Etoposide, doxorubicin and cisplatin (EAP) treatment in advanced gastric carcinoma: a multicentre study of the Italian Trials in Medical Oncology (I.T.M.O.) Group.

Various reports have documented the efficacy of the combination of etoposide, doxorubicin and cisplatin (EAP) in the treatment of advanced gastric cancer, although other studies have not confirmed such results. This multicentre phase II study was designed to try to define the efficacy and tolerability of the original EAP regimen. From January 1990 to May 1992, 96 patients with locally advanced or metastatic gastric cancer were treated every 3 weeks with etoposide (120 mg/m2) on days 4, 5 and 6, doxorubicin (20 mg/m2) on days 1 and 7, and cisplatin (40 mg/m2) on days 2 and 8. All of the patients had measurable lesions, and were to receive a maximum of six cycles. A total of 416 courses was given (median four/patient), 27% with a delay of > or = 2 weeks. Objective responses were achieved in 34 of the 91 evaluable patients (37%: confidence interval 27-47%), with complete response (CR) in 11 (12%) and partial response (PR) in 23 (25%). The median duration of response was 6 months (range 1-19), and the median survival of the 96 eligible patients was 9 months. Side-effects (WHO grade 3-4) were leucopenia (30%), thrombocytopenia (9%) and mucositis (10%). We conclude that the EAP regimen is active in inducing major objective responses (12% of CR), and that treatment is feasible in patients with good performance status.

Neoadjuvant treatment of cancer of the bladder with M-VAC/M-VEC, and bladder-sparing policy: preliminary report of a non-randomized study.

The life expectancy of patients with invasive bladder cancer is limited by the age of incidence and by the natural history of the cancer. Careful selection of patients, independent of age but linked to a neoadjuvant chemotherapy, should be useful for a bladder-sparing policy. Between January 1991 and December 1994, we selected 36 patients with invasive, transitional bladder cancer, but showing good performance status, after a transurethral resection biopsy performed with cytoreductive intention, and after a complete staging. Patients (median age, 65 years) were treated with neoadjuvant M-VAC/M-VEC and then selected for conservative surgery if the downstaging, topography, absence of in situ carcinoma, and residual bladder capacity allowed. At restaging, nine patients (27%) were in complete pathological response; 13 (39%) were in partial pathological response, with a total rate of 67%; and 11 patients (33%) were non-responders, i.e. non-downstaged. Thirty nine percent were treated with radical cystectomy and 60% with limited surgery. Thirteen patients relapsed and seven died of disease during a median follow-up period of 23.5 months. At the end of the study, 68% of patients were alive, with a progression-free survival of 49.8% and a median survival of 32.9 months. Twenty one patients were alive at 31 December 1995, 14 with their bladder. No statistical differences were observed for overall survival and progression-free survival between the two surgery groups. Results were independent of age. A statistically significant difference was found (p = 0.0001) only between non-responders and all the downstaged patients, independent of surgery. These results confirm the feasibility of conservative treatment after a careful selection of patients, even in patients over 65 years, compared with standard available treatments.

Brain dopamine as a target for solvent toxicity: effects of some monocyclic aromatic hydrocarbons.

Adult male rabbits were exposed to toluene, xylene, styrene, ethylbenzene, vinyltoluene or were dosed with hippuric, methylhippuric, mandelic, phenylglyoxylic, and 7-methyl-mandelic acids. Styrene, vinyltoluene and ethylbenzene caused a marked depletion of striatal and tubero-infundibular dopamine. Such an effect was also caused by treatment with mandelic and phenylglyoxylic acids. These results indicate that dopamine is a target for some solvents of their metabolites, the presence of a lateral vinyl- or ethyl-chain which may be biotransformed into alpha-keto acids being crucial for the effect. Experiments in vitro suggest that dopamine condenses non-enzymatically with reactive carbonylic groups of such and other alpha-keto acids, thus becoming ineffective as neurotransmitter. This mechanism might account for the neurobehavioral and neuroendocrine changes which have been reported in workers occupationally exposed to styrene and to some solvent mixtures.

Endocrine effects of psychological stress associated with neurobehavioral performance testing.

Twenty-four healthy subjects were submitted to a computer-based performance evaluation system. The set of tests required sustained attention, and the last test was expressly designed to cause a moderate, acute psychological stress. Compared to baseline levels, both serum ACTH and beta-endorphins were increased after psychological testing in all subjects. Serum prolactin showed a slight and statistically nonsignificant decrease compared to baseline values. These results question the belief that psychological stress stimulates prolactin secretion, whereas it suggests that serum ACTH and beta-endorphins are reliable indicators of acute psychological stress.

Neurobehavioral and neuroendocrine effects of occupational exposure to perchloroethylene.

