The impact of morphological and immunohistological changes in minor salivary glands on the health of the oral cavity in HSCT patients.

The objective of this study was to test the relationship between histological changes in minor salivary glands (MSG) and chronic GVHD (cGVHD) severity and OS of hematopoietic SCT (HSCT) patients, and to discriminate the participation of events preceding HSCT that damage MSG, from those linked to cGVHD. The MSG of 57 HSCT patients who were divided into two groups-oral cGVHD (36 cases) and non-cGVHD (21 cases)-were compared with the MSG of a control group of 19 non-HSCT individuals. cGVHD changes were assessed according to National Institutes of Health (NIH) consensus and the systems of Horn et al. Acinar areas and mononuclear cell subsets were set through morphometry. Horn's 'periductal lymphocytic infiltrate' correlated with an extensive form of cGVHD and NIH 'periductal lymphocytes with exocytosis into duct' correlated with global survival. Measurements of the acinar area differed between the three groups, being the lowest in cGVHD patients, but also reduced in non-cGVHD patients. Significant differences among CD45, CD45RO, CD4 and CD8 immunomarked cells/mm(2) were found by comparing the two groups of HSCT patients. In brief, periductal lymphocytic infiltrate and exocytosis implies inflammatory activity and, consequently, might reflect the cGVHD status and influence survival. Acini loss in non-cGVHD patients may be due to pre-transplant events, but massive lymphocyte infiltrate is part of the cGVHD process.

Taste disorders and oral evaluation in patients undergoing allogeneic hematopoietic SCT.

The aim of this study was to evaluate taste perception, salivary flow rate and oral pathologies in three different groups of patients undergoing hematopoietic SCT (HSCT) classified according to time post transplant. Group I (n=20) up to 150 days after HSCT, group II (n=20) between 151 and 1095 days and group III (n=21) more than 1095 days. Taste acuity was measured by four basic tastes of four solutions, in three concentrations (M): NaCl, sucrose, citric acid and caffeine. Patients classified flavors as sweet, sour, salty, bitter and without flavor. The intensity was considered high, medium and low. Unstimulated saliva was collected and salivary flow rates (ml/min) were determined. Of 61 patients, 31 had chronic GVHD. For the sweet solution, the high and low concentrations represented a challenge for those patients. No patients were sensitive to the low concentration of caffeine solution (P=0.05). Saliva flow rate was diminished in 10 of 61 (16%) patients and hyposalivation was more intense in groups II/III (P=0.007). There was no correlation between taste dysfunction and oral chronic GVHD. The results indicated taste alterations only for the sweet and salty tastes even in patients up to 3 years after HSCT and may not correlate with oral chronic GVHD and with hyposalivation.

IL2 and TNFA gene polymorphisms and the risk of graft-versus-host disease after allogeneic haematopoietic stem cell transplantation.

This study aimed to analyse the association of gene polymorphisms with the outcome of allogeneic haematopoietic stem cell transplantation. We studied 122 donor/recipient pairs who received HLA-identical transplants from siblings at the Universidade Estadual de Campinas, Brazil, between June 1996 and June 2006. Donor/recipient alleles for TNFA-238 and IL2-330/+166 single-nucleotide polymorphisms (SNP) were analysed by PCR-SSP. No association was observed between the risk of acute graft-versus-host disease (GVHD) and these SNP. However, our findings suggest that the polymorphism of promoter gene TNFA-238GA is associated with the occurrence and severity of chronic GVHD. The probability of chronic GVHD in patients with GA genotype at position -238 of TNFA gene is 91.7% in contrast to 59.4% in patients with GG genotype (P = 0.038). In patients with donor GA genotype the probability of chronic GVHD is 90.8%, and 57.9% in patients with donor GG genotype (P = 0.038). The probability of extensive chronic GVHD in patients with TNFA-238GA is 91.7% compared with 46.3% in patients with TNFA-238GG (P = 0.0046). In patients with donor GA genotype at position -238 of the TNFA gene, it is 81.7%, compared with 44.5% in patients with donor GG genotype (P = 0.016). However, further studies with more patients are required to identify cytokine gene polymorphisms and their association with transplant-related complication in Brazil, particularly due to ethnic background, the relatively low power of detection of genetic markers of this study, and the complexity of the MHC region.

Frontline therapy with early intensification and autologous stem cell transplantation versus conventional chemotherapy in unselected high-risk, aggressive non-Hodgkin's lymphoma patients: a prospective randomized GEMOH report.

