Clonorchis sinensis omega-class glutathione transferases are reliable biomarkers for serodiagnosis of clonorchiasis and opisthorchiasis.

OBJECTIVES: To determine the potential for immunodiagnostic application of two recombinant forms of Clonorchis sinensis omega-class glutathione transferases (rCsGSTo1 and rCsGSTo2) against human small liver-fluke C. sinensis and Opisthorchis viverrini infections. METHODS: Specific antibody levels against rCsGSTo1 and rCsGSTo2 in patients' sera of egg-positive opisthorchiasis (n = 87) and clonorchiasis (n = 120), as well as those in sera from patients with other helminthic infections (n = 252) and healthy controls (n = 40) were retrospectively analysed by ELISA. RESULTS: We observed highly positive correlation coefficients between specific antibody levels against rCsGSTo1 and rCsGSTo2 and egg counts per gramme of faeces (EPG) of patients with opisthorchiasis (n = 87; r = 0.88 for rCsGSTo1 and r = 0.90 for rCsGSTo2). Sera from opisthorchiasis patients whose EPG counts >100 (n = 43) revealed high antibody titres against both antigens. Patients' sera with low EPG counts (<100, n = 44) also exhibited reliable sensitivities of 93.2% and 97.7% for rCsGSTo1 and rCsGSTo2, respectively. Sera from clonorchiasis patients showed sensitivities of 90% (108/120 samples) and 89.2% (107/120 sera) for rCsGSTo1 and rCsGSTo2. Overall diagnostic sensitivities for liver-fluke infections were 92.3% for rCsGSTo1 (191/207 samples) and 93.2% for rCsGSTo2 (193/207 samples). Specificities were 89.7% (rCsGSTo1) and 97.6% (rCsGSTo2). CONCLUSIONS: Detection of specific antibody levels against rCsGSTo1 or rCsGSTo2 might be promising for the serodiagnosis of patients infected with these two phylogenetically close carcinogenic liver-flukes.

Dynamic prognostic value of the revised international prognostic scoring system following pretransplant hypomethylating treatment in myelodysplastic syndrome.

This study aimed to analyze the use of the revised International Prognostic Scoring System (IPSS-R) assessed after hypomethylating treatment (HMT) for patients with myelodysplastic syndrome (MDS) undergoing an allogeneic stem cell transplantation (SCT). Among 115 patients who received pre-SCT HMT, comparison analysis of the prognostic values between the IPSS-R at the time of HMT (IPSS-R@HMT) and at the time of SCT after HMT (IPSS-R@SCT) showed a significantly higher predictive power for overall survival (OS) of the latter. Alteration in IPSS-R risk occurred in 60%, while the patients with 'down-staged' IPSS-R@SCT showed better OS compared with those with 'unchanged' or 'up-staged' risk. On multivariate analysis in all 201 patients, IPSS-R@SCT, monosomal karyotype, treatment failure to pre-SCT treatment, and high hematopoietic cell transplantation-comorbidity index were independently associated with OS. Constructed using these factors, the MDS Transplantation Prognostic Scoring System (MTPSS) identified four risk groups with 4-year OS of 76.4% in low, 61.4% in intermediate-1 and 21.9% in intermediate-2 risk groups, whereas all in the high risk group died within 2 years after SCT (P<0.001). Our study emphasizes the need for further studies aiming to evaluate a transplantation prognostic model such as the MTPSS to make appropriate decisions for transplantation in MDS.

Comparable outcomes between younger (⩽40 years) and older (>40 years) adult patients with severe aplastic anemia after HLA-matched sibling stem cell transplantation using fludarabine-based conditioning.

