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.

Transcoronary platelet thromboxane A2 formation without platelet trapping in patients with coronary stenosis-effect of sulphinpyrazone treatment.

Platelet count, and plasma thromboxane B2 (TXB2) and circulating platelet aggregates (CPA) were determined in the coronary sinus (CS), aortic bulb (AO) and cubital vein (V) in 21 patients with stable angina and in 6 control subjects before and after atrial pacing (AP). TXB2 measurements were repeated before and after AP in 6 of the 21 angina patients after 15 days' sulphinpyrazone treatment. Platelet count and CPA ratio were similar in angina patients and controls at all three sampling sites and were unchanged at AP peak. In the controls, basal TXB2 values in CS, AO and V were not significantly different and were unchanged at AP peak. In the angina patients compared with the controls, basal TXB2 values in the AO, CS and V were not significantly different whereas the CS/AO TBX2 ratio was significantly higher; at AP-induced ischaemia, CS TXB2 was significantly increased and the CS/AO TXB2 ratio was increased. A weak but significant direct correlation was found between CS/AO TXB2 ratio and coronary score. Sulphinpyrazone treatment reduced CS TXB2 levels at rest and after AP, but not the ischaemic threshold at AP.

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)

Effects of gamma aminobutyric acid (GABA) and muscimol on endocrine pancreatic function in man.

The high concentrations of gamma aminobutyric acid (GABA) in the pancreatic islets and the neurotransmitter role played by this amino acid in the central nervous system, make it plausible that GABA also intervenes in the control of endocrine pancreatic function. In 12 normal subjects, a single oral dose of 5 or 10 g GABA, as compared to placebo, caused a significant (p less than 0.01) and dose-dependent (p less than 0.01) increase of plasma levels of immunoreactive insulin, C peptide and glucagon, without affecting plasma glucose concentration. By contrast, in 15 additional subjects, a single oral dose of 5 mg muscimol, a specific GABA receptor agonist, did not consistently influence the above parameters. Although the lack of effects of muscimol might indicate that the action of GABA is not mediated through specific receptors, the results with GABA suggest that this amino acid plays a specific role in the regulation of endocrine pancreatic function.

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.

A pharmacokinetic and platelet function study of the combined administration of metoprolol and sulfinpyrazone to healthy volunteers.

In a double-blind study on healthy subjects who underwent three 3-week periods of treatment with metoprolol (M) + sulfinpyrazone (S), M + placebo, and S + placebo, pharmacokinetics and plasma levels of M were not affected by concurrent administration of S. Analysis of variance change-over demonstrated a significant difference between treatments only for serum uric acid levels. Analysis of post-treatment and baseline data within each treatment showed: decreased platelet count by M, lowered serum 6-keto PGF1 alpha by all three treatments, decreased serum TXB2 generation and arachidonic acid-induced platelet aggregation by S + M. No negative interaction between S + M was found.

High heparin released platelet factor 4 in uncomplicated type 1 diabetes mellitus.

The role of platelet activation in diabetic microangiopathy is still controversial. We evaluated the degree of platelet activation in relation to vessel wall damage in three selected, well matched groups of subjects (10 healthy controls; 20 insulin dependent diabetic patients, 10 without microangiopathy and 10 with microangiopathy). We measured beta TG and PF4 plasma levels before and 5, 15 and 90 min after a heparin bolus i.v. (5000 U). beta TG basal levels were increased only in diabetic patients with microangiopathy. Diabetic patients without microangiopathy showed significantly higher levels of heparin released-PF4 (HR-PF4) in comparison with healthy controls. High levels of HR-PF4 seem to be an early marker of in vivo increased platelet activation in uncomplicated diabetes mellitus.

Immunoreactive calcitonin: a tumor marker for myelogenous leukemias.

In a series of 59 patients with chronic or acute myelogenous leukemia (CML, AML) we investigated whether circulating immunoreactive human calcitonin (i-hCT) levels correlate with diagnosis, response to therapy and clinical course. I-hCT was detectable in plasma samples of 88% of patients with CML in the chronic phase and in 100% of patients with CML in blastic transformation. In the AML patients, a significant relation was observed between the cytological subtype and i-hCT levels at diagnosis. In sequentially studied patients the i-hCT plasma concentration was related to the overall mass of leukemic cells, being lower when complete remission was achieved than at diagnosis and increasing at time of recurrence. These data suggest that circulating i-hCT levels can serve as a "tumor marker" in human myelogenous leukemias.

Basal plasma levels of calcitonin and bone mineral mass in normal and uremic women. Effect of menopause.

