Biomarker changes during neoadjuvant anastrozole, tamoxifen, or the combination: influence of hormonal status and HER-2 in breast cancer--a study from the IMPACT trialists.

PURPOSE: To investigate the relationships between biomarker changes in breast cancer during neoadjuvant (preoperative) endocrine therapy. PATIENTS AND METHODS: The IMPACT trial compared the preoperative use of tamoxifen with anastrozole alone or in combination in postmenopausal women (n = 330) with primary breast cancer. Biomarkers were measured in tumor biopsy specimens taken at baseline, and after 2 and 12 weeks of treatment. RESULTS: 52 (93%) of 56, 46 (85%) of 54, and 37 (84%) of 44 patients in the anastrozole, tamoxifen, and combination groups, respectively. There was a significantly greater suppression of Ki67 in the anastrozole-treated group than in the tamoxifen- or combination-treated groups, which is parallel to the greater efficacy seen for anastrozole over these two treatments in the Arimidex, Tamoxifen, Alone or in Combination adjuvant trial. A positive relationship was noted between estrogen-receptor level and Ki67 suppression in all patients. Ki67 was reduced to a greater extent in progesterone receptor-positive tumors compared with progesterone receptor-negative tumors. HER-2-negative tumors tended to show a greater reduction in Ki67 compared with HER-2-positive tumors, but the difference was only significant in the tamoxifen group after 2 weeks, and in the anastrozole group after 12 weeks. CONCLUSION: These results confirm the value of Ki67 as a molecular marker, and provide information regarding the relationships between treatment-induced changes in Ki67 and other important biomarkers. Studies such as this should help integrate agents targeted at growth factor signaling with endocrine agents in breast cancer.     

Detection of alkaline sphingomyelinase activity in human stool: proposed role as a new diagnostic and prognostic marker of colorectal cancer.

OBJECTIVES: Intestinal alkaline sphingomyelinase, by exerting a major role in dietary sphingomyelin digestion, is responsible for the generation of messengers able to trigger the rapid turnover and apoptosis in intestinal epithelial cells. Markedly reduced mucosal alkaline sphingomyelinase activity has been associated with human colorectal neoplasms. The aim of this study was to analyze the alkaline sphingomyelinase activity in feces from healthy subjects and colorectal adenocarcinoma patients and to correlate it with the enzyme activity in intestinal tissues. MATERIALS AND METHODS: The enzyme activity was measured both in the intestinal samples from 12 healthy controls and 51 patients with colorectal adenocarcinoma (tumoral and paratumoral tissue) and in the fecal samples of 34 healthy subjects and 29 patients with adenocarcinoma. The relation between sphingomyelinase activity and Dukes' stage, cell differentiation degree, age, and gender was also analyzed. RESULTS: Alkaline sphingomyelinase was significantly decreased (P < 0.001; mean reduction >90%) in tumoral intestinal mucosa of patients compared with controls independently of Dukes' stage and tumor differentiation grade. Interestingly, the enzyme activity in histologically normal paratumoral tissues was statistically lower than control samples (P < 0.001). As occurs in neoplastic tissues, a relevant mean reduction (P < 0.0001; almost 90%) of alkaline sphingomyelinase was revealed in stool samples from tumor patients when compared with controls. CONCLUSION: These findings may have implications for cancer biology and perhaps also for the design of clinical test, thus suggesting that the fecal sphingomyelinase activity could really reflect the human intestinal mucosa enzyme level and could represent a new marker for human colorectal adenocarcinoma, mainly taking into account its early appearance in intestinal neoplasms.     

Extension of in-use stability of preservative-free nasalia.

