Immune compartmentalization of T cell subsets in chemically-induced breast cancer.

In cancer, the phenotype and/or the function of T cells may differ according to their distribution through immune-associated tissues, namely immune compartments. Here, in N-methyl-N-nitrosourea (MNU)-induced mammary carcinomas of rat as a relevant model for human breast tumors, the impact of tumor burden on the T cell subsets populating the tumor microenvironment, the tumor-adjacent and -opposite mammary lymph nodes, and the spleen was assessed. In the tumors, ratio of CD8(+) cytotoxic and CD4(+) helper T cells were not significantly different than other immune compartments. On the other hand, most of these cells were further identified with CD4(+) CD25(hi) or CD4(+) Foxp3(+) , CD8(+) Foxp3(+) regulatory phenotype. The selective presence of Tregs in the mammary tumors but not in neighboring-mammary tissue was also confirmed by the expression of Treg-associated genes. The percentage of CD161(+) NKT cells was also significantly increased especially in the tumors and mammary lymph nodes. In the lymph nodes of tumor-bearing animals, in contrast to the spleen, total amount of CD8(+) cells and CD4(+) cells were increased but both of these compartments harbored high numbers of CD4(+) CD25(hi) Treg cells. TGF-ß was determined as the major suppressive cytokine secreted by the immune cells of tumor-bearing animals, in addition, proliferation capacity of the T cells was diminished. Hence, the differential distribution of T cell subsets through the spleen, the mammary lymph nodes and the tumor mass in MNU-induced mammary tumor-bearing animals may contribute to a tumor-associated immunosuppression.

Incidence, risk factors, and mortality from pneumonia developing late after hematopoietic stem cell transplantation.

The incidence, etiology, outcome, and risk factors for developing pneumonia late after hematopoietic stem cell transplantation (SCT) were investigated in 1359 patients transplanted in Seattle. A total of 341 patients (25% of the cohort) developed at least one pneumonic episode. No microbial or tissue diagnosis (ie clinical pneumonia) was established in 197 patients (58% of first pneumonia cases). Among the remaining 144 patients, established etiologies included 33 viral (10%), 31 bacterial (9%), 25 idiopathic pneumonia syndrome (IPS, 7%), 20 multiple organisms (6%), 19 fungal (6%), and 16 Pneumocystis carinii pneumonia (PCP) (5%). The overall cumulative incidence of first pneumonia at 4 years after discharge home was 31%. The cumulative incidences of pneumonia according to donor type at 1 and 4 years after discharge home were 13 and 18% (autologous/syngeneic), 22 and 34% (HLA-matched related), and 26 and 39% (mismatched related/unrelated), respectively. Multivariate analysis of factors associated with development of late pneumonia after allografting were increasing patient age (RR 0.5 for <20 years, 1.2 for >40 years, P=0.009), donor HLA-mismatch (RR 1.6 for unrelated/mismatched related, P=0.01), and chronic graft-versus-host disease (GVHD; RR 1.5, P=0.007). Our data suggest that extension of PCP prophylaxis may be beneficial in high-risk autograft recipients. Further study of long-term anti-infective prophylaxis based on patient risk factors after SCT appear warranted.

Research ethics and scientific misconduct in biomedical research.

Scientists have the responsibility of judging what is best for the patient and the optimal conditions for the conduct of the study. All physicians should ensure that research they participate in is ethically conducted. Every clinician should learn and receive training in the responsible conduct of research and publication, and each project must be reviewed by an institutional review committee. Scientific misconduct is defined as any practice that deviates from those accepted by the scientific community and ultimately damages the integrity of the research process. "Sloppy Research" and "Scientific Fraud" include activities which can violate science, records and publication. Sloppy research is due to absence of appropriate training in research discipline and methodologies. In contrast, scientific fraud is defined as deliberate action during application, performance of research, and publication. It includes piracy, plagiarism and fraud. Research institutions should adopt rules and regulations to respond to allegations, start investigational operations and perform appropriate sanctions.

Administration of cyclosporine for 24 months compared with 6 months for prevention of chronic graft-versus-host disease: a prospective randomized clinical trial.

