Long-term outcome of living donors older than 60 years.

Long-term outcomes of renal transplantation using kidneys from donors >60 years old are generally considered to be poor. This retrospective study included 265 living donor (LD) transplants in adult recipients with a mean follow-up of 13.1 +/- 6.1 years (range, 1.3-25.8), all of them under CNI. They were grouped according to the donor age at least (n = 49) or less (n = 216) than 60 years. Graft and patient survivals were compared using the Kaplan-Meier method and Cox multiple regression. At 1, 3, and 10 years, postoperatively patient survivals in the group of older LD recipients were 97%, 96%, and 93%, versus 98%, 97% and 92% among the younger LD recipients. At 1, 3 and 10 years, postoperatively graft survivals uncensored for death were 94%, 92%, and 81% among the older LD recipients versus 93%, 89%, 75% among the control group, respectively, despite a slightly increased creatininemia observed at 10 years among the older LD recipients. Deaths censored graft survivals were 96%, 96%, and 87% among the older versus 94%, 91% and 78% among the younger LD recipients, respectively. Therefore, significantly better noncensored death-censored graft survivals, were observed among the recipients of older LD compared with recipients of the younger donor group.

Malignancies in 2,753 kidney recipients transplanted during a 39-year experience.

An increased development of malignancies has been related to modern potent antirejection drugs. The purpose of this retrospective study was to assess the incidence and risk factors for invasive malignancies among 2753 kidney recipients (KRs), who were transplanted in two periods within our 39-year experience; before (group I) versus after (group II) the introduction of calcineurin inhibitors (CNIs). In group I, formed by 703 KRs under conventional therapy, 45 (6.4%) patients developed a malignancy, while in group II, treated with CNIs, of over 2050 KRs, 182 (8.9%) developed a malignancy different from noninvasive skin cancer. The incidence of malignancies was higher in the group of patients treated with CNIs (8.9% vs 6.4%), despite the shorter follow-up period. Moreover, the malignancy was more precocious in the CNI group, namely a mean time of onset of 75 versus 154 months in the conventionally treated group. The older mean age of recipients in group II affected by malignancies (43.6 years vs 34.6 years of the group I) played a significant (P < .001) role when associated with the more powerful immunosuppressive effect of CNIs, while recipient gender, dialysis period, donor source, and retransplants seemed to have few effects on malignancy development. Recipients over 60 under CNIs showed a 21% incidence of malignancies.

Value of intraoperative resistive index in kidney transplant.

The value of the resistive index (RI) obtained by echo color doppler evaluation of the transplanted kidney is still not well established. Many authors consider the RI to be nonspecific sign of rejection, acute tubular necrosis, or urinary tract obstruction, but its specificity remains low. In this paper, we report our experience with RI determinations in 34 consecutive kidney transplants at different times namely: perioperatively, at 24 hours, at 3 days, at 6 and at 9 days posttransplant. In all patients intraoperative RI was normal. RI increased significantly after transplantation in 10 patients who eventually developed a complication: delayed function, acute rejection, and spontaneous kidney ruptures. This increment from the baseline value was already significant at 24 hours after the kidney transplant, indicating a possible posttransplant complication (0.62 +/- 0.07 vs 0.76 +/- 0.04; P = .0004). We conclude that the value of RI in the early posttransplant phase should be considered an important aid for the early diagnosis of posttransplant complications.

Factors predicting response to splenectomy in adult patients with idiopathic thrombocytopenic purpura.

