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Younger, healthier patients contemplating high-risk (but potentially curative) hematopoietic cell transplants (HCT) may not consider advance care planning (ACP). We investigated the effect of pre transplant ACP in surviving HCT patients and bereaved caregivers using retrospective, audiotaped telephone surveys. Subjects were identified between 2001 and 2003 via databases at two high-volume HCT centers. Transcripts were coded by two investigators, with differences resolved by consensus. HCT survivors (n=18) were interviewed a median of 13 months after HCT for acute leukemia (7), lymphoma (5) or other (6); 50% had living wills, 72% had a formal proxy. Twelve (67%) had discussed mortality risk pre HCT with the medical team. Of those, 92% felt their hope and perception of the medical team's truthfulness was increased or unchanged (I/U) by the conversation, whereas all felt clinician commitment to transplant was I/U. Bereaved caregivers (n=11) were interviewed a median of 10 months post death (median 31 days post HCT, range 13-152). Nine (82%) had discussed mortality risk pre-HCT with the medical team; 7 (78%) felt hope was I/U, all felt clinician commitment to transplant and truthfulness was I/U, and most felt ACP reduced burden (67%). ACP discussions with patients and caregivers pre-HCT did not affect hope and supported confidence in medical teams. [ABSTRACT FROM AUTHOR]

Pulmonary complications are common and often lethal in hematopoietic SCT recipients. The objective of this prospective interventional study was to evaluate the etiology, diagnostic procedures, risk factors and outcome of pulmonary complications in a cohort of hematopoietic SCT recipients followed up for 1 year. For patients suffering from a pulmonary complication, a diagnostic algorithm that included non-invasive and bronchoscopic procedures was performed. We identified 73 pulmonary complications in 169 patients: 50 (68%) were pneumonias; 21 (29%) were non-infectious complications and 2 (3%) were undiagnosed. Viruses (particularly Rhinovirus) and bacteria (particularly P. aeruginosa) (28 and 26%, respectively) were the most common causes of pneumonia. A specific diagnosis was obtained in 83% of the cases. A non-invasive test gave a specific diagnosis in 59% of the episodes. The diagnostic yield of bronchoscopy was 67 and 78% in pulmonary infections. Early bronchoscopy (⩽5 days) had higher diagnostic yield than late bronchoscopy (78 vs 23%; P=0.02) for pulmonary infections. Overall mortality was 22 and 32% of all fatalities were due to pulmonary complications. Pulmonary complications are common and constitute an independent risk factor for mortality, stressing the importance of an appropriate clinical management. [ABSTRACT FROM AUTHOR]

Allogeneic hematopoietic SCT is indicated for children whose disease demonstrates dismal prognosis with chemotherapy. This study aims to analyse the most recent outcomes of unmanipulated haploidentical (HID) HSCT for paediatric patients with acute leukaemia. Those from matched sibling donors (MSD) HSCT provided a parallel cohort to illustrate the benefits of HID. Conditioning regimen was modified BuCy2. Anti-thymoglobulin was used for HID. Mobilised marrow and blood stem cells were used as the grafts. All patients in HID achieved neutrophil recovery and 96.7% platelet recovery. In HID, the incidences of acute GVHD 3-4 and extensive chronic GVHD were 14.3 and 26.6%. Play-performance score 90-100% was recorded in 79.7% of all survivors. The 5-year leukaemia-free survival (LFS) in CR1, CR2, beyond CR2 or non-remission were 68.9%, 56.6%, 22.2% and 82.5%, 59.4%, 42.9% for ALL and AML, respectively. In MSD group, LFS for ALL and AML in CR1 were 62.5 and 71.7%. Outcomes of the HID HSCT for paediatric patients with acute leukaemia showed benefits that were similar to those of the parallel cohort of MSD HSCT. [ABSTRACT FROM AUTHOR]

Allogeneic hematopoietic SCT (HSCT) has been shown to be an effective treatment option for advanced renal cell cancer (RCC). However, tumor resistance/relapse remains as the main post transplant issue. Therefore, enhancing graft-versus-tumor (GVT) activity without increasing GVHD is critical for improving the outcome of HSCT. We explored the GVT effect of haploidentical-SCT (haplo-SCT) against RCC in murine models. Lethally irradiated CB6F1 (H2Kb/d) recipients were transplanted with T-cell-depleted BM cells from B6CBAF1 (H2Kb/k) mice. Haplo-SCT combined with a low-dose haploidentical (HI) T-cell infusion (1 × 105) successfully provided GVT activity without incurring GVHD. This effect elicited murine RCC growth control and consequently displayed a comparative survival advantage of haplo-SCT recipients when compared with MHC-matched (B6D2F1CB6F1) and parent-F1 (B6CB6F1) transplant recipients. Recipients of haplo-SCT had an increase in donor-derived splenic T-cell numbers, T-cell proliferation and IFN-γ-secreting donor-derived T-cells, a critical aspect for anti-tumor activity. The splenocytes from B6CBAF1 mice had a higher cytotoxicity against RENCA cells than the splenocytes from B6 and B6D2F1 donors after tumor challenge. These findings suggest that haplo-SCT might be an innovative immunotherapeutic platform for solid tumors, particularly for renal cell carcinoma. [ABSTRACT FROM AUTHOR]

Success of umbilical cord blood transplantation (UCBT) has been limited by a high rate of graft failure and delayed hematological recovery. It has been postulated that MSCs have hematopoiesis-supportive properties. Therefore, to overcome the limitation of UCBT, third-party UCB-derived MSCs were co-transplanted in recipients receiving unrelated UCBT. Seven patients received UCB and third-party UCB-MSCs. Hematopoietic recovery and transplantation outcomes were compared with historic controls. There was no acute toxicity associated with the infusion of MSCs. The median day to neutrophil engraftment was 19 days in patients, as compared with 24 days in controls (P=0.03). The median day of platelet engraftment was 47 days and 57 days in patients and controls, respectively (P=0.26). In addition, there was no engraftment failure in the MSC group. The incidence of acute and chronic GVHD was comparable between the two groups. However, veno-occlusive disease and TRM did not occur in the MSC group. Third-party UCB-MSCs infusion was safe and feasible. MSCs may also enhance the engraftment of UCBT and prevent rejection. In addition, MSCs may have a role in decreasing TRM. Randomized, controlled trials are required to confirm these results and longer follow-up will determine the effects of MSCs on the risk of relapse. [ABSTRACT FROM AUTHOR]

Peripheral blood used as a source of stem cells for transplantation (PBSCT) is known to exert stronger immune-mediated effects compared with BM (BMT). We decided to retrospectively analyze the impact of stem cell source on the OS of CML patients who relapsed after either matched related donor PBSCT (N=168) or BMT (N=216) and were treated with donor lymphocyte infusions (DLI). Univariate analysis revealed a lower probability of OS after DLI in patients relapsing after PBSCT vs BMT (66% vs 79% at 5 years, P=0.013). However, a multivariate Cox analysis did not reveal any significant impact of PBSCT as a risk factor for decreased OS for patients transplanted in first chronic phase (CP1; hazard ratio (HR) 1.036, 95% confidence interval (CI) 0.619-1.734). A statistical interaction term suggested that the impact of stem cell source on OS after DLI was different for those transplanted in advanced phases (negative impact of previous PBSCT-HR 2.176, 95% CI 0.930-5.091). In summary, the stem cell source does not affect the OS of CML patients who underwent PBSCT in CP1, relapsed and were treated with DLI. However, when the patients were transplanted in advanced phases, previous PBSCT seems to negatively affect OS after DLI compared with BMT. [ABSTRACT FROM AUTHOR]

