Genetically determined type 1 diabetes mellitus and risk of osteoporosis.

BACKGROUND: Observational evidence suggests that type 1 diabetes mellitus (T1DM) is associated with the risk of osteoporosis (OP). Nevertheless, it is not apparent whether these correlations indicate a causal relationship. To elucidate the causal relationship, a two-sample Mendelian randomization (MR) analysis was performed. METHODS: T1DM data was obtained from the large genome-wide association study (GWAS), in which 6683 cases and 12,173 controls from 12 European cohorts were involved. Bone mineral density (BMD) samples at four sites were extracted from the GEnetic Factors for OSteoporosis (GEFOS) consortium, including forearm (FA) (n = 8,143), femoral neck (FN) (n = 32,735), lumbar spine (LS) (n = 28,498), and heel (eBMD) (n = 426,824). The former three samples were from mixed populations and the last one was from European. Inverse variance weighting, MR-Egger, and weighted median tests were used to test the causal relationship between T1DM and OP. A series of sensitivity analyses were then conducted to verify the robustness of the results. RESULTS: Twenty-three independent SNPs were associated with FN-BMD and LS-BMD, twenty-seven were associated with FA-BMD, and thirty-one were associated with eBMD. Inverse variance-weighted estimates indicated a causal effect of T1DM on FN-BMD (odds ratio (OR) =1.033, 95 % confidence interval (CI): 1.012-1.054, p = 0.002) and LS-BMD (OR = 1.032, 95 % CI: 1.005-1.060, p = 0.022) on OP risk. Other MR methods, including weighted median and MR-Egger, calculated consistent trends. While no significant causation was found between T1DM and the other sites (FA-BMD: OR = 1.008, 95 % CI: 0.975-1.043, p = 0.632; eBMD: OR = 0.993, 95 % CI: 0.985-1.001, p = 0.106). No significant heterogeneity (except for eBMD) or horizontal pleiotropy was found for instrumental variables, suggesting these results were reliable and robust. CONCLUSIONS: This study shows a causal relationship between T1DM and the risk of some sites of OP (FN-BMD, LS-BMD), allowing for continued research to discover the clinical and experimental mechanisms of T1DM and OP. It also contributes to the recommendation if patients with T1DM need targeted care to promote bone health and timely prevention of osteoporosis.

Genetic evidence for causal effects of leukocyte counts on risk for rheumatoid arthritis.

Rheumatoid arthritis (RA) is an autoimmune disease characterized by the accumulation of leukocytes and inflammatory mediators within the synovial tissue. Leukocyte counts are proposed to play a role in the pathogenesis of RA. However, the causality remains unclear. To investigate the causal relationship between various leukocytes and RA by implementing two-sample univariable Mendelian Randomization (MR) and multivariable MR. MR analysis was performed using respective genome-wide association study (GWAS) summary statistics for the exposure traits (eosinophil counts, neutrophil counts, lymphocyte counts, monocyte counts, basophil counts, and white blood cell counts) and outcome trait (RA). Summary statistics for leukocytes were extracted from the Blood Cell Consortium meta-analysis and INTERVAL studies. Public GWAS information for RA included 14,361 cases and 43,923 controls. Inverse variance weighted, weighted median, MR-Egger regression, MR pleiotropy residual sum and outlier, and multivariable MR analyses were performed in MR analysis. Univariable MR found elevated eosinophil counts (OR 1.580, 95% CI 1.389-2.681, p = 1.30 × 10-7) significantly increased the risk of RA. Multivariable MR further confirmed that eosinophil counts were a risk factor for RA. Increased eosinophils were associated with higher risk of RA. Further elucidations of the causality and mechanisms underlying are likely to identify feasible interventions to promote RA prevention.

Assessment of causal effects of physical activity on the risk of osteoarthritis: a two-sample Mendelian randomization study.