BACKGROUND AND OBJECTIVES: Splenectomy is the treatment of choice in the majority of patients affected by idiopathic thrombocytopenic purpura refractory to corticosteroid therapy, but it is not free from early and late complications. As the available literature does not seem to contain any precise indications concerning possible factors predicting the response to splenectomy, the aim of this retrospective study of 65 splenectomized patients was to attempt to identify potentially predictive clinical or laboratory parameters. DESIGN AND METHODS: For the purposes of statistical analysis, the patients were divided into two groups: the first included those with a complete (platelets > 100x10(9)/L) or partial response (platelets 50-100 x10(9)/L) to splenectomy; the second, the non-responders (platelets < 50x10(9)/L). The non-parametric tests were based on the Kruskal-Wallis method for independent samples, and the independent samples were compared using the Chi-square test according to Pearson. RESULTS: Univariate analysis did not reveal any significant correlation between successful splenectomy and age, sex, platelet count at diagnosis, anti-platelets antibody positivity, the site of platelet sequestration, the time between diagnosis and surgery, or the response to high intravenous immunoglobulin doses. However, the probability of success was greater in the patients with a complete or partial pre-operative response to steroid therapy (p<0.05). INTERPRETATION AND CONCLUSIONS: The factor most frequently associated with the success of splenectomy is the site of autologous platelet sequestration. Our study did not identify any clinical or laboratory parameter clearly predictive of post-splenectomy cure other than a transient response to steroid treatment. This finding needs further confirmation in larger patient populations.

Histological alterations in bone marrow in patients with late engraftment after autologous bone marrow transplantation.

Bone marrow histology after bone marrow transplantation has rarely been studied. Here, we reviewed the pre- and post-transplant bone marrow biopsies (BMB) of 40 acute myelogenous leukemia (AML) patients autografted in our center, 28 with normal and 12 with delayed peripheral recovery. The two groups were comparable in terms of previous therapy, disease phase and the number of infused cells, and received the same conditioning regimen. In the former group, reduced bone marrow cellularity and mild reticulin abnormalities were usual histological findings; in the latter, five patients had the same pattern, but the other seven had an almost undetectable hematopoietic parenchyma and severe reticulin derangement. One of these seven patients died of reactivated hepatitis B virus infection; the others eventually achieved peripheral recovery, with none of them experiencing a relapse. Autografted AML patients are excellent subjects for histological investigations. They account for the majority of delayed engraftments, the contribution of extramedullary components to the timing of engraftment is minimal, and leukemia relapse cannot be ruled out. These results suggest that BMB is a useful investigation in the work-up of late engraftment. A high degree of reticulin derangement with an almost undetectable hematopoietic parenchyma appear to be the morphological hallmarks of late engraftment.

Prognostic significance of bone marrow biopsy in essential thrombocythemia.

BACKGROUND AND OBJECTIVE: The diagnostic and prognostic value of bone marrow biopsy (BMB) has been widely investigated in patients with chronic myeloproliferative disorders (CMPD). The present study is based on a review of the results of routine BMBs taken from 93 essential thrombocythemia (ET) patients at the time of diagnosis. DESIGN AND METHODS: The common BMB histologic parameters and clinico-hematologic variables were considered for diagnostic and prognostic purposes. Clinico-pathologic correlations were looked for univariately. Moreover, the diagnostic significance of the histologic findings was tested by means of cluster analysis. Overall survival and event-free survival were considered as prognostic endpoints. RESULTS: There were no correlations between the clinic and pathologic findings, and none of the histologic and clinical parameters was predictive of survival or the occurrence of major clinical events. Cluster analysis of the BMB findings revealed two distinct morphologic patterns: one was clearly myeloproliferative; the other had somewhat dysplastic features. The event-free and overall survival rates in the latter group were significantly worse (p = 0.0377 and p = 0.0162 respectively), with major ischemic events accounting for most of the difference in event-free survival. INTERPRETATION AND CONCLUSIONS: These results have no clearcut counterpart in the literature, but we feel that dysplastic BMB findings could be included in the definition of ET prognostic scores in order to allow therapeutic strategies to be adapted to the level of risk.

Cytogenetic and myelodysplastic alterations after autologous hemopoietic stem cell transplantation.