The hypothesis that long-term low-level exposure to perchloroethylene (PERC) may impair the dopaminergic control of prolactin (PRL) secretion and negatively affect neurobehavioral performance, was tested in a cross-sectional survey of dry-cleaners. Sixty female workers exposed to PERC in dry-cleaning shops and thirty controls recruited in a cleaning plant not using solvents were examined. PERC air concentration during four-hour random periods varied from 1 to 67 ppm (median 15 ppm). PERC blood levels ranged 12-864 mg/l (median 145 mg/l). A set of tests from a computer-based performance evaluation system was administered, including Finger Tapping with both dominant and non-dominant hands, Simple Reaction Times, Digit Symbol, and Shape Comparison in two different versions constructed to test Vigilance and the response to moderate stress, respectively. During the proliferative phase of the menstrual cycle, PERC-exposed workers showed increased serum PRL (12.1 +/- 6.7 ng/ml) as compared to their matched controls (7.4 +/- 3.1 ng/ml, p less than 0.001). Prolonged reaction times were also observed in all tests. However, neither the duration of exposure nor air and blood PERC concentrations were significantly correlated with performance. Nor were exposure variables associated with the increased PRL levels.

Milrinone enhances cytosolic calcium transient and contraction in rat cardiac myocytes during beta-adrenergic stimulation.

We have investigated the mechanism that underlies the absence of a positive inotropic effect of milrinone on rat myocardium. The twitch characteristics of enzymatically dissociated left ventricular myocytes from the adult rat and guinea pig were assessed by edge tracking during field stimulation. In some rat myocytes loaded with the ester derivative of the Ca2+ probe Indo-1 we simultaneously measured changes in cell length and in the associated cytosolic Ca2+ (Cai) transient. Our results show that in guinea pig myocytes bathed in 0.5 mM [Ca2+] and field stimulated at 1 Hz, milrinone (10 microM) had a positive inotropic effect. In contrast milrinone had no effect on the contractile properties of rat myocytes studied under similar conditions and field stimulated at 0.2 Hz. In rat myocytes bathed in 0.5 mM [Ca2+] and stimulated at 0.2 Hz isoproterenol (1 nM) increased the amplitude and shortened the duration of the contraction and of the associated Cai transient; these effects of beta-adrenergic stimulation were further enhanced by the addition of milrinone (10 microM) in the presence of isoproterenol. Under conditions of higher cell Ca2+ loading achieved by raising bathing [Ca2+] to 1 mM and isoproterenol to 3 nM the positive inotropic effect of milrinone (10 microM) in rat myocytes saturated when spontaneous oscillatory Ca2+ release appeared in the diastolic intervals between electrically stimulated twitches. Our results suggest that an enhancement in the baseline beta-adrenergic stimulation is required for milrinone to exercise a positive inotropic action on rat myocardial tissue.

Neuroendocrine carcinoma of the skin: a case report of "multiple neuroendocrine carcinoma" onset and long-term remission after chemotherapy.

We herein report a case of "multiple neuroendocrine carcinoma" onset, with a torpid course, metastasis in the left breast, and an initial considerable sensitivity to the chemotherapy. We conclude that a re-evaluation of the studies on this neoplasia carried out to date is needed, in order to identify new regimens, which increase the complete response rates and their duration.

Intermittent dobutamine therapy in patients with advanced congestive heart failure.

Congestive heart failure is an increasingly common condition carrying a poor prognosis and a decay in the quality of life. Usually frequent and lengthy hospitalizations are required with heart failure, with obvious discomfort for the patient and increase in health costs. Heart transplantation is rarely possible due to shortage of donors. Thus, improvement of pharmacological strategies for the management of these patients is desirable. The present study evaluated the effects of intermittent dobutamine infusion in elderly patients (mean age 75.9 years), hospitalized for advanced (NYHA, 1973, class IV) congestive heart failure of ischemic etiology. Dobutamine infusions of 2, 4 and 6 microg/kg/min for 36 h every 2-4 weeks were randomly prescribed to 24 subjects, who were then followed up every three months for an average of ten months. Data on mortality, cardiovascular events and NYHA (1973) functional classifications were systematically collected. Our study shows that while in this series of patients mortality remained high (50% at 12 months), there was an improvement in the NYHA-classification during the follow-up, and a decrease in the need for hospitalization. In addition, side effects were relatively rare, with only two patients interrupting dobutamine treatment. We conclude that intermittent dobutamine infusion is a reasonable treatment option in elderly patients with congestive heart failure unresponsive to conventional treatments.

[Epidermal peripilar nevus]. / Nevus epidérmico peripilar

A classic case of Epidermal Nevus with a particular peripilar arrangement is presented. Histopathologically, acanthosis, hyperkeratosis and papillomatosis is observed. The indemnity of the hair appendages was demonstrated in three biopsies. Some observations are made about the classification of the epidermal nevus following recent research which includes epidermolytic hyperkeratosis and linear includes epidermolytic hyperkatosis and linear inflammatory nevus. Follicular and comedo nevus, which was included in the differential diagnosis of this patient, is discussed.

