Ceftriaxone/Amikacin vs Ceftazidime/Amikacin as Empirical Therapy for Fever in Patients with Haematological Malignancy and Severe Granulocytopenia: Clinical and Economic Outcomes.

To assess the economic outcomes produced when a conventional antibiotic treatment regimen requiring three administrations per day was replaced with a treatment regimen requiring only one daily administration, the efficacy, tolerability and cost of ceftazidime was compared with that of ceftriaxone (both drugs in combination with amikacin) for the empirical treatment of febrile granulocytopenic patients with haematological malignancy. 102 febrile patient-episodes were randomly assigned to receive ceftazidime (6g in three divided doses) or ceftriaxone (2g as a single daily dose), both in combination with amikacin. The response was evaluable in 94 patients (47 in each group). 75 (80%) patients had an absolute granulocyte count lower than 100/mm(3) at the onset of fever or during the first week of antibiotic therapy. 61 (64.9%) were affected by acute leukaemia. Multiple daily ceftazidime plus amikacin was effective in 33 of 47 (70.2%) patients, and single daily ceftriaxone plus amikacin in 31 of 47 (66%) patients (p > 0.2). Among patients successfully treated, median time to defervescence was 3.3 days (range 1 to 11) for ceftazidime plus amikacin and 4.5 days for ceftriaxone plus amikacin (range 1 to 15) [p = 0.14]; study drugs were continued for 12 (range 7 to 26) and 12.3 days (range 7 to 28), respectively. Our study demonstrated that single daily administration of ceftriaxone was as effective and well tolerated as multiple daily administration of ceftazidime when both were administered in combination with amikacin. Cost analysis showed that compared with the thrice daily regimen, administration of single daily doses of ceftriaxone for a 12-day treatment period would result in a net cost saving of $US392 (626 940 Italian lire).

Thrombotic complications in acute promyelocytic leukemia during all-trans-retinoic acid therapy.

A case of acute renal failure, due to occlusion of renal vessels in a patient with acute promyelocytic leukemia (APL) treated with all-trans-retinoic acid (ATRA) and tranexamic acid has been described recently. We report a case of acute renal failure in an APL patient treated with ATRA alone. This case further supports the concern about thromboembolic complications associated with ATRA therapy in APL patients. The patients, a 43-year-old man, presented all the signs and symptoms of APL and was included in a treatment protocol with ATRA. After 10 days of treatment, he developed acute renal failure that was completely reversible after complete remission of APL was achieved and therapy discontinued. We conclude that ATRA is a valid therapeutic choice for patients with APL, although the procoagulant tendency is not completely corrected. Thrombotic events, however, could be avoided by using low-dose heparin.

The pineal hormone melatonin in hematology and its potential efficacy in the treatment of thrombocytopenia.

Recent experimental studies suggested that hematopoietic cell proliferation and differentiation are under a neuroendocrine control and that they change in relation to the 24-hour period. Moreover, it has been shown that the pineal hormone melatonin (MLT) plays a role in mediating the influence of the psychoendocrine system and of the lighting conditions on the hematopoiesis. Finally, MLT has appeared to regulate hematopoietic cell growth by influencing apoptosis-related mechanisms. In particular, preliminary studies have shown that the pineal hormone MLT may determine some benefits in blood cell disorders, mainly platelet diseases. On this basis, a pilot phase II study of MLT therapy was performed in patients suffering from persistent thrombocytopenia due to different causes. The study included 14 patients, and thrombocytopenia was due to bone metastatic involvement in 5, hypersplenism in 3, myelodysplastic syndrome in 3, DIC in 1, genetic factors in 1, and Werlhof's disease in the last case. MLT was given orally at 20 mg/day in the evening for 2 months. No MLT-related toxicity occurred. A normalization of platelet number was achieved in 8/14 (57%), and platelet mean number significantly increased on MLT therapy. This preliminary study would suggest that MLT may be effective in the treatment of thrombocytopenia due to different reasons, for which no effective standard therapy is available.

