Multiple myeloma diagnosed during early pregnancy: a case report

Only five pregnant women with multiple myeloma have been reported in literature. We present the case of one woman with multiple myeloma diagnosed in early pregnancy, who decided to postpone therapy until after delivery. A cesarean section was performed at the 34th week due to the progression of the disease and a normal healthy baby was delivered.     

Prenatal ultrasound diagnosis of Toriello-Carey syndrome

Toriello-Carey syndrome is a rare malformative complex, described for the first time in 1988, characterized by agenesis of the corpus callosum, facial anomalies, cardiac defects and hypotonia. Relatively few neonatal cases have been reported. We describe here the first prenatal ultrasound diagnosis of the syndrome based on the detection of agenesis of the corpus callosum and spongious cardiomyopathy in a 22-week-old fetus of a couple with positive family history. The first sib of the couple was diagnosed with Toriello-Carey syndrome at 1 year of age, and had, in addition to the typical facial anomalies not detectable by ultrasound, agenesis of the corpus callosum and the same heart lesion (spongious cardiomyopathy). This report demonstrates that prenatal diagnosis of Toriello-Carey syndrome is feasible in the second trimester of pregnancy.     

Bone involvement in eugonadal male patients with adrenal incidentaloma and subclinical hypercortisolism

Adrenal incidentalomas (AI) are not associated, by definition, with clinically evident syndromes; however, some AI patients may show biochemical indexes of subclinical hypercortisolism (SH). Previous data on female AI patients indicated that SH may lead to bone loss, at least at spine. No data are available on bone involvement in samples of only AI male patients. We measured bone metabolism and bone mineral density at spine and femur by dual-energy x-ray absorptiometry in 38 consecutive eugonadal male AI patients and 38 healthy matched control subjects. Patients were subdivided according to the presence or absence of SH (group SH+ and group SH-, respectively). Mean Z-score levels of spinal bone mineral density measured by dual-energy x-ray absorptiometry were lower (P < 0.05) in group SH+ (-0.42 +/- 1.62) in comparison with group SH- (0.6 +/- 1.13) and controls (0.47 +/- 1.06). Thus, in order for the most appropriate management to be individually tailored, bone mass evaluation is strongly indicated in AI male patients with SH, irrespective of their gonadal status.     

Optimal requirements for high affinity and use-dependent block of skeletal muscle sodium channel by N-benzyl analogs of tocainide-like compounds

Newly synthesized tocainide analogs were tested for their state-dependent affinity and use-dependent behavior on sodium currents (INa) of adult skeletal muscle fibers by means of the Vaseline-gap voltage clamp method. The drugs had the pharmacophore amino group constrained in position alpha [N-(2,6-dimethylphenyl)pyrrolidine-2-carboxamide (To5)] or beta [N-(2,6-dimethylphenyl)pyrrolidine-3-carboxamide (To9)] in a proline-like cycle and/or linked to a lipophilic benzyl moiety as in N-benzyl-tocainide (Benzyl-Toc), 1-benzyl-To5 (Benzyl-To5), and 1-benzyl-To9 (Benzyl-To9). INa were elicited with pulses to -20 mV from different holding potentials (-140, -100, and -70 mV) and stimulation frequencies (2 and 10 Hz). All compounds were voltage-dependent and use-dependent channel blockers. The presence of a proline-like cycle increased the potency; i.e., To5 was 3- and 10-fold more effective than Toc in blocking INa at the holding potential of -140 and -70 mV, respectively. The benzyl group on the amine further enhanced drug effectiveness with the following scale: Benzyl-To9 >/= Benzyl-Toc > Benzyl-To5. At a holding potential of -100 mV and 10-Hz stimulation, Benzyl-To9 blocked INa with a half-maximal concentration of 0.5 microM, being 60 and 400 times more potent than To9 and Toc, respectively. The similar effectiveness of Benzyl-Toc and Benzyl-To9 was paralleled by a similar spatial arrangement by equilibrium geometry modeling. In addition, the latter had a higher pKa value that probably contributed to a slow kinetic during its high use-dependent behavior. Benzyl-To5 had its lowest energy level at a more folded conformation that justifies the less favorable profile among the N-benzylated analogs. The new compounds are the most potent tocainide-like sodium channel blockers so far described and have high therapeutic potentials.     

Different ability of clenbuterol and salbutamol to block sodium channels predicts their therapeutic use in muscle excitability disorders

Activation of muscle beta(2)-adrenergic receptors successfully counteracted sarcolemma inexcitability in patients suffering from hyperkalemic periodic paralysis (HPP), a hereditary disease caused by mutations in the gene encoding the skeletal muscle sodium channel. Looking for potential modulation of these channels by beta(2)-adrenergic pathway using patch-clamp technique, we found that clenbuterol blocked sodium currents (I(Na)) in rat skeletal muscle fibers and in tsA201 cells transfected with the human channel isoform, whereas salbutamol did not. The effects of clenbuterol were independent of beta-adrenoceptor stimulation. Instead, clenbuterol structure and physicochemical characteristics as well as I(Na) blocking properties resembled those of local anesthetics, suggesting direct binding to the channels. Similar experiments with the chemically similar beta-antagonists propranolol and nadolol, suggested the presence of two hydroxyl groups on the aromatic moiety of the drugs as a molecular requisite for impeding sodium channel block. Importantly, clenbuterol use-dependently inhibited action potential firing in rat skeletal muscle fibers, owing to beta-adrenoceptor-independent I(Na) block. From a clinical point of view, our study defines the rationale for the safe use of salbutamol in HPP patients, whereas clenbuterol may be more indicated in patients suffering from myotonic syndromes, a condition characterized by sarcolemmal overexcitability, because use-dependent I(Na) block can inhibit abnormal runs of action potentials.     

