Biomedical subjects
Publications and source records attributed to J Sierra.
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BACKGROUND: Allogeneic bone marrow transplantation (BMT) is the only potentially curative treatment in multiple myeloma (MM). METHODS: From january 1986 to december 1993, 12 cases (10 males and 2 females) underwent BMT in the authors' institution. The mean age of the series was 39 years (range 23-49). The situation of the myeloma on initiation of the conditioning was: complete remission (CR) in 2 cases, objective response in 5 cases, partial response in 1 case and treatment resistance in 4 cases. The conditioning schedule included cyclophosphamide (120 mg/kg) and total body irradiation (10-14 Gy) with or without melfalan at high doses in 11 patients and busulfan (16 mg/kg) and cyclophosphamide (120 mg/kg) in 1 case. The prophylaxis of graft versus host disease (GVHD) was carried out with methotrexate and cyclosporine A (CsA) in 7 cases, CsA plus prednisone in 2 cases and 3 patients received CsA plus bone marrow partially depleted of T lymphocytes by elutriation. RESULTS: The situation of the myeloma with regard to response following transplantation was: unevaluable in 1 case, resistant in 1 case, objective response in 2 cases and CR in 8 cases. Seven out of the 10 patients at risk presented grades II-IV GVHD. Four of the 8 patients who were in CR following transplantation died due to post transplant complications and 2 out of the 6 relapsed 9 months after the transplant while 2 remain in CR at 5 and 8 years after the transplant, respectively. Nine patients died due to infection in 2 cases, GVHD and infection in 4 cases, GVHD and hemorrhage in 1 case and progression and infection in 2 cases. Of the 3 surviving patients, 1 relapsed at 14 months after the transplant and two remain in CR at 5 and 8 years post transplantation. CONCLUSIONS: Bone marrow transplantation conditioning gives place to a high number of complete remission in multiple myeloma. However, the incidence of acute grade II-IV graft versus host disease and mortality due to complications related to the transplantation are very high. Nonetheless, a proportion of patients may achieve curation with bone marrow transplantation.
BACKGROUND: Bone marrow transplantation (BMT) from a histocompatible donor is the only curative treatment in chronic myeloid leukemia (CML). Only a minority of patients dispose of an adequate donor from among his/her relatives. The remaining transplant receptors must look to unrelated donors (URD). The experience of the Escuela de Hematología Farreras Valentí (Farreras Valentí School of Hematology, Barcelona, Spain) in BMT from URD in CML in the first chronic phase is herein reported. METHODS: Fifteen patients (9 males and 6 females, median age 33 years; range 14-48 years) were transplanted from October 1988 to May 1994. Serologic identity was expressed in the A, B and D loci in 9 cases and minor incompatibility in 6. Conditioning included total body irradiation and cyclophosphamide in 14 patients and busulphan plus cyclophosphamide in 1. Partial and selective T lymphocyte depletion was performed by elutriation in 7 cases. RESULTS: Primary implant failure was detected in 2 out of 14 risk patients (14%) and secondary failure was observed in 3 out of 12 cases (25%). The actuarial probability of acute graft versus host disease (GVHD) was 55 +/- 15% at 7 weeks with a probability of appearance with an intensity of II-IV of 31 +/- 13%. Five out of 7 patients with a survival of greater than 100 days, developed chronic GVHD (71%). Ten presented fatal complications. In 5 cases, death was due to pulmonary problems. Recurrence of CML was not observed in any of the patients in the series. The probability of disease free survival at 2 years was 30 +/- 12%. CONCLUSIONS: Bone marrow transplantation from an unrelated donor is an effective treatment for a proportion of patients with chronic myeloid leukemia although severe complications are frequent and originate a high mortality.
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The use of an HLA-compatible unrelated donor is an option for patients who require an allogeneic transplant but lack a family member match. Grafts from unrelated volunteer donors have provided long-term disease-free survival for a variable proportion of patients, depending on degree of HLA matching with the donor, patient's disease, disease stage, and age. The number of volunteers in marrow donor registries worldwide has increased to more than 2.5 million. The number of unrelated donor transplants facilitated by the US National Marrow Donor Program alone will exceed 900 this year. Progress in HLA-typing technology results in a more precise definition of donor and recipient matching and new assays have been developed with initial success to measure alloreactive T-cell precursors for selection of donors with less antihost reactivity. Prevention and treatment of graft failure, graft-versus-host disease, opportunistic infections, and Epstein-Barr virus-associated lymphoproliferative disease remain a challenge.
