Acute megakaryoblastic leukemia: experience of GIMEMA trials.

The objective of the study was to evaluate the incidence, characteristics, treatment and outcome of acute megakaryoblastic leukemia (AMeL) in patients enrolled in GIMEMA trials. Between 1982 and 1999, 3603 new consecutive cases of AML aged over 15 years were admitted to GIMEMA trials. Of them, 24 were AMeL. The incidence of AMeL among AML patients enrolled in GIMEMA trials was 0.6% (24/3603). Diagnosis was based on morphological criteria. Out of 11 cytogenetic studies performed two presented chromosome 3 abnormalities. Twelve patients (50%) reached a CR, five (21%) died in induction and seven (27%) were unresponsive. The median duration of CR was 35 weeks (range 10-441). Seven patients underwent transplantation procedures (1 BMT, 4 aBMT, 2 aPBSCT). Four patients died in CR due to chemotherapy-related complications. Comparing the CR rate between AMeL and the other cases of AML enrolled in GIMEMA trials, no differences were observed. These results were mirrored for different age groups. The median survival was 40 weeks. At present, after a follow-up of a minimum of 2 years, only two patients are alive in CR, all the others having died. A 5-year Kaplan-Meier curve shows a disease-free survival of 17% and an actuarial overall survival of 10%. AMeL is a rare form of AML. The CR duration and the overall survival in this group of patients are very poor, even if similar to those observed in other AML. Furthermore, a high number of deaths in CR were observed. On the basis of these data, a specific therapeutic approach, possibly with innovative treatments, should be evaluated.

Mucormycosis in patients with haematological malignancies: a retrospective clinical study of 37 cases. GIMEMA Infection Program (Gruppo Italiano Malattie Ematologiche Maligne dell'Adulto).

A retrospective study of 37 patients with haematological malignancy (21 acute myeloid leukaemia, 11 acute lymphoid leukaemia, two lymphoma, two hairy cell leukaemia, one Hodgkin's disease) and histologically documented mucormycosis was conducted to evaluate the clinical characteristics and ascertain the factors which influenced the outcome from mycotic infection. Patients were admitted to 18 haematology divisions in tertiary care or university hospitals in Italy between 1987 and 1995. Fever, thoracic pain, dyspnoea and cough were the most frequent presenting symptoms. At the onset, 89% patients were neutropenic (neutrophil counts < 0.5 x 10(9)/l) with a median duration of previous neutropenia of 14 d (range 6-60). The most frequent sites of infection were lungs (81%), CNS (27%), sinus (16%), liver (16%) and orbital space (10%). Only three patients were asymptomatic. A correct in vivo diagnosis was made in only 13 (35%) patients. When performed, thoracic and cranial CT scan were the most useful diagnostic investigations. Despite the fact that 26 febrile patients were treated with empirical antifungal treatment, 28 of the 37 patients (76%) died from fungal infection at a median time of 17 d from the onset of clinical symptoms. Nine patients were cured by antifungal therapy plus, in five cases, radical surgery procedures. An analysis of factors influencing outcome demonstrated that the resolution of chemotherapy-induced neutropenia and prolonged treatment with amphotericin B and, if feasible, radical surgical debridement treatment, were significantly correlated with recovery from infection. Mucormycosis, a rare filamentous fungal infection that occurs most frequently in neutropenic acute leukaemia patients, is characterized by a high mortality rate. Extensive and aggressive diagnostic and therapeutic procedures are essential to improve the prognosis in these patients.

Recombinant interleukin-2 treatment before and after autologous stem cell transplantation in hematologic malignancies: clinical and immunologic effects.