Allogeneic hematopoietic SCT (allo-HCT) from matched sibling donor (MSD) is recommended for younger patients with intermediate cytogenetic risk AML in first CR (CR1), whereas the role of alternative donor transplants in these patients is unknown. We retrospectively analyzed 605 patients with intermediate-risk AML, who received myeloablative allo-HCT in CR1. The 4-year OS for MSD (n=290) and matched unrelated donor (MUD; n=141) was 65% and 68% (P=0.50), respectively. In multivariate analysis, MUD had a similar risk of overall mortality as MSD (hazard ratio=0.90; 95% confidence interval, 0.62-1.30; P=0.58), whereas older age, female donor/male recipient (FDMR) combination, and requiring more than one course of induction chemotherapy to achieve CR1 were poor prognostic factors for OS. Thus, OS after MUD HCT with sex combinations other than FDMR was significantly higher than that after MSD HCT from female donors to male recipients (4-year OS 72% versus 55%, P=0.04). These results suggest that HCT, not only from MSD, but also from MUD, should be considered in younger patients with intermediate-risk AML in CR1, and that the donor-recipient sex combination is more important than the donor type in donor selection. [ABSTRACT FROM AUTHOR]

Palifermin, a recombinant human keratinocyte growth factor, is commonly given to prevent mucositis following autologous transplantation. In the allogeneic hematopoietic stem cell transplant (allo-HSCT) setting, safety and efficacy data are limited. We conducted a retrospective study in 251 patients undergoing allo-HSCT, 154 of whom received peritransplant palifermin. In all patients, palifermin significantly decreased the mean number of days of total parenteral nutrition (TPN, 13 vs 16 days, P=0.006) and patient-controlled analgesia (PCA, 6 vs 10 days, P=0.023), as well as the length of initial hospital stay (LOS, 32 vs 37 days, P=0.014). However, the effect of palifermin was only significant in patients who received a TBI- but not BU-based chemotherapy conditioning regimen. In TBI recipients, palifermin decreased the mean number of days of TPN (13 vs 17 days, P<0.001) and PCA (7 vs 12 days, P=0.033), and the length of stay (32 vs 38 days, P=0.001). Palifermin did not affect GVHD, graft failure or relapse. Therefore, in the largest analysis with this patient population to date, we demonstrate that palifermin is safe in allo-HSCT patients, decreases TPN and PCA use and decreases LOS following TBI-based but not chemotherapy-based allo-HSCT. [ABSTRACT FROM AUTHOR]

In spite of the safety and efficiency of the classical mobilization protocols, recombinant human G-CSF±chemotherapy, there is still a considerable amount of mobilization failures (10-30%), which warrant novel agents and approaches both in an autologous and an allogeneic transplant setting. Attempts to improve CD34+ yields by using several cytokines and growth factors as adjuncts to G-CSF could not change the standard approaches during the last decade, either because of inefficiency or the adverse events encountered with these agents. As a long-acting G-CSF analog, pegfilgrastim has the advantages of an earlier start of apheresis, reduction in the number of apheresis procedures as well as a reduced number of injections as compared with unconjugated G-CSF. However, dosing and cost-effectiveness especially in cytokine-only mobilizations require further investigation. As interactions between hematopoietic stem cells and the BM microenvironment are better understood, new molecules targeting these interactions are emerging. Plerixafor, which started its journey as an anti-HIV drug, recently ended up being a popular stem cell mobilizer with the ability of rapid mobilization and gained approval as an adjunct to G-CSF for poor mobilizers. At present, it is challenging to search for the best approach by using the available drugs with appropriate timing to provide sufficient CD34+ yield after an initial mobilization attempt, and in a cost-effective manner thereby avoiding further mobilization attempts and exposure to chemotherapy. Approaches not only for increasing stem cell yield, but also aiming to improve the quality of graft content and the associated transplantation outcomes are promising areas of research. [ABSTRACT FROM AUTHOR]

To find an approach to prolong the survival time of cardiac allografts in a BALB/c-to-C57/BL6 heterotopic heart transplant model and to try to figure out related chemokines and cytokines, isogeneic and allogeneic BM cells were obtained from pregnant C57/BL6 (♀C57/BL6 × ♂BALB/c) and regular BALB/c mice and injected to the half lethally irradiated C57/BL6 mice 1 day before heart transplantation. Recipients were treated with CsA or phosphate-buffered saline for 7 days. Isogeneic BMT (iBMT) from pregnant C57/BL6 mice was observed to significantly prolong the survival of BALB/c allografts and reduce the lymphocyte infiltration. Allogeneic BMT (aBMT) and iBMT both exhibited signicantly less T-cell proliferation reactivity and the similar degree of chimerism. There was no significant difference in these groups of IFN-γ and IL-4 production. The level of chemokine MIG (CXCL9) dramatically decreased in aBMT and iBMT groups compared with the control group. But there were no significant differences between aBMT and iBMT group. IL-17 and RORγ(t) (receptor-related orphan receptor) production were downregulated in iBMT recipients. These results indicate that iBMT can prolong the survival of cardiac allografts. IL-17 production downregulated in iBMT recipients. This means that iBMT may have important therapeutic implications. [ABSTRACT FROM AUTHOR]

In this study, we report the comparative result of long-term clinical prognoses for patients with no-option critical limb ischemia (CLI) caused by arteriosclerosis obliterans, who are implanted with autologous bone marrow mononuclear cells (BMMNC; n=74) or G-CSF-mobilized (M)-PBMNC (n=111), as no information is available on how the two treatments compare in terms of long-term prognosis, such as survival or amputation. We performed pooled analysis using data from two previous cohort studies. All patients had disease of Fontaine classification III or IV. The endpoints were OS and amputation-free survival (AFS). After adjustment for history of dialysis and Fontaine classification, there was no significant difference between the two treatments with respect to OS (hazard ratio (HR)=1.49; 95% confidence interval (CI)=0.74-3.03, P=0.26) or AFS (HR=0.96; 95% CI=0.61-1.51, P=0.87). The negative prognostic factors affecting OS or AFS were the small number of CD34-positive cells collected, history of dialysis, Fontaine classification, male sex and older age. These results suggest that there was no significant difference in long-term prognosis between patients treated with BMMNC and those treated with M-PBMNC. The number of CD34-positive cells collected was an important prognostic factor for amputation and death. [ABSTRACT FROM AUTHOR]

Requests for participation of unrelated stem cell donors in research transplant protocols are becoming more frequent. World Marrow Donor Association calls on donor registries to participate in research activities. Here, we discuss various implications of research participation and make some recommendations as how to make this possible. [ABSTRACT FROM AUTHOR]

