Is the prognosis and course of acral melanoma related to site-specific clinicopathological features?

OBJECTIVE: Acral melanoma is an uncommon type of melanoma in Caucasian patients. However, acral melanoma is the most common type of melanoma in African and Asian patients. Comparison analyses between hand-acral melanoma and foot-acral melanoma have been rarely reported in the literature. Acral melanoma is an uncommon melanocytic tumor characterized by an intrinsic aggressiveness, with specific histological and clinicopathological features. Acral melanoma involves the palms, soles and sub-ungueal sites. PATIENTS AND METHODS: A total of 244 patients with acral melanoma were included in our analysis. The current study was performed in three different medical centers: Sapienza University of Rome, San Gallicano Institute of Rome and University of Magna Graecia (Italy). The Kaplan-Meier product was used to estimate survival curves for disease-free survival and overall survival. The log-rank test was used to evaluate differences between the survival curves. Assuming that the effects of the predictor variables are constant over time, the independent predictive factors were assessed by Spearman's test and subsequently data were analyzed performing Cox proportional-hazard regression. RESULTS: In both univariate and multivariate analyses Breslow thickness (p < 0.0001) and ulceration (p = 0.003) remained the main predictors. General BRAF mutation was detected in 13.8% of cases. We found that median Breslow value and the percentage of recurrences were similar in hand-acral melanoma and foot-acral melanoma, as well as there were no differences in both short and long-term. CONCLUSIONS: The absence of differences in survival between hand-acral melanoma and foot-acral melanoma shows that the aggressiveness of the disease is related to distinct mutational rate, as well as to anatomical site-specific features, rather than to the visibility of the primary lesion.

New dibenzothiadiazepine derivatives with antidepressant activities.

A new series of 11-[(aminoalkyl)carbonyl] derivatives of 6,11-dihydrodibenzo[c,f][1,2,5]thiadiazepine 5,5-dioxide (10-39) were synthesized and evaluated for potential antidepressant activity in the apomorphine-induced hypothermia (Apo 16) test. Effects on reserpine-induced hypothermia and toxicity for the most potent antagonists of Apo 16 hypothermia were also studied. Structure-activity relationships are reported. Anticholinergic effects were evaluated for compound 12, identified as the most potent and least toxic in this series, by assessing physostigmine lethality. Compound 12 was also subjected to X-ray analysis.

New arylpyrido-diazepine and -thiodiazepine derivatives are potent and highly selective HIV-1 inhibitors targeted at the reverse transcriptase.

A series of pyridobenzothiodiazepindioxides such as the 11-ethyl-6,8,9-trimethyl-6,11-dihydro-pyrido[2,3-f] [2,1,5]benzothiodiazepine-5,5-dioxide and arylpiridodiazepines such as the 6,7-dihydro-7-methyl-12-ethyl-pyrido[2,3-b] pyrido(2',3'-4,5]furo[2,3-f][1,4]diazepin-6(12H)-thio and the 6,7-dihydro-7-methyl-12-ethyl-pyrido[2,3-b]pyrido- [2,3-4,5]thieno[2,3-f][1,4] diazepin-6(12H)-thione were found to inhibit human immunodeficiency virus type 1 [HIV-1(IIIB)] replication at a concentration of 0.003-0.04 microM without being cytotoxic at a 3,000- to 15,000-fold higher concentration. These compounds proved effective against a variety of HIV-1 strains, including those that are resistant to 3'-azido-3' deoxythymidine (AZT), but not against HIV-2, simian immunodeficiency virus or herpes simplex virus. An HIV-1 strain containing the 188 Tyr-->His mutation in the reverse transcriptase displayed severely reduced sensitivity to the compounds. The specificity of these compounds is due to an interaction with the reverse transcription process. The 6,7-dihydro-7-methyl-12-ethyl-pyrido[2,3-b]pyrido [2,3-4,5]thieno[2,3-f][1,4]diazepin-6(12H)-thione (MEN 10979) enhanced the anti-HIV-1 activity of AZT and dideoxyinosine (ddI) in a synergistic manner. The new arylpyrido-diazepine and -thiodiazepine derivatives appear to be drug candidates for the treatment of HIV-1 infection.

Direct evidence that capsaicin-induced plasma protein extravasation is mediated through tachykinin NK1 receptors.