Autologous bone marrow transplantation (ABMT) for hematologic malignancies is associated with a high relapse rate. Interleukin-2 (IL-2) administration is a therapy that may prevent relapse if used when the tumor burden is minimal. In this study we administered recombinant IL-2 (rIL-2) therapy to 12 patients affected by hematologic malignancies either before or after autologous stem cell transplantation (ASCT). rIL-2 was given by a 6 day continuous intravenous infusion with escalating doses, up to 18 x 10(6)/m2/day, depending on patient tolerance. The functional immune responses of the patients were assessed as natural killer (NK) and lymphokine-activated killer (LAK) cytotoxic activities and in vitro interferon-gamma (IFN-gamma) and tumor necrosis factor alpha (TNF-alpha) synthesis. During rIL-2 treatment, the expected side effects occurred; only 3 patients, who showed severe cardiovascular toxicity, required suspension of the treatment. All toxicities reversed after the end of the therapy. Immunologic monitoring was carried out the day before starting rIL-2 infusion and then repeated on days 3, 7, and 14 after rIL-2 was discontinued. Following every rIL-2 course, a pronounced increase in CD3+, CD8+, CD56+ cells was found, with a peak value on day 3. The NK and LAK activities showed a significant increase on day 3 (p < 0.001) over pretherapy values; the increase lasted until day 14, although the difference at later time points was not significant. Before transplant the synthesis of both IFN-gamma and TNF-alpha decreased following rIL-2 therapy, whereas higher levels of these lymphokines were found after posttransplant rIL-2 courses.(ABSTRACT TRUNCATED AT 250 WORDS)

Alpha-2a-interferon/melphalan/prednisone versus melphalan/prednisone in previously untreated patients with multiple myeloma.

Alpha-2a-interferon (IFN) has demonstrable activity in advance and refractory multiple myeloma (MM), because of the in vitro synergism between IFNs and cytotoxic agents we report the preliminary results of a therapeutic trial of 50 patients with MM. Twenty-eight patients were randomized to receive melphalan plus prednisone (MP) and 22 were randomized to receive IFN plus MP (IFN-MP). Criteria for response, progression and relapse were those of the Southwestern Oncology Group. 95% of the patients receiving IFN-MP responded to therapy as opposed to 68% of the patients receiving MP (P less than 0.05). Response was independent of M-component immunoglobulin class but in stage III it was higher in the IFN-MP group than in the MP group (P less than 0.05). The combination IFN-MP was well tolerated without unusual or unexpected toxic effects. The response duration time was longer in the IFN-MP group than in the MP group (P less than 0.025). The median survival was 80 weeks in the MP group and in the IFN-MP group the 93% of patients were still alive after 90 weeks (P less than 0.025). Our results show that the use of the IFN as an adjuvant to MP improves the percentage of responders, the response duration time and the median survival of untreated patients with MM.

Empiric antibiotic and antifungal therapy for granulocytopenic patients with acute leukemia.

A prospective study was undertaken to determine the effectiveness of an empiric antibiotic treatment employing the combination of a beta-lactam and an aminoglycoside followed in non responders by vancomycin and amphotericin B after 48 and 96 hours respectively. We have evaluated 180 febrile episodes in 102 granulocytopenic leukemic patients. Febrile episodes (44%) were microbiologically documented; 29% were only clinically documented and 27% were possible. In the 180 evaluable episodes treated with a beta-lactam and an aminoglycoside the overall response rate was 61%. In non responders the addition of vancomycin increased the response rate to 83% and the subsequent addition of amphotericin B moved the total responders to 96%. Antibiotic related side effects were minimal. These data suggest the importance of an empiric strategy for treatment of bacterial infections arising in granulocytopenic patients. An early empiric antifungal therapy also appears necessary to control clinically undetected fungal invasion.

[Postcoital contraception using a desogestrel-ethinyl estradiol combination]. / Contraccezione post-coitale con una associazione desogestrel-etinilestradiolo.