This study compared the incidence of clinical extensive chronic graft-versus-host disease (GVHD), transplantation-related mortality, survival, and relapse-free survival among recipients randomly assigned to receive a 24-month or a 6-month course of cyclosporine prophylaxis after transplantation of allogeneic marrow from an HLA-identical sibling or alternative donor. Patients who did not have clinical manifestations of chronic GVHD on day 80 after transplantation were eligible for the study if they previously had acute GVHD or if a skin biopsy showed histologic evidence of chronic GVHD. Clinical extensive chronic GVHD developed in 35 of the 89 patients (39%) in the 24-month group and 37 of the 73 patients (51%) in the 6-month group. The hazard of developing chronic GVHD was not significantly different in the 2 groups (hazard ratio = 0.76; 95% confidence interval, 0.48-1.21; P =.25). In addition, there were no significant differences between the 2 groups in transplantation-related mortality, survival, or disease-free survival.

Expression of adhesion molecules LFA-1, ICAM-1, CD44, and L-selectin in childhood non-Hodgkin lymphomas.

BACKGROUND: The aim of the present study was to analyse the expression of adhesion molecules in childhood non-Hodgkin lymphomas and to correlate the findings with clinical features and prognosis. PROCEDURE: Samples were obtained from pleural and peritoneal fluids, bone marrow aspirates, and tissue biopsies from 21 patients (median age: 8 years). There were 9 T-cell and 12 B-cell lymphomas. The expression of CD18, CD44s, CD54, CD62L were investigated with flow cytometry by using monoclonal antibodies. RESULTS: Absence of CD18, which was independent from immunophenotype, was found in 67% of patients. Positive CD44s and CD62L expression were observed in 48 and 63% of the cases, respectively. In all of the cases with T-cell lymphoma, CD54 was negative, whereas 8 of 12 cases with B-cell lymphoma expressed this molecule (P = 0.005). There was no correlation between location of disease and the expression of adhesion molecules, except CD54 that was negative in all mediasten lymphoma (P = 0.004). CD62L (+) patients had more frequently stage IV disease than CD62L (-) ones (P = 0.01). Two-year overall survival was 83 and 29% in CD18 (+) and CD18 (-) cases; 55 and 36% in CD44s (+) and CD44s (-) cases; 46 and 42% in CD54 (+) and CD54 (-) cases; 42 and 50% in CD62L (+) and CD62L (-) cases. CONCLUSIONS: The expression of LFA-1 on lymphoblasts is lost in the majority of childhood non-Hodgkin lymphomas. ICAM-1 is not detected on neoplastic cells of patients with T-cell lymphoblastic lymphoma. L-selectin positivity correlates with disseminated disease. There is no significant relationship between the expression of adhesion molecules and the survival rates, although CD18(+) cases had better overall survival rate than CD18(-) cases.

Pharmacokinetics of liposomal amphotericin B in neutropenic cancer patients.

This study was conducted to characterise the pharmacokinetics of a liposomal pharmaceutical product of amphotericin B (LAB) in three neutropenic cancer patients complicated by suspected fungal infections. LAB was administered at a constant dose of 50 mg/day over 1--6 h by intravenous infusion, and blood samples were obtained between two infusion intervals without complicating the systemic therapy of the patients. Quantitative analysis of amphotericin B (AB) in plasma was established by a validated reversed-phase high-performance liquid chromatographic (HPLC) assay. Model independent pharmacokinetic parameters were estimated using area and moment analysis. Administration of LAB to the first patient (day 1) diagnosed as malignant melanoma resulted in a mean maximum concentration (C(max)) of 679+/-6 ng/ml and a mean minimum concentration (C(min)) of 139+/-9 ng/ml of AB. Pre-dose, C(max) and C(min) values of AB, after multiple LAB dosing to the other two patients both having acute myeloblastic leukemia were found to be 440+/-6, 1140+/-10, 409+/-11 ng/ml (day 19) and 408+/-3, 1180+/-10, and 283+/-1 ng/ml (day 9), respectively. The area under the plasma concentration-time curve (AUC) and the mean residence time (MRT) calculated between the two infusion intervals were 6180 ngh/ml, 7.79 h (day 1) for the first patient; 13,700 ng.h/ml, 10.5 h (day 19) and 14,000 ng.h/ml, 9.93 h (day 9) for the other two patients, respectively. The pharmacokinetic profiles and non-compartmental parameters calculated were comparable for both patients diagnosed with acute myeloblastic leukemia after multiple dosing at steady state, which also demonstrated a twofold increase in their AUC values compared with the AUC of the first patient. Although C(min) values supported the assumption that there was AB accumulation in plasma and this accumulation could be increased at high doses, LAB was administered safely to these patients and well tolerated at the doses given.