Secondary myelodysplastic syndrome/acute myelogenous leukemia (MDS/AML) are today considered a primary complication of autologous hematopoietic stem cell transplantation. In our Center, 83 autografted patients underwent bone marrow (BM) biopsy and cytogenetic analysis at fixed intervals. Twelve patients developed non-clonal cytogenetic abnormalities and 10 patients clonal abnormalities, five of whom (three - 7, one - 5 and one t(9;11)) developed secondary MDS/AML. MDS was also diagnosed in two patients with a normal karyotype. In brief, seven patients (three males, four females; median age 36 years) developed MDS/AML 12-48 months (median 14) after autografting. The FAB diagnosis was AML-M2 in one, chronic myelomonocytic leukemia in two and refractory anemia with excess of blasts in transformation in four cases. Two patients presented a BM biopsy picture of MDS with fibrosis; none of them experienced leukemic transformation. Four MDS patients died, three of leukemic transformation and one of BM insufficiency; the two remaining patients are still living and untransformed. Our data underline the leukemogenic role of previous treatments, even if it is not possible to exclude that underlying disease and/or conditioning therapy may be involved.

G-CSF after autologous hemopoietic stem cell transplantation in malignant lymphoma.

Forty-eight autografted patients were studied after treatment with granulocyte-colony stimulating factor (G-CSF) and were compared with a historical series of 24 patients autografted with bone marrow (BM) without G-CSF. When the patients were divided on the basis of G-CSF administration, type of lymphoma and the source of hemopoietic stem cells, no significant difference was found in the median number of infused BM cells, duration of febrile episodes, platelet and hemoglobin recovery, or in the number of transfusions. The patients receiving peripheral blood (PB) + G-CSF had significantly shorter median durations of antibiotic therapy, hospital stay and polymorphonucleate (PMN) recovery. When the Hodgkin disease (HD) and non-Hodgkin lymphoma (NHL) cases were considered separately, a significant difference between those receiving and those not receiving G-CSF was observed only in the HD group. The advantage offered by PB + G-CSF over BM + G-CSF was far more evident in the NHL group than in HD. It can be concluded that G-CSF improves the outcome of BM transplant in HD, and that the use of PB + G-CSF adds a further advantage; conversely, in NHL, PB + G-CSF is strikingly superior to BM + G-CSF, but the addition of G-CSF adds little advantage.

Autologous bone marrow transplantation in advanced Hodgkin's disease.

Autologous bone marrow transplantation (ABMT) has been proposed as an alternative treatment of resistant/refractory Hodgkin's disease (HD). Thirty-seven patients in various phases of HD underwent autografting in our Center: fourteen received a CBV conditioning regimen, the others BCNU or VP16 followed by cyclophosphamide and TBI. Three patients died before engraftment, 28 (75.67%) achieved CR and 6 showed persistent disease. As of March 1996, 18 patients had died and 13 were in continuous CR. The median event-free survival (EFS) and 3-year EFS chances were respectively 9 months and 31.3% in the series as a whole, 14 months and 40% in primary resistant disease, 9 months and 28.4% in responsive relapse, and 3 months and 22.2% in resistant relapse. As many of these patients had failed to respond to third-line therapies, their EFS figures are primarily attributable to the therapeutic efficacy of ABMT. Furthermore, since the EFS curves are better in patients seemingly characterized by a lower chance of chemoresistance, our data favour the use of ABMT in the earlier phases of HD.

Multiple autoimmune events after autologous bone marrow transplantation.

A 36-year-old woman with RAEB-t and severe bone marrow fibrosis undergoing autologous BMT, developed a histologically documented GVHD-like skin rash. Thereafter, autoimmune thyroiditis, autoimmune thrombocytopenic purpura and autoimmune hemolytic anemia and a lupus anti-coagulant (LAC) were diagnosed. The patient is still alive, symptom-free and in first complete remission (CR); however, all of the autoantibodies are still detectable, with the exception being the anti-erythrocyte antibody. The most outstanding feature of the present case is the polymorphism of the autoimmune events, in the absence of a coexisting systemic autoimmune disease. This patient has achieved long-term disease-free survival (DFS) in first CR despite high-risk MDS and the repeated immunosuppressant therapy required because of the complications described above; a GVL reaction somewhat similar to the autoimmune events may have contributed towards maintaining disease control.

Bone marrow histology and CD34 immunostaining in the prognostic evaluation of primary myelodysplastic syndromes.

