Increase of bone marrow macrophages and CD8+ T lymphocytes predict graft failure after allogeneic bone marrow or cord blood transplantation.

Graft failure (GF) remains an obstacle to survival after allogeneic hematopoietic stem cell transplantation. However, differentiating GF from delayed engraftment (DE) can be difficult. Host CD8+ lymphocytes have been reported to mediate graft rejection, but the impact of macrophages on DE or GF is yet to be clarified. Peri-engraftment bone marrow (BM) specimens of 32 adult patients with normal engraftment, DE or GF were retrospectively evaluated to identify the potential associations of CD163+ macrophage and CD8+ lymphocyte infiltration into BM. The macrophage or CD8+ lymphocyte number/total nucleated cell number was defined as the Mac ratio and CD8 ratio, respectively. Both DE and GF groups had significantly higher Mac ratios at day 14 than the normal group (P<0.0001), but no significant difference was observed between the DE and GF groups (P=1.000). The CD8 ratio at day 14 was significantly higher in the GF than in the normal group (P=0.005), whereas the CD8 ratios of the DE and normal groups were similar (P=0.07). A high Mac ratio at day 14 was associated with a risk of DE or subsequent GF. Patients with increased CD8 ratio at day 14 had a further risk of GF. The Mac ratio and the CD8 ratio appear to be well suited for predicting engraftment status.

Impact of MRD and TKI on allogeneic hematopoietic cell transplantation for Ph+ALL: a study from the adult ALL WG of the JSHCT.

To assess the impact of minimal residual disease (MRD) and tyrosine kinase inhibitor (TKI) administration on allogeneic hematopoietic cell transplantation (allo-HCT) for Ph-positive ALL (Ph+ALL), we retrospectively analyzed data from a registry database for 432 adult Ph+ALL patients in first CR (CR1) who received pre-transplant TKI administration. Negative MRD (MRD(-)) at allo-HCT was achieved in 277 patients. OS in patients transplanted in MRD(-) was significantly better than that in patients transplanted in MRD(+) (MRD(-): 67% vs MRD(+): 55% at 4 years; P=0.001). MRD(-) at allo-HCT was a significant risk factor for survival along with age at allo-HCT in multivariate analyses. Incidence of relapse in patients transplanted in MRD(-) was significantly lower than that in patients transplanted in MRD(+) (MRD(-): 19% vs MRD(+): 29% at 4 years; P=0.006). In multivariate analyses, MRD(+) at allo-HCT was a significant risk factor for relapse. A post-transplant TKI was administered to 103 patients. In subanalyses regarding the effect of post-transplant TKI administration, post-transplant TKI administration was a significant risk factor for relapse in multivariate analyses (P<0.0001). MRD status at allo-HCT is one of the most important predictive factors for Ph+ALL patients transplanted in CR1.

Reduced-intensity allogeneic stem cell transplantation for patients aged 50 years or older with B-cell ALL in remission: a retrospective study by the Adult ALL Working Group of the Japan Society for Hematopoietic Cell Transplantation.

We retrospectively assessed the outcome and pretransplantation predictors of the outcome in 118 patients aged ≥ 50 years who received fludarabine-containing reduced-intensity allo-SCT (RIST) for B-cell ALL in the first or second CR. Eighty patients received transplants from unrelated donors. Seventy-eight patients were positive for the Ph chromosome. The median follow-up period was 18 months and the 2-year OS rate was 56%. The 2-year cumulative incidence of relapse and non-relapse mortality was 28% and 26%, respectively. The incidence of grades II-IV and III-IV acute GVHD was 46% and 24%, respectively. After 2 years, the incidence of chronic GVHD was 37%. Multivariate analysis of pretransplant factors showed that a higher white blood cell count (≥ 30 × 10(9)/L) at diagnosis (hazard ratio (HR)=2.19, P=0.007) and second CR (HR=2.02, P=0.036) were significantly associated with worse OS, whereas second CR (HR=3.83, P<0.001) and related donor (HR=2.34, P=0.039) were associated with a higher incidence of relapse. Fludarabine-containing RIST may be a promising strategy for older patients with B-cell ALL in their first remission.

