Evaluation of the Role of Tumor-Infiltrating Lymphocytes and CD8+ Cytotoxic Lymphocytes in the Survival of Patients with Breast Cancer.

Background: This study aimed to evaluate the significance of tumor-infiltrating lymphocyte (TIL) and the number of CD8+ T cells in breast cancer and their relationship with the other clinicopathological factors, and overall survival (OS) was investigated. Materials and Methods: The studied samples were breast cancer patients (2005-2017) referring to the medical oncology departments for treatment. Pathologic samples of breast cancer patients were evaluated in terms of TIL and positive immunohistochemical staining for CD8 cytotoxic cells. Results: 299 patients were entered into the study, three were male and 296 female. Their mean follow-up period was 61 months. Statistical findings indicated that lymph involvement is more accompanied by low TIL within the tumor (0.011). Correlations were observed between the estrogen, progesterone receptors, P53 state, and TIL, which were significant by P-value<0.049, P-value=0.024, P-value =0.002, respectively. With any Ki67 value, the number of patients with less than 30% TIL was more considerable than the other two groups with lymphocyte cut-off of 30-50% and more than 50%. Comparison of the OS of patients with positive and negative CD8 cytotoxic lymphocytes in 45 patients with lymphocyte infiltration of equal or more than 40% showed that the OS results were in favor of patients with CD8+ cytotoxic lymphocyte (0.022). Out of 299 patients, 17 died. Conclusion: Our findings showed that in cases of CD8+ cytotoxic lymphocytes in tumors, the OS of the patients will be enhanced which can act as an independent factor.

The Role of Dihydropyrimidine Dehydrogenase and Thymidylate Synthase Polymorphisms in Fluoropyrimidine-Based Cancer Chemotherapy in an Iranian Population.

BACKGROUND: The fluoropyrimidine drug 5-Fluorouracil (5-FU) and the prodrug capecitabine have been extensively used for treatment of many types of cancer including colorectal, gastric, head and neck. Approximately, 10 to 25% of patients suffer from severe fluoropyrimidine-induced toxicity. This may lead to dose reduction and treatment discontinuation. Pharmacogenetics research could be useful for the identification of predictive markers in chemotherapy treatment. The aim of the study was to investigate the role of five genetic polymorphisms within two genes (DPYD, TYMS) in toxicity and efficacy of fluoropyrimidine-based chemotherapy. METHODS: Total genomic DNA was extracted from 83 cancer patients treated with fluoropyrimidine-based chemotherapy. In this study, three polymorphisms were genotyped in dihydropyrimidine dehydrogenase gene c.1905+1 G>A (DPYD*2A; rs3918290), c.1679 T>G (I560S; DPYD*13; rs55886062), and c.2846A>T (D949V; rs67376798) and two polymorphisms, besides the Variable Number of Tandem Repeat (VNTR) polymorphism and 6-bp insertion/deletion polymorphism in thymidylate synthase gene. The analysis of polymorphisms for rs3918290, rs55886062, rs67376798 and 6-bp insertion/deletion in TYMS was done by Polymerase Chain Reaction-restriction Fragment Length Polymorphism (PCRRFLP) TYMS VNTR analysis. 5-FU-related toxicities such as anemia, febrile neutropenia, neurotoxicity, vomiting, nausea, and mucositis were evaluated according to NCI-CTC criteria version 4.0. T-test and chi-square were used and p-values less than 0.05 were considered statistically significant. RESULTS: DPYD gene polymorphisms were not observed in this study. The frequency of the TYMS +6 bp allele was 40.35% and the -6 bp allele was 59.65% in this study. The frequency of VNTR 2R allele was 48.75% and 3R allele was 51.15%. Toxicity grade II diarrhea, mucositis, nausea, vomiting, and neurotoxicity was 2.2, 24.1, 15.7, 6, and 51.8%, respectively. Thymidylate synthase ins/del polymorphisms were associated with increased grade III neurotoxicity (p=0.02). Furthermore, anemia grade III was significantly associated with 2R/2R genotype (0.009). CONCLUSION: Thymidylate synthase gene polymorphisms may play a key role in fluoropyrimidne -based chemotherapy. Although rare DPYD polymorphisms were not observed in our study, according to large population studies, DPYD gene polymorphisms could be used as a predictive biomarker for patient treatments.