Allogeneic stem cell transplantation from HLA-matched siblings (MSD-SCT) for elderly patients with severe aplastic anemia (SAA) is not a widely accepted first-line treatment. Recently, fludarabine, lower-dose cyclophosphamide and antithymocyte globulin conditioning (Flu/lower-dose Cy/ATG) with lower toxicities has been investigated. To determine whether this regimen can overcome the negative effects of age, we analyzed 117 adult patients with SAA who received MSD-SCT using Flu/lower-dose Cy/ATG, and compared outcomes between 63 younger age group (YAG; ⩽40 years) and 54 older age group (OAG; >40 years) patients. No primary graft failure was observed. Neutrophil engraftment was significantly faster in the YAG compared with the OAG (12 vs 13 days; P=0.04). The incidences of acute grade II-IV (9.5% vs 9.3% at day 100; P=0.42) and chronic GVHD (8.1% vs 9.5% at 5 years; P=0.80), secondary graft failure (20.8% vs 7.9% at 5 years; P=0.11) and transplant-related mortality (5.4% and 11.1% at 5 years; P=0.91) were not significantly different between the YAG and OAG. In addition, failure-free (73.7% vs 81.0% at 5 years; P=0.73) and overall survival rates (93.7% vs 88.9% at 5 years; P=0.20) were comparable. Our results suggest that MSD-SCT using Flu/lower-dose Cy/ATG may be a feasible first-line treatment even in older patients with SAA.

Impact of pretransplant red cell transfusion on outcome after allogeneic stem cell transplantation in adult patients with severe aplastic anemia.

The aim of this study was to evaluate the impact of pretransplant transfusion of packed red cells (PRCs) on outcome after allogeneic stem cell transplantation (SCT) in severe aplastic anemia (SAA). A total of 221 adult SAA patients receiving allogeneic SCT were analyzed. The patients were divided into two groups according to the amount of pretransplant transfusion before SCT: the low transfusion group (⩽32 PRC units, n=164) and the high transfusion group (>32 PRC units, n=57). The incidence of engraftment failure was not different between the two groups. The incidence of acute GvHD (grades II-IV) was higher in the high transfusion group than in the low transfusion group (P=0.04), and the incidences of chronic extensive GVHD were not significantly different (P=0.136). The high transfusion group had higher 5-year transplant-related mortality (TRM) (24.8% vs 6.8%, P<0.001) and lower overall survival (OS) (72.3% vs 91.9%, P<0.001) than those in the low transfusion group. Multivariate analysis revealed that the high transfusion group and unrelated donor type were independent prognostic factors affecting OS. These results indicate that a history of higher pretransplant transfusion of PRCs was associated with increased TRM and decreased OS, suggesting that iron overload had a negative impact on outcome after SCT in SAA.

MyD88 in donor bone marrow cells is critical for protection from acute intestinal graft-vs.-host disease.

To understand the role of myeloid differentiation factor 88 (MyD88) expressed by donor bone marrow (BM) in the pathophysiology of graft-vs.-host disease (GVHD), we investigated the effects of transplantation of MyD88-deficient T cell-depleted BM (MyD88KO TCD-BM) on the severity of GVHD. Transplantation with MyD88KO TCD-BM aggravated GVHD; serious gut damage was evident, with high infiltration of T cells into the intestines of recipients and markedly reduced expansion of CD11b(+)Gr-1(+) myeloid-derived suppressor cells (MDSCs). MDSCs from MyD88KO mice were defective in inducing donor T-cell apoptosis and inhibiting T-cell proliferation. Supplementation of transplanted mice with MDSCs from wild-type mice, but not MyD88KO mice, attenuated GVHD severity with reduced intestinal T-cell infiltration in MyD88KO TCD-BM recipients. Pretreatment of BM donors with lipopolysaccharide to increase MDSC levels and MyD88 transcription in the TCD-BM transplant alleviated GVHD severity and intestinal T-cell infiltration. The T cell/MDSC ratios were correlated with intestinal GVHD severity in both animal models and human patients. This study indicates that MyD88-dependent MDSC expansion from donor BM is critical for protection against fatal intestinal GVHD.

Tuberculosis before hematopoietic stem cell transplantation in patients with hematologic diseases: report of a single-center experience.