Busulfan influences engraftment and toxicities during hematopoietic stem cell transplantation (HSCT). We report our single-institution experience of targeted busulfan therapy for myeloablative, matched sibling donor (MSD) HSCT for sickle cell disease (SCD) and assess the relationships of busulfan levels to engraftment and toxicities. Twenty-seven patients with SCD underwent MSD HSCT from 1993 to 2007, 25 with busulfan measurements. The conditioning regimen was busulfan (initial dose 0.875 mg/kg for 16 doses), CY and antithymocyte globulin. Busulfan area under curve (AUC) was determined with the first dose, and dose adjustments were made to target the desired AUC range. Median AUC was 963 μmol min/L (range 780-1305 μmol min/L). Engraftment occurred in all cases: 21 (84%) full donor chimerism (>95% donor cells), 4 (16%) partial donor chimerism. Hepatic veno-occlusive disease (VOD) occurred in 8 (32%) patients. Lower AUC was seen with partial donor chimerism (862±73 μmol min/L) versus full donor chimerism (AUC 1018±122 μmol min/L) (P=0.022). VOD was not associated with busulfan AUC (P=0.153). Of 25 patients, 24 survived with median follow-up of 4.9 years. Our experience shows that targeting busulfan AUC above the range used in previous multicenter trials appears safe and may contribute to sustained engraftment in SCD. [ABSTRACT FROM AUTHOR]

Plerixafor is an inhibitor of CXCR-4 (CXC chemokine receptor-4)/SDF (stromal cell-derived factor)-1 binding used in combination with granulocyte colony-stimulating factor (G-CSF) for mobilization of autologous peripheral blood hematopoietic stem cells (HSCs). We developed a data-generated, cost-saving decision-making algorithm that uses the CD34+ count in the peripheral blood on the fourth day of G-CSF administration (PB-CD34+), and the collection target (T-CD34+) to decide between continuing G-CSF only (G approach) or adding plerixafor to the mobilization regimen (G+P approach) aiming at the lowest cost. The G+P approach was more cost-effective with lower PB-CD34+. It was possible to determine, for each T-CD34+, the maximum PB-CD34+ for which the G+P approach is cost-effective, generating an algorithm for the use of plerixafor. We validated this algorithm in a cohort of 34 patients undergoing HSC mobilization. In all, 11 patients completed collection on the G approach and 23 patients on the G+P approach, with 91% of the patients completing collection within the predicted number of apheresis sessions. All patients who underwent transplantation engrafted with minimal differences in engraftment time between G and G+P approaches. This validated algorithm provides a potential cost-saving decision tool for the use of plerixafor in autologous HSC mobilization. [ABSTRACT FROM AUTHOR]

Fifty-one patients with primary myelofibrosis (PMF) received allogeneic haematopoietic stem cell transplants from related (n=33) or unrelated (n=18) donors. Twenty-seven patients, 19-54 years old, were prepared with myeloablative regimens including CY plus BU (n=4) or TBI (n=23). Twenty-four patients, 40-64 years old, received reduced-intensity conditioning (RIC) regimens. All RIC regimens contained fludarabine, combined with melphalan (n=19) or BU (n=5), and alemtuzumab or anti-thymocyte globulin (ATG) in the majority (n=19). Four patients (17%) in the RIC group had primary graft failure. Previous splenectomy reduced time to engraftment in the RIC group (13 versus 20 days; P=0.008). For MA and RIC groups, respectively, at 3 years, overall survival rates were 44 and 31% (P=0.67), progression-free survival 44 and 24% (P=0.87), and actuarial relapse rates 15 and 46% (P=0.06). Non-relapse mortality at 3 years was 41% for the myeloablative and 32% for the RIC group. Acute GVHD occurred in 29 and 38% of patients in the myeloablative and RIC groups, respectively. Extensive chronic GVHD developed in 30 and 35% of evaluable patients, respectively. [ABSTRACT FROM AUTHOR]

Fluid retention is characteristic of veno-occlusive disease (VOD). We hypothesized that plasma brain natriuretic peptide (BNP), a neurohormone secreted in response to volume expansion, may be associated with VOD after hematopoietic stem cell transplantation (HSCT). BNP was measured before and weekly after HSCT in 46 recipients. Sixteen patients developed VOD. BNP concentrations were similar before and on day 0 in patients with and without VOD, but were significantly higher on day 7 and later in those with VOD. Patients with VOD had significantly higher peak BNP concentrations before engraftment than those without VOD (median, 634.4 versus 80.9 pg ml−1; P=0.01). Multivariate analysis showed that VOD was independently associated with BNP elevation (odds ratio, 50.1; 95% CI: 5.2-478.4; P<0.01). Landmark analysis at day 7 showed that patients with peak BNP concentration of 180 pg ml−1 had significantly worse 100-day survival than patients with peak BNP <180 pg ml−1 (54 versus 91%; P<0.01). In multivariate analysis, BNP elevation before day 7 significantly predicted 100-day survival (hazard ratio 5.3; 95% CI: 1.1-24.3; P=0.03). These findings suggest that plasma BNP may serve as a diagnostic and prognostic marker of VOD. [ABSTRACT FROM AUTHOR]

The hair follicles of recipients of allogeneic hematopoietic SCT (HSCT) constitute the tissue with the greatest need for regeneration after high-dose chemotherapy. Previous studies have shown a lack of donor-derived DNA in the hair follicles of recipients. Therefore, we carried out a study to determine whether male donor-derived genetic material can be found in female recpients' hair follicles after HSCT. Fluorescent-based PCR with analyses of Y-chromosome STR (Y-STR) and RQ-PCR with the sex-determining region Y (SRY) were used independently to evaluate chimerism status. Our results proved the existence of donor-derived stem DNA in the recipients' hair follicle cells. This report undermines the validity of data indicating that hair follicle cells maintain 100% of recipient origin. [ABSTRACT FROM AUTHOR]

Hematopoietic SCT (HSCT) and high-dose chemotherapy are being explored as therapy for various human refractory immune-mediated conditions, including inflammatory bowel diseases (IBD). Nevertheless, the exact immunological mechanisms by which the BM cells (BMCs) or immunosuppression provide remission from these diseases is not yet clear. In this work, we investigated the role of these therapies in the modulation of gut mucosal inflammation in an experimental model of IBD. Colitis was induced in mice by 2,4,6-trinitrobenzenesulfonic acid and after CY was administered (200 mg/kg) alone (CY group) or followed by BMCs infusion (HSCT group). Animals were followed for 60 days. Both HSCT and CY reduced the histopathological features of colitis significantly. Infused cells were localized in the gut, and a marked decrease of CD4+ leukocytes in the inflammatory infiltrate on days +7 and +14 and of CD8+ cells on day +7 was found in both treatments allied to impressive reduction of proinflammatory Th1 and Th17 cytokines. Although chemotherapy alone was the best treatment regarding the induction of immunosuppressive molecules, only HSCT resulted in increased survival rates compared with the control group. Our findings indicate that high-dose CY followed by HSCT is effective in the modulation of mucosal immunity and in accelerating immune reconstitution after BMT, thus providing valuable tools to support the development and understanding of novel therapeutic strategies for IBD. [ABSTRACT FROM AUTHOR]