Correlation of flow cytometric parameters and transferrin receptors with gallium-67 scintigraphic images in lymphoma patients.

The purpose of this study was to determine the correlation of flow cytometric parameters and transferrin receptors with gallium-67 scintigraphic imaging results in Hodgkin's and non-Hodgkin's lymphoma patients. DNA content and cell cycle analyses were performed using flow cytometry and transferrin receptor analysis was carried out by the immunohistochemistry technique in 24 patients aged between 16 and 62 years. All patients underwent gallium-67 scintigraphy, and tumour to background ratios were calculated. The findings were correlated with computed tomography and/or magnetic resonance imaging. A strong relationship was observed between flow cytometry and transferrin receptor expression with gallium-67 tumour scintigraphy [P = 0.005, r = 0.054 and P = 0.038, r = 0.54 (Spearman test), respectively]. The results of this study show that there is a close correlation between each of these modalities and, as they reflect the biological activity of the tumour, together they have a major role in treatment and follow-up.

DNA content and proliferative activity in children with neuroblastoma.

Many studies have reported that neuroblastoma patients with aneuploid DNA content and a low cellular proliferative activity have better outcome; other studies have reported contradictory results. Formalin-fixed, paraffin-embedded archival pretreatment specimens of 56 neuroblastomas were studied. Thick sections from paraffin blocks were deparaffinized, and rehydrated. Following enzymatic digestion and filtration, cellular suspensions were analyzed by flow cytometry. Six tumors were aneuploid (13.3%) and 39 samples were diploid (86.7%). S-phase fraction (SPF) ranged from 1 to 78% with a median of 31%. DNA ploidy and proliferative activity results showed no correlation with the prognostic variables. There was no significant difference between the 5-year overall and event-free survival rates of the aneuploid and the diploid neuroblastomas or between the neuroblastomas with a high and low proliferative activity. The results revealed the prognostic significance of neither DNA ploidy nor the cellular proliferative activity in neuroblastoma in contrast to other studies.

Expression of complement regulatory proteins CR1, DAF, MCP and CD59 in haematological malignancies.

Host cells are protected from the lytic effect of the complement system by complement regulatory proteins. This study was designed to investigate the expression of complement regulatory proteins on leukemic blasts which may be susceptible to the lytic effects of the complement system in the circulation. The surface expressions of complement regulatory proteins, complement receptor 1 (CR1, CD35), decay accelerating factor (DAF, CD55), and homologous restriction factor 20 (HRF20, CD59), on peripheral blood and bone marrow blasts were evaluated by using flow cytometry in 16 acute myeloblastic leukemia (AML), 16 acute lymphoblastic leukemia (ALL), 4 chronic lymphocytic leukemia (CLL), 3 chronic myelocytic leukemia (CML) patients and control granulocytes and lymphocytes obtained from 15 healthy volunteers. mRNA expression was investigated by Northern blot analysis. mRNA abundances were calculated after normalization according to 28s rRNA. Surface expressions of CRI and DAF were marginally (p = 0.08 and p = 0.08, respectively) lower in AML, and DAF expression was significantly lower (p=0.0008) in ALL patients in comparison to their normal counterparts. Except from a slight increase that is detected for CD59 in CML patients (p=0.06), there was no significant difference between the surface expressions of CD59 in any of the groups studied. Densitometric analysis of autoradiographs obtained from Northern blots revealed that in AML patients, CR1 mRNA expression were 5.5-fold lower than controls (p=0.06), while DAF mRNA expression was significantly higher (p=0.0046). Furthermore, the mRNA expression of CRI in ALL patients was found significantly lower than in the control group (p = 0.0419). None of the values obtained from the other groups were significantly different from each other. These results suggest that leukemic blasts are protected from the lytic attack of the complement system at all levels, since all of the complement membrane regulatory proteins were expressed in all leukemia types (although at lower amounts in some cases), and it is also possible to use CRI and DAF as differentiation markers in acute leukemias.