Reduced-intensity vs myeloablative conditioning allogeneic hematopoietic SCT for patients aged over 45 years with ALL in remission: a study from the Adult ALL Working Group of the Japan Society for Hematopoietic Cell Transplantation (JSHCT).

In this study, outcomes for 575 adult ALL patients aged ≥45 years who underwent first allo-SCT in CR were analyzed according to the type of conditioning regimen (myeloablative conditioning (MAC) for 369 patients vs reduced-intensity conditioning (RIC) for 206 patients). Patients in the RIC group were older (median age, 58 vs 51 years, P<0.0001). There were no statistically significant differences in 3-year OS, disease-free survival (DFS) and non-relapse mortality (NRM): 51% vs 53%, 47% vs 39% and 38% vs 36%, respectively. Multivariate analysis showed that CR2 and HLA mismatching were associated with poor OS (P=0.002 and P=0.019, respectively). HLA mismatching was associated with lower rate of relapse (P=0.016), but was associated with higher rate of NRM (P=0.001). RIC was associated with good OS and DFS in patients who received HLA-mismatch transplantation and were aged ≥55 years compared with MAC by multivariate analysis for each event with interaction (hazard ratio (HR) and 95% confidence interval 0.35 and 0.15-0.81, P=0.014 for OS and 0.36 and 0.16-0.81, P=0.013 for DFS). Therefore, patients ≥55 years of age with HLA-mismatch transplantation should be candidates for RIC rather than MAC.

Allogeneic hematopoietic cell transplantation from alternative sources for adult Philadelphia chromosome-negative ALL: what should we choose when no HLA-matched related donor is available?

The best outcome for patients with Ph chromosome-negative ALL (Ph(-) ALL) can be obtained by HLA-matched related donor (mRD) allogeneic hematopoietic cell transplantation (allo-HCT) in first CR. However, only 30% of patients have a mRD. Three alternative sources, unrelated donor (URD), cord blood, and haploidentical related donor (haplo-RD), are available. URD allo-HCT is an old-established alternative source, and recent data have shown that URD allo-HCT can result in OS comparable with that with mRD allo-HCT for patients with Ph(-) ALL in first CR (OS at 4 years: mRD 65% vs URD 62%). Unrelated cord blood transplantation can also be indicated for patients with Ph(-) ALL in first CR (OS at 4 years: 57%), especially for young patients without an HLA-matched URD or patients who are in urgent need for allo-HCT. Limited data for haplo-RD allo-HCT for ALL showed utility in CR (OS at 3 years: up to 65%) but a survival rate of only 5-7% in non-CR. As there are no confirmed data about the utility of allo-HCT from an alternative source for adolescent and young adults who are eligible for pediatric protocols or for elderly patients with reduced-intensity conditioning. Further investigation, including investigation of minimal residual disease detection, may reveal subgroups of patients who can receive benefits from allo-HCT. Selection of the best source based on the patient status and appropriate timing is warranted.

Impact of a donor source on adult Philadelphia chromosome-negative acute lymphoblastic leukemia: a retrospective analysis from the Adult Acute Lymphoblastic Leukemia Working Group of the Japan Society for Hematopoietic Cell Transplantation.

