Epirubicin and etoposide combination chemotherapy to treat hepatocellular carcinoma patients: a phase II study.

Approximately half the patients affected with hepatocellular carcinoma (HCC) present with unresectable disease, so that efficacious systemic chemotherapy protocols are badly needed. We report the results of a phase-II study aimed at testing the efficacy and toxicity of a combination of epirubicin and VP-16. Thirty six patients (80 men and 6 women) received epirubicin (40 mg/m2, on day 1) and VP-16 (120 mg/m2, on days 1, 3 and 5) every 28th day. Chemotherapy was stopped in case of disease progression, while the patients who achieved an objective response or who had stable disease continued treatment for a maximum of 10 cycles. One patient (3%) achieved a complete response, while 13 patients (36%) achieved partial response, i.e. 14 objective responses in all (39%, 95% CI: 23-55%). 11 patients (31%) exhibited stable disease, while in the other 11 patients (31%) the disease progressed. Median overall survival time was 10 months and 13.5 months in the subgroup of patients responding to treatment. Significant, especially haematological, toxicity was documented, but in no case was it so severe as to require discontinuation of treatment or reduction of the dosage. In conclusion, this combination appears to be an active and tolerable therapeutic option for HCC patients who are not candidates for surgical or locoregional procedures, and in our opinion it deserves further exploration within a randomised controlled trial versus best supportive therapy.

Cancer chemotherapy-related thrombotic thrombocytopenic purpura: biological evidence of increased nitric oxide production.

The occurrence of thrombotic thrombocytopenic purpura (TTP) in cancer patients receiving chemotherapy has been well established; although this entity is rare, its clinical importance seems to be growing. We describe 3 cases of TTP developing in cancer patients receiving different chemotherapeutic regimens. Using a sensitive high-performance liquid chromatographic method, we evaluated the stable nitric oxide end products, nitrite and nitrate, in the plasma of these patients. Nitric oxide is one of the key components involved in maintaining the normal nonthrombogenicity of the vascular endothelium. In our 3 patients, we found increased nitrate titers that were substantially higher than those observed in patients with de novo TTP. The observed increased release of nitrate could be interpreted as the consequence of massive disruption of endothelial integrity, with consequent passive nitric oxide release in vivo, or an adaptive mechanism of the endothelium to compensate for diffuse microvascular occlusion. The 2 mechanisms may both be involved, but the normal titers of nitric oxide end products in de novo TTP suggest that the former mechanism is more important, at least in cancer chemotherapy-related TTP.

Cisplatin, mitomycin-C, 5-fluorouracil and leucovorin combination chemotherapy (l-FCM) in locally advanced unresectable or metastatic gastric carcinoma: a phase-II study.

Despite relevant progress, the impact of chemotherapy on advanced gastric cancer patients' survival is still unsatisfactory. Thus, the key objective of our efforts should be palliation of the symptoms and the maintenance of an adequate quality of life. In this phase-II study, we evaluated toxicity and efficacy of the combination of cisplatin, fluorofolates and mitomycin C. Thirty-one advanced gastric cancer patients received cisplatin (15 mg/m2) and 5-fluorouracil (350 mg/m2), both for 5 consecutive days every 4 weeks; 5-fluorouracil infusion was preceded by a rapid i.v. injection of 100 mg/m2 leucovorin, while mitomycin-C (10 mg/m2) was administered on day 1 of odd cycles. Cycles were repeated every 4 weeks until disease progression. We recorded 16 objective responses (51.6%, 95% confidence interval: 42.63-60.57); furthermore, such a response rate was coupled with a moderate degree of toxicity and an extremely good tolerance. In particular, alopecia, a frequent and distressing side-effect in patients, especially women, in our series occurred only in two patients. This treatment appears to be an active and tolerable therapeutic option for patients with advanced gastric carcinoma.

Anti-phospholipid antibodies and thrombotic thrombocytopenic purpura.

Anti-phospholipid antibodies were measured in 9 patients with active thrombotic thrombocytopenic purpura (TTP). 8 patients had primary TTP and one had TTP secondary to systemic lupus erythematosus (SLE). No patient showed circulating 'lupus' anticoagulants or false positive tests for syphilis. A solid phase immuno-assay for anti-cardiolipin antibodies (ACA) gave negative results in the patient with secondary TTP as well as in all but one case with primary TTP. ACA of IgG class were not found in any TTP patient while they were present in 10 out of 18 patients suffering from thrombocytopenia with active SLE. These data indicate that anti-phospholipid antibodies do not have a role in the development of thrombosis and thrombocytopenia with TTP.

Study of release of eosinophil cationic proteins (ECP and EPX) in the hypereosinophilic syndrome (HES) and other hypereosinophilic conditions.

BACKGROUND: Up to date, the etiology and the pathogenesis of HES are still unknown and particularly it is unclear why eosinophils in HES are more aggressive towards tissues than in other eosinophilic conditions. METHODS: We assessed the cationic proteins ECP and EPX serum concentrations, their in vitro release from polymorphonuclear cell culture, and the monoclonal antibodies EG1 and EG2 in 3 patients with HES, 6 patients with other hypereosinophilic conditions and 20 healthy control subjects. RESULTS: Serum ECP and EPX concentrations were higher in eosinophilic patients than in healthy subjects. Hypereosinophilic patients had more EG2+ cells than healthy subjects, but EG2+ rate failed to differentiate HES from other hypereosinophilic conditions (p = 0.074). Moreover, the release in vitro of ECP and EPX was significantly higher in HES patients (p < 0.05). CONCLUSIONS: Our preliminary results seem to suggest the importance of functional data, such as ECP and EPX release, in differentiating HES from other hypereosinophilic diseases. Particularly, ECP and EPX release in vitro is higher in cell cultures from HES patients than from patients with other hypereosinophilic conditions.