This prospective multicenter randomized trial compares conventional with early intensification with high-dose sequential chemotherapy (HDS) and autologous stem cell transplantation (ASCT) as frontline therapy in high-risk non-Hodgkin lymphomas (NHL). Newly diagnosed patients with aggressive high-risk [intermediate-high (HI) and high-risk (HR)] NHL according to the international prognosis index (IPI) were randomized to receive 12-week VACOP-B (arm A, 27 patients) or 6-week VACOP-B followed by HDS and ASCT (arm B, 29 patients). Complete remission rate was 52% in arm A and 55% in B. Nine patients (16%) died early due to progression. According to intention-to-treat, with a median follow-up of 23 months, the 5-year actuarial overall survival, progression-free survival and disease-free survival in arms A and B were 47 and 40% (p = nonsignificant), 47 and 30% (p = nonsignificant), and 97 and 47% (p = 0.02), respectively. Abbreviated chemotherapy followed by intensification with HDS-ASCT does not seem to be superior to conventional chemotherapy in HI/HR aggressive NHL.

Clinical and outcome characteristics of children with adrenocortical tumors: a report from the International Pediatric Adrenocortical Tumor Registry.

PURPOSE: We created a registry for pediatric adrenocortical tumors (ACTs), which are rare and are not well characterized. We provide a descriptive analysis of 254 patients registered on the International Pediatric Adrenocortical Tumor Registry. PATIENTS AND METHODS: Between January 1990 and December 2001, 254 patients younger than 20 years of age with newly diagnosed or previously treated ACTs were registered. A histologic diagnosis of ACT was required, although central review was not mandatory. Follow-up information was periodically requested from the referring physician. Treatment was chosen by the primary physician. RESULTS: The overall female-male ratio was 1.6:1, but it varied widely among age groups. The most common presenting sign (84.2%) was virilization. Cushing's syndrome without virilization was uncommon (5.5%). Tumors were completely resected in 83% of patients. Patients with disseminated or residual disease received mitotane, cisplatin, etoposide, and/or doxorubicin, and rarely, radiation therapy. At a median follow-up of 2 years and 5 months, 157 patients (61.8%) survived without evidence of disease and 97 patients (38.2%) had died. The 5-year event-free survival estimate was 54.2% (95% CI, 48.2% to 60.2%). In a multivariate analysis, disease stage, presenting signs of endocrine dysfunction, and age were independently associated with prognosis. CONCLUSION: Childhood ACTs occur predominantly in females and almost always causes clinical signs. Complete resection is required for cure. Residual or metastatic disease carries a poor prognosis. Our results demonstrate the feasibility of a disease-specific database for obtaining meaningful clinical and outcome information.

The availability of full match sibling donors and feasibility of allogeneic bone marrow transplantation in Brazil.

The feasibility of allogeneic bone marrow transplantation (alloBMT) in a developing country has not yet been demonstrated. Many adverse factors including social and economic limitations may reduce the overall results of this complex and expensive procedure. Our objective was to characterize the most important clinical, social and economic features of candidates for transplantation and their potential donors as well as the influence of these factors on overall survival in a retrospective and exploratory analysis at a university hospital. From July 1993 to July 2001, candidates for BMT were referred to the Bone Marrow Transplantation Unit by Hematology and Oncology Centers from several regions of Brazil. A total of 1138 patients were referred to us as candidates for alloBMT. Median age was 25 years (range: 2 months-60 years), 684 (60.1%) were males and 454 (39.9%) were females. The clinical indications were severe aplastic anemia and hematological malignancies. From the total of 1138 patients, 923 had HLA-typing; 497/923 (53.8%) candidates had full match donors; 352/1138 (30.8%) were eligible for alloBMT. Only 235 of 352 (66.7%) were transplanted. Schooling was 1st to 8th grade for 123/235 (52.3%); monthly family income ranged from US$60 (7%) to more than US$400 (36%). Overall survival for patients with chronic myeloid leukemia, severe aplastic anemia and acute myeloid leukemia was 58, 60 and 30%, respectively. Thus, overall survival rates for the most frequent hematological diseases were similar to those reported in the International Registry, except for acute myeloid leukemia. This descriptive and exploratory analysis suggests the feasibility of alloBMT in a developing country like Brazil.