BACKGROUND: Growing evidence supports an association between physical activity (PA) and the risk of osteoarthritis (OA), but this may be influenced by confounding and reverse causality. Therefore, we performed a two-sample Mendelian randomization (MR) analysis to reveal the causal relationship between PA and OA. METHODS: MR was performed to explore the causation of PA and OA with genetic variants as instrumental variables. The genetic variants were derived from the summary statistics of a large genome-wide association study meta-analysis based on the European population (n = 661,399), including self-reported leisure screen time (LST) and moderate-to-vigorous physical activity (MVPA), and Arthritis Research UK Osteoarthritis Genetics Consortium cohorts (417,596, 393,873 and 403,124 for overall, hip and knee OA, respectively). The major MR analysis used in this work was the inverse variance weighted (IVW) approach, and sensitivity, pleiotropy, and heterogeneity studies were performed to evaluate the validity of the findings. RESULTS: IVW estimates indicated that LST had a risk effect on overall OA (odds ratio (OR) = 1.309, 95% confidence interval (CI): 1.198-1.430, P = 2.330 × 10-9), hip OA (OR = 1.132, 95% CI: 1.009-1.269, P = 0.034) and knee OA (OR = 1.435. 95% CI: 1.286-1.602, P = 1.225 × 10-10). In contrast, no causal relationship was found between MVPA and OA (overall OA: OR = 0.895, 95% CI: 0.664-1.205, P = 0.465; hip OA: OR = 1.189, 95% CI: 0.792-1.786, P = 0.404; knee OA: OR = 0.707, 95% CI: 0.490 -1.021, P = 0.064). In addition, we observed significant heterogeneity in instrumental variables, but no horizontal pleiotropy was detected. CONCLUSIONS: Recent findings demonstrated a protective impact of reducing LST on OA, independent of MVPA. This provides valuable insights into the role of physical activity in OA and offers lifestyle recommendations, such as reducing recreational sedentary behaviors and promoting appropriate exercise, for individuals at risk of OA.

Genetic Evidence Supporting a Causal Association Between mTOR-Dependent EIF-4E Circulating Protein Level and Osteoporosis.

INTRODUCTION: The mechanistic target of rapamycin (mTOR) regulates bone homeostasis, a crucial factor in osteoporosis (OP) development. However, most research is based on observational studies, and the causality remains uncertain. Therefore, we analyzed two samples of mendelian randomization (MR) to determine whether there is a causal relationship between mTOR-dependent circulating proteins and OP. METHODS: Mendelian weighting (weighted median [WM], inverse variance weighting [IVW], and MR-Egger regression) were applied to analyze the causality between bone phenotypes (bone mineral density [BMD] in forearm, femoral neck, lumbar spine, and heel) and mTOR-dependent circulating proteins (RP-S6K, 4EBP, EIF-4E, EIF-4A, and EIF-4G). Horizontal pleiotropy and heterogeneities were detected using Cochran's Q test, MR-Pleiotropy RE-Sidual Sum and Outlier (MR-PRESSO), and "leave-one-out" analysis. The proteomics-GWAS INTERVAL study was used to select the instrumental variables (IVs) for mTOR proteins. RESULTS: As phenotypes for OP, estimations of BMD were taken in four different sites: forearm (FA) (n = 8143), femoral neck (FN) (n = 32,735), lumbar spine (LS) (n = 28,498), and heel (eBMD) (n = 426,824). Based on IVW analysis, EIF4E is causally related to FA-BMD (OR = 0.938, 95% CI 0.887, 0.991, p = 0.024) but not to BMD elsewhere. CONCLUSION: MR analysis revealed a causal relationship between EIF-4E and FA-BMD, which may provide new insights into the underlying pathogenesis of OP and a new therapeutic target for OP.

Genetically Determined Levels of mTOR-Dependent Circulating Proteins and Risk of Multiple Sclerosis.

BACKGROUND: Results from observational studies indicate an association between circulating levels of mammalian target of rapamycin (mTOR)-dependent circulating proteins and the risk of multiple sclerosis (MS). However, a causal association has not been fully elucidated. Mendelian randomization (MR) is used to overcome limitations inherent to observational studies, assess the causal association, and minimize bias due to confounding and reverse causation. METHODS: To explore the causal association between seven mTOR-dependent proteins (AKT, RP-S6K, eIF4E-BP, eIF4A, eIF4E, eIF4G, and PKC-α) and MS, we obtained summary statistics from the genome-wide association study (GWAS) meta-analysis of the International Multiple Sclerosis Genetics Consortium (47,429 patients and 68,374 controls) and the INTERVAL study (genetic associations with 2994 plasma proteins from 3301 healthy individuals). MR analyses were conducted using inverse variance weighted, weighted median estimator, and MR-Egger regression methods/models. Sensitivity analyses were performed to ensure the reliability of the findings. Single nucleotide polymorphisms (SNPs) that are independent (r2 < 0.01) and strongly associated to minerals (p < 1e-5) were selected as instrumental variables. RESULTS: The results of the MR analyses revealed that among the seven mTOR-dependent proteins selected for study, the circulating level of PKC-α (odds ratio [OR] 0.90, 95% confidence interval [CI] 0.82-0.98; P = 0.017) and RP-S6K (OR 1.12, 95% CI 1.00-1.25; P = 0.045) were associated with MS risk and that there was no sign of pleiotropy or heterogeneity. PKC-α was negatively related to MS, while RP-S6K was positively related to MS. No significant causation was found between the other proteins studied (AKT, eIF4E-BP, eIF4A, eIF4E, eIF4G) and MS. CONCLUSION: Molecules in the mTOR signaling pathway may bidirectionally regulate the occurrence and development of MS. PKC-α is a protective factor, while RP-S6K is a risk factor. Further explorations of pathways underlying the association between mTOR-dependent proteins and MS are required. PKC-α and RP-S6K might be used as future therapeutic targets for screening high-risk individuals and potentially improving opportunities for targeted prevention strategies.