BACKGROUND: We aimed to clarify the impact of the donor source of allogeneic stem cell transplantation (allo-SCT) on Philadelphia chromosome-negative acute lymphoblastic leukemia [Ph(-) ALL] with focus on cord blood (CB). PATIENTS AND METHODS: We retrospectively analyzed data of 1726 patients who underwent myeloablative allo-SCT for adult Ph(-) ALL. The sources of the allo-SCT were related donors (RD; N = 684), unrelated donors (URD; N = 809), and CB (N = 233). RESULTS: Overall survival (OS) in patients after CB allo-SCT in first complete remission (CR1) was comparable with that after RD or URD allo-SCT (RD: 65%, URD: 64% and CB: 57% at 4 years, P = 0.11). CB was not a significant risk factor for relapse or non-relapse mortality as well as for OS in multivariate analyses. Similarly, the donor source was not a significant risk factor for OS in subsequent CR or non-CR (RD: 47%, URD: 39% and CB: 48% in subsequent CR, P = 0.33; RD: 15%, URD: 21% and CB: 18% in non-CR, P = 0.20 at 4 years). CONCLUSION: Allo-SCT using CB led to OS similar to those of RD or URD in any disease status. To avoid missing the appropriate timing, CB is a favorable alternative source for adult Ph(-) ALL patients without a suitable RD or URD.

Mast cells promote the growth of Hodgkin's lymphoma cell tumor by modifying the tumor microenvironment that can be perturbed by bortezomib.

Hodgkin's lymphoma is frequently associated with mast cell infiltration that correlates directly with disease severity, but the mechanisms underlying this relationship remain unclear. Here, we report that mast cells promote the growth of Hodgkin's tumor by modifying the tumor microenvironment. A transplantation assay shows that primary murine mast cells accelerate tumor growth by established Hodgkin's cell lines, and promote marked neovascularization and fibrosis. Both mast cells and Hodgkin's cells were sensitive to bortezomib, but mast cells were more resistant to bortezomib. However, bortezomib inhibited degranulation, PGE(2)-induced rapid release of CCL2, and continuous release of vascular endothelial growth factor-A from mast cells even at the concentration that did not induce cell death. Bortezomib-treated mast cells lost the ability to induce neovasculization and fibrosis, and did not promote the growth of Hodgkin tumor in vivo. These results provide further evidence supporting causal relationships between inflammation and tumor growth, and demonstrate that bortezomib can target the tumor microenvironment.

Clinical significance of hemophagocytosis in BM clot sections during the peri-engraftment period following allogeneic hematopoietic SCT.

The effects of macrophage activation on the outcome of allogeneic hematopoietic SCT (allo-HSCT) have yet to be fully examined. A total of 70 adult patients who received a first allo-HSCT for hematological diseases were studied. We counted the number of hemophagocytic cells in BM clot sections on day +14±7, and analyzed its impact on subsequent outcome. In all, 23 patients were diagnosed as having increased numbers of hemophagocytic cells (HP group), whereas 47 were not (non-HP group). The HP group was not associated with an increased incidence of acute or chronic GVHD, but was associated with worse hematopoietic recovery than the non-HP group. The 2-year OS for the HP group and the non-HP group was 30 and 65% (P<0.01), respectively, and 2-year non-relapse mortality was 48% and 27% (P<0.01), respectively. Multivariate analysis confirmed that the HP group was associated with a lower OS (hazard ratio (HR)=2.3; 95% confidence interval (CI), 1.0-5.4; P=0.048) and higher non-relapse mortality (HR=4.0; 95% CI, 1.6-9.9; P<0.01). The HP group had higher incidences of death due to graft failure (P<0.01) and endothelial complications, such as sinusoidal obstruction syndrome and transplant-associated microangiopathy (P=0.01). Macrophage activation is a previously unrecognized complication with negative impact on outcome of allo-HSCT.

A prospective dose-finding trial using a modified continual reassessment method for optimization of fludarabine plus melphalan conditioning for marrow transplantation from unrelated donors in patients with hematopoietic malignancies.