The prognostic impact of bone marrow biopsy (BMB) histology and CD34 immunoreactivity was compared with that of the more conventional parameters (the FAB diagnosis, peripheral blood values, percentage of BM blasts and some common prognostic scores) in 100 MDS patients. Statistical correlations among the cytological, haematological, histological and immunohistochemical parameters and their relationship with clinical outcome were searched for. At univariate analysis, FAB classification (P < 0.001), pattern of blastic infiltration at BMB (P < 0.005), presence of CD34+ aggregates (P < 0.0005), percentage of blasts in BM aspirate (P < 0.0001) and percentage of CD34 positivity (P < 0.0001) proved to be linked to leukaemic transformation and, except for FAB classification, retained a high degree of prognostic significance in terms of survival. Leukaemic transformation occurred in 16/18 patients simultaneously presenting 'large' blastic infiltrates at BMB and CD34+ aggregates (P < 0.00001); 9/17 evaluable patients died within 12 months of diagnosis (P < 0.001)> Discriminant functions for leukaemic transformation and survival did not offer any advantage over univariate analysis in the prognostic work-up. The results indicate that the size of blastic aggregates and CD34 positivity allowed patients with a worse prognosis to be identified irrespective of their FAB subtype, but the prognostic impact is considerably greater when both parameters are simultaneously taken into account, as testified by the restricted and homogeneous subgroup of patients with both 'large' and CD34-positive aggregates.

Efficacy of different prophylactic antifungal regimens in bone marrow transplantation.

BACKGROUND: Fungal infections still represent a major clinical problem in neutropenic patients; the recent availability of active imidazole derivatives, particularly fluconazole and itraconazole, has increased interest in prophylaxis. MATERIALS AND METHODS: Fifty-nine consecutive bone marrow transplant (BMT) recipients were randomized to receive either itraconazole 400 mg/day or fluconazole 300 mg/day as oral antimycotic prophylaxis during the pancytopenic phase; they were retrospectively compared with a historical control group of 30 patients who had received fluconazole 50 mg/day. Every febrile episode was treated with the same empirical antibiotic combination; amphotericin-B was added after 4-5 days in the case of persistent fever. Proven or suspected mycotic infections and the empirical use of amphotericin-B were considered as failures of prophylaxis. RESULTS: There were no differences in the number of febrile episodes in the three groups. Five patient died of bacterial sepsis: two in the fluconazole 300, two in the itraconazole and one in the fluconazole 50 group. The addition of amphotericin-B was required in 12, 16 and 11 cases, respectively, in the three groups. There were four documented fungal infections in the intraconazole and one in both fluconazole groups; three suspected fungal infections were observed in the fluconazole 300 group and two in both the itraconazole and the fluconazole 50 group. None of the differences were statistically significant. CONCLUSIONS: The present results indicate that high-dose fluconazole and itraconazole are equivalent; neither of them was superior to low-dose fluconazole, which is regarded as being devoid of prophylactic activity against systemic mycoses.

Intestinal calcium absorption as shown by stable strontium test in celiac disease before and after gluten-free diet.

OBJECTIVES: To investigate the effect of gluten-free diet on mineral and bone metabolism in women with celiac disease and, using the strontium test, to assess intestinal calcium absorption. METHODS: We studied body mass index, biochemical and bone mineral indices, strontium absorption test, and bone mineral density in 18 women (mean age 36.8 yr, range 18-68 yr) with celiac disease at diagnosis and after 12 months of gluten-free diet. RESULTS: Mean strontium absorption at diagnosis was markedly decreased with respect to control values (13.84 +/- 9.03% vs 22.47 +/- 4.21%, p < 0.0001), and 11 of the 18 patients (61%, subgroup A) had low values. In all patients, mean hemoglobin, serum potassium, magnesium, plasma calcium, urinary calcium, and phosphorus were significantly abnormal at diagnosis, whereas only the subgroup A had significantly reduced body mass index, 25 OH vitamin D, and elevated alkaline phosphatase. This subgroup differed in body mass index (p < 0.003) and calciuria (p < 0.035) with respect to the other patients. Strontium absorption correlated with body mass index, calcemia, and 25 OH vitamin D. After the gluten-free diet, all biochemical variables and strontium absorption normalized (23.23 +/- 5.54%), whereas bone mineral density did not change. CONCLUSIONS: At diagnosis, the patients frequently had intestinal calcium malabsorption, as demonstrated by strontium test, with an early renal compensatory mechanism. After the gluten-free diet, the normalization of calcium absorption and the decrease of mid-molecule parathyroid hormone suggested a normalization of mineral metabolism, although a positive effect on bone mineral density was not evident at that time.

