Multiple myeloma: comparison of two dose-intensive melphalan regimens (100 vs 200 mg/m(2)).

Several trials have shown the superior impact of high-dose melphalan (usually 200 mg/m(2), MEL200) vs standard therapy in myeloma patients. Intermediate-dose melphalan (100 mg/m(2), MEL100) is also superior to the standard dose, but has not been clinically compared with MEL200. A total of 90 patients at diagnosis were treated with two MEL100 courses. Their clinical outcome was compared with that of a control group of 90 pair mates matched for serum beta2-microglobulin levels and Durie and Salmon clinical stage. These patients were treated at diagnosis with two MEL200 courses. Patient characteristics were similar in both groups except that the median age of the MEL100 group was significantly higher (P<0.0001). Complete remission was 35% after MEL100 and 48% after MEL200 (P=0.08). Median event-free survival (EFS) was 32 months in the MEL100 group and 42 months in the MEL200 group (P<0.005), but overall survival (OS) was not different. Transplant-related mortality was not significantly different. Haematological and extra-haematological toxicity was significantly reduced after MEL100. Despite the significant age difference, tandem MEL100 was less toxic than tandem MEL200, and MEL100 was inferior to MEL200 in terms of EFS but not in terms of OS. The intensified nonmyeloablative MEL100 regimen is an effective first-line treatment.

Sebaceous nevus syndrome: report of two cases.

Sebaceous nevus (SN) syndrome is a neurocutaneous disorder characterized by a distinctive skin lesion in association with epilepsy and mental retardation. In one group of patients, brain lesions may be consequent to vascular abnormalities ("vascular variant"); another group of SN patients presents ipsilateral hemimegalencephaly, gyral anomalies, and facial hemihypertrophy ("neurologic variant" or "SN with hemimegalencephaly"). In the latter group, facial hemihypertrophy does not appear to be a constant feature and was not present in our 2 SN patients with hemimegalencephaly. Considering that about half of the SN patients with hemimegalencephaly described so far do not have facial asymmetry, we suggest the existence of a separate subgroup of SN patients with hemimegalencephaly and without facial hemihypertrophy. In these patients, the only clinical diagnostic clue is a nevus that is barely visible until puberty.

Autosomal recessive mode of inheritance of a Coffin-Siris like syndrome.

Autosomal recessive mode of inheritance of a Coffin-Siris like syndrome: Coffin-Siris syndrome is a rare mental retardation/multiple congenital anomalies syndrome; so far its pattern of inheritance is under debate. We report a child affected by this syndrome, the pedigree of which is consistent with autosomal recessive inheritance.

Reversal activity of cyclosporin A and its metabolites M1, M17 and M21 in multidrug-resistant cells.

Cyclosporin A (CSA) is an effective inhibitor of the P-glycoprotein (P-gp) activity and has been shown to modulate multidrug resistance (MDR) in in vitro experimental models. During degradation of CSA, the metabolites arising from the parental compound reach high levels in the serum of patients, and it is not clear whether these metabolites maintain the reversal activity of the parental compound, like the metabolites of verapamil. In an in vitro experimental model, we compared the reversal activity of CSA and 3 CSA metabolites (M1, M17, and M21) in the range of concentrations obtained in whole blood during a clinical trial with CSA used as a revertant agent. As experimental model we used LoVo-resistant cells. Our in vitro studies indicated that the metabolic hydroxylation and demethylation of CSA lead to molecules that greatly differ from the parent drug in their reversal activity. In the range of concentration detected in the whole blood of the patients (1-3 microM), CSA had a significant reversal activity. It decreased the IC50 of antineoplastic drugs involved in MDR (vincristine, taxol, doxorubicin and etoposide) but not the IC50 of platinum or methotrexate. CSA increased intracellular doxorubicin content and inhibited P-gp 3[H]azidopine photolabeling. Conversely, CSA metabolite concentrations superimposable to those observed in the patients (0.5-2.2 microM) had no sensitizing effects on the cytotoxicity of MDR-related anti-neoplastic drugs, nor did they affect 3[H]azidopine photolabeling or doxorubicin uptake. This study demonstrates that, during degradation of CSA, metabolite derivatives arise that have a very different reversal activity from that of the parental compound.

Effect of cyclosporin A on protein binding of teniposide in cancer patients.

We investigated the effect of cyclosporin A (CSA) on protein binding of teniposide (VM26) in 16 patients with metastatic renal cell carcinoma receiving i.v. VM26 alone over 24 h (total dose, 200 mg/m2) and in association with CSA (5 mg/kg/2 h followed by 30 mg/kg/48 h i.v.). CSA was used in an attempt to overcome multidrug resistance. The unbound fraction (%fu) of VM26 was significantly (p=0.04) higher in the cycles with CSA (median 0.8; range 0.4-1.9) than in the cycles with VM26 alone (median 0.5; range 0.1-1.6). Both total VM26 area under curve concentration (AUC0-infinity) and free VM26 AUC0-infinity increased after treatment with CSA, but the median increase in free AUC0-infinity was higher (2.7-fold) than total AUC0-infinity (1.5-fold) (p = 0.04). Bilirubin was significantly (p<0.01) increased after CSA but no association was observed between bilirubin level and %fu of VM26. Albumin was in the normal range after both VM26 alone and VM26 plus CSA. The nadir of absolute neutrophil count (ANC) after VM26 plus CSA (median 700/microl, range <100-2860/microl) was lower than after VM26 alone (median 1900/microl, range 200-6000/microl) (p = 0.0007). The median percentage of ANC compared to the pretreatment value (ANC nadir/ANC pretreatment x 100) was 39.0% (range 3.1-98.8%) in the cycles with VM26 alone and 16.9% (range 1.4-97.9%) (p = 0.007) after VM26 plus CSA. Percentage change of neutrophils significantly correlated with free AUC0-infinity VM26 in the cycles with VM26 alone and VM26 plus CSA (p = 0.04, r = -0.53 and p = 0.04, r = -0.52, respectively). Only a trend which failed to reach significance was observed between total AUC0-infinity VM26 and percentage change of neutrophils in the cycles with VM26 alone and in association with CSA (p = NS, r = -0.33 and p = 0.055, r = -0.49, respectively). In conclusion, patients treated with CSA had higher systemic exposure to unbound VM26.