BACKGROUND: Because of the less graft-facilitating effect by bone marrow (BM), we need to assess a dosage of conditioning more accurately particularly in combination with reduced-intensity conditioning. Thus we examined that modified continual reassessment method (mCRM) is applicable for deciding appropriate conditioning of allogeneic BM transplantation. PATIENTS AND METHODS: The conditioning regimen consisted of i.v. fludarabine (125 mg/m2) plus an examination dose of i.v. melphalan. The primary endpoint was a donor-type T-cell chimerism at day 28 with successful engraftment defined as >90% donor cells. Five patients per dose level were planned to be accrued and chimerism data were used to determine the next dose. RESULTS: Seventeen patients were enrolled at doses between 130 and 160 mg/m2. The dose was changed from 160 to 130 mg/m(2) (second level) after five full-donor chimerisms. With one patient of 0% chimera in the second level, the dose was increased to 135 mg/m2 (third level). Following five full-donor chimerisms in the third level, the study was complete as projected. CONCLUSIONS: mCRM was shown to be a relevant method for dose-finding of conditioning regimen. The melphalan dose of 135 mg/m2 was determined as the recommended phase II dose to induce initial full-donor chimerism.

"Transmural air leak": a computed tomographic finding following endoscopic submucosal dissection of gastric tumors.

BACKGROUND AND STUDY AIMS: A small amount of free air, visible on CT but not on plain chest radiography, which appeared following endoscopic submucosal dissection (ESD) of a gastric neoplasm without endoscopically visible perforation, was defined as a "transmural air leak", and a prospective, consecutive entry study was performed to determine its incidence and clinical significance. PATIENTS AND METHODS: Between January 2006 and September 2008, ESD was performed for 246 gastric lesions in 246 consecutive patients. Abdominal CT scan was performed 1 day after ESD. In addition, chest radiography and blood biochemistry tests were performed at different time points before and after ESD. RESULTS: Two hundred and nineteen lesions (89 %) were curatively removed by ESD. Among the total of 246 patients, we encountered endoscopically visible perforation during ESD in 2 patients (0.8 %), and clinically suspected perforation diagnosed by the presence of free air on chest radiography but invisible during ESD in 3 patients (1 %), while transmural air leak was observed in another 33 (13 %). Air leak occurred in cases where resection size was larger, procedure time longer, and the muscularis propria on the ulcer base was exposed at the end of ESD. Patients with air leaks developed pyrexia at a higher rate than those without (36 % vs. 16 %, P = 0.018). These patients recovered with antibiotics and required no endoscopic or surgical intervention. The presence of an air leak did not affect the duration of hospital stay. CONCLUSIONS: A transmural air leak was observed in 13 % of the patients undergoing ESD. Larger resection size, prolonged procedure time, and exposure of the muscularis propria on the ulcer base were risk factors for transmural air leak, but the outcome of patients with this complication was good.

Eosinophilia predicts better overall survival after acute graft-versus-host-disease.

The prognostic significance of eosinophilia after allogeneic hematopoietic SCT (HSCT) and the relationship between eosinophilia and acute GVHD are not well studied. We retrospectively analyzed 201 adult patients who underwent their first allogeneic HSCT. Seventy-three (36%) patients developed eosinophilia within the first 100 days after HSCT. Eosinophilia was observed more frequently among those patients with acute GVHD than those without it (48 vs 25%, P=0.009). However, it was associated with milder acute GVHD and lower incidence of gut and liver acute GVHD. Among patients with acute GVHD, the 3-year OS for patients with and without eosinophilia was 63.4 and 47.2% (P=0.02), respectively, and 3-year nonrelapse mortality (NRM) was 20.2 and 37.5% (P=0.01), respectively. Multivariate analysis confirmed that eosinophilia was associated with a better OS (P=0.03) and lower NRM (P=0.046) in patients with acute GVHD, whereas it was not associated with a higher relapse rate (P=0.45). In contrast, eosinophilia was not associated with outcomes in those patients without acute GVHD. In conclusion, eosinophilia was associated with milder acute GVHD and better prognosis among patients with acute GVHD. The pathophysiology behind eosinophilia after allogeneic HSCT remains to be investigated.