The involvement of tachykinin NK1 receptors in the plasma protein extravasation (measured by the Evans blue leakage technique) produced by intravenous administration of capsaicin was investigated in the urinary bladder and trachea of anesthetized rats. Capsaicin-induced plasma extravasation was markedly inhibited by (+/-)-CP-96,345, a novel and potent non-peptide antagonist of tachykinin NK1 receptors. The same dose of (+/-)-CP-96,345 markedly inhibited the plasma protein extravasation induced by the selective NK1 receptor agonist, [Sar9]substance P sulfone, but had no effect on the response to histamine.

Activity of peptide and non-peptide antagonists at peripheral NK1 receptors.

We investigated the affinity of several tachykinin antagonists reportedly selective for NK1 receptors at various tachykinin receptors and NK2 receptors subtypes. The four antagonists tested were: L 668,169, Spantide II, Ac-Thr-DTrp(for)-Phe-NMeBzl (FR 113680) and the novel nonpeptide antagonist (+/-)-CP-96,345. The four antagonists were found to be effective against NK1 receptor-mediated responses in the guinea-pig ileum with the following rank order of potency (pKB values in parentheses): (+/-)-CP-96,345 (8.11) greater than Spantide II (7.08) greater than FR 113680 (6.61) greater than or equal to L 558,169 (6.44). (+/-)-CP-96,345, Spantide II and FR 113680 were distinctly more potent at NK1 receptors than at NK2 receptors (NK2A in the rabbit pulmonary artery, NK2B in the hamster trachea). L 668,169 antagonized neurokinin A-induced contractions in the hamster trachea with an affinity similar (pKB value 6.16) to that found in the guinea-pig ileum for NK1 receptors (pKB value 6.44). All antagonists were inactive at NK3 receptors of the rat portal vein. In a second series of experiments, the affinities of test antagonists for NK1 receptors in the guinea-pig ileum were compared to those for NK1 receptors in the guinea-pig vas deferens, the rabbit jugular vein and the rat urinary bladder. For each antagonist, the affinity measured in the guinea-pig vas deferens and the rabbit jugular vein was comparable to that found in the guinea-pig ileum. In the rat urinary bladder, (+/-)-CP-96,345 was about 100 times less potent in blocking NK1 receptor-mediated contractions than in the guinea-pig ileum.(ABSTRACT TRUNCATED AT 250 WORDS)

Role of NK1 tachykinin receptors in thermonociception: effect of (+/-)-CP 96,345, a non-peptide substance P antagonist, on the hot plate test in mice.

We have tested the ability of (+/-)-CP 96,345, a novel nonpeptide substance P (SP) antagonist, to block the aversive behaviour induced by intrathecal (i.t.) administration of SP and to induce thermal antinociception in mice. (+/-)-CP 96,345 administered i.t. or i.p. selectively blocked the effect of i.t. SP while leaving the response to i.t. bombesin unaffected. At the same dose proven effective against i.t. SP, (+/-)-CP 96,345 produced thermal analgesia in the hot plate test (52 degrees C). Using isolated organs for bioassay evaluation of activity at tachykinin receptor, (+/-)-CP 96,345 was found to be a potent (pA2 8.11, c.l. 7.9-8.3) and competitive NK1 receptor antagonist while it was devoid of activity at NK2 or NK3 receptors. These findings provide clear indication for the participation of SP, via NK1 receptors, in thermal nociception.

Synchronous and metachronous cancer of the stomach.

In the last 10 years 407 cancers of the stomach were observed at the 1st Department of Surgery of the University of Bologna. 248 were subjected to curative resection (59 were Early Gastric Cancers and 189 were Advanced Gastric Cancers). Among them 14 gastric cancers with multiple foci (synchronous cancers) and 7 cancers of the gastric stump (metachronous cancers) were found in the same period. Each lesion was histologically proved and a tract of normal mucosa was found between two cancers both macroscopically and microscopically. The frequency of primary multiple tumoural foci was higher for early Gastric Cancer (E.G.C.) in comparison with Advanced Gastric Cancer (A.G.C.), being 8.4% for the former and 4.7% for the latter.

Synthesis, characterization, and analytical studies of adosupine, a potential new drug for urinary incontinence.