The high doses of chemotherapy used for the preparatory regimens before autologous blood or marrow stem cell transplantation leave patients at risk for neutropenic complications. The administration of filgrastim post transplant reduces the time to neutrophil recovery and therefore has become a standard practice at many institutions. In 2006, we implemented a practice change from filgrastim to pegfilgrastim. We present data on 164 consecutive patients (82 patients who received filgrastim compared with 82 patients who received pegfilgrastim) who received an auto-SCT between January 2006 and November 2007. Patients who received pegfilgrastim had faster engraftment (9.6 days compared with 10.9 days, P<0.0001), a lower incidence of febrile neutropenia (59% compared with 78%, P=0.015), as well as shorter hospital stay, fewer days of treatment with i.v. antibiotics (6.3 days compared with 9.6 days, P=0.006), and fewer radiographic tests, which translated to an estimated total cost savings of over $8000 per patient. Overall, there were no differences in toxicity with these two agents. We conclude that a single dose of pegfilgrastim is a safe and efficacious alternative to daily injections of filgrastim and can be a cost-effective approach in auto-SCT patients. [ABSTRACT FROM AUTHOR]

We have developed a new BMT method, intra-BM-BMT (IBM-BMT), in which donor BM cells (BMCs) are directly injected into the recipient’s BM, resulting in a rapid recovery of donor hematopoiesis and a reduction in the severity of GVHD. In the present experiment, we attempted to retain the number of injected BMCs using magnetic beads and a magnet. The BMCs of donor mice were conjugated with magnetic beads, and these cells were then injected into the BM of recipient mice with a magnet (magnet-IBM group) and compared with conventional IBM-BMT without a magnet (IBM group). A significantly higher number of transplanted cells were detected in the injected BM in the magnet-IBM group. We next carried out day-12 colony-forming units of spleen (CFU-S) assays to examine the early stage of hematopoiesis of the injected host hematopoietic stem cells after IBM-BMT. The spleens of mice in the magnet-IBM group showed considerably higher CFU-S counts than those in the IBM group. Excellent reconstitution of donor hematopoietic cells in the magnet-IBM group was observed 1 month after IBM-BMT. These results suggest that the IBM-BMT using the combination of magnetic beads and a magnet is superior to the conventional IBM-BMT. [ABSTRACT FROM AUTHOR]

Treatment options for secondary progressive multiple sclerosis (SPMS) are limited. Mitoxantrone is routinely used to stabilize disease progression; however, evolving evidence suggests clinical benefit from intensive treatment with autologous haematopoietic stem cell transplantation (HSCT). Given differences in cost and outcomes, preliminary cost-effectiveness studies are warranted if this approach is to be developed for more widespread application in SPMS. We developed a decision-analytic Markov model to explore the potential cost-effectiveness of autologous HSCT versus mitoxantrone in SPMS, using patient-level data from registry sources. The model evaluates the lifetime costs and health outcomes associated with disability progression and relapse. Sensitivity analyses were undertaken to examine the uncertainty surrounding cost-effectiveness outcomes. In the absence of randomised controlled trial (RCT) evidence, conditions for comparative analysis were not ideal. Under optimistic assumptions, HSCT is estimated to cost below £3000 per quality adjusted life year gained. However, when a strict 6-month sustained progression rule is adopted, HSCT may be less effective and more expensive than mitoxantrone. The model results were sensitive to reducing procedural costs and HSCT-related mortality. We conclude that HSCT could potentially achieve an acceptable level of cost-effectiveness. However, caution should be exercised as large, high-quality RCTs comparing HSCT versus mitoxantrone are necessary to validate these findings. [ABSTRACT FROM AUTHOR]

GVHD is partly mediated by host APCs that activate donor T cells. Extracorporeal photopheresis (ECP) can modulate APC function and benefit some patients with GVHD. We report the results of a study using ECP administered before a standard myeloablative preparative regimen intended to prevent GVHD. Grades II–IV acute GVHD developed in 9 (30%) of 30 recipients of HLA-matched related transplants and 13 (41%) of 32 recipients of HLA-matched unrelated or HLA-mismatched related donor transplants. Actuarial estimates of overall survival (OS) at day 100 and 1-year post transplant were 89% (95% CI, 78–94%) and 77% (95% CI, 64–86%), respectively. There were no unexpected adverse effects of ECP. Historical controls receiving similar conditioning and GVHD prophylaxis regimens but no ECP were identified from the database of the Center for International Blood and Marrow Transplant Research and multivariate analysis indicated a lower risk of grades II–IV acute GVHD in patients receiving ECP (P=0.04). Adjusted OS at 1 year was 83% in the ECP study group and 67% in the historical control group (relative risk 0.44; 95% CI, 0.24–0.80) (P=0.007). These preliminary data may indicate a potential survival advantage with ECP for transplant recipients undergoing standard myeloablative hematopoietic cell transplantation. [ABSTRACT FROM AUTHOR]

Chronic GVHD (cGVHD) of the liver is an important cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (allo-SCT). It is characterized by the destruction of bile duct epithelium followed by progressive cholestasis, which resembles primary biliary cirrhosis (PBC) clinically and histologically. Bezafibrate (BF) is a widely used agent for hyperlipidemia that is also effective in ursodeoxycholic acid (UDCA)-resistant PBC patients. The putative mechanism in cholestasis is that BF upregulates the expression of phosphatidylcholine flippase on bile canaliculi, facilitates phospholipid output into bile and relieves bile duct damage caused by hydrophobic bile salts. Therefore, the effects of BF in patients with cGVHD of the liver were investigated. Of 87 patients with cGVHD who survived more than 100 days after SCT, 8 were given BF to treat liver cGVHD because of a poor therapeutic response to UDCA and immunosuppressants. The serum alkaline phosphatase (ALP) and γ-glutamyl transpeptidase (γ-GTP) levels decreased significantly within 1 month after initiation of BF therapy compared with those before BF therapy in all patients (ALP, 964.9.0±306.9 to 597.8±102.5 IU/l, P=0.012; γ-GTP, 528.8±299.0 to 269.0±119.9 IU/l, P=0.012). BF was effective in patients with liver cGVHD, including UDCA-resistant patients. BF could be a novel therapeutic option for liver cGVHD that helps to preserve normal immunity with the antileukemic effect of cGVHD. [ABSTRACT FROM AUTHOR]

Nearly half of the unrelated hematopoietic SCTs facilitated worldwide involves an exchange of products between countries. The process is information intensive and requires coordination through regional hubs of complex data transactions of demographic, clinical and genetic information, laboratory samples and results. Each registry has developed its own unique systems for representing data and process leading to transplantation. The WMDA Information Technology Working Group was formed in the autumn of 2001 as a forum to discuss and develop standards for information technology (IT) in support of hematopoietic stem cell registries. Its membership includes experts in IT from the WMDA member registries. The group has focused its standardization efforts on three areas: Standardized reference data sets for validation and plausibility controls for HLA and other data domainsMatching algorithm standards for determining histocompatibilityCommunication standards between registries. [ABSTRACT FROM AUTHOR]

Since the beginning of hematopoietic stem cell harvesting from volunteer unrelated donors, ensuring donor safety has been a necessary goal of all parties involved in the process. As donation of BM or PBSCs is not in the interest of the donor's own physical health, donor registries and transplantation centers must take into account both medical and ethical aspects involved in the donation procedure. One of the principal goals leading to the formation of the World Marrow Donor Association (WMDA) was to establish internationally acceptable standards for all aspects of unrelated donor care. [ABSTRACT FROM AUTHOR]