Genetic Evidence Supporting Causal Roles of mTOR-Dependent Proteins in Rheumatic Fever: A Two-Sample Randomized Mendelian Study.

BACKGROUND: The expression of signaling molecules downstream of the mammalian target of rapamycin (mTOR) is dysregulated in patients with rheumatic fever (RF), but the causality of mTOR on RF remains unknown. This study aimed to investigate the causal effects of the mTOR-dependent proteins in RF. METHODS: The summary data for targets of the mTOR signaling were acquired from the publicly available INTERVAL study GWAS data. Data on RF have been obtained from the Integrated Epidemiology Unit GWAS database (38,209 cases and 156,711 healthy controls). A two-sample Mendelian randomization (MR) study was conducted to examine the association of RF risk and mTOR-dependent proteins (EIF4EBP2, EIF-4E, EIF-4G, EIF-4A, RP-S6K, and ATG7), including the inverse-variance weighted (IVW) method, MR-Egger, and weighted median, which was followed by sensitivity analyses. RESULTS: RP-S6K is associated with a lowered risk of RF with an odds ratio (OR) of 0.97, 95% confidence interval (95% CI) of 0.94-0.99 (p = 0.027). In contrast, ATG7 accounts for higher risk of RF with an OR of 1.05 (95% CI = 1.00-1.12, p = 0.047). No apparent heterogeneity and no horizontal pleiotropy were observed in the sensitivity analysis (p > 0.05). No statistical significance was identified for levels of EIF4A, EIF4G, EIF4E-BP2, and RP-S6K with RF risk (p > 0.05). CONCLUSION: MR found robust evidence of a causal association between RF and mTOR. RP-S6K and ATG7 may be targeted for intervention by repurposing existing therapeutics to reduce the risk of RF.

[Flow cytometric monitoring of minimal residual diseases in patients with acute leukemia after allogeneic hemapoietic stem cell transplantation].

OBJECTIVE: To study the significance of flow cytometric monitoring minimal residual diseases (MRD) in patients with acute leukemia (AL) after allogeneic hemapoietic stem cell transplantation (HSCT). METHODS: From January 2007 and January 2008 MRD were detected by flow cytometry (FCM) in 402 bone marrow (BM) in 102 AL patients without leukemic gene and chromosomal changes at first diagnosis after HSCT (1, 2, 3, 6,12 months after HSCT; adding detection frequency in part of high risk patients), The relationship between the MRD results and clinical prognosis were observed. Patients with significantly higher MRD were treated and the effectiveness was monitored by FCM (MRD > 0.01% considered as positive). RESULTS: (1) 71 cases were persistently negative for MRD after HSCT and all them were in hematologic complete remission (CR). Only 3 cases had extramedullary relapse. The disease free survival (DFS) and overall survival (OS) were 66.2% and 90.1%, respectively. (2) Of 27 MRD(+) cases 11 converted to MRD negativity after chemotherapy plus donor lymphocyte infusion (DLI), CIK, NK cells. The DFS and OS were 63.6% and 72.7%, respectively. Other 16 cases had hematologic relapse. The DFS and OS were 11.1% and 25.0%, respectively. The median time from MRD increasing to hematologic relapse was 48 days (7-69 day). (3) Four cases had hematologic relapse after HSCT and died in the end. CONCLUSIONS: (1) The DFS and the OS in MRD(-) cases are significantly higher than those of MRD(+) cases. (2)MRD(+) patients after HSCT coveted to MRD(-) after intervention. Therapy, whose DFS and the OS are still significantly higher than those of MRD(+) cases. (3) Patients with hematologic relapse after HSCT have the worst prognosis and the DFS and OS are significantly low. FCM monitoring of MRD in patients after HSCT is a sensitive, specific, quick and simple method. It can indicate recurrent state in time, facilitates early intervention, reduces the hematologic relapse risk and improves DFS.

[Efficacy of allogeneic hematopoietic stem cell transplantation in treatment of childhood myelogenous leukemia: the observation of 24 cases].