Single-institution results of autologous bone marrow transplantation in acute myeloid leukemia.

BACKGROUND: Current results of autologous bone marrow transplantation (ABMT) suggest that this procedure may prolong disease-free survival (DFS) in patients with acute myeloid leukemia (AML). MATERIALS AND METHODS: Over the last ten years, 29 AML patients received unpurged autologous bone marrow (BM) after a conditioning regimen including Ara-C (3 g/m2/12h, days -9, -8), CTX (60 mg/kg/day, days -6, -5) and TBI (3.33 Gy/day, days -3 through -1). In 21 patients, ABMT was performed as late intensification after first CR. Eight more relapsing patients were autografted after the achievement of second CR. RESULTS: Three patients died from transplant-related complications. In the remaining patients, mean times to WBC and platelet recovery were, respectively, 23 days (range 13-55) and 55 days (range 22-790). Follow-up for censored patients ranged from 1 to 120 months. Relapse occurred in 7 patients (5 in first and 2 in second CR). Overall 5-year DFS and event-free survival (EFS) chances were, respectively, 67.3% and 60%, with no statistically significant differences between first (DFS = 67.3%, EFS = 60.3%) and second CR (DFS = 68.6%, EFS = 60%). DISCUSSION: Apart from obvious selection biases, our study suggests that outcome in first CR AML patients is improved by ABMT. Long-term DFS and EFS are clearly better than when conventional post-remission chemotherapies are used. The greater antileukemic potential of ABMT is further underlined by the results in patients autografted in second CR, when conventional chemotherapy is almost never curative.

CD34 immunohistochemistry of bone marrow biopsies: prognostic significance in primary myelodysplastic syndromes.

Bone marrow (BM) biopsies from 58 patients with primary myelodysplastic syndrome (MDS) were studied using QBEND10, a monoclonal antibody that recognizes the human progenitor CD34 antigen in routine aldehyde-fixed paraffin-embedded samples. FAB subtypes were RA (5 patients), RARS (9 patients), RAEB (20 patients), RAEBt (11 patients), CMML (3 patients). In addition, 10 MDS patients whose BM biopsies revealed heavy reticulum fibrosis were included. Neither the percentage of CD34+ cells nor the number of CD34+ aggregates (defined as clusters of 3 or more cells) correlated with the presence and morphology of abnormal localizations of immature precursors (ALIP). When all patients were considered, median survival was 69 months in those with less, and 25 months in patients with more than 1% CD34+ cells (P < 0.05). Median survival was 15 months in patients with CD34+ aggregates and 41 months in those without aggregates (P = 0.0017). When RAEB patients were considered median survival was 41 months in those with less than 1%, and 29 months in those with more than 1% CD34+ cells; the 4-year survival chance was 45% in the former and 18.3% in the latter group. Therefore, CD34 positivity of more than 1% identifies a subset of RAEB patients with shorter life expectancy. In addition, leukemic transformation was observed in 11 of 35 patients (31%) with no CD34 aggregates, but in 14 of 23 patients (60%) with aggregates (P < 0.05). CD34 immunostaining, which can be easily performed on routinely prepared BM biopsies, was found to be a powerful prognostic tool for predicting survival and outcome in MDS.

Idarubicin in the therapy of acute myeloid leukemia: final analysis in 57 previously untreated patients.

