P. Rossi Ferrini

Platelet-derived growth factor(s) mitogenic activity in patients with myeloproliferative disease

Summary. Platelet‐derived growth factor has been invoked in the pathogenesis of medullary fibrosis during myeloproliferative disorders. In this study we compared the mitogenic activity of heat‐stable platelet‐derived growth factor(s) from 13 patients suffering from myeloproliferative disorders with that of a normal group. The test was carried out on G0 growth arrested Balb/c 3T3 fibroblasts incubated with various concentrations of platelet extracts, determining the entrance into the S phase by means of [14C]thymidine uptake. The incorporation curves of [14C]thymidine by the fibroblast culture, under the effect of pathological extracts, were consistently lower than the control curve, indicating a lower level of PDGF(s) in platelets from patients. The greatest depression of this activity was found to be associated with highest degree of medullary fibrosis (agnogenic myeloid metaplasia patient group), in agreement with the hypothesis that fibroblast activation within bone marrow during myeloproliferative disorders might be correlated with a PDGF(s) release in the bone marrow environment.

Combined surgery and chemotherapy for the treatment of primary gastrointestinal intermediate- or high-grade non-Hodgkin's lymphomas.

Fifty-five consecutive patients with primary gastrointestinal intermediate or high grade non-Hodgkins lymphoma were analysed to assess the efficacy of chemotherapy following surgical tumour resection. Histological subtypes were high grade (n = 18), intermediate grade (n = 36) and unclassified (n = 1). The majority of patients had gastric presentation (71%) and localised disease (84%). Surgery consisted of radical resection in 25 patients (45%) and partial or palliative excision in the remaining cases (22 and 8 respectively). Four subjects died within 3 months of surgery, two patients refused adjuvant chemotherapy and 49 completed the postoperative chemotherapeutic programme. Chemotherapy included either Fi2/74 (adriamycin + vincristine + bleomycin + cyclophosphamide + prednisone) or Fi3/74 (adriamycin + VM26 + bleomycin + cyclophosphamide + prednisone). Excluding the group who underwent radical tumour resection, postoperative chemotherapy induced complete remission in 81% of the remaining 30 patients. The 10-year cause-specific survival for the 53 treated patients was 76% (median follow-up 58 months) with a stable curve plateau after 80 months. Proportional-hazard multivariate statistics showed that survival was influenced by type of surgical resection (P less than 0.05) and stage (P less than 0.05), whereas age, sex and histological subtype were not influential. Our data indicate that chemotherapy following surgical resection of gastrointestinal lesion induces long-term remission in primary gastrointestinal lymphomas.

Attenuated-dose idarubicin in acute myeloid leukaemia of the elderly: pharmacokinetic study and clinical results.

AML in the elderly is characterized by intrinsic biological features implying an enhanced chemoresistance. Intensive chemotherapy should be the treatment of choice, but the standard doses could induce unacceptable rates of aplastic deaths. We evaluated the efficacy of an induction protocol with attenuated‐dose idarubicin (IDA) 8 mg/m2 for 3 d plus cytarabine and etoposide in 26 AML patients aged >60. 18 patients (69%) achieved CR, five (19%) were non‐responders and three (12%) died during induction. To compare the pharmacokinetics of IDA between elderly and young patients, we assayed daily the serum level of the drug and of its metabolite (idarubicinol, IDAol) in a group of eight elderly patients who received a dose of 8 mg/m2 (group A) and in a group of nine younger AML patients treated with 12 mg/m2 (group B). The apparent terminal half‐life of IDAol was significantly longer in the elderly than in the younger patients (mean half‐life 59–7h versus 41–4h, P< 0–05). The values of the area under the serum concentration curve of IDAol indicated that the two patient groups received a very similar exposure to the drug despite the different doses.

Multi-variate analysis of factors governing the pharmacokinetics of exogenous factor VIII in haemophiliacs

SummaryThe pharmacokinetics of Factor VIII was evaluated by mathematical modeling in a large-scale study in 62 haemophilia-A subjects, in whom 137 plasma Factor VIII-time curves were measured during single dose (n=87) and repeated-dose (n=47) treatments for prophylaxis or minor bleeding episodes. The pharmacokinetic parameters [mean (SD)] estimated from single-dose curves were: clearance 3.85 ml·h−1·kg−1, volume of distribution 58.2 ml·kg−1, mean residence time 15.9 h. Parameters calculated from repeated-dose curves were: clearance 3.93 ml·h−1·kg−1, volume of distribution 61.8 ml·kg−1, and half-life 12.2 h. In patients with mild haemophilia, pharmaco-statistical analysis revealed that the endogenous synthesis of Factor VIII was constant and was not influenced by the administration of exogenous Factor VIII. The coefficient of variation for intra-individual variability of Factor VIII kinetics (estimated according to the Standard Two-Stage method) was 20.7% in single-dose curves and 23.2% in repeated-dose curves.