BACKGROUND: Few reports discuss the optimal management of patients diagnosed with tuberculosis (TB) before scheduled stem cell transplantation (SCT), who then proceed with transplantation. METHODS: We found 13 patients with TB before SCT (proven, n = 9; probable, n = 3; possible, n = 1) in the medical records of our institution. RESULTS: Most of the patients had pulmonary TB (n = 8; disseminated, n = 2; extrapulmonary, n = 3). Eight of 9 patients with proven disease had SCT after at least 100 days of anti-tuberculous medication, ranging from 103 to 450 days. None of those patients suffered TB-related events after SCT. However, 1 patient with proven pulmonary TB who underwent SCT after only 40 days of anti-tuberculous therapy subsequently died of TB meningitis. Patients with possible and probable disease had their transplants after 6-176 days of anti-tuberculous medication, and all were alive at the time of analysis. The entire duration of anti-tuberculous medication was 12 months in most cases. With a follow-up duration ranging from 0.7 to 87.5 months, 4 patients died, but TB was the cause of death in only 1 case. CONCLUSION: In conclusion, for proven cases of TB, SCT after >100 days of anti-tuberculous medication is probably feasible and safe, in terms of TB control, in patients with various hematologic diseases.

Impact of IKZF1 deletions on long-term outcomes of allo-SCT following imatinib-based chemotherapy in adult Philadelphia chromosome-positive ALL.

We investigated the prognostic relevance of IKZF1 deletions in 118 adult Ph-positive ALL patients who had minimal residual disease (MRD) data under a uniform treatment of allo-SCT following first-line imatinib-based chemotherapy. IKZF1 deletions were identified in 93 patients (78.8%). IKZF1-deleted patients had a lower proportion of early-stable molecular responders compared with wild-type patients (28.0 vs 56.0%, P=0.028). After a median follow-up of 72 months, IKZF1-deleted patients had a trend for higher cumulative incidence of relapse (CIR) (38.0 vs 13.3%, P=0.052), particularly in a subgroup of early-stable molecular responders (n=40; 21.4 vs 0%, P=0.088), but comparable disease-free survival to wild-type patients. Patients with biallelic-null deletions showed higher CIR (74.6 vs 13.3%, P=0.003) and lower disease-free survival (20.0 vs 67.5%, P=0.022) than wild-type patients. In multivariate analysis, MRD kinetics were closely related to outcomes, while neither IKZF1 deletions nor their functional subtypes retained an independent statistical power. Within the limitation of sample size, however, considering both the negative impact of IKZF1 deletions on MRD kinetics and a trend for relationship between IKZF1 deletions and relapse in early-stable molecular responders, IKZF1 deletions may have a potentially additive effect on unfavorable prognosis in a specific MRD-based subgroup of adult Ph-positive ALL transplants.

Identification of molecular and cytogenetic risk factors for unfavorable core-binding factor-positive adult AML with post-remission treatment outcome analysis including transplantation.

Emerging molecular studies have identified a subgroup of patients with unfavorable core-binding factor-positive (CBF)-AML who should be treated by intensified post-remission treatments. We analyzed 264 adults with CBF-AML from 2002 to 2011, and focused on 206 patients who achieved CR after standard '3+7' induction chemotherapy. Patients who achieved CR with an available donor were treated with allogeneic hematopoietic SCT (allo-HSCT, n=115) and the rest were treated with autologous (auto) HSCT (n=72) or chemotherapy alone (n=19). OS was not significantly different between CBFß/MYH11 (n=62) and RUNX1/RUNX1T1 (n=144), and auto-HSCT showed favorable OS compared with allo-HSCT or chemotherapy alone. Cytogenetic analysis identified that inv(16) without trisomy had a favorable OS and t(8;21) with additional chromosomes had an unfavorable OS, but multivariate analysis revealed those were NS. Patients with c-kit mutation showed inferior OS. For transplanted patients, residual post-transplant CBF-minimal residual disease quantitative PCR with higher WT1 expression at D+60 showed the worst OS with a higher incidence of relapse. Conclusively, we found that unfavorable CBF-AML can be defined with risk stratification using cytogenetic and molecular studies, and a careful risk-adapted treatment approach using frontline transplantation with novel therapies should be evaluated for this particular risk subgroup.

PBSC vs BM grafts with myeloablative conditioning for unrelated donor transplantation in adults with high-risk ALL.