Fifty-seven previously untreated adult acute myeloid leukemia patients received idarubicin (IDA) in sequential combination with cytarabine as induction therapy; post-remission treatment included two courses of IDA and cytarabine alternating with two courses of VP-16 and cytarabine. As late intensification, patients received either high-dose cytarabine or, in 10 cases, autologous bone marrow transplantation. Complete remission (CR) was achieved in 48 patients (84.2%), 41 after one induction course and seven after two courses. Median length of disease-free survival (DFS) was 26 months. Univariate analysis did not identify any of the investigated variables as having prognostic significance in predicting DFS. On the other hand, patients achieving CR after one induction course had a better DFS than those requiring two courses. Furthermore, the analysis of DFS slightly favors autologous bone marrow transplantation. In conclusion, the antileukemic activity of the present IDA protocol is testified by the high CR rate and by the possibility of minimizing the role of prognostic factors. The better outcome of patients achieving CR after one induction course further supports the opinion that the intensity of the induction treatment, offered by an agent as potent as IDA, might significantly influence DFS.

Long-term results of autologous bone marrow transplantation in adult acute lymphoblastic leukemia.

Autologous bone marrow transplantation (BMT) is widely performed in both adult and high-risk pediatric acute lymphoblastic leukemia (ALL). Nevertheless, there is still a lack of definitive data concerning its real effectiveness in prolonging the survival of these patients. Between 1984 and 1992, 20 ALL patients in first, second and third complete remission (CR) underwent autografting in the BMT Unit of the University of Milan. This series included 3 children in CR after one or more hematological relapses while all the other patients were adult. Autologous bone marrow was harvested during the same disease phase as that in which the autologous BMT was performed. The conditioning regimen included high-dose Ara-C, cyclophosphamide and TBI 1000 cGy. Successful engraftment occurred in all patients; no early deaths or deaths in CR were recorded, making disease-free survival and event-free survival (EFS) curves superimposable. The overall chance of EFS at 72 months was 41%: 57% for patients in first CR, 53% for patients autografted after one or more isolated meningeal relapse, 14% for patients autografted after one or more hematological relapse. The present data do not provide any evidence to support a role for autologous BMT in prolonging EFS in first CR ALL patients. Nevertheless, the results after meningeal relapse seem to be favourable when compared with the disappointing prospects of these patients after conventional chemotherapy. The EFS after hematological relapse revealed by this study does not significantly differ from that reported in the majority of other studies: the efficacy of autologous BMT in these ALL patients is doubtful.

Prognostic relevance of histological findings on bone marrow biopsy in myelodysplastic syndromes.

Bone marrow biopsy (BMB) has aroused growing interest as a possible aid in the diagnostic and prognostic evaluation of myelodysplastic syndromes (MDS). Previous reports have pointed out that MDS patients with blastic aggregates or severe bone marrow (BM) fibrosis are characterized by a worse clinical outcome. BMBs of 106 MDS patients were retrospectively reviewed, and relationships among the different histological parameters as well as clinicopathological correlations were looked for. Three patterns of BM blastic infiltration ("diffuse," "cluster," and "large") were recognized. Overt leukemic transformation and overall survival were selected as prognostic end points. BM infiltration was "diffuse" in 18, "cluster" in 48, and "large" in 40 cases. RAEB-t patients accounted for about half of the "large" cases, and none had a "diffuse" pattern (p < 0.01). Nineteen patients showed extensive BM fibrosis; most of them were characterized by "cluster" blastic infiltration and megakaryocyte hyperplasia. Leukemic transformation occurred in 67% of "large" cases (p< 0.001) and in none of the "cluster" cases with severe BM fibrosis (p < 0.01); however, survival was equally poor in these two groups because of early leukemic transformation (large cases) and BM failure (cluster cases). The FAB classification did not significantly correlate with prognosis. Patients with "cluster" BM infiltration and severe fibrosis can be regarded as a true separate MDS subset characterized by unique clinicopathological and prognostic features. Because of the subacute clinical behavior of most cases, and the poor performance status of many elderly patients, there is still controversy as to the best therapeutic approach in MDS. Histological analysis allowed two groups of MDS patients to be identified, both characterized by poor life expectancy, who could benefit from early aggressive chemotherapy.