OBJECTIVE: To retrospectively analyze the effects of allogeneic hematopoietic stem cell transplantation (allo-HSCT) on childhood chronic myelogenous leukemia (CML). METHOD: Of the 24 consecutive cases, 16 were boys and 8 were girls. The median age of patients was 12 (3 - 16) years old; 16 cases were in chronic phase (CP) of CML, 1 case in accelerated phase (AP) and 5 cases in blastic phase (BP). Allo-HSCT from HLA identical siblings were performed for 5 cases, HLA haplotype was performed for 14 cases and unrelated allo-HSCT for 5 cases. Twenty-four cases underwent allo-HSCT with conditioning regimen of BUCY. Prophylaxis of graft versus host disease (GVHD) included CsA + MTX plus MMF. The average follow-up was 36 months. RESULT: All of patients were successfully engrafted. The 5-year overall survival (OS) of the 24 cases was 81%. Four patients died after allo-HSCT including 3 cases in BP from haploidentical donors and 1 case in CP from HLA identical sibling. The 5 cases who received unrelated allo-HSCT have been alive. Among the 10 cases who survived over 5 years, 3 had chronic GVHD. CONCLUSION: Children with CML could be treated effectively with allo-HSCT. There were no significant differences among different donors. Transplantation to children with CML should be performed as early as possible. Preparative regimen adjustment before transplantation, the transplantation of associated comorbidities and effective prevention and treatment for CML patients after prolonged graft survival of high quality have important significance.

[Allogeneic stem cell transplantation for patients with Philadelphia positive leukemia resistant to imatinib].

OBJECTIVE: To investigate the effect of allogeneic hemopoietic stem cell transplantation (HSCT) in patients with acute lymphocytic leukemia (ALL) or chronic myelocytic leukemia (CML) resistant to imatinib mesylate (IM). METHODS: Fourteen patients with ALL [n=4, all with Ph (+) chromosome] or CML (n=10, 1 in acceleration phase and 4 in blastic crisis) resistant to IM received allogeneic HSCT. The hematopoietic stem cells transplanted to 7 cases were from identical sibling donors, and hematopoietic stem cells transplanted to the other 7 were from mismatched related donors. Eight cases received recombinant human granulocyte-colony stimulating factor (rhG-CSF) mobilized bone marrow transplantation plus peripheral blood stem cell transplantation (PBSCT), and 6 only received PBSCT. Ten cases were given rhG-CSF mobilized donor lymphocyte infusion (DLI) to prevent or treat relapsing. RESULTS: All patients achieved complete allogeneic engraftment and the median times of neutrophil recovery and platelet recovery were 16 and 13 days respectively. There was no treatment related death. Nine of the 14 patients developed acute graft versus host disease (GVHD), 7 being in the grade II and 2 being in grade III; and 6 of the 13 evaluable patients developed extensive chronic GVHD. The hematological relapse was 9. CONCLUSION: Allo-HSCT can be an important salvage option for patients with Ph (+) chromosome with leukemia resistant to IM.

[A clinical study of allo-hematopoietic stem cell transplantation in HBsAg positive leukemia].

OBJECTIVE: To explore the incidence and risk factors of hepatic events and overall survival among HBsAg positive leukemia patients after allo-hematopoietic stem cell transplantation (allo-HSCT). METHODS: A retrospective clinical study was conducted at the bone marrow transplant unit in our hospital between March 2001 and November 2006. A total of 26 HBsAg positive leukemia patients were included in the study. 18 patients received HLA-identical sibling allo-HSCT, 7 patients received HLA-mismatched related and 1 patient received HLA-identical unrelated. All the patients were free from hepatitis C infection before and after allo-HSCT. HBV serologic markers, including HBsAg, HBeAg, HBsAb, HBeAb and HBcAb were tested. 2 patients were positive for HBV-DNA before allo-HSCT. RESULTS: The cumulative incidence for acute graft vs host disease (aGVHD) grades I -IV was 50.0%. The cumulative incidence for chronic GVHD was 25.0%. 15 (57.7%) of all the patients had abnormalities of liver function after allo-HSCT. The types of hepatic disease were reactivation of HBV and hepatic GVHD. The cumulative incidence in 5 years for hepatitis B reactivation was 33.4%, the median day of hepatitis B reactivation was 82th (65th-159th) day. The virologic and clinical outcomes were compared between two groups; one received lamivudine as prophylactic (group 1) and the other did not receive lamivudine (group 2). After transplantation, 1 patient in group 1 and 7 patients in group 2 had hepatitis due to reactivation of HBV. The cumulative incidence for hepatitis B reactivation was statistically different between the two groups (P= 0.006). None in group 1 but 4 in group 2 died of HBV-related hepatic failure. 10 of the 26 patients died after transplantation. The overall survival (OS) in 5 years was 59.0%. The causes of death included hepatic failure (5 cases), lung infection (3 cases) and relapse of leukemia (2 cases). By multivariate Cox analysis, development of hepatic failure was a significant predictor of mortality (P = 0.000). CONCLUSION: HBsAg positive leukemia patients often suffered from hepatic injury after allo-HSCT. The principal cause of hepatic damage was the reactivation of HBV. Hepatic failure caused by HBV was the principal reason of death. Prophylaxis with lamivudine in HBsAg positive leukemia recipients can reduce the reactivation of HBV.