Correlation of HER2, MDM2, c-MYC, c-MET, and TP53 Copy Number Alterations in Circulating Tumor Cells with Tissue in Gastric Cancer Patients: A Pilot Study

Background: The analysis of the gene copy number alterations in tumor samples are increasingly used for diagnostic and prognostic purposes in patients with gastric cancer (GC). However, these procedures are not always applicable due to their invasive nature. In this study, we have analyzed the copy number alterations of five genes (HER2, MDM2, c-MYC, c-MET, and TP53) with a fixed relevance for GC in the circulating tumor cells (CTCs) of GC patients, and, accordingly, as a potential approach, evaluated their usage to complete primary tumor biopsy. Methods: We analyzed the status of the copy number alterations of the selected genes in CTCs and matched biopsy tissues from 37 GC patients using fluorescence in situ hybridization. Results: HER2 amplification was observed in 2 (5.41%) samples. HER2 gene status in CTCs showed a strong agreement with its status in 36 out of 37 patients' matched tissue samples (correlation: 97.29%; Kappa: 0.65; p < 0.001). MDM2 amplification was found only in 1 (2.70%) sample; however, the amplification of this gene was not detectable in the CTCs isolated from this patient. c-MYC amplification was observed in 3 (8.11%) samples, and the status of its amplification in the CTCs indicated a complete agreement with its status in the matched tissue samples (correlation: 100%; Kappa: 1.0). Conclusion: Our work suggests that the amplification of HER2 and c-MYC is in concordance with the CTCs and achieved biopsies, and, consequently, CTCs may act as a non-invasive alternative for recording the amplification of these genes among GC patients.

Impact of preexisting diabetes mellitus on transplantation outcomes in hematopoietic stem cell transplantation.

New onset diabetes mellitus is frequently observed following hematopoietic stem cell transplantation (HSCT) and is associated with adverse transplantation outcomes. However, the outcomes of patients with preexisting diabetes mellitus undergoing HSCT are largely unknown. We aimed to explore the impact of preexisting diabetes on transplantation outcomes in HSCT. In a retrospective study, medical charts of 34 HSCT recipients with diabetes mellitus undergoing allogeneic or autologous transplantation were reviewed and compared with 71 HSCT recipients without diabetes. Primary outcome was overall survival. Secondary outcomes included hematopoietic recovery, length of hospital stay, febrile neutropenia, acute and chronic graft-versus-host disease (GVHD), primary disease recurrence, and non-relapse mortality (NRM). On univariate analysis, there was no difference in transplantation outcomes in recipients with diabetes compared with recipients without diabetes. However, after adjusting for potential covariates, multivariate analysis demonstrated that having diabetes before HSCT significantly predicted outcome and decreased overall survival (hazard ratio 0.51, 95% confidence interval: 0.27-0.97, p value: 0.04). This study suggests that patients with diabetes mellitus undergoing allogeneic or autologous HSCT may have inferior survival rates and warrant further attention.

The outcome of allogeneic hematopoietic stem cell transplants without total body irradiation in pediatric patients with acute lymphoblastic leukemia: single centre experience.

The most widely accepted conditioning regimen to allogeneic hematopoietic stem cell transplantation consists of total body irradiation, especially in patients affected by acute lymphoblastic leukemia (ALL). In this retrospective study, we report our experience on hematopoietic stem cell transplantation in 44 pediatric patients with acute lymphoblastic leukemia using a non-radiation-based conditioning regimen (busulfan/cyclophosphamide). Median age at transplantation was 12.5 years (range, 4 to 14 y). 39 out of 44 patients received transplants in complete remission. At a median follow-up of 390 days, the probabilities of 3-year disease-free survival and overall survival were 50% and 68%, respectively. Disease status of hematopoietic stem cell transplantation was the only significant variable affecting the overall survival. Acute and chronic graft-versus-host disease occurred in 23 (64%) and 12(18%) patients, respectively. Relapse was significantly higher among patients transplanted in advanced disease status. The results of the study indicate that non-radiation-based preparative regimens can be used in pediatric patients with ALL. However, well-designed comparative trials are needed to better clarify the difference between radiation and non-radiation-based conditioning regimens in pediatric ALL.