PIP: Post-coital contraception or rather interception, a term suggested here since it is non-preventive, per definition is applied after the hypothetical time of contraception. Various methods have been proposed for "day after" interventions among which the administration of estro-progestins are the simplest, least expensive and least likely to cause serious side effects. In order to reduce side effects, a trial involving 35 women was conducted at the hospital in Avigliana. A biphasic combination of .150 mg desogestrel + .030 mg ethinyl estradiol was administered in the form of 2 pills within a period of 12 hours or 24 hours after intercourse. 6 tables display age, educational level, occupation, motive, day during menstrual cycle, time after intercourse that treatment was begun. 65.7% of the women were less than 30, 8% less than 20 years old. Almost 80% were treated during their mid-cycles, where the chance of becoming pregnant is greatest, i.e., 20%. Not one pregnancy was observed. It is impossible to ascertain how many conceptions actually did occur due to the nonexistence of methods for determining avoided pregnancies. The only side effects reported were nausea and vomiting of short duration. Menstruation reoccurred within 21 days of treatment for 98%. A small possibility of ectopic pregnancy, however, does exist. Fetal damage from the steroids seems excludable, due to the extremely early period of administration. An increased demand for post-coital interception has been registered for the youngest users, especially among students and employees, which indicate a high or medium high level of education, but it is probably also due to erratic, occasional and inexperienced sexual behavioral patterns, and a lack of knowledge concerning the choice of the right kind of contraception.^ieng

Phenotype of chronic lymphocytic leukemia (CLL) B-cells. B-CLL cells express the Leu-8 antigen.

In the present report we studied the phenotype of peripheral blood mononuclear cells (PBMC) from 25 patients with B-cell chronic lymphocytic leukemia (CLL). Cells from all the cases expressed monoclonal surface immunoglobulins (SmIg), formed rosettes with mouse erythrocytes (MRFC) and were positive with OKB 2 and OKIa monoclonal antibodies. In addition, CCB 1 monoclonal antibody was positive in 17 out of 20, Leu-1 in 18 out of 21 and Leu-8 in 23 out of 25 cases. Double labelling experiments confirmed that the Leu-8 antigen was co-expressed on Leu-1+, CCB2+, HLA-DR+ B-CLL cells. Thus, B-CLL cells generally express the SmIg+, MRFC+, Leu-1+, OKB2+, Leu-8+ phenotype. Since it is known that normal peripheral blood B cells may be divided into two subpopulations according to Leu-8 expression, our data indicate that B-CLL cells originate from the more immature Leu-8+ B-cell subset which will respond to anti-IgM, whereas it reacts poorly to pokeweed mitogen.

Unusual phenotype (Leu 7+, OKT4+, OKM1+) expressed by cells from a patient with an abnormal expansion of granular lymphocytes.

We report the case of a 70-year-old female with a lymphocytosis which was casually detected during a routine examination. Immunological studies revealed the expansion of granular lymphocytes (GL) with the following, previously undescribed phenotype: Leu 7+, OKT3+, OKT4+, OKT8-, OKM1+. These cells were tested for their functional activities and found to exert neither helper nor suppressor functions in in vitro tests. Cytotoxic activities demonstrated a strong ADCC and a markedly reduced NK function. 1 year later the clinical course has remained good without any treatment and we suggest that this case should be classified as an abnormal expansion of GL, despite the OKT4 positivity of the cells. Our data point out the importance of a careful immunological study of cells from these rare patients and suggest the existence of a normal GL population expressing the OKT4 phenotype, which is possibly expanded in this patient.

Plasma cell leukemia: a report on three patients.

Three patients with plasma cell leukemia are reported. Two of them has a previous history of myeloma; the third one started with a plasma cell leukemia. Diagnosis was made from the required presence of 20% plasma cells in the peripheral blood. In all 3 cases, bone marrow aspiration and peripheral blood showed plasma cells strongly positive for acid phosphatase and alpha-naphthyl acetate esterase, and negative for periodic acid-Schiff. The first patient was treated with a polychemotherapy regimen that included vincristine, cyclophosphamide, chlorambucil and prednisone, and the second patient with melphalan and prednisone; the third one, who started with plasma cell leukemia, received total body irradiation at the dose of 600 rad. The results of the therapy and survival time, which was never more than 3 months, are in accord with other reports in the literature.

[A case of allergy to a copper-medicated IUD. Etiopathogenetic and clinical aspects]. / Su di un caso di allergia a I.U.D. medicato al rame. Considerazioni etiopatogenetiche e cliniche.