Folinic acid does improve 5-fluorouracil activity in vivo. Results of a phase III study comparing 5-fluorouracil to 5-fluorouracil and folinic acid in advanced colon cancer patients.

We report the results of a phase III trial in which we compared 5-fluorouracil (5-FU) to 5-FU and folinic acid (FA) in 150 previously untreated metastatic colon cancer patients. Patients were randomized in the ratio of 1:2 to receive 5-FU (370 mg/m2, i.v., for 5 days) in arm A or equidose 5-FU plus FA (200 mg/m2, i.v., for 5 days) for arm B, each cycle being repeated every 4 weeks. Five of 49 evaluable arm A patients (10.2%) and 31 of 97 arm B (31.9%) achieved a complete or partial response (p < or = 0.01). Median survival time of arm A patients was 6 months (mean: 6.18), while it was 8 months (mean: 9.01) for arm B cases (p < or = 0.05). In conclusion, our data indicate that FA can enhance 5-FU activity and that this combination is an effective palliative treatment for metastatic colon cancer patients.

Thrombotic thrombocytopenic purpura resistant to plasma-exchange: salvage treatment with high-dose IgG or vincristine. Italian Cooperative Group for TTP.

Even though plasma-exchange (PE), either alone or combined with cortisone or platelet anti-aggregating substances is the treatment of choice for TTP, 10-15% of patients is resistant to treatment. Since immunoglobulin (IgG) infusion was reported to cure the clinical symptoms of PE-resistant TTP, and vincristine (VCR) has been recently successful in treating TTP, we reviewed the results obtained with both drugs in 20 PE-resistant patients. Of 12 patients receiving IgG and 8 receiving VCR, 3 (25%) and 4 (50%), respectively, achieved complete remission. Even though no conclusions can be drawn from such results, if complete remission can be achieved in a however small number of PE-resistant patients, the use of these drugs is suggested as a salvage treatment for TTP.

[Importance of bone biopsies in the diagnosis of cancer metastases]. / Importanza della biopsia ossea nella diagnosi delle metastasi carcinomatose.

A 39-year-old woman was hospitalized at our Institute following a diagnosis of "suspected systemic lymphopathy". The patient exhibited mediastinal tumefaction, moderate anemia, thrombocytopenia, leucoerythroblastic streak in peripheral blood, diffuse bone pain, slight fever, cough and dyspnea. The clinical picture, radiological findings and hematochemical data apparently suggested a diagnosis of epithelial neoplasia of bronchial origin, or a primary hemopathy. Only by means of an osteomedullary biopsy was it possible to establish that the disease was actually a bronchogenic carcinoma invading the marrow. In conclusion, both for a correct staging of patients with carcinoma, and for histological diagnosis, when the primary side can not be identified or attacked, the osteomedullary biopsy, if feasible carried out at different sites, proves to be the test of choice.

[The diagnostic difficulties in a case of Behçet's disease]. / Difficoltà diagnostiche in un caso di malattia di Behçet.

Behçet's disease is a chronic, heterogeneous, multisystem disorder caused by a vasculitis involving arterial and venous vessels of all sized. In 1990, a new set of diagnostic criteria has been proposed as a guide to diagnosis of Behçet's disease, requiring the presence of oral ulcerations plus two of the following symptoms or signs: genital ulcerations, characteristics eye lesions, typical skin lesions, and a positive pathergy test. Nevertheless, both clinic and pathologic diagnosis of Behçet's disease remains sometimes very difficult. Diagnostic procedures and therapeutic implications in a case of Behçet's disease are reported and discussed.

Thrombotic thrombocytopenic purpura treatment in year 2000.

BACKGROUND AND OBJECTIVE: For several decades clinicians worldwide considered TTP a severe and frustrating therapeutic problem. Fortunately, however, the prognosis of TTP patients has greatly benefited from the use of plasma manipulation techniques, particularly plasma-exchange (PE), so that the overall rate of complete responses currently ranges between 70-85% and may even exceed these figures. Despite this dramatic improvement, a number of questions remain concerning the best treatment for TTP patients. Analyzing acquired data and discussing future perspectives, this review will address the following key issues: is PE really the treatment of choice for TTP and what is the role of PE with cryosupernatant? what is the role of all the drugs which are commonly combined with PE, antiplatelet drugs and steroids in particular? what, if any, is the role of cytotoxic agents, especially vincristine? is there a treatment for PE-resistant patients? does secondary TTP need different treatments? DESIGN AND METHODS: The authors have been involved in the study and treatment of TTP for years; furthermore, they extensively searched the PubMed database of the National Library of Congress through the Internet. INTERPRETATION AND CONCLUSIONS: PE remains the treatment of choice for TTP. A large randomized trial now in progress will assess whether exchange with cryosupernatant plasma can improve treatment efficacy. The administration of antiplatelet drugs in combination with PE was fiercely debated over the past years but seems indicated both in acute TTP and as a prophylactic treatment to prevent relapses. It appears that steroids cannot be avoided, especially in light of the latest findings on TTP pathogenesis, but only specific trials will assess the optimal cortisone type and dose. Presently, different treatments can be suggested only to patients failing to respond to PE, while no specific therapy can be indicated for secondary TTP, which usually has a very poor prognosis. Finally, we would like to stress that only international co-operative (multicenter) trials on large series of patients will be able to shed light on a still obscure, if fascinating, disease. Our hope and wish is that the new century will see TTP among the diseases defeated by man's clever mind and heart.