Ivo Pannacciulli

MYELODYSPLASTIC SYNDROME ASSOCIATED WITH INCREASED BONE MARROW FIBROSIS AND TRANSLOCATION (5;12)(q33:p12·3)

In primary myelodysplastic syndromes (MDS ) striking myelofibrosis with collagenization is unusual (Tricot rt nl. 1984: Pagliuca rt al, 1989; Lambertenghi-Deliliers rt nl. 199 1 : Verhoefet al, 1991). We report on a patient with primary MDS. leucoerythroblastosis. a n uncommon chromosomal abnormality and diffuse bone marrow fibrosis with areas of collagenization. In August 1989 the patient, a 52-year-old white male. had been found to have haemoglobin of 8.6 g/dl with normal leucocyte and platelet counts. The bone marrow aspirate was hypercellular with granulocytic hyperplasia, normal megakaryopoiesis and erythroid hypoplasia and dysplasia. Neither splenomegaly nor chromosomal abnormalities were observed. A diagnosis of refractory anaemia was made: the patient remained asymptomatic for 16 months. In December 1990 no pathological findings were observed except for a mildly enlarged liver: ecotomography confirmed the normal size of the spleen. A thorough search for primitive or metastatic cancer yielded no result. For peripheral blood parameters see Table I . On peripheral blood cells a clonal

The in vitro and in vivo effect of recombinant interferon α‐2a on circulating haemopoietic progenitors in polycythaemia vera

In four patients with polycythaemia vera (PV) who received interferon alpha (IFN‐α) (3 MU subcutaneously three times a week) for 5 months, peripheral blood levels of granulocyte‐macrophage colony‐forming units and erythroid burst‐forming units were assessed monthly. Circulating progenitors significantly decreased throughout the treatment period. Moreover, we observed an inhibitory activity of IFN‐α on haemopoietic progenitor cells (HPC) from patients with PV in vitro.

Regional pharmacokinetic selectivity of intrapleural cisplatin

The pharmacokinetics and toxicity of cisplatin were investigated in 3 patients affected by malignant mesothelioma who received 90 mg/m2 of the drug intrapleurally. The mean area under the pleural Pt concentration versus time curve (AUC) [12.83 (S.D. 4.06) mg.min/ml] was about 50 times greater than that detected in plasma [0.27 (0.03) mg.min/ml], indicating a clear pharmacological advantage for this route of administration. The mean plasma total Pt concentration was 1.1 micrograms/ml and the apparent total body clearance was 268 (101) ml/min. Platinum plasma pharmacokinetic data measured following intrapleural cisplatin administration (4 patients) were compared with those observed in 7 patients treated intravenously with the same dose of cisplatin (90 mg/m2) under the same modalities of hydration. Intrapleural administration of cisplatin resulted in significantly lower plasma total partial AUC (P less than 0.05) and prolonged plasma levels of filterable Pt compared with intravenous administration. No difference between the two routes of cisplatin administration in the renal clearance (S.D.) of filterable Pt [132 (64) ml/min and 122 (39) ml/min for intravenous and intrapleural cisplatin, respectively] were observed. None of the mesothelioma patients developed clinical symptoms or signs of pleural inflammation. The intrapleural treatment did not produce haemotoxicity and the emetic toxicity was lower compared with that observed in patients receiving cisplatin intravenously.

Effect of diethyldithiocarbamate on toxicity of doxorubicin, cyclophosphamide and cis-diamminedichloroplatinum (II) on mice haemopoietic progenitor cells

DBA/2NCr1BR F1 mice received a single i.v. injection of doxorubicin (4.32, 7.20 or 12.00 mg kg-1), cyclophosphamide (70, 120 or 200 mg kg-1) or cis-diamminechloroplatinum (5.4, 9.0 or 15.0 mg kg-1), alone or 2 h before an i.p. injection of 1,000 mg kg-1 of diethyldithiocarbamate (DDTC). Twenty-four hours after, survival of bone marrow colony forming units-spleen and granulocyte-macrophage colony forming cells, was determined. On the whole, administration of DDTC reduced the toxic effect of the three anticancer drugs on haemopoietic progenitors. The effect was in general more evident at the lower than at the higher doses of the antitumour drugs.

Dexamethazone-induced acute tumor lysis syndrome in a T-cell malignant lymphoma.