Thalidomide neuropathy: clinical, electrophysiological and neuroradiological features.

OBJECTIVE: Thalidomide is a promising therapy for multiple myeloma. Sensory neuropathy is a side effect of thalidomide and resulted to be partially reversible in 50% of cases, suggesting a sensory ganglionopathy. Spinal cord magnetic resonance imaging (MRI) was found to be useful in the diagnosis of sensory ganglionopathies and we use it to determine if thalidomide neuropathy has features of a ganglionopathy. MATERIAL AND METHODS: Six patients with multiple myeloma developed thalidomide-induced polyneuropathy. Nerve conduction studies, somatosensory-evoked potentials (SEPs) and cervical and dorsal spinal cord MRI were obtained in all. RESULTS: All patients had a sensory neuropathy, with clinical or electrophysiological abnormalities involving all four limbs. Spinal cord MRI showed high signal intensity in the posterior columns in only one patient, with abnormal central conduction time at SEPs. CONCLUSION: Our results suggest that thalidomide can induce either an axonal length-dependent neuropathy or, less frequently, a ganglionopathy.

Interactions of antineoplastic chemotherapy with zidovudine pharmacokinetics in patients with HIV-related neoplasms.

To evaluate the perturbations in zidovudine (ZDV) pharmacokinetics as a consequence of antineoplastic chemotherapeutic treatments, we performed a prospective crossover study in 13 HIV-infected patients with cancer. The subjects received 2-day regimens of ZDV (250 mg x 2/day). On the first day ZDV was administered alone, whereas on the second day it was combined with antitumor chemotherapies specific for the histological type (ZDV + chemotherapy). Blood sample and urine collections were performed over a 12-hour period following oral administration of the antiretroviral agent. ZDV was measured with high-performance liquid chromatography. Pharmacokinetic parameters of ZDV were calculated by a noncompartmental model. The mean ZDV area under curve (AUC) was not significantly different in the patients treated with ZDV alone and ZDV + chemotherapy. Comparison of plasma elimination half-life (t((1/2))), apparent systemic clearance (CL/F), and apparent volume of distribution (Vd/F) of ZDV did not show any significant difference before and after chemotherapy. Conversely, some significant differences were observed for both mean peak concentration (C(max)) of ZDV and the corresponding time (T(max)). There was a 57% reduction in C(max) (p<0.05) and a 66% increase in T(max) (p<0.05) after chemotherapy compared with treatment with ZDV alone. No differences were observed in the urinary excretion of ZDV and ZDV glucuronide and urinary metabolic ratio, as a consequence of antineoplastic treatment. In conclusion, this study demonstrates that some minor perturbations in ZDV pharmacokinetics (i.e. C(max) and T(max)) derived from antineoplastic chemotherapy. Based on the observation that antineoplastic chemotherapy had no significant effect on plasma ZDV concentration expressed as AUC, the observed pharmacokinetic interaction would not warrant by itself a change in the ZDV dosage during chemotherapy.

Low-dose thalidomide plus dexamethasone is an effective salvage therapy for advanced myeloma.

BACKGROUND AND OBJECTIVES: The immunomodulatory drug thalidomide can inhibit angiogenesis and induce apoptosis in experimental models. It can also induce marked and durable response in advanced myeloma patients. Thalidomide has been used at doses ranging from 200 to 800 mg with significant toxicity. No data are available on the impact of low-dose thalidomide plus dexamethasone as salvage therapy for relapsed patients. DESIGN AND METHODS: To address this issue, myeloma patients were treated with 100 mg/day thalidomide continuously and dexamethasone 40 mg, days 1-4, every month. Between June 1999 and August 2000, 77 patients (median age 65 years) who had relapsed or were refractory to chemotherapy were treated with thalidomide plus dexamethasone. RESULTS: After a minimum of 3 months of treatment, 14 patients (18%) showed a myeloma protein reduction of 75%-100%, 18 patients (23%) showed a response of 50-75%, 19 patients (25%) a response of 25-50% and 26 patients (34%) a response of < 25% or disease progression. After a median follow-up of 8 months, median progression-free survival was 12 months. Thalidomide was well tolerated. Constipation (12%) and sedation (6%) were mild. Tingling or numbness were present in 17% of patients, discontinuation of treatment was required in 10% of patients. INTERPRETATION AND CONCLUSIONS: The association of low-dose thalidomide plus dexamethasone is active against advanced myeloma. A significant proportion of patients benefit from this treatment as a salvage therapy postponing the delivery of chemotherapy.