Fragile X syndrome is the major cause of inherited mental retardation. The molecular basis for the expression of the fragile X phenotype is the expansion of an unstable CGG repeat element which inhibits transcription of the FMR1 gene. The fragile X syndrome shows great diversity in its phenotype as well as in its cytogenetic and molecular status. We have studied, in a large fragile X family, the correlation between the molecular data and the phenotypic expression of the syndrome. We report two brothers who carry identical unmethylated premutated alleles but present different clinical phenotypes. We also suggest that reductions in allele size from one generation to another may be, as in other diseases, because of triplet amplifications, more common at the FRAXA locus than previously thought.
Rat fetal adrenal cortex ultrastructure was studied in fetuses of 20 days of gestation coming from control (C) pregnant rats and from mothers undergoing two experimental conditions: maternal bilateral adrenalectomy on day 1 of gestation (ADX) and maternal bilateral adrenalectomy plus posterior dexamethasone administration the days 15, 16 and 17 of gestation (A+D). Our results show ultrastructural changes in the ADX rat fetal adrenal cortex, consisting of hyperactive steroidogenical features as response to the absence of maternal glucocorticoids, and the restoration of the control structural characteristics after dexamethasone administration to adrenalectomized animals.
Unrelated-donor transplants have been a realistic option for an increasing number of patients, and the results of these transplants are favorable for patients with good prognostic features. Timing of the transplant early in the course of disease, before malignant clones become resistant to therapy and while the patient remains in good clinical condition, is a critical variable. Further improvements in the safety and efficacy of unrelated-donor transplants will require new approaches to GVHD prevention, better supportive care, acceleration of immune reconstitution and facilitation of tolerance induction without loss of the graft-versus-leukemia effect.
BACKGROUND: To evaluate the efficacy of i.v. amphotericin B (AmB) as prophylaxis of deep mycosis (DM) in allogenic bone marrow transplantation (BMT). METHODS: From July 1991 to May 1993, 45 consecutive patients treated by allogenic BMT with no previous history of systemic mycosis and with normal renal function were administered prophylactic AmB at a dose of 0.5 mg/kg/48 h from day + 1 BMT until hemoperipheral recovery (group A). These were compared with an historic control group made up of 45 consecutive patients submitted to BMT from January 1990 to June 1991 who did not receive prophylactic AmB (group B). During the neutropenic phase all the patients remained in isolation units with laminar flow of filtered air and were administered oral non absorbable antibiotic therapy and diet of low bacterial content. The incidence of DM and the dose of AmB administered during the first 120 days post BMT were evaluated. RESULTS: In the first 30 days following BMT 3 (7%) cases of DM were observed in group A and 3 (7%) in group B. Four (9%) additional cases were found from days 30 to 120 in group A and 3 (7%) in group B. In 3 (7%) patients of the group which received prophylaxis and in 4 (9%) of the control group Candida spp. was isolated. In 3 (7%) patients from group A and 1 (2%) patient from group B the infection was due to Aspergillus. Although the patients from group A received therapeutic AmB less frequently (78% vs 91%) and later (13 [SD +/- 5.9] vs 9.2 [SD +/- 4.6] days) than those of group B (p < 0.002) the mean dose of AmB per patient treated was similar in both groups (11.3 [SD +/- 8.8] vs 11.8 [SD +/- 7] mg/kg). CONCLUSIONS: The prophylactic use of systemic amphotericin during the neutropenic phase of bone marrow transplantation does not reduce either the incidence of deep mycosis or the mean dose of amphotericin administered.
Two patients with tendinitis by ciprofloxacin are described. In both patients isolated involvement of the Aquilles tendon was produced. The symptoms initiated at 2 to 4 weeks of the beginning of treatment. The two patients had undergone chemotherapy and bone marrow transplantation due to chronic myeloid leukemia and acute promyelocytic leukemia, respectively with no data on recurrence of leukemia being obtained at the time of the tendinitis. Suppression of ciprofloxacin achieved disappearance of the symptomatology.