Anthracycline drugs and MDR expression in human leukemia.

We investigated the expression of P-glycoprotein (P-gp) in 50 adults with de novo acute myeloid leukemia (AML) at the initial diagnosis in order to further define the relationship between the presence of P-gp on leukemic cells and the efficacy of two different anthracycline drugs, Daunorubicin (DNR) and Idarubicin (IRR), in terms of remission, induction and survival. We found that 30 (60%) of the 50 patients were negative for P-gp expression (group 1) and 20 patients (40%) were positive (group 2) for P-gp expression by MRK16MoAb using a cut of 10% positive cells. Among the 50 patients, 35 (70%) obtained complete remission (CR); depending on P-gp expression the CR rate was 80% for group 1 and 45% for group 2 (p < 0.005). The median duration of overall survival (OS) was 20 months for patients in group 1, compared to 10 months for patients in group 2 (p < 0.005). Regarding the anthracycline used, no difference in CR has been observed in patients of group 1 (75% CTR with DNR versus 90% CR with IDR); on the contrary in group 2 we observed 40% CR with DNR versus 70% CR with IDR (p < 0.005). No significant difference has been achieved in group 1 terms of median duration of overall survival between DNR and IDR regimen; on the contrary the median duration of OS in patients of group 2 treated with IDR regimen was significantly longer than DNR regimen (p < 0.005). These results confirm the prognostic value of P-gp expression in AML at diagnosis and we suggest that Idarubicin could be a valid anthracycline drug for reversing multidrug resistance.

Role of granulocyte colony-stimulating factor in relapsed/resistant intermediate and high-grade non-Hodgkin's lymphoma patients treated with the E-SHAP regimen.

AIMS AND BACKGROUND: The study assessed the role and potential benefit of rhG-CSF in reducing the frequency, duration and severity of neutropenia following cytotoxic chemotherapy according to the E-SHAP protocol and, at the same time in improving the response rate. METHODS: Twenty patients with resistant/relapsed intermediate or high-grade non-Hodgkin's lymphoma were treated with the E-SHAP regimen (etoposide+methyl prednisolone+high dose cytosine arabinoside and cisplatin), and in 15 of them, we administered rhG-CSF between chemotherapeutic courses. RESULTS: The 15 patients who received G-CSF after E-SHAP were neutropenic for a short time and experienced no febrile episodes or infective complications. In contrast, in the group (5 patients) who did not receive G-CSF, the WBC nadir was lower and the number of days with a neutrophil count below 1.0 x 10(9)/L was longer, with a greater risk of inferctious complications. Of the 15 patients, only one had a delay in chemotherapy administration, and the RDI was 95% in the 65% of patients who received G-CSF. Of 5 patients treated with chemotherapy alone, 4 had a delay and the RDI was over 95% in only one patient. We obtained a good overall response rate (70%) in the group who received G-CSF. In the historical group of 5 non-Hodgkin lymphoma patients, we observed only 1 partial response and 4 had progression of disease. CONCLUSIONS: Administration of G-CSF is associated with an acceleration of neutrophil recovery, indicating its potential to reduce the risk of infection. The use of G-CSF permitted us to administer intensive chemotherapy without delay and according to standard dosage, with an improved response rate.

L-asparaginase in acute lymphoblastic leukemia treatment: the role of human antithrombin III concentrates in regulating the prothrombotic state induced by therapy.

It is well known that L-asparaginase (L-Ase) treatment may cause thrombotic events in patients with acute lymphoblastic leukemia (ALL). The mechanism of this effect is not well understood although a reduction in plasma antithrombin III (AT III) levels is observed. In our study, a group of patients treated with L-Ase received AT III concentrates as adjuvant treatment. This adjuvant treatment reduced the levels of plasma D-dimer and thrombin-antithrombin complex, which are considered as early markers of a hypercoagulability state. These preliminary data suggest that large randomized trials will have to be conducted to improve our understanding of the role of AT III concentrates in ALL therapy.