The effect of zinc sulfate in the prevention of high-dose chemotherapy-induced mucositis: a double-blind, randomized, placebo-controlled study.

The purpose of this study was to evaluate the effect of oral zinc sulfate in the prevention of chemotherapy-induced mucositis in patients undergoing hematopoietic stem-cell transplantation (HSCT). This study was a double-blind, randomized, placebo-controlled design, with 60 patients undergoing HSCT, divided proportionally in experimental group who received zinc sulfate, and in placebo group. They all had received high-dose chemotherapy conditioning regimen for allogenic transplantation. Oral mucositis assessed was based on World Health Organization (WHO) oral mucositis scale. There were no significant differences in the development of mucositis between the two groups. Severity of mucositis was not significantly different between the two groups either. The same result was obtained regarding the duration of mucositis. Zinc sulfate did not show any significant adverse effects in experimental group. In conclusion, Zinc sulfate did not have any clinical benefits in prevention or reduction of severity, and duration of high-dose chemotherapy-induced mucositis in patients undergoing HSCT.

Development and validation of limited sampling strategies for estimation of cyclosporine area under the concentration-time curve in hematopoietic stem cell transplant patients.

The aim of this study was to develop and validate limited sampling strategies for accurately predicting 12-hour area under the concentration-time curve (AUC(0-12 h)) to provide a practical method for more precise therapeutic drug monitoring of cyclosporine A in stem cell transplant patients. Steady-state cyclosporine blood concentrations were measured within a dosing interval (12 hours post administration) in 35 allogeneic bone marrow transplant patients receiving 238 mg (±117 mg) twice-daily dose of cyclosporine. Limited sampling strategies were developed by multiple linear regression analysis of relationship between cyclosporine A full AUC(0-12 h) values and different combinations of preselected blood concentrations. Validation of the estimating equations was done by a bootstrap-like cross-validation method. Cross-validation results showed that cyclosporine AUC(0-12 h) could be estimated using either 2 or 3 samples within the first 4 hours after drug administration with good accuracy and precision (absolute prediction error of less than 6.2%). The number of estimated area under the drug concentration-time curves within 15% of observed values was greater than 26 (74%) for models used predose concentration with either c(2h) and c(4h) or both. Most of the previously reported single-sample models showed a systematic error in predicting AUC(0-12 h). Although a statistically significant difference in precision of prediction was seen between 3-sample model using c(0), c(2h), and c(4h) and 2-sample models (c(0), c(2h) or c(0), and c(4h)), such a difference (2%) could not be of clinical importance. Other 2-sample estimating equations (models using c(2h) with either c(6h) or c(10h)) with the same degree of precision appear to be less feasible clinically. Cyclosporine AUC(0-12 h) in bone marrow transplant patients could be estimated using 2 or 3 samples within the first 4 hours after drug administration with good accuracy and precision.

Long-term results of non-fludarabine versus fludarabine-based stem cell transplantation without total body irradiation in Fanconi anemia patients.

BACKGROUND AND OBJECTIVE: Hematopoietic cell transplantation (HCT) is the only therapeutic modality capable of correcting the hematologic manifestations of Fanconi anemia (FA). The development of well-tolerated immunosuppressive conditioning regimens for FA patients undergoing HCT has proven to be a challenging task for hematologists. DESIGN AND SETTINGS: Retrospective, patients referred to the hematology, oncology and stem cell transplantation research center. PATIENTS AND METHODS: We analyzed the outcome of 53 FA patients who had undergone HCT between 1992 and 2010. The median age at transplantation was 9 years. Patients received transplants from an HLA-identical sibling (n=39) or matched relative (n=9) and one-antigen locus mismatched other relative/sibling (n=5). All of the patients underwent transplantation with fludarabine and non-fludarabine-based conditioning regimens. No radiation therapy was given. RESULTS: The median follow-up period for survivors was 13.5 months (range, 3 months-13.5 years). The 3-year overall survival (OS) was 60.6%. The 3-year OS for patients who did or did not receive fludarabine-based preparative regimens for the allograft was 36.4%, and 70%, respectively. However, there were no statistically significant differences in OS rates between these two groups (P=.112). Graft failure occurred in 4 patients (7.5%). All of these 4 patients had received fludarabine-based conditioning regimens. The incidence of acute GVHD after fludarabine-based regimens was 45% versus 79% in non-fludarabine-based regimens (P=.03). CONCLUSION: Despite the high incidence of acute GVHD (78.6%) in the non-fludarabine group, which resulted in the death of some patients, the OS rate was significantly better than in fludarabine recipients. Therefore, in spite of the fact that recent studies advocate the fludarabine-based conditioning regimens, we propose to conduct a multicenter, prospective study to evaluate the outcomes of regimens employed in FA patients.