Few studies are available that compare PBSC and BM from unrelated donors, especially in adult high-risk ALL. To determine which graft source is superior in adult high-risk ALL, we analyzed the long-term outcomes of 106 consecutive transplants from 8/8-matched or 7/8-matched unrelated donors (38 PBSC vs 68 BM). All patients received a uniform strategy of pre-transplant therapy, myeloablative conditioning and GVHD prophylaxis. At 5 years, PBSC transplants showed higher incidence of chronic GVHD than did BM transplants (74.3% vs 46.7%, P=0.001). PBSC transplants showed outcomes comparable to those of BM transplants for relapse (23.7% vs 28.1%), non-relapse mortality (18.4% vs 25.0%), disease-free survival (57.9% vs 46.9%) and OS (57.9% vs 50.0%). In a separate comparison of outcomes between the two graft sources according to the presence of a Ph chromosome, no significant advantage of PBSC over BM was found in both subgroups of patients. Our data suggest that the outcomes of unrelated donor transplantation are similar between PBSC and BM in adult high-risk ALL. Whether PBSC should be the preferred graft source for a specific subgroup of adult ALL needs to be further investigated.

Experiences of t-PA use in moderate-to-severe hepatic veno-occlusive disease after hematopoietic SCT: is it still reasonable to use t-PA?

Hepatic veno-occlusive disease (VOD) remains one of the most severe complications of hematopoietic SCT (HSCT). Anticoagulation and thrombolytic therapies using tissue-plasminogen activator (t-PA) have been used, but are reported to be ineffective and are associated with significant bleeding complications. We analyzed 56 moderate-to-severe post HSCT hepatic VOD cases treated with t-PA. We analyzed clinical outcomes according to the maximal daily dose of t-PA (t-PAmax) and the severity of VOD. Patients were stratified by t-PAmax10 mg (n=37) vs t-PAmax>10 mg (n=19). A higher t-PAmax was associated with increased mortality. Bleeding complications were more likely at higher t-PAmax in both moderate and severe VOD (P=0.036, 0.063), especially if patients had concomitant use of anticoagulants (36.4% vs 13.3%). In moderate VOD, the response rate was 86.4% for t-PAmax10 mg/day and 80% for t-PAmax>10 mg compared with 33.3% and 7.1%, respectively, for severe VOD (P=0.106). The 5-year OS in moderate and severe VOD was 49% and 7%, respectively, and it was 32% for t-PAmax10 mg and 18% for t-PAmax>10 mg. Our data demonstrate that lower bleeding complications and bleeding-related deaths may result from strict limitations on the t-PAmax without concomitant use of anticoagulation therapy. However, the overall response and survival outcomes should be re-evaluated by a well-validated study in the future.

Infectious complications following allogeneic stem cell transplantation: reduced-intensity vs. myeloablative conditioning regimens.

BACKGROUND: In allogeneic stem cell transplantation (allo-SCT), reduced-intensity conditioning (RIC) is known for producing less regimen-related toxicity. However, whether or not RIC reduces the risk for infection and infection-related mortality (IRM) remains controversial. METHODS: We retrospectively analyzed infectious episodes and IRMs after allo-SCTs by time period and by the intensity of the conditioning regimen (RIC [n = 81] vs. myeloablative conditioning, MAC [n = 150]). RESULTS: The cumulative incidence of any kind of infection was lower in the RIC group through the entire period (72% vs. 87%; P = 0.007). The onset of infections was deferred in the RIC group as compared with the MAC group (P = 0.012). Bacteremia occurred less frequently in the RIC group through the entire period (5% vs. 14%; P = 0.044). However, the incidences of cytomegalovirus reactivation and disease, herpes zoster, virus-associated hemorrhagic cystitis, and invasive fungal infection were not different between the two groups. Furthermore, there was no difference in relapse-free survival and IRM between the two conditioning regimens. CONCLUSION: Careful monitoring and appropriate preventive/therapeutic strategies for infectious complications, comparable to those for allo-SCT recipients with MAC, should also be applied to those with RIC, especially after engraftment.

Risk and prognostic factors for acute GVHD based on NIH consensus criteria.