Mesenchymal stem cells as delivery vehicle of porphyrin loaded nanoparticles: effective photoinduced in vitro killing of osteosarcoma.

Mesenchymal stem cells (MSC) have the unique ability to home and engraft in tumor stroma. These features render them potentially a very useful tool as targeted delivery vehicles which can deliver therapeutic drugs to the tumor stroma. In the present study, we investigate whether fluorescent core-shell PMMA nanoparticles (FNPs) post-loaded with a photosensitizer, namely meso-tetrakis (4-sulfonatophenyl) porphyrin (TPPS) and uploaded by MSC could trigger osteosarcoma (OS) cell death in vitro upon specific photoactivation. In co-culture studies we demonstrate using laser confocal microscopy and time lapse imaging, that only after laser irradiation MSC loaded with photosensitizer-coated fluorescent NPs (TPPS@FNPs) undergo cell death and release reactive oxygen species (ROS) which are sufficient to trigger cell death of all OS cells in the culture. These results encourage further studies aimed at proving the efficacy of this novel tri-component system for PDT applications.

[Efficacy and tolerability of a preconstituted combination of captopril 50 mg + hydrochlorothiazide 25 mg in aged subjects with isolated systolic hypertension]. / Efficacia e tollerabilità dell'associazione precostituita captopril 50 mg + idroclorotiazide 25 mg in soggetti anziani con ipertensione sistolica isolata.

In this study we evaluated in open the efficacy and tolerability of the preconstituted association Captopril 50 mg + Hydrochlorothiazide 25 mg, for a six-month period, in a population of 201 aged patients affected by isolated systolic hypertension. The results showed a good antihypertensive efficacy of the association Captopril-Hydrochlorothiazide 25 mg and also an optimal safety of use.

Polyamine effects on [Ca2+]i homeostasis and contractility in isolated rat ventricular cardiomyocytes.

In electrically stimulated myocytes loaded with the fluorescent Ca2+ indicator indo 1-acetoxymethyl ester, spermine induced a dose-dependent (100-500 microM) negative inotropic effect, which was associated with a decrease in the magnitude of the cytosolic Ca2+ concentration ([Ca2+]i) transient but not with changes in myofilament responsiveness to Ca2+. Spermidine induced a less pronounced negative inotropic effect, whereas putrescine did not modify myocyte contraction. In the unstimulated state, spermine did not alter resting [Ca2+]i. Superfusion of the cardiac myocytes with 10 mM alpha-difluoromethylornithine, an inhibitor of polyamine synthesis, did not modify cellular responses to isoproterenol (10(-9)-10(-7) M). beta-Adrenergic stimulation did not affect either ornithine decarboxylase activity or intracellular polyamine levels within a 10-s to 15-min period of treatment. In summary, only exogenously administered polyamines were able to influence myocyte contractility. Their negative inotropic effect resulted from changes in [Ca2+]i homeostasis and required cellular depolarization.

A novel positive inotropic substance enhances contractility without increasing the Ca2+ transient in rat myocardium.

We have investigated the mechanism of action of a novel positive inotropic agent, the thiadiazinone derivative 5-(1-(3,4-dimethoxybenzoyl)-1,2,3,4-tetrahydrochinolin-6-yl)-6- methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-on (EMD 53998). This substance inhibits phosphodiesterase III and, in skinned myocardial fibers, it increases myofilament sensitivity to Ca2+. However the effects of EMD 53998 on intact myocardial preparations are still undefined. In isolated rat hearts EMD 53998 (0.5 to 5 microM) had a dose-dependent effect to increase left ventricular systolic pressure. In isolated left ventricular myocytes loaded with the ester derivative of the Ca2+ probe indo-1, EMD 53998 (0.5 to 5 microM) enhanced twitch amplitude without increasing the associated indo-1 transient. The myofilament responsiveness to Ca2+ was assessed as the relationship between twitch and the indo-1 transient amplitudes as the latter is varied by altering the bathing [Ca2+], or stimulation pattern. EMD 53998 reversibly shifted this relationship to the left which indicates that for indo-1 transients of the same amplitude in the absence and presence of the drug, twitch amplitude was enhanced by EMD 53998. In isolated myocytes studied in the absence of electrical stimulation, EMD 53998. (1.5 to 5 microM) had a concentration-dependent effect to markedly and reversibly decrease cell length without increasing indo-1 fluorescence ratio. Thus, the cellular basis for the positive inotropic action of EMD 53998 in rat myocardium is related to the unique effect of this substance to enhance myofilament responsiveness to Ca2+ and not to an increase in the indo-1 transient amplitude.