Treatment of relapsed acute promyelocytic leukemia by arsenic trioxide in Iran.

BACKGROUND: Although standard first line treatment of acute promyelocytic leukemia is All trans retinoic acid (ATRA) and chemotherapy, some patients relapse and need a second line of treatment. Relapsed cases of promyelocytic leukemia can be salvaged with arsenic trioxide. METHODS: Between May 1999 and Jan. 2010, we treated 31 relapsed cases of promyelocytic leukemia with arsenic trioxide. These cases relapsed after previous treatment with ATRA and chemotherapy. We applied arsenic trioxide as 0.15 mg/kg iv infusion until complete remission. After achieving complete remission patients received 2-4 consolidation therapy in the same schedule as remission induction. RESULTS: The median age of patients was 27 years. Complete remission rate was 77.4%. We observed four mortalities during remission induction. With a median follow up of 32 months, ten more relapses occurred. Two year disease-free survival and overall survival for the entire cohort was 54.6% and 81.1%, respectively. CONCLUSION: Our result is the same as other studies. Thus, we suggest that arsenic trioxide can be used as salvage therapy in patients who relapsed. Despite a good complete remission rate, the relapse rate during the first two years of treatment is high and hematopoietic stem cell transplantation should be considered after achieving complete remission.

Comparison of peripheral blood stem cell transplant with bone marrow transplant in class 3 thalassemic patients.

OBJECTIVES: This study aimed to compare outcome of bone marrow transplant with peripheral blood stem cell transplant in class 3 thalassemic patients. MATERIALS AND METHODS: Respectively, 32 and 20 class 3 thalassemic patients received bone marrow transplant and peripheral blood stem cell transplant from human leukocyte antigen identical sibling donors. Conditioning regimen consisted of busulfan (16 mg/kg) and cyclophosphamide (160 mg/kg) followed by cyclosporine and methotrexate as graft-versus-host disease prophylaxes. RESULTS: Median time to absolute neutrophil count was significantly shorter in the peripheral blood stem cell transplant group (12 vs 23 days); however, there was no significant difference regarding platelet recovery between the 2 groups (20 vs 28 days). Acute graft-versus-host disease occurred in 47% of patients. Chronic graft-versus-host disease developed in 28% of patients which was significantly higher in the peripheral blood stem cell transplant group (P = .06). During 50 months follow-up, thalassemia recurrence, overall survival, and thalassemia-free survival were 17%, 80%, and 65%, respectively, and there were no significant differences between the 2 groups. CONCLUSIONS: These results showed that stem cell transplant is an effective treatment in class 3 thalassemic patients with the outcome relatively similar to bone marrow transplant. Although engraftment time is shorter in peripheral blood stem cell transplant method, it is associated with higher rate of chronic graft-versus-host disease.

Serum electrolyte changes at engraftment time in patients undergoing allogeneichematopoietic stem cell transplantation.