PIP: The use of copper medicated IUDs has replaced the use of inert IUDs, thanks to their increased effectiveness, a Pearl index of 1% as compared to 2.5%. There are very few reported cases of copper allergy due to IUDs; this article presents 1 such case. A 22 year old healthy woman was inserted with a Cu 250 IUD; 1 week after insertion she presented widespread erythematous patches all over her body, excluding her face. Cortisone and antihistamine treatment were ineffective; the IUD was removed, and all symptoms disappeared in less than 20 days; subsequent tests revealed the patient to be allergic to copper sulphate.^ieng

[Analysis of the results and considerations on the organizational aspects of the implementation of the Law 194/78 in a provincial hospital]. / Analisi dei risultati, considerazioni di ordine organizzativo circa la legge 194/78 applicata in un Ente Ospedaliero di provincia.

PIP: Law number 94 legalizing abortion passed in Italy in May 1978. This article reports on the situation of induced abortion in the small provincial hospital of Avigliana, Torino, 1 year after the implementation of the law. The paramedical personnel were supportive of the medical and obstetrical personnel who, not being conscientious objectors, accepted to perform abortions. Every woman was thoroughly checked and counseled prior to the operation by the same doctor who was going to perform the abortion; the procedure was always done under general anesthesia and by vacuum aspiration. There were 66 abortions between June-December 1978, and 115 between January-July 1979. Contrary to expectations the number of deliveries also increased, from 66 during the 1st half to 145 during the 2nd half of operations. More than half the number of patients were referred from the ambulatory clinic within the same hospital, as compared to only 25% during the 1st half; only 7.8% were referred by private physicians, as compared to 30% during the 1st half. Almost 50% of patients were housewives both during the 1st and during the 2nd half; age of patients was, for the great majority, between 24-35; parity was 2 in 43.8% of cases for the 1st half, and in 40% of cases in the 2nd half. The majority of operations was performed within the 1st 8 weeks of pregnancy, and many women came from districts outside that of Avigliana. 34.8% of requests for abortion were because of failure of contraception, and almost 40% for socioeconomic reasons; only 8.2% of requests were motivated by reasons of health. Misinformation about contraceptive practices was widespread among the patients.^ieng

[Neonatal malformations and hormone therapy during pregnancy]. / Malformazioni neonatali e terapia ormonale in gravidanza.

PIP: The use of pharmacological treatment during pregnancy has always been extremely controversial, especially if the drugs involved are sex hormones, such as diethylstilbestrol. The percentage of congenital malformations attributable to hormonal therapy during pregnancy is 3%; the period of maximum susceptibility to teratogenic agents is between the 3rd-10th week of gestation, or the period of organogenesis. The 1st reported case of congenital malformation due to hormonal therapy during pregnancy goes back to 1957; since then the literature has published more on this subject. One of the most important studies was done in 1977 by Heinonen on a group of 50,282 pregnant women; 1042 had been treated with sex hormones. 19 infants, or 18.2/1000, had cardiovascular defects. Among the remaining 49,240 patients there were 385 cardiovascular malformations, or 7.8/1000. The problem is still far from being resolved; it is up to the individual physician to give the best possible advice, after careful consideration of the clinical situation of every pregnant patient.^ieng

Therapy of acute nonlymphocytic leukemia in children: a review of 73 patients.

Since 1969, 73 children with acute nonlymphocytic leukemia have been admitted for evaluation and treatment at the Institute of Hematology of the University of Rome. Various drug regimens, basically including daunomycin and/or cytosine arabinoside, were employed both for induction and maintenance treatment. Overall, the incidence of complete remission was 63%. The availability of intensive supportive measures starting in 1974 appears to be the most likely explantation for the higher response rate observed since then. Duration of remission and overall survival were disappointingly short owing to the high frequency of bone marrow relapse. Carefully controlled clinical studies will in the future be necessary to explore better methods of preventing leukemic relapse.