The availability of full match sibling donors and feasibility of allogeneic bone marrow transplantation in Brazil

The feasibility of allogeneic bone marrow transplantation (alloBMT) in a developing country has not yet been demonstrated. Many adverse factors including social and economic limitations may reduce the overall results of this complex and expensive procedure. Our objective was to characterize the most important clinical, social and economic features of candidates for transplantation and their potential donors as well as the influence of these factors on overall survival in a retrospective and exploratory analysis at a university hospital. From July 1993 to July 2001, candidates for BMT were referred to the Bone Marrow Transplantation Unit by Hematology and Oncology Centers from several regions of Brazil. A total of 1138 patients were referred to us as candidates for alloBMT. Median age was 25 years (range: 2 months-60 years), 684 (60.1 percent) were males and 454 (39.9 percent) were females. The clinical indications were severe aplastic anemia and hematological malignancies. From the total of 1138 patients, 923 had HLA-typing; 497/923 (53.8 percent) candidates had full match donors; 352/1138 (30.8 percent) were eligible for alloBMT. Only 235 of 352 (66.7 percent) were transplanted. Schooling was 1st to 8th grade for 123/235 (52.3 percent); monthly family income ranged from US$60 (7 percent) to more than US$400 (36 percent). Overall survival for patients with chronic myeloid leukemia, severe aplastic anemia and acute myeloid leukemia was 58, 60 and 30 percent, respectively. Thus, overall survival rates for the most frequent hematological diseases were similar to those reported in the International Registry, except for acute myeloid leukemia. This descriptive and exploratory analysis suggests the feasibility of alloBMT in a developing country like Brazil

Immature reticulocytes as an early predictor of engraftment in autologous and allogeneic bone marrow transplantation.

The purpose of this study was to evaluate reticulocyte parameters by means of flow cytometric reticulocyte counting in a group of patients who had undergone autologous and allogeneic bone marrow transplantation (BMT). The pattern of reticulocyte response and the predictive value of absolute neutrophil count (ANC), platelet count, number of CD34+ cell infused and graft source for reticulocyte response were studied. We compared absolute reticulocyte count (RetAbs), mean fluorescence index (MFI) and mean reticulocyte volume/mean corpuscular volume (MRV/MCV) ratio with conventional criteria (ANC and platelet count) in 22 allogeneic and 20 autologous BMT recipients. An abrupt increase in MRV/MCV ratio or a rise in MFI value were the earliest signs of erythropoietic recovery following allogeneic transplantation (63.6 and 22.8% of cases, respectively). In 13.6% of the cases, both parameters were observed simultaneously. All but three autologous transplant recipients showed changes in reticulocyte parameters earlier than ANC recovery. Granulocyte recovery and peripheral blood progenitor cells (PBPC) graft were predictive variables for RetAbs response in allogeneic transplant recipients. In the autologous group, predictive variables for RetAbs response were a high number of CD34+ infused cells and platelet recovery. An increase in the immature reticulocyte population is the earliest sign of haematopoietic recovery following BMT.

Correlation of mixed lymphocyte culture with chronic graft-versus-host disease following allogeneic stem cell transplantation.

The purpose of the present study was to evaluate the mixed lymphocyte culture as a predictive assay of acute and chronic graft-versus-host disease (GVHD). We studied 153 patients who received a first bone marrow transplantation from human leukocyte antigen-identical siblings. Acute GVHD was observed in 26 of 128 (20.3%) patients evaluated and chronic GVHD occurred in 60 of 114 (52.6%). One-way mixed lymphocyte culture (MLC) assays were performed by the standard method. MLC results are reported as the relative response (RR) from donor against patient cells. The responses ranged from -47.0 to 40.7%, with a median of 0.5%. The Kaplan-Meier probability of developing GVHD was determined for patients with positive and negative MLC. There was no significant difference in incidence of acute GVHD between the groups studied. However, the incidence of chronic GVHD was higher in recipients with RR >4.5% than in those with RR < or =4.5%. The Cox Proportional Hazards model was used to examine the effect of MLC levels on incidence of chronic GVHD, while adjusting for the potential confounding effect of others suspected or observed risk factors. The relative risk of chronic GVHD was 2.5 for patients with positive MLC (RR >4.5%), 2.9 for those who received peripheral blood progenitor cells as a graft, and 2.2 for patients who developed previous acute GVHD. MLC was not useful for predicting acute GVHD, but MLC with RR >4.5% associated with other risk factors could predict the development of chronic GVHD, being of help for the prevention and/or treatment of this late complication.

Correlation of mixed lymphocyte culture with chronic graft-versus-host disease following allogeneic stem cell transplantation