BACKGROUND: Metabolic abnormalities have been reported in patients undergoing hematopoietic stem cell transplantation (HSCT). Potential causes, risk factors and outcomes of electrolyte imbalances have thoroughly been investigated. On HSCT recipients, multiple pathophysiologic contributors are inflicting electrolyte abnormalities, with special attention being paid to engraftment per se as an important contributor. Engraftment contribution to electrolyte imbalances has been reported for hypophosphatemia and for other electrolyte abnormalities in autologous setting. However in the allogeneic setting serum electrolyte level changes and the timing of any probable abnormality are unknown. MATERIAL AND METHODS: We performed a retrospective study in order to evaluate the pattern of phosphorous, magnesium, potassium and uric acid serum changes, timing of any probable abnormality and their possible association with WBC and platelet engraftment in 65 allogeneic HCT recipients from day -9 to +32 after transplantation. Besides we assessed frequency and severity of the abnormalities. RESULTS: We observed a declining pattern of electrolyte concentrations with nadirs antedating WBC and platelet engrafments. Phosphorous and potassium serum changes were correlated with natural logarithm of WBC and platelet level changes. Observed overall incidence of hypophosphatemia (9.2%) and hypomagnesemia (3%) was lower than those previously reported. CONCLUSION: Abnormalities found reflect a combination of pathophysiologic mechanisms. Occurrence of electrolyte nadirs antedating engraftment confirms increased consumption by rapidly replicating cells as a contributor in allogeneic setting and specifies a susceptible period requiring intensive monitoring. Considering high risk patients and managing various organ system complications lower incidence of some electrolyte abnormalities may be observed.

The prevalence of low selenium levels in adult patients undergoing bone marrow transplantation: a brief communication.

Selenium (Se) is an essential trace element, and its deficiency is considered to be important in various types of cancer. There are just a few data regarding this issue among adult patients with hematological malignancy. Serum Se levels were determined in 22 adult patients candidates for bone marrow transplantation (BMT) in Iran. The mean serum Se levels before BMT was 19.91 microg/l (from 12.00 to 62.00 microg/l), and almost all the patients had low Se serum levels (normal serum Se level: 46-143 microg/l). The level of Se 20 days after BMT was 22.53 microg/l, which did not show any significant changes. Most of the patients did not suffer from malnutrition, as they had mostly normal albumin levels. Even though the results of this study showed that Se deficiency is common among our hematological malignant patients, it can not be concluded that these low Se levels are causally related to cancers for which BMT is undertaken. Further studies are needed to evaluate the Se levels at diagnosis before treatment effects.

Erythroid-lineage-specific engraftment in patients with severe hemoglobinopathy following allogeneic hematopoietic stem cell transplantation.

OBJECTIVE: We aimed to create a molecular assay to monitor erythroid (red blood cell [RBC]) engraftment in any patient following allogeneic hematopoietic stem cell transplantation, independent of disease-specific mutations. MATERIALS AND METHODS: We identified 10 common single nucleotide polymorphisms (SNPs), expressed by genes encoding RBC antigens and structural proteins. These SNPs were polymerase chain reaction-amplified from total RNA extracted from peripheral blood, which contains nucleated erythroid progenitors. Mixing studies validated that each SNP can quantitatively measure donor/recipient DNA and RNA. RESULTS: We directly genotyped 23 patients who underwent hematopoietic stem cell transplantation and their human leukocyte antigen-matched donors and found a median of three informative SNPs (i.e., discordant between donor and recipient) per pair. By using the informative RBC SNPs to quantify donor-derived RBC transcripts, we compared rates of RBC engraftment in 13 patients with hemoglobinopathies vs donor mononuclear cell (white blood cell [WBC]) engraftment. Consistent with known ineffective erythropoiesis associated with hemoglobinopathies, we detected up to threefold greater RBC-specific compared to overall WBC engraftment in five of eight patients who were mixed chimeras by transplant day 30. The remaining three of eight who received ABH-incompatible grafts, demonstrated at least 0.5-fold lower RBC compared to WBC engraftment that was related to persistence of host-derived anti-isohemagglutinin antibodies. CONCLUSION: This RNA-based assay can be used to monitor RBC-specific engraftment regardless of a patient's specific hemoglobin mutation or even diagnosis. We propose that panels of expressed SNPs informative for other cell lineages can be created to comprehensively assess the impact of novel stem cell-based therapies on lineage-specific engraftment.

Continuous bladder irrigation prevents hemorrhagic cystitis after allogeneic hematopoietic cell transplantation.