To investigate the risk factors for acute GVHD (aGVHD), based on NIH consensus criteria (NCC), we evaluated 775 patients who underwent allogeneic transplantation. Of them, 346 patients developed aGVHD by NCC, in whom we also analyzed factors affecting aGVHD-specific survival. The cumulative incidence of aGVHD was 44.7%, consisting of classic aGVHD (n=320) and late-onset (n=26). Multivariate analyses revealed that younger age (P=0.015), unrelated donors (P=0.004) and acute leukemia compared with other hematologic malignancies (P=0.005) were significant risk factors for aGVHD, whereas PBSCs showed no association (P=0.720). Multivariate analyses, with only aGVHD patients, revealed that late-onset aGVHD had superior aGVHD-specific survival to classic aGVHD (P=0.044), and identified the association of visceral organ involvement (P=0.002), severity of aGVHD at onset (P=0.035) and advanced disease status (P<0.001) with inferior aGVHD-specific survival. In conclusion, this study demonstrates the risk and prognostic factors for aGVHD by NCC with some differences with the previous reports that were based on old criteria. The difference in the risk factors according to different criteria will give insights about the pathophysiology of GVHD. The better prognosis of late-onset aGVHD than of classic aGVHD raises the necessity for prospective trials with a large cohort focusing on the onset time.

Influence of enzyme and transporter polymorphisms on trough imatinib concentration and clinical response in chronic myeloid leukemia patients.

BACKGROUND: This study explored the impact of genetic polymorphisms in cytochrome P450 (CYP) enzymes and transporters on the plasma trough concentration of imatinib mesylate (IM) and clinical response in chronic myeloid leukemia (CML). PATIENTS AND METHODS: In total, 82 patients with CML who had been administered 400 mg IM daily for over 6 months were genotyped for 11 single-nucleotide polymorphisms in nine genes (CYP3A4, CYP3A5, CYP2C9, CYP2C19, CYP2D6, ABCB1, SLC22A1, SLC22A2 and ABCG2) using blood samples. The trough imatinib concentration and clinical responses were assessed 6 months after the initiation of IM therapy. RESULTS: The CC, CA and AA genotypes in ABCG2 421C>A gave significantly different frequencies for the major molecular response (MMR) (P = 0.02). However, no significant differences were found between the genotypes of the CYP enzymes and transporters identified in this study and the imatinib plasma trough concentrations and clinical response frequencies, except for the correlation of ABCG2 with MMR. CONCLUSIONS: The results of the present study may indicate that the ABCG 421C>A genetic polymorphism influences the MMR of imatinib in patients with CML.

Survival benefits with transplantation in secondary AML evolving from myelodysplastic syndrome with hypomethylating treatment failure.

The prognosis for patients with myelodysplastic syndrome with hypomethylating treatment failure (MDS-HTF) has been known to be poor. However, the clinical outcomes and optimal treatment options for secondary AML evolving from MDS-HTF (sAML/MDS-HTF) are not well known. This retrospective analysis was conducted to evaluate the clinical outcomes and influences of treatment options on survival in 46 consecutive patients with sAML/MDS-HTF. The median OS rates were 1.4 months in the best supportive care group (n=15) and 9.4 months in the active treatment group (n=31). One-year OS rates were 13.3% and 36.8%, respectively (P=0.001). Active treatment (P<0.001), lower BM blast (<33%) at sAML (P=0.007), non-poor NCCN (National Cancer Comprehensive Network) cytogenetics (P=0.001) and good performance status (ECOG (Eastern Cooperative Oncology Group) 1) (P=0.024) were significant predictors affecting favorable OS in a multivariate analysis. Of the active treatment options, allo-SCT with prior chemotherapy (CTx) showed better OS compared with CTx only or SCT without CTx (P=0.019). Our analyses suggest that active treatment, particularly SCT following CTx, should be considered in patients with sAML/MDS-HTF if the patient is medically fit.

Impact of minimal residual disease kinetics during imatinib-based treatment on transplantation outcome in Philadelphia chromosome-positive acute lymphoblastic leukemia.

We conducted a systemic evaluation to describe the effect of minimal residual disease (MRD) kinetics on long-term allogeneic transplantation outcome by analyzing 95 adult transplants with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph-positive ALL) who received first-line two courses of imatinib-based chemotherapy (median follow-up 5 years). MRD monitoring was centrally evaluated by real-time quantitative PCR (4.5 log sensitivity). After the first course of imatinib-based chemotherapy, 33 patients (34.7%) achieved at least major molecular response. On the basis of MRD kinetics by the end of two courses of imatinib-based chemotherapy, we stratified entire patients into four subgroups: early-stable molecular responders (EMRs, n=33), late molecular responders (LMRs, n=35), intermediate molecular responders (IMRs, n=9) and poor molecular responders (PMRs, n=18). Multivariate analysis showed that the most powerful factor affecting long-term transplantation outcome was MRD kinetics. Compared with EMRs, IMRs or PMRs had significantly higher risk of treatment failure in terms of relapse and disease-free survival (DFS). LMRs had a tendency toward a lower DFS. Quantitative monitoring of MRD kinetics during the first-line imatinib-based chemotherapy course is useful in identifying subgroups of Ph-positive ALL transplants at a high risk of relapse.

