.

Broadening the applicability of stem cell therapies requires safer preparative regimens for patients. The CD45 antigen is present on all cells of the hematopoietic lineage, and using a murine model, we determined whether a lytic CD45 monoclonal antibody could produce persistent aplasia and whether it could facilitate syngeneic or allogeneic stem cell engraftment. After its systemic administration, we found that all leukocyte subsets in peripheral blood were markedly diminished, but only the effect on the lymphoid compartment was sustained and marrow progenitor cells were spared from destruction. Given the transient effects of the monoclonal antibody on myelopoiesis and the more persistent effects on lymphopoiesis, we asked whether this agent could contribute to donor hemopoietic engraftment after subablative transplantation. Treatment with anti-CD45 alone did not enhance syngeneic engraftment, consistent with its inability to destroy progenitor cells and permit competitive repopulation with syngeneic donor stem cells. By contrast, the combination of anti-CD45 and an otherwise inactive dose of total-body irradiation allowed engraftment of H2 fully allogeneic donor stem cells. We attribute this result to the recipient immunosuppression produced by depletion of CD45-positive lymphocytes. We next assessed a pair of unconjugated rat anti-human CD45 monoclonal antibodies (MAbs), YTH54.12 and YTH25.4, in a clinical trial in patients who were to receive stem cell transplantation for acute leukemia. The maximum tolerated dose of these MAbs, 400 microg/kg/day, produced a pattern of response identical to that seen in the mice, with marked reductions in circulating lymphoid and myeloid cells and sparing of early marrow progenitors. In two of three patients with active leukemia, the MAbs also produced a decrease in the percentage of leukemic blast cells in bone marrow. These pre-clinical and clinical results warrant further evaluation of anti-CD45 MAbs in subablative preparative regimens for stem cell transplantation.

The CD45 antigen is present on all cells of the hematopoietic lineage. In some rodent models, lytic CD45 monoclonal antibodies (MAbs) induce complete marrow aplasia. In others, only transient myelolymphodepletion are observed, which are nonetheless sufficient to permit engraftment with fully allogeneic stem cells after otherwise ineffective doses of radiation. The in vivo effects of unconjugated cytolytic CD45 MAbs on myeloid and lymphoid cells in humans are unknown, so it is unclear if they could contribute in a similar way to conventional ablative or to nonmyeloablative preparative regimens used for stem cell transplantation (SCT). We therefore assessed the safety, myeloreductive activities, and lymphoreductive activities of the unconjugated rat anti-human CD45 MAbs, YTH25.4 and YTH54.12, in subjects who were to undergo SCT for advanced hematologic malignancy. The MAb pair bind to contiguous but nonoverlapping epitopes on CD45 and work synergistically to fix complement and recruit cellular lytic mechanisms. The MAbs were given in increasing doses up to 1600 microg/kg during 4 days, after which the patients began their conventional transplantation preparative regimen. The maximum tolerated dose of these MAbs, 400 microg/kg/d, produced marked reduction in circulating lymphoid and myeloid cells while largely sparing marrow progenitors. In 2 of 3 patients who had active leukemia at the time of study, the MAbs reduced the percentage of leukemic blast cells in bone marrow. Seven of 14 patients are disease free 610 to 1555 days post-SCT. The in vivo myeloreductive and lymphoreductive properties of lytic CD45 MAb in humans, therefore, closely parallel the activity seen in a murine model and, therefore, may be of similar value., (Copyright 2003 American Society for Blood and Marrow Transplantation)

The hematopoietic stem cell underlying acute myeloid leukemia (AML) is controversial. Flow cytometry and the DNA-binding dye Hoechst 33342 were previously used to identify a distinct subset of murine hematopoietic stem cells, termed the side population (SP), which rapidly expels Hoechst dye and can reconstitute the bone marrow of lethally irradiated mice. Here, the prevalence and pathogenic role of SP cells in human AML were investigated. Such cells were found in the bone marrow of more than 80% of 61 patients and had a predominant CD34(low/-) immunophenotype. Importantly, they carried cytogenetic markers of AML in all 11 cases of active disease examined and in 2 out of 5 cases in complete hematological remission. Comparison of daunorubicin and mitoxantrone fluorescence emission profiles revealed significantly higher drug efflux from leukemic SP cells than from non-SP cells. Three of 28 SP cell transplants generated overt AML-like disease in nonobese diabetic--severe combined immunodeficient mice. Low but persistent numbers of leukemic SP cells were detected by molecular and immunological assays in half of the remaining mice. Taken together, these findings indicate that SP cells are frequently involved in human AML and may be a target for leukemic transformation. They also suggest a mechanism by which SP cells could escape the effects of cytostatic drugs and might eventually contribute to leukemia relapse. (Blood. 2001;98:1166-1173)

After bone marrow transplantation (BMT) using T-cell-depleted marrow from an unrelated donor or HLA-mismatched related donor, the risk of developing lymphoproliferative disease associated with the Epstein-Barr virus (EBV) ranges from 1% to 25%. We have shown that administration of donor-derived EBV-specific cytotoxic T lymphocytes (CTL) is effective prophylaxis and treatment for this complication, and we routinely generate CTL for high-risk patients. However, EBV lymphoma can occur in recipients of matched-sibling transplants for whom CTL are unavailable or in patients for whom CTL administration is contraindicated. We report on 3 such patients, who were successfully and safely treated with rituximab, a CD20 monoclonal antibody. The patients remain disease free 7, 8, and 9 months, respectively, after therapy. We conclude that CD20 antibody may be a useful alternative treatment strategy in patients with EBV lymphoma after BMT. (Blood. 2000;95:1502-1505)