Basal plasma levels of immunoreactive calcitonin (iCT), forearm bone mineral content (BMC) as measured by 125I photon absorptiometry and 24-hour urinary hydroxyproline/creatinine ratio (OHPr/Cr) were determined in 32 healthy women (13 pre-menopausal, aged 40 to 54 years, and 19 post-menopausal, aged 41 to 54 years). The basal plasma levels of iCT were significantly higher in the pre-menopausal group (mean value 96 vs 54 pg/ml, P less than 0.025). The BMC value of the radius was also significantly greater in the same group (mean +/- SEM 656 +/- 13 vs. 620 +/- 9 mg/cm2, P less than 0.05), while the urinary OHPr/Cr ratio was higher in the post-menopausal group (29.9 +/- 1.5 vs. 38.7 +/- 2.7 mg/g, P less than 0.02). These results suggest that basal plasma levels of iCT decrease after the menopause and support the hypothesis that a deficiency of CT could be involved in the pathogenesis of post-menopausal bone loss. Similar results were obtained in 25 uremic women on maintenance hemodialysis (9 pre-menopausal and 16 post-menopausal) aged 30 to 65 yrs.: both basal iCT levels and BMC values were significantly higher in the pre-menopausal group.

Calcium metabolism in multiple myeloma.

45Calcium metabolism and circulating levels of iPTH (N-terminal fragment) and iCT were investigated in normocalcemic patients with multiple myeloma (12) in an attempt to ascertain early changes in calcium metabolism, which may occur before hypercalcemia develops. The same parameters were also investigated in patients with senile osteoporosis (11), corticosteroid-induced osteoporosis (6), Paget's disease (6) and controls without bone disorders (13). In the myeloma group, the exchangeable calcium pool (7,678 +/- 321 mg) was significantly higher (P less than 0.01) than in the control group (4,405 +/- 374 mg), the senile osteoporosis group (4,108 +/- 407 mg) and the corticosteroid-induced osteoporosis group (3,015 +/- 161 mg) and nearly as high as in the Paget's disease group (8,876 +/- 1,173 mg). Calcium pool turnover rate was higher in the myeloma group than in controls, as were bone anabolism and bone catabolism, although differences were not statistically significant. There were no statistically significant differences among the groups in the plasma iPTH or iCT, although the mean value of the latter was higher in the myeloma group than in controls (86 +/- 24 vs. 47 +/- 13 pg/ml). These data suggest that an increase in the exchangeable calcium pool and in turnover rate may occur early in the course of multiple myeloma, preceding the development of hypercalcemia. The role of some homeostatic mechanisms in maintaining normal plasma calcium levels in multiple myeloma despite increased bone calcium resorption is discussed.

Reduction of plasma levels of betathromboglobulin and platelet factor 4 during hemodialysis: a possible role for a short acting inhibitor of platelet aggregation.

Plasma levels of the platelet markers betathromboglobulin and platelet factor 4 are elevated in patients with chronic renal failure, and their levels in hemodialysis patients increase further during exposure to the dialysis membrane. The effectiveness of a short acting inhibitor of platelet aggregation in reducing the blood levels of betathromboglobulin and platelet factor 4 was assessed by means of a double blind cross over study. A statistically significant reduction of betathromboglobulin and platelet factor 4 levels was observed during treatment with the platelet inhibitor.

Radiologic features of the solitary rectal ulcer syndrome.

A radiologic study of 4 biopsy-proven cases of the solitary rectal ulcer (S.R.U.) syndrome was undertaken. The radiologic findings of S.R.U. were rectal stenosis (one with ulcer), polypoid rectal mass, and multiple sub-mucosal defects with shallow ulcers. The S.R.U., which is benign and requires only dietetic treatment, must be differentiated from other more serious entities such as neoplastic and inflammatory bowel disease.

Therapeutic activity of 4-demethoxydauno-rubicin (idarubicin) in adult acute leukemia.

Twenty-six patients affected by acute leukemia were treated with 4-demethoxydaunorubicin (idarubicin), a new anthracycline compound which in experimental leukemias showed an antitumoral activity superior to daunorubicin (DNR) and doxorubicin (DX), with a higher ratio of active to cardiotoxic doses. A group of 16 patients in relapse received idarubicin at a dosage of 5-6 mg/m2/day for 3 consecutive days; a second group of 6 relapsing and 4 previously untreated cases was treated with a sequential combination of idarubicin and arabinosyl cytosine. In all patients, a significant fall of bone marrow and peripheral blast cells was obtained. These preliminary results suggest that idarubicin has a therapeutic activity against human acute leukemias usually responsive to DNR or DX. The duration of myelosuppression varied from 7 to 50 days, leading in some cases to a high risk of infections. As regards other toxic effects (gastrointestinal, hepatic and acute cardiac toxicity, alopecia), idarubicin appears to be, in our experience, a well-tolerated drug; however, it is too early to comment on delayed cardiac effects.

Oral idarubicin in adult acute leukemia: a preliminary experience.

Twelve patients affected by different types of acute leukemia received idarubicin (4-demethoxy-daunorubicin) by oral route at the total dosage of 45, 60 or 90 mg/m2 distributed over three consecutive days. Drug response was assessed by the decrease in blast cells in peripheral blood and showed some variations between the different types of leukemia. Acute myelogenous leukemia patients and those with blastic crisis of chronic myeloid leukemia appeared to be the more responsive groups; however, the lower dose schedule could explain the less satisfactory results obtained in lymphatic leukemia patients. Data suggest that idarubicin is absorbed rapidly after oral ingestion, in spite of nausea and vomiting, which appeared 3-4 h later and were easily controlled by antiemetic therapy. The purpose of fractionating the drug dosage over three consecutive days is to prolong in the blood an elevated concentration of the main idarubicin metabolite (13-dihydro-derivative), which presents in experimental models an antileukemic potency similar to the parent compound. This study confirms that idarubicin is effective in acute leukemia also by oral route. This formulation could offer some advantages for subjects who cannot tolerate parenteral chemotherapy and it could be proposed in maintenance leukemia protocols.