Fibrosis and excessive extracellular matrix production are characteristic features of lacrimal gland chronic GVHD (cGVHD). Tranilast (n-[3,4-anthoranilic acid]), used for fibrotic skin disease, inhibits transforming growth factor-β-induced matrix production. We conducted a non-randomized study comparing 8 patients (five men, three women; median age, 47 years) given topical tranilast with 10 patients (three men, seven women; median age, 37 years) receiving therapy with topical artificial tears, sodium hyaluronate and vitamin A for mild ocular cGVHD. The tranilast group instilled topical tranilast and artificial tears q.i.d., beginning the day of dry eye diagnosis. The ocular surface and tear dynamics of each patient were evaluated before hematopoietic stem cell transplant, at the onset of dry eye and after 3 months of treatment. At 3 months, the scores of the Rose Bengal test and Schirmer test with nasal stimulation had significantly improved in the tranilast group compared with that in the control group (P<0.05). Furthermore, although five control patients (50%) developed severe dry eye within the treatment period, only one tranilast-treated patient (12.5%) did; the rest still had mild dry eye (P<0.05). These results suggest the hypothesis that topical tranilast may effectively retard the progression of mild dry eye associated with cGVHD. [ABSTRACT FROM AUTHOR]

Donating BM or peripheral stem cells is a challenging process that requires a considerable commitment on the part of the donating individual, especially when there is a relationship between donor and recipient. In order to develop a better understanding of related donor management, the research subcommittee of the European Group for Blood and Marrow Transplantation-Nurses Group (EBMT-NG) designed a questionnaire to survey European transplant centres. This questionnaire investigated several key areas, including guidelines, patient information, donor consent and follow-up services. It was distributed to a sample of delegates (N=150) at the 2005 meeting of the EBMT-NG. Guidelines for the information given to patients were primarily from local (33, 52%), and a combination of local and national (13, 21%) sources. Transplant information was predominantly given to related donors by the recipient's transplant team (36, 57%). A total of 33 (52%) centres indicated that donors were also consented by transplant doctors, whereas 16 (25%) identified that consent was obtained by doctors who were not connected with the transplant team. At present, there is a lack of recognized standardized guidelines for the management of related donors. The development of such guidelines would assist in maintaining patient autonomy, confidentiality and access to accurate and objective information. [ABSTRACT FROM AUTHOR]

To determine the effects of TBI dose, fractionation and lung shielding on hematopoietic stem cell homing to the BM, BM cells were extracted from tibiae and femurs of B6-green fluorescent protein (GFP) mice and transplanted into B6 mice. Recipient mice had either: (i) no radiation, (ii) single-dose TBI at 13.6 Gy, (iii) single-dose TBI at 13.6 Gy with reduced lung exposure to 0.4 Gy by shielding, (iv) split-dose TBI at 12 Gy to twice per day over 4 days or (v) split-dose TBI at 12 Gy to twice per day over 4 days with reduced lung exposure to 0.36 Gy by shielding. The last radiation exposure preceded tail vein injection by 4–6 h. Mice were killed after 18 h. The homing of GFP-positive, lineage-negative cells was not significantly improved in any irradiated group compared with control. The homing of GFP-positive, lineage-negative, Kit-positive cells was significantly worse in all irradiated groups. TBI does not improve the homing of lineage-negative donor BM cells to the recipient marrow. The homing of lineage-negative, Kit-positive donor BM cells was significantly worse following TBI, with or without lung dose reduction. [ABSTRACT FROM AUTHOR]

Since the first human cord blood transplant, performed 20 years ago, cord blood banks have been established worldwide for the collection and cryopreservation of cord blood for allogeneic hematopoietic stem cell transplant. A global network of cord blood banks and transplant centers has been established for a common inventory and study of clinical outcomes. Results of unrelated allogeneic cord blood transplants in malignant and nonmalignant diseases, in adults and children, show that, compared with HLA-matched unrelated BM transplant, cord blood has several advantages, including prompt availability of the transplant, decrease of GVHD and better long-term immune recovery resulting in a similar long-term survival. Several studies have shown that the number of cells is the most important factor for engraftment, although some degree of HLA mismatches is acceptable. Developments are expected to facilitate engraftment, including ex vivo expansion of stem cells, intrabone injection of cord blood cells and double cord blood transplants. In addition to hematopoietic stem cells, cord blood and placenta contain a large number of nonhematopoietic stem cells. In the absence of ethical concern, the unlimited supply of cells explains the increasing interest of using cord blood for developing regenerative medicine. [ABSTRACT FROM AUTHOR]

A marked increase in the utilization of umbilical cord blood (UCB) transplantation has been observed in recent years; however, the use of UCB as a hematopoietic stem cell (HSC) source is limited primarily by the number of progenitor cells contained in the graft. Graft failure, delayed engraftment and profound delay in immune reconstitution lead to significant morbidity and mortality in adults. The lack of cells available for post transplant therapies, such as donor lymphocyte infusions, has also been considered to be a disadvantage of UCB. To improve outcomes and extend applicability of UCB transplantation, one potential solution is ex vivo expansion of UCB. Investigators have used several methods, including liquid suspension culture with various cytokines and expansion factors, co-culture with stromal elements and continuous perfusion systems. Techniques combining ex vivo expanded and unmanipulated UCB are being explored to optimize the initial engraftment kinetics as well as the long-term durability. The optimal expansion conditions are still not known; however, recent studies suggest that expanded UCB is safe. It is hoped that by ex vivo expansion of UCB, a resulting decrease in the morbidity and mortality of UCB transplantation will be observed, and that the availability of additional cells may allow adoptive immunotherapy or gene transfer therapies in the UCB setting. [ABSTRACT FROM AUTHOR]

Efforts are needed to enhance the efficacy of cord blood (CB) transplantation. Laboratory information set the stage for the first and subsequent CB transplants, and will be instrumental in continuing to advance the field. This paper offers a brief understanding of the current state of hematopoietic stem cell (HSC) and hematopoietic progenitor cell (HPC) biology, a look back at laboratory studies leading to the first CB transplants, and a discussion of the possible means to enhance CB transplantation. Results show that physical recovery of greater numbers of HPCs is possible after CB is collected by perfusing the placenta, but how realistic this procedure is for collection of CB to be banked is open to question. We also show that the chemokine stromal cell-derived factor-1/CXCL12 can enhance the ex vivo expansion of CB HPCs beyond that of the combination of SCF, Flt3-ligand and TPO. Advances in cytokine and stromal cell biology, and in intracellular signals mediating the effects of cytokines/stromal cells should be considered in the context of future efforts to enhance functional activities of donor CB HSCs and HPCs and the microenvironmental niche of the recipient, which is required for acceptance and nurturing these HSCs/HPCs. [ABSTRACT FROM AUTHOR]

The use of umbilical or placental donor cord blood transplantation (CBT) in children with malignant and non-malignant diseases has witnessed important progress, mainly because of better cord blood donor choice and patient selection translating into better patient outcome. Approximately 2000 children with malignant diseases (about 75 % with acute leukemias) have been transplanted with a related (n=199) or unrelated CBT (UCBT, n=1663) and reported to Eurocord registry from 1990–2008. Disease-specific studies have been carried out after UCBT for acute lymphoblastic and myeloid leukemia and myelodysplastic syndromes in others to identify the risk factors that may improve outcomes. Outcomes after CBT have been compared with other alternative allogeneic hematopoietic SCT (HSCT) donors. Briefly, after CBT, myeloid engraftment is delayed, acute and chronic GVHD decreased and disease-free survival was not statistically different when compared with HLA identical and other alternative HSCT donor. Therefore, any physician has to carefully evaluate, for each single pediatric patient in need of an allograft, all the possible alternatives in order to choose the best hematopoietic stem cell donor, taking into account type of disease, urgency of transplantation, donor characteristics and center experience. This review will analyze the current results of CBT for pediatric patients with malignant diseases and the advantages and limitations of using this stem cell source. [ABSTRACT FROM AUTHOR]