Hemorrhagic cystitis is 1 of the most troublesome complications of hematopoietic cell transplantation conditioning regimens. We conducted a nonrandomized controlled clinical study to investigate the role of continuous bladder irrigation in addition to mesna, hydration, and alkalization in the prevention of hemorrhagic cystitis after allogeneic hematopoietic cell transplantation. A total of 80 eligible patients entered the study. From May 2006, 40 patients who underwent allogeneic hematopoietic cell transplantation received continuous bladder irrigation in addition to the common protocol. A historical control group of 40 consecutive patients with same inclusion criteria who did not receive bladder irrigation was enrolled from before May 2006. Hemorrhagic cystitis occurred in 50% of patients in the no bladder irrigation group versus 32% in bladder irrigation group (P = 0.11). The mean duration of hemorrhagic cystitis was significantly reduced in the bladder irrigation group (10 vs. 18 days; P = 0.02). Duration of hospitalization was significantly shorter in the bladder irrigation group (30.2 vs. 39.6; P < 0.001). Late-onset hemorrhagic cystitis that occurred beyond 4 weeks after allo-hemorrhagic cystitis happened more significantly in the no bladder irrigation group (P = 0.001). High-grade hemorrhagic cystitis was more frequently associated with high-grade graft-versus-host disease within 30 days after transplant (P = 0.06). In general, continuous bladder irrigation added to mesna, hydration, and alkalization regimens was well tolerated, decreased the complications of hemorrhagic cystitis, and may be useful in hematopoietic cell transplantation patients. However, more investigations with randomized controlled clinical trials with more patients are needed.

Hematopoietic stem cell transplantation in Iran: 1991 to 2008.

Since 1991, 2042 first hematopoietic stem cell transplants (HSCT) have been performed at the Hematology-Oncology and Stem Cell Transplantation Research Center at Tehran University of Medical Sciences. Acute myelogenous leukemia (548 patients), thalassemia major (335 patients) and acute lymphoblastic leukemia (275 patients) have been the most common transplanted disorders. There were 1418 cases that received allogeneic HSCT and 624 cases that have received autologous HSCT. The numbers of allogeneic and autologous HSCT have increased, but the allogeneic to autologous ratio has remained constant. The first peripheral blood hematopoietic stem cell transplantation was performed in 1996; since then, 1671 have been done. The donor types for 1418 allogeneic first HSCT were 1367 (96.4%) human leukocyte antigen (HLA) matched-identical siblings, 29 (2%) HLA-mismatched sibling/other relative, 13 (0.9%) syngeneic twins, 5 (0.4%) HLA-matched other relatives and 4 (0.3%) unrelated. The first cord blood hematopoietic stem cell transplantation was performed in 1998 and since then there have been 14 patients that have obtained cord blood transplantations. Recently, new methods have been used like donor lymphocyte infusion (DLI) and cellular therapy. There were 111 patients with cellular therapy for post-myocardial infarction, cirrhosis, thalassemia major, multiple sclerosis, head of femur necrosis and renal cell carcinoma.

Flow cytometric evaluation of red blood cell chimerism after bone marrow transplantation in Iranian patients: a preliminary study.

The aim of this study was to evaluate mixed red cells population and red blood cell chimerism after hematopoietic stem cell transplantation. Red blood cell chimerism after hematopoietic stem cell transplantation was analyzed using a series of fluorescein isothiocyanate-conjugated monoclonal antibodies (BioAtlantic, France) directed against ABH, Rh (D, C, E, c, e), Kell, Duffy, Kidd, and Ss antigens on blood samples of 14 patients with hematologic disorders undergoing hematopoietic stem cell transplantation, by flow cytometric method on days 15, 30, and 60 after transplantation. All patients showed expression of donor red cell antigens within days 15 - 30 after hematopoietic stem cell transplantation. Graft versus host disease and ABO incompatibility did not affect the expression of chimerism. Flow cytometric analysis is a simple, accurate, and valuable test which is of significant help in monitoring chimerism in allogeneic hematopoietic stem cell transplantation.

Effects of chimerism on graft-versus-host disease, disease recurrence, and survival after HLA-identical marrow transplantation in Iran.

