Induction of follicle maturation and ovulation by gonadotropin administration in women with beta-thalassemia.

The objective of this paper was to assess the ability of gonadotropin administration to induce ovarian steroidogenesis, follicle maturation and ovulation in hypogonadal women affected by beta-thalassemia. Thirteen hypogonadal thalassemic women underwent a test with gonadotropin-releasing hormone (GnRH), with estimation of serum follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels. They were then administered human menopausal gonadotropin (hMG) for a period ranging from 11 to 15 days with a total dose variable from 3,300 to 4,200 IU. In each patient, the initial dosage of 300 IU daily, adopted for the first 9 days, was modified subsequently according to the ovarian morphology, as shown by serial echographic examinations and by serum estradiol levels. In those patients in whom a dominant follicle was evidenced and the occurrence of pregnancy could be excluded, induction of ovulation was attempted by administration of 10,000 IU of human chorionic gonadotropin (hCG). All patients displayed a reduced LH and FSH rise in response to GnRH. Upon hMG administration, they exhibited echographic evidence of follicular growth with a clear-cut increase of serum estradiol, which peaked between the 9th and the 16th day from the start of treatment. In two out of three patients in whom a dominant follicle developed, ovulation was induced successfully by hCG injection, as shown by the increase of serum progesterone and by the ultrasonographic demonstration of a corpus luteum. This study has shown that, by proper pharmacological stimulation, the steroidogenic function of the gonads and even ovulation can be reinstated in hypogonadal thalassemic women.(ABSTRACT TRUNCATED AT 250 WORDS)

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.

Incidence and histological features of bone marrow involvement in malignant lymphomas.

Bone marrow biopsy (BMB) is a routine investigation in the diagnosis and staging of Hodgkin's disease (HD) and non-Hodgkin's lymphoma (NHL), and there is evidence supporting its prognostic importance in some histological varieties. The histological characteristics of BMB in 433 NHL and 155 HD patients were reviewed for clinicopathological correlations; 36 of these cases were also studied by means of immunohistochemistry. BM infiltrates were discovered in 171 NHL patients. In 36 cases, the diagnosis of NHL was directly established by BMB; a discordance between lymph node and BM histology was observed in 38 of the other 135 cases. BM-positive centroblastic and immunoblastic NHL were significantly associated with larger infiltrates, BM fibrosis, and megakaryocytic hyperplasia. Leukemization at diagnosis was more frequent in low-malignancy NHL. No correlation was found between histology and prognosis, although immunohistochemistry revealed a B-cell phenotype in all but two cases. BMB was positive in 18 of the 155 HD patients and directly diagnostic in two; Reed-Sternberg and Hodgkin cells were CD-30 positive and surrounded by T-cell infiltration. The concordance between BM and lymph node histology was fairly satisfactory, although the relationships between BM infiltration and other histological parameters may reflect peculiar interactions with BM microenvironmental factors. The usefulness of BMB in the diagnosis of malignant lymphomas has been demonstrated, and further progress can be expected from the availability of reliable immunohistochemical markers of clonality reacting on paraffin-embedded BM sections.

Evaluation of hypothalamic-pituitary function in patients with thalassemia major.

The increased survival of patients with thalassemia major, made possible by more adequate therapeutic regimens, has emphasized the importance of the endocrine abnormalities often associated with this disease. In twelve thalassemic patients, we evaluated the hypothalamic-pituitary function by measuring plasma levels of anterior pituitary hormones under basal conditions and in the course of provocative tests. An impairment of growth hormone (GH) secretion was demonstrated in a considerable proportion (7/12) of these patients. In some of them failure of GH response to insulin-hypoglycemia and normal hormone rise after growth hormone-releasing hormone indicate a hypothalamic defect. A defective prolactin secretion was observed in the female hypogonadic but not in the male thalassemic patients. This abnormality appears to be dependent on estrogen deficiency rather than on a hypothalamic-pituitary dysfunction. In our series a high prevalence (8/12) of hypogonadism was also noticed. In these cases, the low gonadotropin levels and their unresponsiveness to gonadotropin-releasing hormone are compatible with a hypothalamic and/or pituitary damage. Lastly, the enhanced ACTH responses to the stimuli associated to a reduced cortisol release suggest the existence, in these patients, of a diminished adrenocortical reserve. On the whole, this study has shown several derangements of the hypothalamic-pituitary function in thalassemia. This emphasizes the need for careful endocrine surveillance in this disease.