The importance of HLA donor–recipient matching in unrelated haematopoietic SCT (HSCT) is the subject of debate. In this retrospective study, we analyzed 805 adult patients from the Italian Registry receiving HSCT for a haematological malignancy from January 1999 to June 2006 and correlated the degree of HLA matching with transplant outcome. All patient–donor pairs had high-resolution typing at HLA-A, -B, -C, -DRB1 and -DQB1. There was a significantly higher risk of overall mortality, non-relapse mortality, graft failure and acute GVHD (aGVHD) for patients receiving HSCT from an unrelated donor with one or more low- or high-resolution mismatch/es (Mm/s). When only a single HLA Mm is present (9/10 matched pairs), mortality risk is higher than among 10/10 matched pairs in patients transplanted with acute leukaemia in the first CR (‘early’ patients) but not in the other patients (advanced patients): HR=1.69, 95% CI=0.94–3.02, P=0.08; HR=1.03, 95% CI=0.80–1.32, P=0.82, for early and advanced patients, respectively. These results confirm that the advantage of a 10/10 match has a greater effect in early patients, thus suggesting that a 9/10 matched donor can be chosen in patients with advanced disease lacking a rapidly available 10/10 matched one. [ABSTRACT FROM AUTHOR]

The aim of this study was to investigate the influence of intracoronary injection of mononuclear BM cells (mBMCs) on inflammatory mediators in swine with acute myocardial infarction (AMI) in two groups. Group 1 received the therapy immediately after AMI, but group 2 received it after 3 weeks. The levels of cytokines and heart functions, respectively, were examined 3 weeks after cell therapy. The serum levels of TNF-α and IL-8 were significantly lower than in the control group: in contrast, IL-10 was significantly elevated in the cell recipients, especially in group 1. TNF-α correlated with IL-8 between groups. The ventricular functions were significantly improved. These results show that although the intracoronary injection of mBMCs induces a marked short-term inflammatory response in the acute stage, mBMCs may play an anti-inflammatory role topically and systematically and early cell therapy may be preferable. [ABSTRACT FROM AUTHOR]

We examined the effects of intra-BM-BMT (IBM-BMT) plus adult thymus transplantation (ATT) from the same donor after 5.5 Gy sublethal irradiation (SubLI) or low-dose (3 × 106) BM cell injection (LDBMCI). With SubLI, BALB/c mice that had received 1 × 107 bone marrow cells by IBM-BMT plus ATT from B6 mice showed 73% donor chimerism, whereas those treated with IBM-BMT alone showed 45% chimerism. In the LDBMCI with 7Gy irradiation, IBM-BMT plus ATT resulted in a 90% survival rate with 90% chimerism, whereas IBM-BMT alone resulted in a 55% survival rate with 44% chimerism. Although the number of CD4 T cells was higher in IBM-BMT plus ATT than in IBM-BMT alone, the percentages of FoxP3+/CD4+ T cells and lymphocyte functions in the former were almost identical to those in the latter. When treated with IBM-BMT plus donor lymphocyte infusion (DLI), the mice showed a reduced survival time as a result of GVHD, with low numbers of FoxP3+CD4 T cells under either condition, although 100% chimerism was induced. These results suggest that IBM-BMT plus ATT is effective in reconstituting the recipients with donor-derived cells even after SubLI or LDBMCI.Bone Marrow Transplantation (2009) 43, 829–837; doi:10.1038/bmt.2008.396; published online 15 December 2008 [ABSTRACT FROM AUTHOR]

We demonstrated that non-adherent BM cells (NA-BMCs) can be expanded in suspension and give rise to multiple mesenchymal phenotypes including fibroblastic, osteoblastic, chondrocytic and adipocytic as well as glial cell lineages in vitro using the ‘pour-off’ BMC culture method. Mesenchymal stem cells (MSCs) derived from NA-BMCs (NA-MSCs) from wild-type mice were transplanted into VDR gene knockout (VDR−/−) mice that had received a lethal dose of radiation. Results revealed that NA-MSC can be used to rescue lethally irradiated mice and become incorporated into a diverse range of tissues. After lethal dose irradiation, all untransplanted mice died within 2 weeks, whereas those transplanted with NA-MSCs were viable for at least 3 months. Transplantation rescued these mice by reconstructing a hematopoietic system and repairing other damaged tissues. WBC, RBC and platelet counts recovered to normal after 1 month, and VDR gene expression was found in various tissues of viable VDR−/− recipients. Adult BM harbors pluripotent NA-MSCs, which can migrate in vivo into multiple body organs. In an appropriate microenvironment, they can adhere, proliferate and differentiate into specialized cells of target tissues and thus function in damaged tissue regeneration and repair.Bone Marrow Transplantation (2009) 43, 69–81; doi:10.1038/bmt.2008.260; published online 18 August 2008 [ABSTRACT FROM AUTHOR]

Peripheral blood hematopoietic progenitor cells (PBHC) are the standard source of support for high-dose chemotherapy because of faster recovery of marrow function. Unfortunately, a proportion of patients are unable to mobilize adequate progenitors to proceed to autologous hematopoietic cell transplant (AHCT). Granulocyte-CSF-stimulated BM-derived hematopoietic progenitor cells (BMHC) may circumvent this problem. From 1999 to 2006, 52 patients (cases) with AML, Hodgkin (HL) or non-Hodgkin's lymphoma (NHL) in whom PBHC mobilization failed underwent a G-CSF-stimulated bone marrow harvest and proceeded to AHCT. Their outcome was compared with 422 patients (controls) with AML, HL and NHL undergoing AHCT using only PBHC. Twenty-three patients received BMHC alone and 29 patients recieved a combination of PBHC and BMHC. Median engraftment time for neutrophils (>0.5 × 109/l) and platelets (>20 × 109/l) were 14 and 27 days, but significantly longer when compared with controls (11days, 11 days, P<0.0001). Patients receiving both PBHC and BMHC had faster engraftment, when compared with those receiving BMHC alone (P<0.001). In conclusion, performing an AHCT using G-CSF-stimulated BMHC in patients failing PBHC collection is feasible with faster engraftment seen in patients receiving both BMHC and PBHC over BMHC alone.Bone Marrow Transplantation (2008) 42, 733–737; doi:10.1038/bmt.2008.249; published online 18 August 2008 [ABSTRACT FROM AUTHOR]

Long-term effects of autologous mononuclear bone marrow cell transplantation were studied in patients with severe peripheral arterial disease (PAD) and critical limb ischemia. Ten patients with end-stage disease were infused twice with autologous bone marrow cells and they completed the 12-month follow-up study. Substantial improvement of blood flow and increasing capillary densities were seen when compared with a concomitant control group comprising patients who did not enroll in the study. The ankle–brachial index (ABI) and pain-free walking distance improved significantly in treated patients. The improvement was sustained 12 months after treatment. These results confirm that the autologous bone marrow transplantation is an effective therapeutic strategy in critical limb ischemia.Bone Marrow Transplantation (2008) 42, 667–672; doi:10.1038/bmt.2008.228; published online 11 August 2008 [ABSTRACT FROM AUTHOR]