A group of 56 patients with immunophenotyped acute lymphoblastic leukemia had their bone marrow purged using monoclonal antibody (MAb) and complement. Mononuclear marrow cells were treated with panels of MAb directed against T cells (n = 19), CD10-CALLA (n = 16), and B cells (n = 21), resulting in median specific cell depletions of 96.50, 97.59, and 96.97%, respectively. The resulting CFU-GM recoveries were 60.15, 110.6, and 72.9%. Long-term bone marrow cultures showed normal formation of adherent cell layers in 17 of 23 cases, and failure to form an adherent layer correlated with poor hematological reconstitution. A total of 32 patients (aged 4-40 years) received purged marrow grafts containing a median of 1.32 x 10(7) mononuclear cells/kg and 1.64 x 10(4) CFU-GM/kg; 7 patients required backup marrow. Time to engraftment of 500 granulocytes, 1000 leukocytes, 20,000 platelets, and 50,000 platelets was 37, 38, 39, and 57 days, respectively. A total of 16 patients (50%) remain alive and in complete remission 313-913 days posttransplant (median 565 days); 13 patients (41%) relapsed between 50 and 365 days posttransplant (median 100 days), and 3 patients (9%) died from transplant-associated complications.
Clinical and prognostic studies were carried out in a series of 143 patients with low-grade (small-lymphocytic, follicular small cleaved cell, follicular mixed small- and large-cell) lymphoma. After treatment with alkylating agents (21.5% cases), combination chemotherapy (73.3%) or other therapies (5.2%), complete response (CR) was obtained in 40.7% of cases and partial response (PR) in 43.7%. The stage of the disease was the most important factor for response. With a median follow-up of 6.5 years, 48.0% (95% Cl: 37.5-58.5) of patients were alive 10 years after diagnosis. Among the initial parameters, advanced stage. B-symptoms, poor performance status, nodal involvement > 3 sites, extranodal involvement > or = 2 sites, WBC count > or = 10 x 10(9)/L, leukemic expression, high serum LDH levels, and bone marrow infiltration were all related to survival; treatment modality, however, had no influence on survival. In the multivariate analysis, stage (p = 0.008) and age (p = 0.053) were the most important prognostic factors. When considering response to therapy, both CR (p < 0.001) and PR (p = 0.003) emerged as the most important predictive variables, with only the absence of B-symptoms retaining its prognostic significance (p = 0.014) among the other parameters. In addition, in CR patients the duration of the response (< or = 1 year vs. > 1 year) was the most significant parameter for survival (p < 0.001). Finally, the initial stage (p = 0.011) and the histologic subtype (those patients with follicular mixed lymphoma relapsing less frequently than the others) (p = 0.052) were the only significant factors for relapse.
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INTRODUCTION: The use of bone marrow transplantation (BMT) in leukemia treatment is associated with high early morbid-mortality rates. Therefore, to identify morbid-mortality risk factors in this setting can be useful to improve therapeutic ratio. METHODS: We studied 15 variables in 46 patients with chronic myeloid leukemia (CML) treated with cyclophosphamide, total body irradiation (TBI) and allogeneic BMT. A multivariant analysis with an unconditional logistic regression model was used. RESULTS: Variables found to be related with early mortality included general state of health and acute graft versus host disease. Patients with a Karnofsky index (KI) between 60% and 80% had a higher risk of early death than those with a KI between 90 and 100%. Patients who developed severe (grade II-IV) acute graft versus host disease (AGVHD), had a relative risk of 15.62 (IC 95%: 3.16-77.34) compared with those who do not. Time between diagnosis and BMT contributed to the creation of the mathematical model without reaching statistical significance. CONCLUSIONS: In this series and in the range of the parameters analysed, general state of health according to KI, and the appearance of severe AGVHD are the variables related with a higher risk of early mortality.