BACKGROUND: The coexistence of recipient's and donor's hematopoietic systems after allogeneic marrow transplantation is called mixed chimerism. OBJECTIVE: The objective of this study was to evaluate the effects of MC on graft-versus-host disease (GVHD), disease recurrence, and survival after HLA identical marrow transplantation in a transplant center in Iran. METHODS: The association of MC with acute GVHD, disease recurrence, survival, and relapse-free survival was investigated in 91 patients who underwent either bone (n = 12) or peripheral blood (n = 79) HLA-identical marrow transplantation. Chimerism was assessed using multiplex amplification of short tandem repeats (STR). Patients had thalassemia (n = 19), acute myelogenous leukemia (AML) (n = 29), acute lymphocytic leukemia (ALL) (n = 20), chronic myelogenous leukemia (CML) (n = 18), and other diseases (n = 5). The median age was 21 (range: 3 - 50) years. There were 38 (42%) female and 53 (58%) male participants. Conditioning was made through busulfan plus cyclophosphamide in 34 patients; busulfan plus fludarabin in 51 patients; and busulfan plus fludarabin plus antithymocyte globulin in 6 patients. The median follow-up was 13 months. RESULTS: On day +30, complete chimerism (CC) was observed in 72 (79%) patients, MC in 15 (17%), and no chimerism in 4 patients. The incidence of acute GVHD was significantly (P = 0.01) lower in mixed chimeras than in complete chimeras. There was no significant difference in acute GVHD grade (I, II vs. III, IV) between the two groups. The incidence of relapse was 18%. There was no difference in relapse rate between MC and CC groups. Overall survival was 89%. There was no significant difference in the overall survival between MC and CC group (96% vs. 85%, respectively). Relapse-free survival was 80% that was not significantly different between the two groups. CONCLUSION: Despite some previous reports, we found no significant difference in the survival and relapse rates between MC and CC groups.

Effect of IL-18 and sIL2R on aGVHD occurrence after hematopoietic stem cell transplantation in some Iranian patients.

BACKGROUND: Graft-versus-host disease is one of the major complications after allogeneic bone marrow transplantation, but it is not easy to anticipate the onset. Cytokines released by type 1 T helper cells are thought to play a pivotal role in acute graft-versus-host disease aGVHD. The ability to predict the likely occurrence of graft-versus-host-disease (GVHD) after Hematopoietic Stem cell Transplantation (HSCT) would be extremely valuable. By serially measuring serum levels of soluble IL-2 receptor (sIL-2R), IL-18 and following allogeneic HSCT we tried to define their effect on aGVHD as a complication of transplantation and determine useful markers for aGVHD predictors. SAMPLES AND METHODS: Serum sIL-2R, IL-18, levels were measured by sandwich ELISA in 219 sera samples from 39 patients (with hematological disorders before and after allogeneic HSCT) and 28 controls. All patients received transplants from HLA-identical siblings. RESULTS: 23 (58.9%) patients developed aGVHD (I-IV) and serum levels of sIL-2R and IL-18, in sera drawn before transplantation, in patients with acute graft-versus-host disease (aGVHD(+)), were increased in comparison to patients without acute graft-versus-host disease (aGVHD(-)) and to a control group and there were no significant differences in serum levels of sIL-2R and IL-18 in aGVHD(-) patients and controls. Serum level of IL-18, in aGVHD(+) patients, was increased during days 3-24 after HSCT, and there was a significant difference according to GVHD severity. In majority of patients with acute GVHD (60%), the peak levels of IL-18 and sIL-2R were achieved on day 10 after HSCT and the rise in sIL-2R and IL-18 preceded the clinical signs of GVHD (mean day 15 after BMT). The level of IL-18 in patients with aGVHD strongly correlated with the severity of aGVHD on Day 10 after HSCT. IL-18 level (before HSCT), in patients who received Busulfan and Fludarabin which were used to treat aGVHD, was lower than in patients who received Busulfan and Cyclophosphamide. CONCLUSION: Our data concluded that IL-18 plays an important role in the development of aGVHD and the IL-18 level might be an indicator of aGVHD, reflecting the severity of the disease. These findings suggest that IL-18 may play an important role in the pathogenesis of aGVHD and that measurement of serum IL-18 levels can be a useful indicator of aGVHD.