Reversal of multidrug resistance in mouse lymphoma cells by phenothiazines

Various compounds were tested with regard to their reversal of multidrug resistance (MDR) in mouse tumor cells transfected with the human MDR1 gene. Phenothiazines containing aromatic moieties were bound through stacking interaction involving the polarization of the aromatic aminoacid substituents at the target site of p-glycoprotein (Pgp) 170, as a consequence of their large dipoles (as in the binding of phenothiazine to calmodulin-like structures). Acting as a calcium channel blocker, verapamil may induce conformational changes in the calcium channel-like structures of the transmembrane regions of Pgp. Most probably the tyrosine moieties of Pgp are involved in the action of verapamil and phenothiazines. Tomato lectin specifically binds to the polylactosamine moiety of Pgp170 at the first loop of Pgp. Other targets in the membrane may exist in close proximity to Pgp170, such as conA-reactive glycoproteins with terminal mannosyl residues. WGA-reactive N-acetyl glucosamine residues can also be modified resulting in conformational changes in trans-membrane regions of the ABC transporter. Our results demonstrate that MDR can be reversed by interaction of various compounds with Pgp or by modification of the membrane structure around the Pgp.     

HER-2/neu amplification by fluorescence in situ hybridization in cytologic samples from distant metastatic sites of breast carcinoma

BACKGROUND: Amplification of the HER-2/neu oncogene has been proposed as a target for antibody-based therapies and as a predictor of chemoresponsiveness in advanced breast carcinoma. Few studies have concentrated on HER-2/neu gene evaluation by fluorescence in situ hybridization (FISH) on distant metastatic sites and none have been performed on cytologic samples. The current study evaluated HER-2/neu amplification by FISH on cytologic samples obtained from distant metastatic lesions of breast carcinoma to update HER-2/neu characterization through a safe and easier procedure than biopsy. METHODS: Twenty-two cytologic samples from distant metastases (12 hepatic samples, 4 skin samples, 3 pleural samples, and 3 peritoneal samples) were submitted to HER-2/neu evaluation by FISH. Seventeen corresponding primary breast tumors also were evaluated by FISH on paraffin histologic sections or on destained archival cytologic smears. RESULTS: Seven of the 22 metastases (32%) were amplified. Amplification was observed in 4 of the 12 liver metastases, in 1of the 3 ascitic fluid specimens, and in 2 of the 4 skin metastases. In all the three pleural fluid specimens, HER-2/neu was unamplified. Matched results from primary and metastatic lesions were obtained in 14 cases (5 were amplified and 9 were unamplified on both primary and metastatic tumors). CONCLUSIONS: The results of the current study emphasized the feasibility and advantages of two rapid and very informative techniques, such as fine-needle aspiration biopsy and FISH. Both procedures were performed to ascertain the malignant nature of a suspicious lesion and to obtain predictive markers for response. Since the advent of trastuzumab, the characterization of the molecular profile in metastatic breast disease has become increasingly important for targeted therapy selection.     

Amifostine as chemoprotectant in metastatic breast cancer patients treated with doxorubicin

Amifostine has shown to selectively protect normal tissues against cytotoxic and mutagenic effects of several anti-neoplastic drugs, such as alkylating agents, organoplatinum compounds, anthracyclines, taxanes, and ionising radiation. This cytoprotection is broad-spectrum and selective, without loss of therapeutic efficacy. In this study we have treated 31 patients affected with inoperable or metastatic breast cancer, not previously submitted to chemotherapy for advanced disease, with amifostine 910 mg/m(2) followed by doxorubicin 75 mg/m(2). The overall response rate was 52% with a median response duration of 13 months (range 6-53+) and a median overall survival of 21 months (range 3-59+). With regard to toxicity, 14 patients (45%) experienced transient g4 neutropenia which was febrile only in one case (3%). Grade 3-4 thrombocytopenia was not recorded. Nausea and vomiting occurred in 14% of cycles. Grade 3 mucositis was observed in only 1 patient, whereas 2 patients (6%) developed an asymptomatic drop of left ventricular ejection fraction (LVEF) >10% below basal value. In conclusion, this study suggests that amifostine can reduce doxorubicin related toxicity, thus improving the patients' quality of life and the efficacy/toxicity ratio of this drug.     

The dog mast cell tumour as a model to study the relationship between angiogenesis,mast cell density and tumour malignancy

Substantial experimental data suggest that tumour progression is associated with angiogenesis and that increase in microvessel density (MVD) is associated with increase in mast cells density (MCD). Dog mast cell tumour (MCT) is common in dog with an incidence much higher than that found in human and in both species several common biological and clinical characteristics have been demonstrated. To evaluate the role of angiogenesis in progression of this tumour and to correlate MVD and MCD, in this study a series of 78 MCT was investigated. Serial sections obtained from biopsy specimens were processed with toluidine blue staining, specific for MC identification, and by immunohistochemistry using a polyclonal antibody anti factor VIII-related antigen (FVIII-RA), used as an endothelial marker, and MVD and MCD were determined. Results showed that MVD was significantly higher in poorly differentiated (G3) MCTs than in intermediate (G2) and well differentiated (G1) MCTs and that MCD and MVD were significantly correlated in G3, but not in G1 and G2 subgroups. These data indicate that angiogenesis and MCD are significantly correlated in MCTs progression.