Hemorrhagic cystitis following hematopoietic stem cell transplantation: incidence, risk factors and association with CMV reactivation and graft-versus-host disease.

BACKGROUND: The definite pathogenesis of hemorrhagic cystitis (HC) after allogenic hematopoietic stem cell transplantation (allo-HSCT) has not been well elucidated. The role of cytomegalovirus (CMV) reactivation and graft-versus-host disease (GVHD) in the development of HC remains obscure. This study determined the incidence and risk factors for HC after allo-HSCT and analyzed its association with CMV reactivation and GVHD. METHODS: We retrospectively studied 250 patients at high risk for CMV disease who underwent allo-HSCT all based on busulfan/cyclophosphamide (BU/CY) myloablative regimens. The incidence, etiology, risk factors and clinical management of HC were investigated. RESULTS: HC developed within 180 days of transplant in 72 patients, with an overall incidence of 28.8% and an incidence of 12.6% in patients with HLA-matched related donors (MRD), 34.38% in those with HLA-matched unrelated donors (MUD), 49.45% in those with mismatched related donors (MMRD). CMV-viremia significantly increased the incidence of later onset HC (LOHC); however, only 9 out of 15 patients with CMV viruria actually developed LOHC. Multiple regression analysis identified grade II - IV acute GVHD (RR = 2.75; 95% CI 1.63 +/- 4.66; P < 0.01) and grafts from MUD or MMRD (RR = 2.60; 95% CI 1.52 +/- 5.20; P < 0.01) as independent risk factors for HC. Event sequence analysis indicated a majority of HC episodes began around GVHD initiation. CONCLUSIONS: CMV-viremia is a high risk factor for LOHC. Our data also showed a correlation between acute GVHD and HC, which suggested that alloimmunity may be involved in the pathogenesis of HC.

[Analysis of etiology of hemorrhagic cystitis after allogeneic hematopoietic stem cell transplantation].

OBJECTIVE: To analyze the etiology and clinical features of late onset hemorrhagic cystitis (LOHC) after allogeneic hematopoietic stem cell transplantation (HSCT). METHODS: The medical records of 200 patients undergoing allogeneic HSCT from 2004 to 2005 were analyzed retrospectively. RESULTS: HC developed in 57 patients within 180 days after the transplantation with a cumulative incidence of 28.8%. The etiology of 31 patients (54.39%) was infection, caused by infection of cytomegalovirus (CMV) or adenovirus and cured by anti-virus therapy, thus the cause of disease could be classified as infection agent. Viremia was seen in 12 patients (21.53%) with CMV and disappeared in urine after anti-virus therapy but bleeding still persisted. For these patients the cause of disease was classified as infection agent combined with non-infection factor. Evidence of infection agent could not be discovered in 14 patients (24.56%) and they failed to respond to anti-infection therapy. For them the cause of disease was classified as non-infection agent. 13 patients with refractory HC underwent tentative treatment with corticosteroids, 9 of them achieved a complete remission, 2 of them achieved partial remission, and 2 of them remained non-responsive. CONCLUSION: LOHC after allo-HSCT is a common complication and caused by multiple factors. Differentiation of the possible causes may benefit its clinical outcome.

[Allogeneic hematopoietic stem cell transplantation for high-risk acute leukemia].

OBJECTIVE: To retrospectively analyze the results of a consecutive series of 90 refractory/relapsed acute leukemia (AL) patients receiving allogeneic hematopoietic stem cell transplantation (allo-HSCT) in our center. METHODS: Of the 90 refractory/relapsed AL patients, 56 were male and 34 female, with a median age of 37 (13 - 59) years. Among them, 73 patients suffered from AL including 11 Ph+ acute lymphoid leukemia in first complete remission, 23 in second or greater complete remission, 39 in non-remission or relapse and 17 patients suffered from myelodysplastic syndrome (MDS-RAEB or RAEB-T) before transplant. Allo-HSCT from HLA identical siblings was performed for all the patients, of whom 27 received bone marrow transplantation (BMT), 30 peripheral blood stem cell transplantation (PBSCT) and 33 BMT + PBSCT. Eleven patients underwent allo-HSCT with conditioning regimen of CY/TBI and 79 with BU/CY. CsA + MTX regimen was use for prophylaxis of graft-versus-host disease (GVHD). The average follow-up was 15 months. RESULTS: At the last follow-up, 56/90 (62.2%) survived, 50/90 (55.5%) survived without leukemia and 28/90 (31.1%) relapsed. The estimated 4-year overall survival (OS) and disease-free survival (DFS) of the 90 cases was 45.5% and 34.9%. The 4-year OS and DFS were significantly higher for patients in CR (54.0%) or MDS (70.1%) than in non-remission and relapsed (28.2%) patients before allo-HSCT (P = 0.027). The outcome of grade 0-I acute GVHD was better than that of II-IV GVHD (57.6% vs 26.7%, P = 0.015). Sex, age, central nervous system leukemia, conditioning regimen and the source of stem cell were not the factors affecting OS, DFS, cumulative incidences of relapse rate and treatment related mortality. Multivariate analysis showed the most significant factor associated with high DFS was the disease state. CONCLUSIONS: allo-HSCT can cure a significant proportion of refractory/relapsed AL patients, especially for those in CR. Early allo-HSCT is recommended for MDS patients.