Clinicopathological manifestations and treatment of intestinal transplant-associated microangiopathy.

Intestinal transplant-associated microangiopathy (i-TAM) is an important complication after allogeneic hematopoietic SCT. From 1997 to 2006, 87 of 886 patients with diarrhea after transplantation received colonoscopic biopsy. i-TAM, GVHD and CMV colitis were diagnosed histopathologically. The median duration from transplantation to the onset of diarrhea was 32 days (range: 9-130 days) and that from the onset of diarrhea to biopsy was 12 days (range: 0-74 days). The median maximal amount of diarrhea was 2 l/day (range: 130-5600 ml/day). Histopathological diagnosis included i-TAM (n=80), GVHD (n=26), CMV colitis (n=17) and nonspecific findings (n=2) with overlapping. Among 80 patients with i-TAM, abdominal pain was a major symptom, and only 11 patients fulfilled the proposed criteria for systemic TAM. Non-relapse mortality (NRM) among patients without resolution of diarrhea was 72% and i-TAM comprised 57% of NRM. NRM was 25% among patients without intensified immunosuppression, but was 52, 79 and 100% among those with intensified immunosuppression before diarrhea, after diarrhea, and before and after diarrhea, respectively. In conclusion, i-TAM is a major complication presenting massive refractory diarrhea and abdominal pain, which causes NRM. Avoiding intensified immunosuppression that damages vascular endothelium until the resolution of i-TAM may improve transplant outcome.

Inter-ictal and post-ictal psychoses in frontal lobe epilepsy: a retrospective comparison with psychoses in temporal lobe epilepsy.

There have been few studies of the psychopathology of patients with frontal lobe epilepsy (FLE). The majority of studies of both inter-ictal and post-ictal psychoses have strongly suggested the influence of temporal lobe disturbance on psychoses. Patients with organic brain damage or schizophrenia, however, sometimes show frontal lobe dysfunction. The purpose of this study was to better understand the effect, if any, of frontal lobe disturbance and seizure on psychopathology. Patients were divided into four groups based on epilepsy type and preceding seizures; 8 with FLE/inter-ictal psychosis, 3 with FLE/post-ictal psychosis, 29 with temporal lobe epilepsy (TLE)/inter-ictal psychosis, and 8 with TLE/post-ictal psychosis. Psychopathologic symptoms were retrospectively reviewed based on case notes, using a modified brief psychiatric rating scale (BPRS). Psychomotor excitement, hostility, suspiciousness, and hallucinatory behaviour were prominent features in all four groups. Six orthogonal factors were derived by factor analysis from the original data based on the 18 BPRS items. FLE patients with inter-ictal psychosis showed marked hebephrenic characteristics (i.e. emotional withdrawal and blunted effect). Our findings suggest that patients with FLE can exhibit various psychiatric symptoms. However, their psychotic symptoms, hebephrenic symptoms in particular, may often be overlooked.

Topology optimization design of flextensional actuators.

Flextensional actuators can be defined as a piezoceramic (or a stack of piezoceramics) connected to a flexible mechanical structure that converts and amplifies the output displacement of the piezoceramic. Essentially, the actuator performance depends on the distribution of stiffness and flexibility in the coupling structure and, therefore, on the coupling structure topology. In this work, we propose a general method for designing flextensional actuators with large output displacement (or generative force) by applying the topology optimization method. The goal is to design a flexible structure coupled to the piezoceramic that maximizes the output displacement (or force) in some specified direction. Static and low frequency applications are considered. To illustrate the implementation of the method, 2-D topologies of flextensional actuators are presented because of the lower computational cost; however, the method can be extended to 3-D topologies. By designing other types of coupling structures connected to the piezoceramic, new designs of flextensional actuators that produce output displacements or forces in different directions can be obtained, as shown. This method can be extended for designing flextensional hydrophones and sonars.