We report a case of steroid-induced acute tumor lysis syndrome and review the literature. A 60-year-old woman was started on steroid therapy for dyspnea due to bilateral pleural effusion and a large mass involving the anterior mediastinum. The final diagnosis was precursor T-lymphoblastic lymphoma-leukemia. Following steroid therapy, the patient developed acute renal failure and laboratory evidence of metabolic changes induced by massive cytolysis. She received vigorous hydration, diuretic and allopurinol therapy, and haemodialysis. Her diuresis, renal function and laboratory data returned to normal within 2 weeks. A review of the medical literature on T-cell lymphoma revealed only one similar case of steroid-induced acute tumor lysis syndrome, a life-threatening metabolic emergency. This risk should be kept into account in the management of patients with lymphoproliferative disorders.

Splenectomy induced complete remission in a patient with multicentric Castleman's disease and autoimmune hemolytic anemia

Abstract Castlemans disease (CD) is a rare disorder of the lymphoid tissue in which the clinical manifestations often mimic a malignant lymphoma. Despite the absence of monoclonality of the lymphoid proliferation, the multicentric variant of the disease (MCD) is characterized by severe symptoms and poor prognosis. Etiologic, pathogenetic, and therapeutic aspects of MCD are still uncertain. We report the case of a 57-year-old patient affected by MCD complicated by severe immunohemolytic anemia. Whereas the clinical and laboratory response to steroids and chemotherapeutic agents was only partial, splenectomy induced a complete remission of hemolysis and disappearance of the constitutional symptoms and of all generalized lymphadenopathies.

Effect of Bleeding on in vivo and in vitro Colony-Forming Hemopoietic Cells

The effect of bleeding on spleen colony-forming units (CFU-S) and on in vitro colony-forming cells with colony-stimulating factor (CFU-C) and erythropoietin (CFU-E) has been evaluated. The in vivo and in vitro colony-forming cells of the bone marrow show a decrease which for the CFU-E, CFU-C follows a short-lived increase. In the spleen, all progenitor cells assayed have shown a significant and sustained increase.

Preclinical in vitro evaluation of hematotoxicity of the cisplatin–procaine complex Dpr

We evaluated in vitro the inhibitory effect of cis-diaminechloro-[2-(diethylamino) ethyl 4-amino-benzoate, N4]-chlorideplatinum(II) monohydrochloride monohydrate (DPR) on colony formation by granulocyte/macrophage (CFU-GM) peripheral blood progenitor cells, representing a method to quantitate the toxicity of drugs to the hematopoietic system, and human leukemic cell lines. The results were compared with those obtained exposing cells to cisplatin and carboplatin. Our data showed that while DPR had a significantly better cytotoxic activity than cisplatin and carboplatin against HL60 and K562, and than carboplatin against Molt 4 cells, it showed 12 and 43 times less inhibitory effect on CFU-GM than cisplatin and carboplatin, respectively. These results suggest that the myelosuppressive activity of DPR could be lower than that of cisplatin and carboplatin, and, furthermore, that leukemic cells represent a preferential target for its cytotoxic activity compared to normal committed hemopoietic progenitor cells. All our results speak in favor of a better therapeutic index for DPR than for the other platinum compounds considered here.

Failure of N-acetylcysteine to protect against cis-dichlorodiammine-platinum(II)-induced hematopoietic toxicity in mice

In view of the results showing a decrease in cis-dichlorodiammineplatinum(II) (cis-DDP) nephrotoxicity after administration of thiol donors, this study was carried out to test the possibility that N-acetylcysteine (NAC) was active against myelodepressive effects of the anticancer drug. Cis-DDP (15.5 mg/kg body weight, i.v.) was administered to control mice and to mice treated simultaneously or 1 h later with NAC (800 mg/kg body weight, i.v.). At various times after treatment, up to 11 days, assessments were made of peripheral blood cell levels and bone marrow progenitor cell (CFUs and CFUc) concentrations. Cis-DDP caused a decrease in hemopoietic precursor cells in the order of that caused by other hemopoietic precursor cells in the order of that caused by other myelodepressive drugs, whereas there was only a slight decrease in peripheral blood WBC. In this experimental setting, NAC administration did not afford significant protection against platinum toxicity on bone marrow precursors or peripheral blood cells.

Pulmonary toxicity in mice after high-dose methotrexate administration with and without leucovorin rescue.

Interstitial lung lesions were induced in mice by high-dose methotrexate with high frequency. They appeared early after treatment; their onset, evolution and recovery parallelled those of lesions to the hemopoietic tissues and the intestine. The pathogenesis of methotrexate lung toxicity in mice is discussed. Leucovorin rescue was ineffective in preventing the lung lesions induced by high-dose methotrexate.