[A comparative study of peripheral blood stem cell vs bone marrow transplantation from unrelated donors].

OBJECTIVE: To compare the outcomes in hematological patients receiving unrelated peripheral blood stem cell transplants (UPBSCT) with those receiving unrelated bone marrow transplants (UBMT) in a retrospective analysis. METHODS: Sixty-three patients with hematological diseases with HLA-matched (65%) or mismatched (35%) unrelated donors were receiving UPBSCT (n = 33) or UBMT (n = 30) between May 2001 and June 2005 in our institute. They all received standard conditioning regimens with Bu/Cy (n = 53) or TBI/Cy (n = 10) with the addition of ATG for 3 - 4 days (n = 58) or CD3 antibody (n = 5). There were more patients receiving rabbit ATG in the UPBSCT group than UBMT (21/33 vs 8/25, P = 0.02) and the remaining patients received pig ATG. Graft versus host disease (GVHD) prophylaxis consisting of cyclosporine, methotrexate and mycophenolate mofetil were the same. RESULTS: The two groups were matched for the following factors: gender, diagnosis, HLA-compatibility and conditioning regimens. The median age in the UPBSCT group was 29.5 (10 - 47) years and in the UBMT 21.5 (7 - 42) years (P < 0.05). The UPBSCT group consisted of 10 females and 23 males and the UBMT group 7 females and 23 males. Eleven patients in the UPBSCT and 8 patients in the UBMT group were diagnosed with as chronic myeloid leukemia (CML); 9 and 12 as acute myelocytic leukemia (AML); 11 and 10 as acute lymphatic leukemia (ALL); 2 and 0 as severe aplastic anemia (SAA). There were more patients in aggressive stage (>CR1) in the UBMT group than in the UPBSCT group (9/30 vs 3/33, P = 0.06). Median follow-up was 12 months after UPBSCT and 20 months after UBMT (P < 0.05). UPBSCT group had a higher number of infused MNC as comparison with UBMT group (6.16 x 10(8)/kg vs 2.80 x 10(8)/kg, P < 0.05). Both neutrophil and platelet recovery were faster after UPBSCT (11 days vs 17 days, 14 days vs 27.5 days, P < 0.01). Although the cumulative incidence of grades II - IV acute GVHD and severe aGVHD in the UPBSCT group were less than in the UBMT group (33.04% vs 66.69%, 7.26% vs 34.52%, P < 0.05), there was no difference after the source of ATG was counted. The incidence of chronic GVHD did not differ between the two groups (18/25 vs 14/22). Relapse including molecular relapse occurred in 6 of the 31 patients after UPBSCT and in 4 of the 30 patients after UBMT (P > 0.05). Finally, fifteen of the 30 patients died after UBMT, as compared with 8 of the 33 patients after UPBSCT. The cumulative overall survival was 62.45% after UPBSCT and 47.22% after UBMT (P = 0.114). CONCLUSION: Our results indicate that UPBSCT led to significantly faster leukocyte and platelet engraftment without increasing the incidence of aGVHD and the overall survival was comparable between the two methods of therapy.

[Surveillance of cytomegalovirus for antiviral efficacy and risk factors in allogeneic hematopoietic stem cell transplantation].

The study was aimed to investigate the pp65 antigen of human cytomegalovirus (CMV) and its clinical significance in patients revived allogeneic hematopoietic stem cell transplantation (HSCT). 104 patients received allogeneic HSCT were studied. Anticoagulant blood samples were obtained from the recipients before and after transplantation and in the convalescence. CMV pp65 antigen in leukocytes was detected by indirect immunofluorescence assay using CMV Brite Kit weekly. The results showed that among the 104 patients, 29 cases were CMV pp65 positive (27.88%). Out of 29 cases 16 were CMV antigenemia and 13 cases were CMV disease. There were 25 cases who positively responded to antiviral therapy (effective ratio 86.21%) and 4 cases died (case-fatality ratio 13.79%). The detection revealed a significant difference in the incidence of CMV infection between the patients received unrelated or haploidentical family donor HSCT (39.29%) and HLA-identical sibling donor HSCT (14.58%) (P < 0.05). The incidence rate of CMV infection in patients with 0-I grade aGVHD and patients with II-IV grade aGVHD were 19.44% and 46.88% respectively, which had significant difference (P < 0.05). There was significant difference in the occurrence of aGVHD between the patients with and without positive CMV pp65 (P < 0.05). It is concluded that infection of CMV can be detected by the CMV pp65 monoclonal fluorescence immunohistochemistry, The detection of CMV pp65 antigen in peripheral blood leukocytes as a indicator for CMV disease surveillance after HSCT, which may be used to early diagnose the CMV infection, to guide the antiviral treatment and evaluate its efficacy.