Chronic myelogenous leukemia: state of the art.

Recent contributions from molecular biology, biotechnology and recombinant DNA applications have led to important clinical and therapeutic advances in chronic myelogenous leukemia (CML). Developments in the methodology of genetic investigation have clarified the molecular alterations brought about by the appearance of the Philadelphia chromosome. It is possible that the hybrid bcr/abl gene plays an important role in the pathogenesis of CML by subverting the mechanism of homeostasis through the uncoordinated activation of cell growth stimulating and regulating factors. Further improvements have been brought about by the polymerase chain reaction (PCR) which permits an indirect identification of the fusion gene and the study of minimal residual disease during remission after chemotherapy and bone marrow transplantation (BMT). Clinical trials have shown that alpha-interferon, alone or in association with chemotherapy, induces long term clinical and cytogenetic remission in those CML patients in whom BMT from either related or unrelated donors cannot be performed. Allogeneic BMT seems to be the treatment of choice in younger people. However, since a minority of subjects have HLA identical siblings, the possibility of using unrelated donors to provide long term disease free survival has been explored even if the availability of a compatible donor is the primary limiting factor. The development of in vivo and in vitro purging procedures has aroused new interest in autologous bone marrow transplantation. This procedure benefits particularly from biotherapeutic agents which selectively act on the marrow by suppressing bcr/abl positive cells.

Idarubicin in blastic crisis of chronic myelogenous leukemia.

BACKGROUND: Blastic crisis (BC) is the terminal event in the natural history of most chronic myelogenous leukemia (CML) patients. Depletion of the normal stem cell compartment, as well as the proliferative advantage and frequent pharmacoresistance of the blastic clone, contribute to the poor prognosis of CML patients in this phase. Recent clinical trials have shown that idarubicin (IDR) in combination with cytosine arabinoside (ARA-C) is more active than daunorubicin at comparable doses in acute myelogenous leukemia (AML). Furthermore, IDR alone also exhibits antitumoral activity in the BC of CML. METHODS: Twelve Ph+ CML patients in BC (male 8, female 4; median age 45 yrs., range 19-55 yrs.) were treated with IDR 12 mg/m2/die for 3 consecutive days in sequential combination with Ara-C (1 hour i.v. infusion) 120 mg/m2/12 hrs. for 7 consecutive days. BC exhibited a myeloid phenotype in 9 and a lymphoid phenotype in 3 cases. Median duration of the previous chronic phase had been 36 months (range 6-180). RESULTS: Clearing of peripheral and bone marrow blasts was achieved in all but one patient. Three other patients were classified as resistant because of blastic regrowth, and 3 died of infection during postchemotherapeutic aplasia. Two patients achieved complete remission (CR) and 3 partial remission (PR). The median duration of response was 11 months (range 6-32). CONCLUSIONS: In BC of CML the IDR/Ara-C combination led to an encouraging rate of either partial or complete responses. The relatively long duration of unmaintained response was even more interesting, with the duration of PR approaching that of CR. These data suggest that IDR should be considered as one of the first-line drugs in the treatment of BC of CML.

No correlation between response and survival in patients with multiple myeloma treated with vincristine, melphalan, cyclophosphamide, and prednisone.