Detection of BCR/ABL gene rearrangement and the elimination of rearranged clone in chronic myelocytic leukemia patients.

Cytogenetic and molecular studies were performed on 20 interferon-alpha receiving Turkish chronic myelocytic leukemia patients. Four different restriction endonucleases and bcr-G probe were used for southern blot analysis to detect rearrangements of the bcr gene. The RT-PCR method was also applied to detect chimeric bcr/abl mRNA. Seventeen patients showed a chromosomal break within the 5.8 kb M-bcr region by southern blot analysis while three cases out of 20 have not shown any rearrangement. These three cases were further analysed by RT-PCR and they were also found to be carrying the Philadelphia translocation (Ph). However, in four years of follow-up this RT-PCR positivity has disappeared, which suggests an elimination of Ph clone with prolonged interferon-alpha treatment.

The significance of the bone marrow biopsy pattern in chronic lymphocytic leukemia: a prognostic dilemma.

Although bone marrow biopsy pattern (BMBP) has long been suggested to be an independent prognostic factor in chronic lymphocytic leukemia (CLL), conflicting reports continue to appear in the literature. To investigate this issue we retrospectively reviewed 70 CLL patients who had undergone bone marrow biopsy at the time of diagnosis in a multivariate Cox regression analysis together with other prognostic factors. There were 51 (72.8%) males and 19 (27.2%) females with a median age of 60 years (range, 38-77). The median follow-up time was 24 months (range, 1-76), and median survival was 44 months. Thirtyfour patients (48.6%) had diffuse and 36 patients (51.4%) had nondiffuse BMBP (14 nodular, 11 interstitial, and 11 mixed). The median survival for diffuse and nondiffuse BMBP groups were 17 and 53 months, respectively (P= 0.05). Sixteen patients (22. 9%) had stage A, 28 (40.0%) stage B, and 26 (37.1%) stage C disease according to the Binet system, and four patients (5.7%) had low-risk, 39 (55.7%) intermediate-risk, and 27 (38.6%) high-risk disease according to the modified Rai staging system. The difference between the median survivals of patients in different stages was statistically significant (P < 0.0001). The BMBP and staging systems that are thought to be significant predictors of prognosis were used to build a multivariate Cox proportional hazard model. BMBP was not found to add additional information to the prognostic value of the staging systems. Our results underline two points: first, the significance of BMBP must be investigated in multivariate analysis including the stage, and second, BMBP is not a dynamic prognostic parameter, it is an index of tumor burden and does not add any prognostic information beyond that provided by clinical stage.

Reduced dose intravenous immunoglobulin does not decrease transplant-related complications in adults given related donor marrow allografts.

Graft-vs.-host disease (GVHD) and infection are major complications of allogeneic bone marrow transplantation. Intravenous immunoglobulin (IVIg) given at a dose of 500 mg/kg/wk has been shown to decrease the risk of acute GVHD, interstitial pneumonia, and infection in adults early after allogeneic transplantation. The current study is a controlled trial to determine whether a lower total dose of IVIg given with pretransplant loading reduces the incidence of transplant-related complications. In a randomized trial of 241 patients > or =20 years of age who were given related donor marrow allografts, 121 individuals receiving Ig prophylaxis (500 mg/kg/d loading from day -6 to -1 and then 100 mg/kg every 3 days from day 3 to 90) were compared with 120 control patients who did not receive IVIg. Randomization was stratified by human leucocyte antigen-matching, remission status of malignancy, GVHD prophylaxis, and cytomegalovirus (CMV) serology. The study was powered to detect a reduction in acute GVHD by 18% and a decrease in transplant-related mortality by 17%. Pretransplant IVIg loading and posttransplant maintenance achieved median serum IgG levels >1350 mg/dL, which were approximately twofold greater than the untreated controls (p<0.01). White blood cell and platelet recoveries were similar for the two groups, although control patients required fewer units of platelets per day (2.5 vs. 3.3, p = 0.008). No significant differences in the incidence of CMV infection, interstitial pneumonia, or bacteremia were observed. The incidence of acute GVHD did not differ between the two groups; however, acute GVHD was less frequent among IVIg recipients achieving maximum serum IgG levels >3000 mg/dL (60 vs. 79%). Neither transplant-related mortality nor disease-free survival was significantly altered by Ig prophylaxis. However, the cumulative incidence of relapse of malignancy was higher in IVIg recipients than in controls (31 vs. 18%, p = 0.03). Multivariable regression analysis demonstrated a 1.89 increased relative risk of relapse for individuals given IVIg (p = 0.021). We conclude that pretransplant loading and a shorter course and lower total dose of IVIg prophylaxis did not appear to decrease the risk of acute GVHD or mortality among adults receiving related donor marrow transplants. Note, IVIg administration may be associated with an increased risk of recurrent malignancy, a finding that warrants further investigation.