The purpose of the present study was to evaluate the mixed lymphocyte culture as a predictive assay of acute and chronic graft-versus-host disease (GVHD). We studied 153 patients who received a first bone marrow transplantation from human leukocyte antigen-identical siblings. Acute GVHD was observed in 26 of 128 (20.3 percent) patients evaluated and chronic GVHD occurred in 60 of 114 (52.6 percent). One-way mixed lymphocyte culture (MLC) assays were performed by the standard method. MLC results are reported as the relative response (RR) from donor against patient cells. The responses ranged from -47.0 to 40.7 percent, with a median of 0.5 percent. The Kaplan-Meier probability of developing GVHD was determined for patients with positive and negative MLC. There was no significant difference in incidence of acute GVHD between the groups studied. However, the incidence of chronic GVHD was higher in recipients with RR >4.5 percent than in those with RR <=4.5 percent. The Cox Proportional Hazards model was used to examine the effect of MLC levels on incidence of chronic GVHD, while adjusting for the potential confounding effect of others suspected or observed risk factors. The relative risk of chronic GVHD was 2.5 for patients with positive MLC (RR >4.5 percent), 2.9 for those who received peripheral blood progenitor cells as a graft, and 2.2 for patients who developed previous acute GVHD. MLC was not useful for predicting acute GVHD, but MLC with RR >4.5 percent associated with other risk factors could predict the development of chronic GVHD, being of help for the prevention and/or treatment of this late complication

High-dose cyclophosphamide followed by autologous peripheral blood progenitor cell transplantation improves the salvage treatment for persistent or sensitive relapsed malignant lymphoma

Trials have demonstrated that high-dose escalation followed by autologous transplantation can promote better long-term survival as salvage treatment in malignant lymphomas. The aim of the present nonrandomized clinical trial was to demonstrate the role of high-dose cyclophosphamide (HDCY) in reducing tumor burden and also to determine the effectiveness of HDCY followed by etoposide (VP-16) and methotrexate (MTX) in Hodgkin's disease plus high-dose therapy with peripheral blood progenitor cell (PBPC) transplantation as salvage treatment. From 1998 to 2000, 33 patients with a median age of 33 years (13-65) affected by aggressive non-Hodgkin's lymphoma (NHL) (60.6 percent) or persistent or relapsed Hodgkin's disease (39.4 percent) were enrolled and treated using high dose escalation (HDCY + HDVP-16 plus HDMTX in Hodgkin's disease) followed by autologous PBPC transplantation. On an "intention to treat" basis, 33 patients with malignant lymphomas were evaluated. The overall median follow-up was 400 days (40-1233). Thirty-one patients underwent autografting and received a median of 6.19 x 10(6)/kg (1.07-29.3) CD34+ cells. Patients who were chemosensitive to HDCY (N = 22) and patients who were chemoresistant (N = 11) presented an overall survival of 96 and 15 percent, respectively (P<0.0001). Overall survival was 92 percent for chemosensitive patients and 0 percent for patients who were still chemoresistant before transplantation (P<0.0001). Toxicity-related mortality was 12 percent (four patients), related to HDCY in two cases and to transplant in the other two. HDCY + HDVP-16 plus HDMTX in only Hodgkin's disease followed by autologous PBPC proved to be effective and safe as salvage treatment for chemosensitive patients affected by aggressive NHL and Hodgkin's disease, with acceptable mortality rates related to sequential treatment

High-dose cyclophosphamide followed by autologous peripheral blood progenitor cell transplantation improves the salvage treatment for persistent or sensitive relapsed malignant lymphoma.

Trials have demonstrated that high-dose escalation followed by autologous transplantation can promote better long-term survival as salvage treatment in malignant lymphomas. The aim of the present nonrandomized clinical trial was to demonstrate the role of high-dose cyclophosphamide (HDCY) in reducing tumor burden and also to determine the effectiveness of HDCY followed by etoposide (VP-16) and methotrexate (MTX) in Hodgkin's disease plus high-dose therapy with peripheral blood progenitor cell (PBPC) transplantation as salvage treatment. From 1998 to 2000, 33 patients with a median age of 33 years (13-65) affected by aggressive non-Hodgkin's lymphoma (NHL) (60.6%) or persistent or relapsed Hodgkin's disease (39.4%) were enrolled and treated using high dose escalation (HDCY + HDVP-16 plus HDMTX in Hodgkin's disease) followed by autologous PBPC transplantation. On an "intention to treat" basis, 33 patients with malignant lymphomas were evaluated. The overall median follow-up was 400 days (40-1233). Thirty-one patients underwent autografting and received a median of 6.19 x 10(6)/kg (1.07-29.3) CD34+ cells. Patients who were chemosensitive to HDCY (N = 22) and patients who were chemoresistant (N = 11) presented an overall survival of 96 and 15%, respectively (P<0.0001). Overall survival was 92% for chemosensitive patients and 0% for patients who were still chemoresistant before transplantation (P<0.0001). Toxicity-related mortality was 12% (four patients), related to HDCY in two cases and to transplant in the other two. HDCY + HDVP-16 plus HDMTX in only Hodgkin's disease followed by autologous PBPC proved to be effective and safe as salvage treatment for chemosensitive patients affected by aggressive NHL and Hodgkin's disease, with acceptable mortality rates related to sequential treatment.