A vincristine, melphalan, cyclophosphamide, and prednisone (VMCP) multi-drug regimen was used in 85 previously untreated patients with multiple myeloma (MM) (symptomatic Durie Stages II and III) until they became refractory. The prognostic significance of various pretreatment characteristics was evaluated in terms of therapeutic response (according to Southwest Oncology Group [SWOG] and Chronic Leukemia-Myeloma Task Force [TF] criteria) and survival. Therapeutic responses, obtained in 31.2% (SWOG) and 68.7% (TF) of patients, had a significant inverse correlation with myeloma cell mass, serum calcium, and bone status. Median survival time of Stage II and Stage III patients was 39 and 34 months, respectively. Serum B2 microglobulin greater than or equal to 6 micrograms/ml was the only variable correlating unfavorably with survival duration after multi-variate analysis (increased risk = 2.79), although therapeutic response as a time-dependent variable had no effect on survival. These data suggest no correlation between response and survival, partially because of inadequate response assessment criteria and partially because no existing treatment is curative (although current therapeutic approaches may prevent death from complications).

Age, time since menopause, and body parameters as determinants of female spinal bone mass: a mathematical model.

The study of mathematical models to describe bone mass behavior throughout life is a possibility for assessing the main factors of peak bone mass and bone loss. We developed a mathematical model to predict spinal bone mass behavior on a sample of 181 healthy Italian women whose lumbar bone mineral content was determined by Gd-153 dual photon absorptiometry. This model proved to be both efficient, showing the best fit (r = 0.7 on spinal bone mineral content) when compared to other previously suggested models, and also reliable as its fit remained the best when applied to a subsequent sample of 519 women whose lumbar spine was measured by dual X-ray photon absorptiometry. This model suggests that body height and body weight (but not age) are determinants of bone mass in premenopausal women. In postmenopausal women, an accelerated phase of bone loss starting at menopause is dependent on age and time since menopause, whereas body mass index acts as a protective factor. This model confirms the influence on spinal bone mass not only of age and time since menopause but also of body size parameters.

Spinal and forearm bone mass in relation to ageing and menopause in healthy Italian women.

Most studies concerning bone status have been performed in Nordic and Anglo-Saxon countries and few data are available on southern European populations. We performed a cross-sectional study on spine and forearm bone mass in 234 healthy Italian women and related the results to age and time since menopause. Forearm bone mass does not decline in premenopausal age, whereas, as far as the spine is concerned, a significant reduction appears 3 years before the mean age of menopause; in both cases, the occurrence of menopause accounted for an accelerated phase of bone loss. In postmenopausal women both spine and forearm bone mass show a stronger correlation with years since menopause than with age. According to a linear exponential model, the rate of spinal bone loss per year since menopause is around 4% in the first 3 years which slows down to around 2% in the 5th year; the corresponding rates of forearm bone loss are 2% and 1.3%, respectively.

Relevance of red cell distribution width (RDW) in the differential diagnosis of microcytic anaemias.

The authors studied the red cell distribution width (RDW) index (obtained by Coulter Counter S Plus IV) in normal subjects and in patients with beta-thalassaemia trait and iron deficiency anaemia. Statistics and reference limits for the above three conditions are given. In order to make a differential diagnosis between beta-thalassaemia trait and iron deficiency anaemia, linear discriminant analysis was carried out. Global correct classification was 91.5% on our first sample of patients and 88.8% on a subsequent validation sample of microcytic patients. The percent of correct beta-thalassaemia trait diagnoses was 94.4% and 86.7% for the first and validation samples respectively. For iron deficiency anaemia correct diagnoses of 86.2% and 90.9% were achieved.

[Hematopoietic tissue growth factors: clinical factors]. / I fattori di crescita del tessuto emopoietico: applicazioni cliniche.