Combination chemotherapy for marrow relapse in children and adolescents with acute lymphocytic leukaemia.

38 children with acute lymphocytic leukaemia (ALL) in haematologic relapse were retreated with vincristine, daunomycin and prednisone (VPD) together with intrathecal methotrexate and prednisone, followed by asparaginase in those patients not in complete remission after 4 weeks. The overall complete remission (CR) rate was 79%; asparaginase was needed to achieve CR in 7 of the 30 responding patients. The median duration of second remission was only 36 weeks, but 6 out of 15 children receiving the COAP-POMP-CART consolidation regimen remain in continuous second remission after 37-260 weeks; 3 of them are currently off all therapy. It is concluded that a prolonged second remission can be achieved in children with ALL in bone marrow relapse by combining intensive chemotherapy with the prevention of meningeal leukaemia.

Discontinuing therapy in childhood acute lymphocytic leukemia. A multicentric survey in Italy.

The results of discontinuing therapy in children with acute lymphocytic leukemia observed at four associated institutions are presented. Of the 247 patients who achieved complete remission, 122 (49.3%) reached the point of discontinuing therapy after 2-4 years of continuous remission. The median period off therapy was 13 months with a range of 1-69 months. Of the 122 children removed from therapy, 27 (22.1%) relapsed, mainly in the bone marrow; relapses occurred 1-32 months after cessation of therapy (median ten months) with only two relapses occurring later than two years. By actuarial analysis, 57% of the patients are projected in continuous remission after five years from cessation of therapy. Neither selected features at diagnosis nor single modalities of treatment were found to predict whether relapse would occur after discontinuing therapy. Long-term remission and possibly cure can be expected in over one-third of newly diagnosed children with ALL after 2-4 years of antileukemic treatment.

Sequential combination of methotrexate and L-asparaginase in the treatment of refractory acute leukemia.

Seventy-six patients with advanced acute leukemia refractory to conventional chemotherapy were treated with a sequential combination of methotrexate (MTX) and L-asparaginase (L-ASP), based on the reported schedule-dependent synergism between the two drugs in human leukemic cells in vitro. On Day 1, patients received 60 mg/m2 of MTX iv, followed 24 hours later by L-ASP at a dose of 10,000 IU/m2 iv. This sequence was repeated weekly with 50% escalations in the dose of MTX with each course. Overall, 31 of 76 patients (40.7%) achieved complete remission after a median of three courses; the response rate was 35.5% in patients with acute nonlymphocytic leukemia (21 of 59 patients) and 58.8% in patients with acute lymphocytic leukemia (ten of 17). Increasing the starting dose of MTX to 200 mg/m2 did not improve the response rate. Maintenance therapy with the same combination given every 2 weeks produced a median complete remission of 10 weeks. Toxicity was manifested by: acute hypersensitivity reactions to L-ASP (five patients), stomatitis (36 patients), and mild liver abnormalities (five patients). MTX in doses up to 200 mg/m2 caused minimal myelosuppression. We conclude that the MTX-L-ASP combination is a well-tolerated, highly effective induction regimen for refractory acute leukemia.

[Special obstetrico-gynecologic hospital structure and local service units. Considerations on the availability and need for ULS 35 and 36]. / Struttura specialistica ospedaliera ostetrico-ginecologica e unità locale dei servizi. Considerazioni sulle disponibilità e necessità delle U.L.S. 35 e 36.

The underlying principles of the national health reform measures and those approved by the Piedmont Region's programmes with regard to social and health reorganisation are recalled. Reference is made to anomalies with respect to local health services No. 35 and No. 36 in the case of obstetrics and gynaecology, there being three maternity departments for 97,251 inhabitants in the area concerned. The main aspects of the division are examined. It is shown that implementation will only be possible if there is a usership capable of feeding every branch of the structure set up. It is suggested that the specialist activities of obstetrics and gynaecology be concentrated at Susa and Avigliana, though oven this division will not ensure a proper flow of users. The position could be improved by better employment of the basic structures, i.e. the consulting surgeries and SAUB out-patient departments.