One hundred and four patients with low grade (9 patients), intermediate grade (31 patients) and high grade (64 patients) non-Hodgkin's lymphoma received an autologous bone marrow transplantation (BMT). Disease status at transplant was first complete remission (CR) in 46 patients, second CR in 14 patients, third CR in 7 patients, chemosensitive disease in 16 patients and chemoresistant disease in 21 patients. Estimated 5 year disease-free survival (DFS) for all 104 patients was 49% (95% confidence interval (CI), 36-63%) with a median follow-up of 24 months. Five year relapse rate for 80 evaluable patients was 26% (95% CI, 14-44%). The 8 year DFS and relapse for the 46 patients transplanted in first CR were 75% (95% CI, 63-82%) and 15% (95% CI, 7-33%), respectively, with a median follow-up of 27 months (range 13-104 months) and a median time to relapse of 5 months (range 4-20 months). In the univariate analysis, variables correlated with DFS were performance status at autologous BMT, disease status at autologous BMT, LDH level at autologous BMT, failure to achieve CR at diagnosis, front-line chemotherapy (1 vs 2 or more regimens) and Working Formulation. Variables correlated with relapse were disease status at autologous BMT, preparative regimen and Coiffer's index at diagnosis. Multivariate analysis showed that performance status was the only independent predictor of DFS and that disease status at autologous BMT was the best relapse predicting variable. In patients transplanted in first CR, the variables correlated with DFS were stage at diagnosis and performance status at autologous BMT.(ABSTRACT TRUNCATED AT 250 WORDS)
Acute promyelocytic leukemia (M3) is a distinct subtype of AML considered to have better response to chemotherapy and a higher cure rate than other subtypes. We analyzed the outcome for 362 M3 patients transplanted in Europe from November 1979 to December 1992 and reported to the acute leukemia registry of the European Cooperative Group for Bone Marrow Transplantation (EMBT). Of these 362 patients, 187 received an autograft, 129 in first remission (CR1) and 58 in second remission (CR2), and 175 an allograft, 142 in CR1 and 33 in CR2. Patients autografted in CR1 had at 7 years a leukemia-free survival (LFS) of 48 +/- 5%, a relapse rate (RR) of 41 +/- 5% and a probability of transplant-related mortality (TRM) of 18 +/- 6%. Patients allografted in CR1 had a LFS of 42 +/- 6%, a RR of 28 +/- 5% and a TRM probability of 42 +/- 8%. For patients transplanted in CR2, the respective figures after auto and allotransplantation were: LFS: 31 +/- 7% and 22 +/- 8%, RR: 54 +/- 8% and 64 +/- 11%, TRM: 23 +/- 9% and 40 +/- 9%. These data, which do not permit comparison between autologous and allogeneic BMT, indicate that roughly 45% of M3 patients achieving CR1 may be cured by a marrow transplant. Since the recent use of transretinoic acid-containing induction regimens has increased early control for patients with AML M3, it will be important to find out how these results affect outcome following allogeneic or autologous BMT.
Echocardiography was performed in 94 patients with a total of 99 normally functioning Labcor-Santiago bioprostheses, 62 in the aortic and 37 in the mitral position. The following variables were measured: peak and mean transvalvular velocities, peak and mean instantaneous pressure gradients as calculated from the modified Bernoulli equation, pressure half-time, cardiac index, stroke volume and effective orifice area (using continuity and Hatle equations). Regurgitation patterns were sought by transthoracic echocardiography (all valves) and, for selected mitral bioprostheses, by transesophageal echocardiography. Calculated mean aortic pressure gradient ranged from six to 10 mmHg and calculated effective aortic orifice area increased with ring diameter, with means of 1.27 cm2 for the 19 mm valve and 2.58 cm2 for the 27 mm valve. For mitral bioprostheses, mean pressure gradient ranged from 3.0 to 4.5 mmHg and calculated effective orifice area from 2.27 to 2.73 cm2. Only central regurgitation was observed. The Labcor-Santiago pericardial bioprostheses created little resistance to forward flow. In the small aortic root their hemodynamic performance was as good or better than that of other currently available devices. It is hoped that this new design will contribute increased in vivo mechanical durability.
Between 1977 and 1992, 30 consecutive episodes of infective endocarditis in 28 patients involving pericardial bioprostheses were diagnosed and treated in our hospital. Eleven (37%) were early pericardial valve endocarditis occurring in the first 60 days following valve surgery, and 19 (63%) were late endocarditis. In both the early and late groups, more aortic that mitral valves were affected (19/30). The most frequent pathogen in the early cases was staphylococcus, (S. epidermidis in five cases, S. aureus in one). The most frequent pathogen among late cases was streptococcus: (St. viridans in four, St. faecalis in two, St. bovis in one). In four cases (13%) no pathogen was isolated. Twelve patients received antibiotic treatment alone, six specific for the pathogen and other six only arbitrarily chosen regimen. All patients were cured in the former and all patients died in the latter group (four with negative blood cultures and two in whom identification of the pathogen was delayed-Proteus mirabillis in one case and Brucella mellitensis in the other). Valve replacement during the infective endocarditis episode was necessary in 18 cases, either because of failure of the antibiotic treatment or because of heart failure secondary to prosthetic malfunction. Peri-annular abscess was present in five cases. Surgical mortality was 22.2% (4/18). In all, 11 patients (39%) died during the active stage of infective endocarditis. The most frequent cause of death was heart failure (45.5%). All four patients with negative blood cultures died. The most advisable strategy for treating bacterial endocarditis of pericardial bioprostheses is a combination of antibiotic therapy and early surgery, especially in cases of staphylococcus endocarditis.(ABSTRACT TRUNCATED AT 250 WORDS)