Pathophysiology and treatment of graft-versus-host disease.

Acute graft-versus-host disease denotes a distinctive syndrome characterized by a triad of dermatitis (rash), hepatitis (jaundice), and gastroenteritis (abdominal pain, diarrhea) developing in the first 100 days after allogeneic hematopoietic cell transplantation. Chronic graft-versus-host disease designates a more diverse syndrome, usually presenting with multiorgan involvement and commonly developing 100 days after hematopoietic cell transplantation. This article discusses the pathophysiology, incidence and predictive factors, clinical manifestations, diagnosis and grading, prevention, and treatment for both types of the disease.

Comparison of meropenem with amikacin plus ceftazidime in the empirical treatment of febrile neutropenia: a prospective randomised multicentre trial in patients without previous prophylactic antibiotics. Meropenem Study Group of Turkey.

Eighty three patients with neutropenia and cancer were randomised to receive either 1 g meropenem tds or amikacin 15 mg/kg single dose daily plus ceftazidime 2 g tds. No prophylactic antibiotics were allowed before entry to the trial. Seventy seven patients were available for analysis. Infection was microbiologically or clinically documented in 53 episodes (69%). The overall success rate without adjustment was 49% in monotherapy, 37.5% in the combination group. These rates were increased to 65% and 56%, respectively when secondary infection episodes requiring a different class of chemotherapy were taken into account. Median duration for defervescence was 3 days in successfully treated patients in both groups. Only minor reversible side effects were noted in both treatment arms. Meropenem monotherapy seemed as effective and safe as amikacin plus ceftazidime for the empirical treatment of neutropenic cancer patients with fever.

Influence of perioperative whole blood transfusions on lymphocyte subpopulations in patients with stage II breast cancer.

Preliminary reports have suggested an adverse relationship between blood transfusion and survival after surgery in patients with solid tumour. One might postulate that from these studies, perioperative blood transfusions alter host immune defences. We therefore examined the influence of homologous whole blood transfusion on circulating lymphocyte subpopulations in transfused patients compared with non-transfused patients. Fifty-one women with Stage II breast cancer who underwent surgical procedures were studied. Patients were classified into two groups on the basis of whether or not they had received blood transfusion. The lymphocyte subpopulations were analyzed by flow cytometry before cancer surgery and three weeks after the operation. CD3+, CD4+, CD8+, and CD20+ cells as the lymphocyte subsets were quantitated using appropriate monoclonal antibodies. No significant differences between pre- and postoperative lymphocyte subset levels were seen in non-transfused patients. However, there was a statistically significant increase in the CD8+ cell count; decreasing CD4+ cell count and decreased CD3+ cells levels were observed in the transfused group (P < 0.05). Although these early results of the study suggest that the blood transfusions could be associated with alterations in lymphocyte populations, additional studies are needed to elucidate the possible mechanism of the transfusion-induced immunological modulations.

Periodontal findings and systemic antibody responses to oral microorganisms in Behçet's disease.