Continuous subdural irrigation and drainage for intracranial subdural empyema in a 92-year-old woman.

INTRODUCTION: Intracranial subdural empyema (ISDE) is a life-threatening intracranial infection. Early and precise detection, timely surgery, and appropriate antibiotic therapy are the keys to a more favorable clinical outcome. Treatment is aimed at complete evacuation of the empyema and eradication of the source of infection. However, in the case of elderly patients or patients with poor health, doctors hesitate to perform open cranial surgery under general anesthesia; thus, the choice of appropriate surgical method is fraught with many limitations. CASE REPORT: We present a case of ISDE in a 92-year-old woman who was successfully treated with continuous irrigation of the subdural space with antibiotics and drainage through 2 burr holes for 1 week without any complications. CONCLUSION: Continuous subdural irrigation is useful for the evacuation of pus and eradication of the source of infection, thereby resulting in a favorable outcome, especially in elderly patients and patients with poor health.

Donor-specific differences in long-term outcomes of myeloablative transplantation in adults with Philadelphia-negative acute lymphoblastic leukemia.

We analyzed long-term outcomes of myeloablative stem cell transplantation (SCT) in 292 adults with Philadelphia (Ph)-negative acute lymphoblastic leukemia (ALL). Donors were related (RD; n=132), unrelated (URD; n=68; 30 well-matched (WM), 19 partially matched (PM), 19 mismatched (MM)) and autologous (AUTO; n=92). After a median follow-up of 85 months, the risk of relapse was higher for AUTO-SCT than for RD-SCT (P<0.001). MM-URD-SCT yielded higher risk of non-relapse mortality than RD-SCT (P=0.010). As a result, disease-free survival (DFS) at 5 years was inferior using AUTO (46.1%; P=0.010) or MM-URD (26.3%; P=0.036), whereas DFS from other donor sources was approximately equivalent (53.5% for RD, 63.3% for WM-URD and 57.0% for PM-URD). Other factors associated with poorer DFS included SCT beyond first complete remission (CR), older age and adverse cytogenetics. In a pairwise comparison of outcomes between RD-SCT and AUTO-SCT for patients in first CR, the inferiority of AUTO-SCT was observed, particularly in high-risk patients. Conversely, in standard-risk patients, AUTO-SCT yielded comparable outcomes to RD-SCT. SCT using RD, WM-URD or PM-URD may be considered the best donor sources for adult high-risk Ph-negative ALL.

HLA-matched sibling transplantation with BM and CD34(+)-purified PBSCs in adult patients with high-risk severe aplastic anemia to overcome graft rejection without an increase in GVHD.

The transplantation of a large number of stem cells can overcome graft rejection but with the increased risk of GVHD. In this study, we analyzed the outcome of 32 adult patients with acquired severe aplastic anemia (SAA) who were at a high risk for graft rejection, including multiple transfusions (median 147 units, range 20-680) and long disease duration (median 67 months, range 3-347), and who had received both BM and CD34(+)-purified PBSCs from an HLA-matched sibling donor to reduce graft rejection. T cells in PBSCs were depleted using a magnetic-activated cell sorting method (CliniMACS system). Conditioning regimens consisted largely of CY and antithymocyte globulin (ATG) with fludarabine (FLU) or procarbazine (PCB). With a median follow-up of 89 months, the 8-year probability of survival was 87.5%. Neutrophils and plts promptly recovered, and none of the patients developed graft failure. The cumulative incidences of acute and chronic GVHD were 9.4 and 18.0%, respectively. Sustained engraftment and excellent survival without an apparent increase in the rate of GVHD in high-risk patients using the current approach showed that high-dose SCT with both BM and CD34(+)-purified PBSCs may yield better outcomes in heavily transfused and/or allo-immunized patients with SAA.