Hematopoietic growth factors (HGF) are glycoproteins controlling proliferation, differentiation and function of bone marrow derived cells. Results of recent studies, both in vitro and in vivo, in animal models, indicate that these molecules might have a therapeutical value in several different clinical settings. Thanks to advances in the expression of recombinant genes. HGF have recently become available in sufficient quantities to be tested in clinical investigation. During the last few years, a number of phase I/II trials have been performed with the use of recombinant colony stimulating factors and erythropoietin, suggesting the efficacy of these substances in treating diseases associated with hematopoietic failure or impaired cell function. This review article takes a critical look at the most important recent preclinical and clinical experience on HGF, and also examines some of the future directions in which clinical medicine will probably benefit from these molecules.

The role of haematopoietic growth factors in bone marrow transplantation.

Bone marrow transplantation (BMT) is being increasingly used for treating a large number of diseases. The recent availability of haematopoietic growth factors (HGFs) for therapeutic purposes has offered a powerful tool in order to overcome one of the most important BMT-related complications, namely severe myelosuppression. This article, besides an overview on the main results achieved with the clinical use of HGFs for haematopoietic reconstitution after BMT, also deals with some innovative applications of these molecules in BMT setting, as their use for peripheral stem cell transplantation and bone marrow failure after BMT.

Immunophenotypes in "classical" B-cell chronic lymphocytic leukemia. Correlation with normal cellular counterpart and clinical findings.

This study evaluates the expression of a series of membrane antigens, normally expressed by B-lymphocytes of the lymphocytic mantle and marginal zone, in 90 selected cases of "classical" (mouse red blood cell-receptor+, CD20+, CD5+, surface immunoglobulin +/-) B-chronic lymphocytic leukemia (B-CLL) with the aim of contributing toward identifying the normal counterpart of B-CLL and any correlations between surface antigen pattern and certain clinical characteristics. Clustered (CD23, 25, 39, 40, 27, 1c, w75) and unclustered (NuB1, 7F7, KiB3) monoclonal antibodies (MoAb) were tested. Almost all cases showed high reactivity to CD23, 27, w75, 39, 40, and NuB1: expression of CD1c was very low and that of 7F7, KiB3, and CD25 was variable. The reactivity of 7F7 and KiB3 was strictly correlated, and they correlated individually with CD25. Results show that the most frequent B-CLL phenotype (CD19+, 5+, 23+, 27+, 39+, NuB1+, KiB3 +/-, 7F7 +/-, and CD25 +/-) corresponds to one or more cellular subsets in the mantle zone. No correlation was found between MoAb expression, surface immunoglobulin (SIg) class or type, clinical stage, disease activity, or age at diagnosis. The only difference (statistically borderline) was the expression of 7F7 and KiB3 (in young versus old patients). This suggests that modulations in the expression of surface antigens do not affect the clinical behavior of the disease.

Recombinant gamma-interferon as first line therapy for high risk myelodysplastic syndromes. Italian MDS Study Group.

Thirty patients affected by previously untreated high risk myelodysplastic syndromes (MDS) were treated with human recombinant gamma-interferon (r-IFN-gamma): 15 of them with a higher dose (HD) of 0.1 mg/sqm, three times a week and 15 with a lower dose (LD) of 0.01 mg/sqm, three times a week, both doses administered subcutaneously (s.c.). The therapy was fairly well tolerated and few major toxic events were documented. Sustained improvement of one or more clinico-hematologic parameters was observed in 43.3% of the patients (26.6% and 60.0% for the lower and higher dose, respectively). Median survival time from the start of IFN-gamma therapy was 15+ months (range: 1-26) for patients with refractory anemia with excess of blasts (RAEB) versus 5 months (range 2-12) for patients with RAEB in transformation (RAEB-t); 15+ months (range 1-26) for HD patients versus 8 months (range 2-23) for patients treated with LD regimen; 16+ months (range 9-26) for responders versus 7 months (range 1-22) for nonresponders. All these three variables (diagnosis, treatment, and response to treatment) turned out to be statistically significant (p = at least less than 0.01) at Cox's analysis.