BACKGROUND: Behçet's disease is a multisystem disorder of unknown etiology, affecting predominantly the oral mucosa, skin, and eyes. Recurrent and painful episodes of oral ulcerations interfere with regular oral hygiene leading to rapid bacterial plaque accumulation. The aims of this study were to evaluate the periodontal status of patients with Behçet's disease and determine serum antibody responses to selected oral microorganisms, including major periodontopathogens in these patients. METHODS: Thirty-three patients with Behçet's disease and 15 healthy subjects were included in the study. Plaque, sulcular bleeding, periodontal index scores, probing depths, and total number of teeth were recorded. Serum IgG antibody levels to a panel of 13 oral microorganisms were determined. RESULTS: Significantly higher values for each of the clinical measures were observed in patients with Behçet's disease compared to healthy subjects (P <0.0001). Antibody levels to selected members of plaque, including Actinomyces viscosus, Streptococcus mutans, Streptococcus sanguis, Streptococcus oralis, Eikenella corrodens, Campylobacter rectus, and Prevotella intermedia were significantly lower in patients with Behçet's disease than in controls (P <0.001-0.05). In contrast, these patients exhibited significantly elevated antibody levels to Actinobacillus actinomycetemcomitans Y4 compared to controls (P <0.01). CONCLUSIONS: Our data indicate that the patients with Behçet's disease generally exhibit clinical findings of established periodontal disease. Decreased antibody responses to early colonizers of both supra- and subgingival plaque were observed along with the elevation in antibody levels to A. actinomycetemcomitans. These results suggest that the bacterial plaque ecology and/or immune responses to these microorganisms may be affected in Behçet's disease which could lead to changes in the expression of periodontal disease.

Dihydropteridine reductase activity and neopterin levels in leukemias and lymphomas: is there any correlation between these two parameters?

Urinary neopterin levels, blood dihydropteridine reductase activity as well as other frequently used clinical parameters were evaluated in 110 patients suffering from various types of lymphomas and leukemias. Among them neopterin was detected as the most sensitive marker representing the severity of malignancy (p<0.00001). All patients with active diseases had significantly raised urinary neopterin levels compared to those in remission and healthy controls. Of 69 patients with active disease 66 (96%) were above the upper limit seen in healthy subjects. In addition, the highest neopterin excretion was found in patients with active chronic myeloid leukemia (1469+/-479 micromol/mol creatinine n=16). In contrast, only 1 of 41 patients in stable responsive disease and remission (2.4%) had increased urinary neopterin levels above the upper limit. Dihydropteridine reductase (DHPR) activities were also detected in all patients and control groups. In active disease slightly reduced (DHPR) activities were evident (3.42+/-0.37 for controls, 2.92+/-0.39 in active disease and 3.28+/-0.42 nmol red cytochrome C/min/5 mm diameter disc in remission patients). However in patients under medication this was strengthened. This data also suggest that DHPR activity can be effected by chemotherapy. The results of the present study support the fact that urinary neopterin levels may be an useful and reliable early prognostic marker for neoplasia when used together with other prognostic indicators. Our data also suggest that reductions in DHPR activities may also be an underlying cause for the neurological disorders that are commonly seen in patients with haematological malignancies.

Intravenous immunoglobulin and the risk of hepatic veno-occlusive disease after bone marrow transplantation.

Recent reports using historical controls or registry cohorts suggest, respectively, either an increase in the mortality or a decrease in the incidence of hepatic veno-occlusive disease (VOD) with the administration of intravenous immunoglobulin (i.v.Ig) after bone marrow transplantation. These divergent results prompted us to conduct a retrospective analysis of two randomized clinical trials conducted at our center to determine the effect of i.v.Ig infusions on the development and severity of VOD. Patients were randomized to receive (n=318) or not to receive (n=315) i.v.Ig prophylaxis after human leukocyte antigen-identical sibling (n=414), mismatched or unrelated (n=178), or autologous or syngeneic (n=41) marrow transplantation. To determine the relationship of i.v.Ig to the development and severity of VOD, a single observer reviewed data displays created for each patient for grading VOD without knowledge of patient i.v.Ig use. In this analysis, VOD was defined as hyperbilirubinemia > or =2.0 mg/dL before day 20 and abrupt weight gain > or =2% before day 14 posttransplant in the absence of other causes of liver disease. Hepatic VOD developed in 235 (37%) of the 633 randomized patients. No evidence for VOD was found in 230 (36%) patients. The remaining 168 (27%) patients were classified as having liver disease of uncertain etiology. Hepatic VOD was judged to be severe in 63 (10%) and mild or moderate in 172 (27%) patients. The number of patients developing any VOD or severe VOD was similar between those randomized to i.v.Ig prophylaxis and untreated controls (115 vs. 120 and 32 vs. 31, respectively). Logistic regression models identified several covariates as significant (p < 0.01) factors associated with the development of severe VOD. Increased risk occurred with elevated pretransplant serum aspartate aminotransferase (odds ratio [OR] = 2.64) and earlier year of transplant (OR = 3.73); decreased risk occurred with autologous or twin donors (OR = 0.09) and acute myeloid leukemia (OR = 0.39). The development of any VOD was associated with an elevated pretransplant alkaline phosphatase (OR = 4.1), pretransplant use of vancomycin (OR = 1.6) or amphotericin (OR = 3.0), posttransplant use of cyclosporine (OR = 2.5), older patient age (OR = 1.03), and obesity (OR = 0.78). We concluded from the controlled trials of 633 patients that the administration of i.v.Ig did not influence the development or severity of VOD after bone marrow transplantation.