[Multiple myeloma. Role of prognostic factors and staging in a therapeutic program]. / Il mieloma multiplo. Ruolo dei fattori prognostici e della stadiazione in un programma terapeutico.

Patients affected with multiple myeloma constitute an heterogeneous population with very different clinical patterns, varying from asymptomatic to very compromised patients with severe and uncontrolled disease. Most common clinical and biological staging systems have been in use for many years. Recently new prognostic factors have been identified; among them, serum levels of beta-2 microglobulin, C-reactive protein and interleukin-6 employed with already known parameters have been useful in the new staging system, permitting a more focalized therapy. As today is not yet possible to define the best treatment schedule, as the most common treatments are incapable to eradicate myeloma neoplastic clone even in responsive patients. Nevertheless extensive use of biologic response modifiers in the last years, as alpha interferon, have added new powerful and hopeful therapeutic tools even if the results need to be confirmed in future trials. It is important to remind the primary role of bone marrow transplantation associated with high dose polychemotherapy even if just a minority of patients is eligible for this therapeutic chance.

Lymphocyte subsets in patients with idiopathic thrombocytopenic purpura during high-dose gamma globulin therapy.

Peripheral lymphocyte subsets (OKT3+, OKT4+, OKT8+) were studied by monoclonal antibodies in 10 patients with chronic idiopathic thrombocytopenic purpura (ITP), before and after high-dose intravenous gamma globulin therapy at a daily dose of 0.4 g/kg/body weight for 5 consecutive days followed by several boosters every 10-15 days. A stable increase of platelet count was obtained in 5 patients, whereas the other 5 showed a transient improvement of platelet count but then became refractory to the treatment. Phenotypic analysis of T cell subsets showed a decrease of the OKT4+/OKT8+ ratio following therapy, with non change in the percentage of OKT3+ cells. A significant decrease of lymphocyte count and platelet associated IgG was shown in 80% of our patients. These data suggest the possible long term efficacy of repeated iv IgG inchronic ITP patients through a mechanism of specific enhancement of suppressor T cell function.

[Pulmonary mycosis as a complication of acute leukemia in the adult. Diagnostic study]. / La micosi polmonare come complicanza della leucemia acuta dell'adulto. Contributo diagnostico.

Pulmonary fungal infections complicating hematological malignancies are difficult to diagnose antemortem because clinical findings are actually considered to be not specific. From December 1984 to June 1986 we documented the clinical findings in sixteen patients, 9 with ANLL, 6 with ALL and 1 with CML + BC; all patients were diagnosed as pulmonary fungal infection and treated for this complication. Pulmonary infiltrates occurred after severe aplasia (range 5-90 days) or during bone marrow relapse. We studied pulmonary signs and symptoms (pleuritic pain, cough, hemoptysis, shortness of breath, rales, rub, bronchial murmur) both at the beginning and during the management of this infectious complication and we related them to chest x-ray findings, the duration of granulocytopenia, and fever. Our purpose was to identify clinical characteristics for these episodes and establish roentgenological criteria for prognosis. These findings should improve the possibilities for an early diagnosis and prompt treatment.

CNS metastasis in ovarian cancer with microangiopathic hemolytic anemia associated with diffuse intravascular coagulation.

We present the case of a woman affected by ovarian cancer metastatic to multiple lymph node and the CNS. She was affected by hemorrhagic diathesis with microangiopathic alterations, whereas coagulopathy developed only after some days in coincidence with disease worsening. Our patient is probably one of those in which cancer leads to microangiopathy and coagulopathy by means of a tissue factor-like activity, a common event in mucin secretory tumors. Fibrinolytic activity was also increased in our patient as in others of the same type. The main aspect of this case report is metastasis to the CNS and to other multiple sites, which is quite uncommon in such cancers. We retain that tumor procoagulant activity could have played a role in this phenomenon.