Conditioning including antithymocyte globulin followed by unmanipulated HLA-mismatched/haploidentical blood and marrow transplantation can achieve comparable outcomes with HLA-identical sibling transplantation.

The outcomes of 293 patients with leukemia undergoing HLA-identical sibling (n = 158) or related HLA-mismatched (n = 135) hematopoietic cell transplantation (HCT) performed during the same time period were compared. Patients received BUCY2 in HLA-identical sibling HCT or BUCY2 + ATG in mismatched HCT as conditioning regimens, followed by unmanipulated marrow and/or peripheral blood (PB) transplantation. All patients achieved full engraftment. The cumulative incidences of grades II to IV acute graft-versus-host disease (aGVHD) in the matched and mismatched cohorts were 32% (CI, 25%-39%) versus 40% (CI, 32%-48%, P = .13), respectively, with the relative risk (RR) = 0.64 (95% CI, 0.43-0.94), P = .02. The incidence of chronic GVHD did not differ significantly between the cohorts (P = .97). Two-year incidences of treatment-related mortality and relapse for matched versus mismatched were 14% (range, 9%-20%) versus 22% (range, 15%-29%) with P = .10 and 13% (range, 8%-19%) versus 18% (range, 10%-27%) with P = .40, respectively. Two-year adjusted leukemia-free survival (LFS) and overall survival were 71% (range, 63%-78%) versus 64% (range, 54%-73%) with P = .27 and 72% (range, 64%-79%) versus 71% (range, 62%-77%) with P = .72, respectively. Multivariate analyses showed that only advanced disease stage and a diagnosis of acute leukemia had increased risk of relapse, treatment failure, and overall mortality. In summary, HCT performed with related HLA-mismatched donors is a feasible approach with acceptable outcomes.

[Efficacy of intravenous administration of itraconazole on fungal infections in immunocompromised patients with hematological diseases].

OBJECTIVE: To investigate the efficacy of intravenous administration of itraconazole on fungal infections in immunocompromised patients with hematological diseases according to stratified diagnoses. METHODS: Twenty-five patients with hematological diseases who were diagnosed according to the criteria of European Organization for Research and Treatment of Cancer (EORTC), including 6 cases with confirmed diagnosis diagnosis, 12 cases with clinical diagnosis, and 7 cases with recommended diagnosis, underwent intravenous injection of itraconazole 125 approximately 200 mg bid for 2 days and then qd for at most 2 weeks and then oral administration of itraconazole 0.4 g/day for at most 2 weeks, and then the repeated regimen with a course of treatment of 1 approximately 3 months from 2002 to 2004. Eighteen cases were diagnosed with lung infection, 1 case with sinuses and trachea infection, and the infection sites were not documented for other 7 cases. The clinical results were analyzed. RESULTS: The effective rates of the patients with confirmed diagnosis, with clinical diagnosis, and with recommended diagnosis were 66.7% (4/6), 83.3% (10/12), and 14.3% (1/7) respectively. The effective rates of the patients with major imaging signs and those with secondary imaging signs were 90.0% (9/10) and 97.1% (4/7). There was a significant difference between the curative effects of the patients with confirmed diagnosis and those with recommended diagnosis (P = 0.006). CONCLUSION: Fungal infections in immunocompromised patients with hematological diseases can be successfully treated with intravenous administration of itraconazole.

[Methotrexate for treatment of graft versus host disease after allogeneic hematopoietic stem cell transplantation].

OBJECTIVE: To evaluate the efficacy and safety of low-dose methotrexate in patients with graft versus host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (Allo-HSCT). METHODS: Thirty-one patients with minor or moderate grade acute GVHD (aGVHD), chronic GVHD (cGVHD) or GVHD post donor lymphocyte infusion (post-DLI GVHD) after Allo-HSCT received intravenously administrated methotrexate at a dose of 5 or 10mg every 5 to 7 days until achieving complete or partial responses, treatment failure or intolerable side effects. RESULTS: The overall response rate was 93.8% (15/16 patients) in patients with aGVHD, 75% (12/16 patients) in patients with cGVHD and 100% (2/2 in patients) with post-DLI GVHD. The response rate for GVHD involving organs was 100% in skin, 60% in gut, 71% in liver, 75% in mouth and 100% in eyes. Side effects were minor. During the therapy, the other immunosuppressive agents were reduced. CONCLUSION: Short-term low-dose methotrexate is a tolerable and effective regimen for patients with minor or moderate grade aGVHD, cGVHD or post-DLI GVHD after Allo-HSCT.