P-glycoprotein expression by technetium-99m-MIBI scintigraphy in hematologic malignancy.

UNLABELLED: Our aim was to ascertain the relationship between the degree of 99mTc-MIBI uptake and the level of p-glycoprotein (Pgp) expression determined by flow cytometry and reverse transcription-polymerase chain reaction (RT-PCR) techniques in patients with hematologic malignancy. METHODS: A total of 21 samples (19 patients) were evaluated. Two patients had repeat studies after therapy. Thirteen samples were studied at the time of initial diagnosis and 8 during relapse after therapy. After MIBI imaging, either bone marrow aspiration or peripheral blood was obtained for flow cytometric and RT-PCR analyses. Flow cytometry was performed using two different antibodies. After the injection of 555 MBq MIBI, whole-body and pelvic spot images were acquired using a dual-head gamma camera. The uptake in the bone marrow was evaluated against the background (adjacent soft tissue) by both qualitative (scoring system) and quantitative (tm/bkg ratios) analyses. RESULTS: For flow cytometry, the limit for Pgp overexpression was set at >15% Pgp-positive mononuclear bone marrow or peripheral blood cells. There was an inverse correlation between the levels of Pgp and MIBI imaging using both the qualitative (scoring system) and quantitative (tm/bkg ratios) analyses (p = 0.022). Mean values were statistically different between Pgp+ and Pgp- groups for both qualitative and quantitative analyses (p = 0.009 and 0.024, respectively). For RT-PCR, there was statistical support toward a difference in the mean values between Pgp+ and Pgp- groups by qualitative analysis (p = 0.061); however, no statistical difference was found between these two groups by quantitative analysis (p = 0.179). CONCLUSION: Based on the strong correlation between the imaging and flow cytometry and a statistical support toward the correlation between the imaging and RT-PCR, MIBI imaging may be used for the in vivo detection of Pgp in patients with hematologic malignancy.

Bolus and continuous infusion mitoxantrone in newly diagnosed adult acute lymphoblastic leukemia: results of two consecutive phase II clinical studies.

Two consecutive phase II clinical studies were designed to evaluate the efficacy and safety of bolus and continuous infusion (CI) mitoxantrone (MTZ) in 39 patients with newly diagnosed acute lymphocytic leukemia (ALL). MTZ was used as part of the classical ALL induction regimen. Twenty patients were treated with bolus MTZ (10 mg/m2 for 3 days) combined with vincristine and prednisone. The same regimen was given to a second set of 19 patients, except that MTZ was administered as a 24-hr CI. Both groups received bimonthly intensifications with vincristine and prednisone for 3 years, along with oral maintenance therapy. Patients in the CI-MTZ study arm received additional MTZ on the first day of intensification cycles. Seventeen patients (85%) in the bolus arm and 15 patients (79%) in the CI arm achieved complete remission (CR). Median disease-free survivals (DFS) in the bolus and CI groups were 11 and 15 months after median follow-ups of 16 (3.5-96) and 13 (2.3-32) months, respectively. At 2.5 years, DFS rates were 29.4% and 34.4% in the bolus and CI groups (p > 0.05). There were no significant differences between two groups in rates of early death, degree of organ toxicity, or duration of neutropenia and thrombocytopenia. Significant cardiac toxicity was not observed in either group. Bolus or CI administration of MTZ was equally effective and was well tolerated. Neither the mode of administration nor increasing the dose intensity of MTZ by incorporating intensification cycles reduced relapse rates. Development of new antileukemia agents and novel treatment approaches are still needed to improve the high relapse rates in adult ALL once a complete response is achieved.