[Evaluation of the effects of some non-steroid anti-inflammatory agents on the gastric mucosa]. / Valutazione degli effetti di alcuni farmaci anti-inflammatori non steroidei sulla mucosa gastrica

300 mg/day phenylbutazone, 210 mg/day indomethacin, and 600 mg/day pyrasanone were administered for 14 days to three randomised groups of patients respectively, consisting of a total of 76 subjects with various forms of non-infectious inflammation (osteoarthritis, fibrositis, rheumatoid arthritis, gout, phlebitis), in a double-blind trila designed to determine the activity of the three drugs and their tolerance. In 36 cases, gastroscopy was performed before and after the treatment. On the basis of doses that were equivalent as far as their anti-inflammatory effect was concerned, epigastric pain and pyrosis were noted in about 31% of the series, though no significant difference could be made out between the three drugs. Gastroscopic evidence of erythema (8 cases), multiple erosion (2 cases), pomphoid gastritis (1 case), and duodenal ulcer (1 case) was obtained in subjects treated with phenylbutazone or indomethacin, and of erythema only (1 case) after pyrasanone. No relation could be established between the clinical symptoms and the gastroscopic findings.

[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.

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.

[rt-PA in extracardiac thromboembolic vascular occlusions]. / L'rt-PA nelle occlusioni vascolari trombo-emboliche extra-cardiache.

Recombinant tissue plasminogen activator (rt-PA) is a thrombolytic agent characterized by elevated but not absolute fibrin specificity. However, its therapeutic dose is high and associated with a variable degree of systemic activation of the fibrinolytic system. Thrombolytic drugs are widely used in acute myocardial infarction and have now begun to be considered for deep vein thrombosis (DVT), pulmonary embolism (PE), and peripheral artery thrombosis (PAT) as well. Although anticoagulant therapy is effective in reducing the immediate complications of venous thromboembolism, thrombolytic therapy has various advantages over anticoagulant therapy, including lysis of thrombi with recanalization of venous circulation, reduction of venous valve damage and prevention of post-phlebitic syndrome. The different dosage regimens of rt-PA recently evaluated (0.71 to 1.76 mg/kg/24 h for 2-4 days) in DVT have caused consistent thrombolysis but also excessive bleeding. The optimal therapeutic range for rt-PA in DVT remains to be determined. Thrombolytic therapy is superior to heparin treatment only in hemodynamically compromised patients with massive PE. The minor systemic fibrinolytic effect and the faster action on thrombi of rt-PA compared with the first generation thrombolytic agents, streptokinase (SK) and urokinase (UK), are very interesting and explain the positive results recently obtained in PE with this drug (50 mg over 2 h, followed, if necessary, by 40-50 mg over 4-5 h) by Goldhaber and Verstraete.(ABSTRACT TRUNCATED AT 250 WORDS)

[Whole-body osseous scintigraphy and Ca++ kinetics in patients with renal transplants]. / La scintigrafia ossea whole-body e la cinetica del Ca++ nel paziente con trapianto renale.

Bone scintigraphy with 99mTc-diophosphonate and a whole body scanner was performed on 18 subjects with good renal function who had received a kidney transplant more than six months previously. This demonstrated scintigraphyc abnormalities in 17 of the cases. The alterations were characterized in 44,5% of the cases by focal uptake of the tracer. Diffuse alterations were observed in 4 of the 18 cases studied (22%). In these patients increases of serum alkaline phosphatase and in PTH levels were present. Ca++ exchangeable pool values and accretion rate were normal in the subjects with focal lesions. In the cases where scintigraphy showed diffuse lesions both the above parameters were much increased.

[Ocular complications in patients undergoing long-term hemodialysis and renal transplants from cadavers]. / Le complicanze oculari nel paziente sottoposto ad emodialisi cronica e trapianto renale da cadavere.

In 36 subjects in chronic hemodialysis treatment and in 36 patients with a renal transplant, well functioning for more than one year, the ocular complications related to the specific form of treatment were evaluated and compared. In the group of the dialyzed subjects ocular pathology was composed by: lens opacities in 9 cases, corneal calcifications in 7 cases, hypertensive fundus in 8 cases. In no patient these lesions produced measurable visus reductions. In the transplant group ocular pathology was composed by: lens opacities in 28 patients, hypertensive fundus in 7 and intraocular hypertension in one. One case of herpes cheratytis and one case of endophtalmytis have also been observed. In 9 patients these lesions produced a remarkable visus reduction. In conclusion renal transplantation shows a greater incidence of ocular complications if compared to hemodialysis. This situation has not important consequences on the rehabilitation of the transplanted subject for the possibility of surgical correction of the cataract.