[Analysis of risk factors for the development of acute graft-versus-host disease in 151 cases of allo-hematopoietic stem cell transplantation].

OBJECTIVE: To investigate the incidence and risk factors of acute graft-versus-host disease (aGVHD) after allogeneic hematopoietic stem cell transplantation (HSCT). METHODS: The clinical data of 151 cases of allo-HSCT in 150 patients from Nov 2001 to Jan 2004 was analyzed. RESULTS: aGVHD was developed in 60 cases (40.2%), including 43 cases with grade I - II and 17 with grade III - IV aGVHD, the mean time of aGVHD development was 21 days (range 1 - 85 days) after allo-HSCT, 35 out of 55 cases achieved complete response (CR) (63.6%). The early survival rate for grade I - II aGVHD was more than 90%, while that for grade III - IV aGVHD was 46%. Nineteen factors possibly correlated with the development of aGVHD were analyzed. The univariate analysis showed that recipient age, donor's sex, recipient's sex, sex and ABO blood group disparity between donor and recipient, diagnosis, the status of disease, the stage of disease, stem cell source, conditioning regimen (TBI/without TBI), CD34(+) cell number, CD3(+) cell number, early engraftment and neutropenic infection were not closely associated with the occurrence of aGVHD (P > 0.05). On the Cox regression model, 2 independent factors for grade I - IV aGVHD were identified:HLA mismatch (RR = 1.681, P < 0.05) and positive surface antigen (HBsAg) (RR = 1.907, P < 0.05). In addition, the univariate analysis showed aGVHD was strongly associated with CMV infection (P < 0.01). CONCLUSION: aGVHD is a common complication after HSCT, HLA mismatch and HBsAg positivity are independent risk factors for aGVHD.

[Allogeneic hematopoietic stem cell transplantation for treatment of Philadelphia chromosome positive acute lymphoblastic leukemia].

OBJECTIVE: To explore the optimal time of allogeneic hematopoietic stem cell transplantation (allo-HSCT) applied in patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL), and the optimum order of donor selection. METHODS: From Mar 2000 to Jul 2004, 32 patients with Ph+ ALL were treated by Allo-HSCT, and the follow up ended at Dec 30.2004 with medium of 13 months. Of whom, 24 were male, and 8 were female. Twenty-three patients have been transplanted in CR1, 9 patients beyond CR1 (1 in CR2, 8 in refractory or relapse status). Twelve cases received HSCT from identical sibling donor, 4 unrelated Cord Blood Transplantation (CBT), 3 HSCT from matched unrelated donor (MUD), and 13 HSCT from mismatched related donor (MMRD), of which, 6 cases were M(BCR/ABL) subtype, and 20 m(BCR/ABL) subtype. The Kaplan-Meier method was used to estimate the probabilities of leukemia-free survival (LFS), overall survival (OS) and relapse incidence (RI), and the factors were compared by means of the Log-rank test. Simultaneous effect of multiple covariates were estimated with Cox model. RESULTS: Of all the 32 cases engrafted, 4-year OS was 57.19%, LFS 37.09%, and RI 56.36%. In univariate prognostic analysis model, the OS was higher in CR1 group pre-HSCT than that in non-CR1 group (74.50% vs 22.22%, P=0.0046), LFS was higher (49.06% vs 11.11%, P=0.0057), RI was lower (44.80% vs 84.76%, P=0.0157); the OS was higher in M(BCR/ABL) group than that in m(BCR/ABL) group (100% vs 40.91%, P=0.0318), LFS was higher (75% vs 17.72%, P=0.0057), RI was lower (25% vs 77.88, P=0.0116); OS was similar in HLA MM RD group to that in HLA identical group (52.65% vs 55.56%, P=0.6247), LFS was similar (45.12% vs 30.00%, P=0.8315), and RI was also similar (50.77% vs 60.62%, P=0.8217). In multiple covariate analysis model, the BCR/ABL type was the risk factor of LFS [P=0.005, Exp(B)=9.971] and RI (P=0.006, Exp(B)=9.488), the status of disease pre-HSCT and BCR/ABL subtype was the risk factor of OS [P was 0.010 and 0.038, Exp(B) was 4.532 and 37.537 respectively]. CONCLUSION: We had better do HSCT in CR1 to treat Ph+ ALL, if patient is refractory to chemotherapy, we can try STI571, and HSCT should be done as soon as possible if the patients get CR. Mismatched related donor is considered as regular donor for Ph+ ALL patients without identical donors. We should pay more attention to monitoring and prophylaxis of relapse in m(BCR/ABL) patients after HSCT.