The best method to mobilize PBSCs in patients with non-Hodgkin's Lymphoma (NHL) is uncertain. We hypothesized that PBSC mobilization using an intensive chemotherapy regimen would improve outcomes after autologous hematopoietic stem cell transplantation (ASCT) in NHL patients at high risk for relapse. Fifty NHL patients were prospectively allocated to intense mobilization with high-dose etoposide plus either high-dose cytarabine or CY if they were ‘high risk’ for relapse, whereas 30 patients were allocated to nonintense mobilization with CY if they were ‘standard risk’ (all patients, ±rituximab). All intensely mobilized patients were hospitalized compared with one-third of nonintensely mobilized patients. The EFS after ASCT was the same between the two groups, but overall survival (OS) was better for intensely mobilized patients (<0.01), including the diffuse large B-cell subgroup (P<0.04). We conclude that the intense mobilization of PBSCs in patients with NHL is more efficient than nonintense mobilization, but with greater toxicity. The equalization of EFS and superiority of OS in patients intensely mobilized to those nonintensely mobilized suggests that a treatment strategy using intensive chemotherapy for mobilization may be improving NHL outcomes after ASCT.Bone Marrow Transplantation (2008) 42, 649–657; doi:10.1038/bmt.2008.236; published online 4 August 2008 [ABSTRACT FROM AUTHOR]

Prevention of GVHD is one of the most desirable goals of BMT in aplastic anemia (AA). We reviewed the medical records of 24 consecutive patients treated with BMT for acquired AA using two different GVHD prevention strategies. Ten patients were given alemtuzumab-based GVHD prophylaxis (50–60 mg in three divided doses on days −8, −7 and −6), and 14 patients were given conventional GVHD prophylaxis with calcineurin inhibitors plus MTX before the introduction of the alemtuzumab-based protocols. The incidence of acute, chronic and ‘serious GVHD’ was significantly reduced in alemtuzumab-treated patients compared to conventionally treated patients [11 vs 64% (P=0.03), 0 vs 78% (P=0.002) and 0 vs 57% (P=0.007), respectively]. Engraftment time and rates of graft failure appeared similar in the two groups. A significantly higher proportion of alemtuzumab-treated patients developed CMV reactivation compared to control patients (83 vs 12%; P=0.03); none developed CMV disease. The rates of other infectious complications did not appear significantly different. Our data suggest that 50–60 mg of alemtuzumab given according to the current schedule significantly reduces the risk of GVHD without increasing the risk of graft failure or serious infections.Bone Marrow Transplantation (2008) 42, 51–56; doi:10.1038/bmt.2008.88; published online 31 March 2008 [ABSTRACT FROM AUTHOR]

We performed a retrospective analysis of muscle strength testing obtained following sibling or unrelated donor hematopoietic stem cell transplant (HSCT) between 1 January 1999 and 31 December 2003 in a cohort of 44 subjects at Tufts-New England Medical Center. Maximal inspiratory pressure (PImax) was 80% predicted in 52% of subjects and 60% predicted in 20% of subjects; maximal expiratory pressure (PEmax) was 80% predicted in 88% of subjects and 60% predicted in 74% of subjects. Patients with a PImax 60% predicted spent significantly longer time in hospital following HSCT compared with subjects with PImax 60% predicted. Grip strength (n=32) was reduced to 80% predicted in 75% of subjects and 60% predicted in 47% of subjects following HSCT. Analysis of paired measurements obtained before and after HSCT in 20 of the 44 subjects (45%) showed significant reduction in both PImax and PEmax between the two measures. Respiratory and skeletal muscle weakness is present in a significant percentage of subjects undergoing pulmonary function testing in the post-HSCT period, and may contribute to pulmonary morbidity in subjects with pulmonary complications of HSCT.Bone Marrow Transplantation (2008) 41, 965–969; doi:10.1038/bmt.2008.15; published online 11 February 2008 [ABSTRACT FROM AUTHOR]

Our purpose was to determine the prevalence and features of metabolic syndrome (MS) in a series of long-term hematopoietic stem cell transplantation (HSCT) survivors. We assessed the clinical, metabolic and endocrinological data, and plasma TNF, leptin, resistin and adiponectin levels relating to 85 HSCT recipients. MS was diagnosed on the basis of the National Cholesterol Education Program-Adult Treatment Panel III criteria. Its prevalence was compared with that observed in an Italian population, and its relationship with the clinical and laboratory parameters was assessed univariately and multivariately. Twenty-nine HSCT recipients had MS instead of the 12.8 expected (P<0.0001), with hypertriglyceridemia being the most common feature. Univariate analysis indicated that high insulin and leptin levels, low-adiponectin levels and hypogonadism were significantly related to a diagnosis of MS; multivariate analysis indicated plasma leptin, insulin resistance, age and hypogonadism. We conclude that HSCT recipients are at increased risk of a form of MS that has particular clinical features. Plasma leptin levels are independently related to MS, thus suggesting that leptin resistance may play a role as a pathogenetic clue, as in other conditions in which MS occurs as a secondary phenomenon. MS deserves consideration as a life-threatening complication in patients who are probably cured of their underlying disease.Bone Marrow Transplantation (2008) 41, 797–804; doi:10.1038/sj.bmt.1705972; published online 14 January 2008 [ABSTRACT FROM AUTHOR]

Allogeneic hematopoietic stem cell transplantation (ASCT) and its conditioning with chemoradiotherapy often results in liver toxicity, the most severe form being veno-occlusive liver disease (VOD). N-acetyl-L-cysteine (NAC), an antioxidant glutathione precursor, may provide protection from liver toxicity. Patients with elevated bilirubin (>26 mmol/l) and/or elevated (ALT) (>1.4 μkat/l) and/or aspartate aminotransferase (AST) (>1.4 μkat/l) levels were randomized to treatment with NAC or no treatment. Among 522 transplanted patients, 160 were included in the trial. NAC was given, 100 mg/kg per day, as a 6-h i.v. infusion until normalization of bilirubin, ALT and AST values. Maximum bilirubin level was the same in patients randomized to NAC (n=72) or controls (n=88). Increase and recovery of ALT and AST were the same in patients randomized to NAC or controls. There were two patients in the NAC group who developed VOD, as compared to three of the controls. To conclude, NAC does not improve liver toxicity after ASCT.Bone Marrow Transplantation (2008) 41, 785–790; doi:10.1038/sj.bmt.1705969; published online 7 January 2008 [ABSTRACT FROM AUTHOR]

The impact of thrombotic microangiopathy (TMA) on outcome was studied in 148 patients with acute graft-versus-host disease (GVHD) (grade II). The Blood and Marrow Transplant Clinical Trials Network's definition for TMA was used to diagnose definite TMA. Probable TMA was diagnosed when none of the features of nephropathy and neurologic abnormalities associated with definite TMA were present. Overall, TMA developed in 43 (29%) patients; 16 definite and 27 probable. The occurrence of TMA, the maximum grade of acute GVHD and initial treatment failure were associated with shorter overall and GVHD-specific survival. The development of probable as well as definite TMA affected the survival of patients with acute GVHD adversely. These results show the clinical impact of TMA on patients with acute GVHD, and suggest that the proposed definitions and grading of TMA may need to be modified.Bone Marrow Transplantation (2008) 41, 813–820; doi:10.1038/sj.bmt.1705976; published online 21 January 2008 [ABSTRACT FROM AUTHOR]