Searching for the Magic Bullet Against Cancer: The Butyrate Saga

n -Butyric acid and its “polymorphic” derivatives have been largely but somehow “blindly” studied in oncology and in red cell diseases with consistent results through decades indicating a strong maturative effect determined by enhancement of gene transcription. Although these effects have been observed mainly in vitro, the relative absence of systemic toxicity of butyrates render these compounds appealing as specific therapeutic agents. More interestingly, their specific mechanism of action, i.e. inhibition of histone deacetylase and de-repression of transcription represents at present an unique tool for diseases such as acute leukemias which are characterised by a disregulation of co-repressors and co-activators of gene transcription. More insight into specificity and modalities of action of different butyrate derivatives may be a guarantee for excellent tailored antileukemic therapy in the future.

Chemoprophylaxis of Bacterial Infections in Granulocytopenic Patients with Ciprofloxacin vs Ciprofloxacin plus Amoxicillin

Ciprofloxacin was compared to ciprofloxacin plus amoxicillin as antibacterial prophylaxis in 53 evaluable patients with neutropenic episodes, because an oral penicillin may help to decrease the incidence of gram-positive infections. The two groups were randomized and evaluated in a number of febrile episodes, in days at fever/at risk, in mean interval of first febrile episode, in duration of antibiotic therapy and in causative organisms in febrile episodes. In conclusion, no significant difference was observed between the two groups in prevention of gram-positive bacteremias.

A new protocol (MiCEP) for the treatment of intermediate or high-grade non-hodgkin's lymphoma in the elderly

Age has proved to be an important prognostic factor in patients with advanced non-Hodgkin lymphoma (NHL) and these patients require intensive and extensive therapy. Dose-reduction and therapy attenuation have reduced treatment-related toxicity, but have also decreased therapeutic efficacy. Between January 1990 and December 1992, 41 previously untreated patients, 65 years with stage 2-4 intermediate- or high-grade NHL were treated with a new therapeutic scheme which included Mitoxantrone, Etoposide, Cyclophosphamide and Prednisone (MiCEP). Twenty-eight patients achieved a complete remission, ten patients partial remission (overall response rate of 93%) and two cases were resistant. The overall survival was 66% with a median follow-up of 24 months from diagnosis: three patients relapsed after a median period of 7 months. The relapse-free survival was 92% after a median follow-up of 18 months. Blood and other organ toxicity was acceptable and 12% of patients experienced a grade 4 (WHO) neutropenia. In conclusion, MiCEP was effective in inducing a good remission rate with moderate toxic effects in elderly patients with intermediate- or high-grade NHL and appears to be a useful combination to use in this group of patients.

Low-Dose Cytosine Arabinoside in Patients with Acute Myeloid Leukemia Not Eligible for Standard Chemotherapy

The results of treatment with low dose cytosine arabinoside (LDARA-C) in 131 AML patients ineligible for standard regimens were analyzed retrospectively. Eighty-seven were previously untreated, 25 were refractory to conventional chemotherapy and 19 were relapsed patients. The median age was 66 years (15-84). An antecedent hematological disorder (AHD) was documented in half of the patients. Overall, 22 (17%) achieved complete remission, 14 (11%) partial remission, 77 (59%) had resistant leukemia and 18 died during induction. Median disease free survival was 57 weeks and median survival, for the 87 previously untreated patients, was 22.5 weeks. The prognostic value of initial parameters was analyzed for response. Bone marrow cellularity was the only significant factor. We observed 33% vs 81% (p < 0.01) of responses in patients with normo-hypercellular and hypocellular marrow, respectively. Accordingly, there was a trend to more responses in patients with leukocyte counts of less than 10 x 10(9)/L. M4-M5 FAB subtypes were frequently resistant to LDARA-C, resulting in a lower response rate compared to M0-M2 (18% vs 32%). Other parameters, including age, sex, hemoglobin, platelet count, AHD and fever at diagnosis, had no prognostic value. Our findings suggest that LDARA-C may be an effective treatment for some patients who are not eligible for first line conventional chemotherapy. However, this schedule is not advised in patients with monocytic leukemia or those with an hypercellular marrow.

Suppression of autoantibodies to factor VIII and correction of factor VIII deficiency with a combined steroid-cyclophosphamide-porcine factor VIII treatment in a patient with rheumatoid arthritis

Abstract. The presence of autoantibodies against factor VIII is an unusual but serious complication in rheumatoid arthritis. We describe the case of a patient who developed this kind of complication, with spontaneous bleeding and marked changes in the haematological parameters, that was unsuccessfully treated with a high dose of intravenous gammaglobulin. Subsequently, combined therapy with porcine factor VIII concentrate, cyclophosphamide and steroids led to the disappearance of the anti‐factor VIII autoantibodies.

The influence of ofloxacin versus trimethoprim-sulfamethoxazole on the aerobic flora in granulocytopenic subjects.

Ofloxacin (300 mg twice a day) and trimethoprim-sulfamethoxazole (TMP-SMZ) (160 mg trimethoprim and 800 mg sulfamethoxazole twice a day) were given prophylactically to 19 adult patients with acute leukemia undergoing induction chemotherapy. The influence of the two regimens on the bacterial aerobic flora was evaluated. Both of the prophylactic regimens conditioned the aerobic microflora of the patients. Both groups acquired new microorganisms, prevalently gram-positive cocci, but also gram-negative bacteria with the TMP-SMZ regimen. Both treatment groups acquired yeasts.