The synthesis and the spectroscopic characterization of a new potential drug for urinary incontinence, adosupine, is described. Adosupine and its potential synthesis impurities were analyzed by a new HPLC method that was developed with a C18 reversed-phase column. The analysis was made under isocratic conditions, with a mobile phase of acetonitrile:water (15:85, v/v). Resolution of all synthesis impurities was allowed. The method was also applied to stability studies of adosupine in solid state and in solution under different conditions. With the conditions used, only one degradation product was shown by HPLC analysis; it was isolated, characterized, and identified as the hydrolysis product of the lactam ring present in the adosupine structure.

[Pheochromocytoma with hypotension. Study of an unusual clinical case]. / Feorcromocitoma con ipotensione. Osservazioni su un raro caso clinico.

A case of pheochromocytoma marked by clinostatic hypotensive crises and otherwise normal or low blood pressure is described. The aetiopathogenetic explanations put forward by other workers are cited and a deductive reconstruction is made of the clinical course.

Synthesis and properties of human gamma-lipotropin.

The synthesis of human gamma-lipotropin by the solid-phase method is described. The synthetic product was characterized by Rf in partition chromatography on Sephadex G-50, paper electrophoresis, polyacrylamide gel electrophoresis, thin-layer chromatography, HPLC, end group determination, peptide mapping of a tryptic digest, and amino acid analyses of acid and enzymic digests. The synthetic material is identical to natural human gamma-lipotropin when assayed against natural human beta-lipotropin for lipolytic activity.

Exocrine pancreatic function after total gastrectomy.

The secretion of bicarbonate, lipase, and chymotrypsin into the duodenum in response to exogenous stimulation with secretin, 1 CU/kg-h, plus caerulein, 100 ng/kg-h, was investigated in 12 patients, on an average, 20.7 months after total gastrectomy and in 14 control subjects. The secretion of bicarbonate and lipase was significantly lower in patients than in controls. The reduction in outputs compared with the control values was 47.9%, 38.7%, and 24.2% respectively for bicarbonate, lipase, and chymotrypsin. Eight of the 12 patients (67%) had steatorrhoea. No significant correlation was found between this parameter and lipase output. It is concluded that the exocrine pancreatic function is impaired in the majority of patients subjected to total gastrectomy. The impairment, which particularly affects bicarbonate and lipase, is generally mild to moderate.

Sonographic evaluation of liver, spleen, and splanchnic vessels following partial liver resection.

The liver and spleen size and the splanchnic vessel caliber were evaluated by means of real-time ultrasonography in 12 consecutive patients who underwent a partial hepatic resection for benign or malignant lesions. All parameters were evaluated before surgery and 14 days, 28 days, two months, and six months after the partial hepatic resection. The liver size, which was halved after the resection, progressively increased during the follow-up. The splanchnic veins showed, at 14 and 28 days, a significant increase in caliber and a reduced compliance to breathing, which progressively returned to normal levels. The spleen size increased after partial hepatectomy and remained enlarged throughout the study. Ultrasonography was able to detect that partial hepatic resection is followed by a progressive regeneration of the residual parenchyma and by a transient increase in portal pressure, which returns to normal levels when the liver regenerates.

Evaluation of liver volume and liver function following hepatic resection in man.

In a longitudinal study liver volume and liver function were measured in a series of 12 patients undergoing partial liver resection for focal hepatic lesions. Ultrasonography revealed that liver volume, reduced by about 50% by the resection, progressively increased, and 6 months after surgery it returned to nearly normal values. A variable reduction in routine liver function tests was observed, possibly reflecting the influence of the different reserve synthetic capacity of the liver and, in the early postoperative phase, plasma half-life of liver products and blood loss or changes in plasma volume. The galactose elimination capacity was only marginally reduced in the early period (from a pre-surgery value of 2.49 +/- SE 0.21 mmol/min to 2.31 +/- 0.14 after 7 days; p = ns) and reached a nadir at 14 days (1.97 +/- 0.16; p less than 0.001). When expressed per unit of liver volume, the galactose elimination (22 +/- 2 mumol/min per unit before resection) progressively decreased during the regeneration phase from 36 +/- 4 at 14 days to 26 +/- 3 at 6 months (P vs 14-day: less than 0.01). At 6 months both galactose elimination and galactose elimination per unit of liver volume were no longer different from baseline values. Our data show that, following hepatic resection, both liver volume and liver function increase and progressively return to nearly normal values. In agreement with data obtained in animal studies, it appears that the metabolic activity of the remaining parenchyma is increased in the early postoperative phase, and it slows down in the course of regeneration.