The outcome of patients with acute lymphoblastic leukemia (ALL) receiving therapeutic donor lymphocyte infusions (DLIs) in relapse after stem cell transplantation (SCT) is poor. We analyzed the impact of prophylactic DLIs in ALL on chimerism and sustained complete remission (CR). Eighty-five patients with ALL were allografted between January 1998 and September 2004. Twenty-six of them received prophylactic DLIs and were included in this analysis. A total of 12 of 13 patients, who were treated with mixed chimerism (MC) converted to complete donor chimerism (92%) and 10 of 12 patients had persistent donor chimerism and sustained CR during subsequent follow-up. Overall, 18 of 26 patients developed graft-versus-host disease (GVHD) after DLIs (69%), acute GVHD in 46 and chronic GVHD in 62%. After a median follow-up of 42 months (14–72) after SCT, 18 of 26 patients (70%) are alive, 16 in CR. Probability of event-free survival (EFS) for patients treated with DLIs is 62%, and overall survival is 70% at 3 years. Our preliminary data support a graft-versus-leukemia effect of prophylactic DLIs able to induce stable donor chimerism and ongoing CR after SCT. As the accompanying GVHD rate was considerable, careful selection of patients for prophylactic DLIs is mandatory.Bone Marrow Transplantation (2008) 41, 805–812; doi:10.1038/sj.bmt.1705981; published online 14 January 2008 [ABSTRACT FROM AUTHOR]

Severe pain syndromes may be recorded during all phases of haematopoietic stem cell transplantation (HSCT) for haematological malignancies: from stem cell mobilization to the long-term post transplant period. Although the major cause of pain in the setting of HSCT is injury to mucosal tissues induced by the conditioning regimen, pain from several other causes has been reported. In this paper, we review pain and its management in the setting of HSCT.Bone Marrow Transplantation (2008) 41, 757–764; doi:10.1038/bmt.2008.3; published online 4 February 2008 [ABSTRACT FROM AUTHOR]

Achievement of complete donor chimerism (CDC) after allogeneic nonmyeloablative hematopoietic stem cell transplantation (NMHSCT) is important for preventing graft rejection and for generating a graft-vs-malignancy effect. The alloreactivity of NK cells and some T-cell subsets is mediated through the interaction of their killer immunoglobulin-like receptors (KIRs) with target cell HLA/KIR ligands. The influence of KIR matching on the achievement of T-cell CDC after NMHSCT has not been previously described. We analyzed 31 patients undergoing T-cell replete related donor NMHSCT following fludarabine and 200 cGy TBI. Recipient inhibitory KIR genotype and donor HLA/KIR ligand matches were used to generate an inhibitory KIR score from 1 to 4 based upon the potential number of recipient inhibitory KIRs that could be engaged with donor HLA/KIR ligands. Patients with a score of 1 were less likely to achieve T-cell CDC (P=0.016) and more likely to develop graft rejection (P=0.011) than those with scores greater than 1. Thus, patients with lower inhibitory KIR scores may have more active anti-donor immune effector cells that may reduce donor chimerism. Conversely, patients with greater inhibitory KIR scores may have less active NK cell and T-cell populations, which may make them more likely to achieve CDC.Bone Marrow Transplantation (2008) 41, 709–714; doi:10.1038/sj.bmt.1705954; published online 14 January 2008 [ABSTRACT FROM AUTHOR]

Several high-dose therapy regimens are used for autologous hematopoietic stem cell transplantation (auto-HSCT) for relapsed and refractory Hodgkin's lymphoma (HL) with variable disease response. An intensified regimen of etoposide (VP-16) 2400 mg/m2, cyclophosphamide 7200 mg/m2 and carmustine (BCNU) 600 mg/m2 (VCB) pre-auto-HSCT was developed to overcome disease recurrence. A total of 43 relapsed and refractory HL patients underwent auto-HSCT between January 1992 and December 2004. At day 100 there were 37 (86%) complete responses. A total of 40 patients survived beyond day 100, 14 of whom subsequently relapsed/progressed. At a median follow-up of 4.9 years (range 1.5–11.4 years), 26 patients (60%) are alive and disease free. Five-year actuarial event-free survival (EFS) was 53% (95% CI 35–70%) and median EFS was 5.9 years. Median progression-free and overall survivals have not been reached. EFS was reduced with an increasing number of prognostic factors (Karnofsky performance status, KPS <90, chemotherapy-resistant disease and 3 chemotherapy regimens prior to transplant 1 vs 2; P=0.049). Grade III–IV regimen-related toxicity was 9% (n=4). The 1-year cumulative incidence of interstitial pneumonitis (IP) was 36%, however only two patients died of IP complications. Disease progression was the most common cause of death (n=10, 23%). Intensive VCB is an effective and well-tolerated preparative regimen for relapsed and refractory HL auto-HSCT.Bone Marrow Transplantation (2008) 41, 613–619; doi:10.1038/sj.bmt.1705951; published online 10 December 2007 [ABSTRACT FROM AUTHOR]

We attempted to rescue supralethally irradiated (SLI) mice by transplantation of hematopoietic stem cells (HSCs) plus thymus from variously aged donors (fetus, newborn and adult). Although the transplantations of these kinds of HSCs alone showed a very short survival, newborn liver cells (NLCs) (as the source of HSCs) plus newborn thymus (NT) transplantation markedly improved the survival rate. The transplantation attenuated severe damage in the small intestine, which is one of the major causes of death by SLI. In addition, the donor-derived CD4+ T cells significantly increased with additional NT transplantation. The production of interleukin (IL)-7 and keratinocyte growth factor, which plays a crucial role in protection against radiation injury in the intestine, was the highest in NT. Finally, SLI mice that had received NLC plus IL-7−/− NT transplantation plus IL-7 injection showed improved survival, weight recovery and an elevated number of CD4+ T cells compared with the mice that had received NLC plus IL-7−/− NT or plus IL-7 injection alone. These findings suggest that NLCs plus NT transplantation can rescue SLI mice most effectively, and that high production of IL-7 in NT plays a crucial role with induction of CD4+ T cells.Bone Marrow Transplantation (2008) 41, 659–666; doi:10.1038/sj.bmt.1705957; published online 7 January 2008 [ABSTRACT FROM AUTHOR]

Allogeneic hematopoietic stem cell transplantation (HSCT) can prolong life and improve its quality in patients with inherited metabolic diseases. HSCT offers a permanent source of enzyme replacement therapy and also might mediate nonhematopoietic cell regeneration or repair. Unrelated cord blood is an exciting newer graft source for treatment of patients with these fatal disorders, providing increased access to donors and significant clinical efficacy, particularly when transplantation is performed in early stages. Pre-transplant performance status is highly predictive of overall survival.Bone Marrow Transplantation (2008) 41, 99–108; doi:10.1038/sj.bmt.1705970; published online 7 January 2008 [ABSTRACT FROM AUTHOR]