Nasal drops and nasal sprays are commonly supplied in multi-dose containers that usually include suitable levels of an appropriate preservative in order to kill or prevent growth of any microorganisms which might enter the dispensing system. Preservatives should both protect the patient from infection and prevent spoilage of the product. Unfortunately, preservatives often cause unwanted side effects; in particular, the nasal mucosa is irritated frequently. Consequently, the use of preservatives in nasal preparations should be avoided. The technical design of the 3K system, a new multi-dose container, combines several microbiological safety features and therefore allows use without preservatives. Earlier tests have shown its safety for 6 weeks after the first opening. In order to test the microbiological safety of this multi-dose system over longer time periods, an in-use stability test was designed. The results revealed that the first dose as well as the contents complied with the requirements of the European Pharmacopoeia. Therefore, from a microbiological point of view for the tested nasalia in the 3K system, the stability after opening could be extended from 6 weeks up to several months without loss of microbiological quality.     

Anti-inflammatory and antinociceptive activities of Campomanesia adamantium

Ethnopharmacological relevance

Campomanesia species are used in folk medicine as anti-inflammatory, anti-rheumatic, anti-diarrheal and hypocholesterolemic.

Aim of the study

The present study investigated the in vivo anti-inflammatory and antinociceptive properties of ethyl acetate (AE) and aqueous (Aq) extracts from leaves of Campomanesia adamantium and in vitro anti-inflammatory activity of AE and its isolated flavonols, myricitrin and myricetin.

Materials and methods

The antinociceptive activity of AE and Aq was evaluated using acetic acid-induced writhing and formalin methods. The in vivo anti-inflammatory effect of AE and Aq was evaluated using carrageenan-induced paw oedema in mice. AE, myricitrin and myricetin were evaluated for their abilities to modulate the production of NO, TNF-α and IL-10 in LPS/IFN-γ stimulated J774.A1 macrophages.

Results

It was found that orally administrated AE and Aq (125 and 250 mg/kg) inhibited carrageenan-induced paw oedema in mice. AE (125 and 250 mg/kg) and Aq (125 mg/kg) reduced the time to licking at the second phase of the formalin method in vivo in mice. AE (250 mg/kg) and Aq (125 mg/kg) also reduced the number of writhes. AE, myricitrin and myricetin inhibited NO (320 μg/mL and 6.25–100 μM, respectively) and TNF-α production by macrophages (320 μg/mL for AE, 100 μM for myricitrin and 25–100 μM for myricetin). AE (160 and 320 μg/mL), myricitrin (50 and 100 μM) and myricetin (25–100 μM) increased IL-10 production by macrophages.

Conclusions

The ethyl acetate and aqueous extracts from Campomanesia adamantium showed antinociceptive and anti-inflammatory effects supporting the use of the plant in folk medicine. The results suggest that anti-oedematogenic effect promoted by aqueous extract involves several anti-inflammatory mechanisms of action. The antinociceptive effect shown by aqueous extract can be due to the modulation of release of inflammatory mediators involved in nociception. The anti-inflammatory effects of AE and of its isolated flavonols may be attributed to inhibition of pro-inflammatory cytokines production, TNF-α and NO and to the increased of IL-10 production.     

Dose-response comparison of broxaterol and salbutamol pressurized aerosols

Summary The bronchodilating activity and tolerability of broxaterol and salbutamol administered by pressurized metered dose inhalers have been compared in 9 adult patients with bronchial asthma and clinically stable and reversible bronchospasm. Placebo was used as a control. On 3 different days broxaterol and salbutamol in cumulative doses of 100, 200 and 400 g and placebo were administered every 30 min according to a double-blind, Latin-square design.After each dose of broxaterol and salbutamol the increases in FVC and FEV₁ were always significantly larger than after placebo. Broxaterol at the doses tested induced a bronchodilator response which depended on the dose according to a relation not significantly different from a straight line, and with a potency at least comparable to that of salbutamol. The tolerability of the two drugs was good: only in 1 patient were slight tremors observed after the highest dose of each drug.The bronchodilating activity and the tolerability of broxaterol were not significantly different from those of salbutamol at the same doses.     

Intra-arterial hepatic chemoembolization in liver metastases from neuroendocrine tumors: a phase II study

Neuroendocrine tumors, particularly those of gastrointestinal tract origin, have a predisposition for metastasizing to the liver, causing parenchymal substitution and paraneoplastic syndrome. Lipiodol embolization combined with anticancer drugs is a recent tool in regional therapy. It has been proven that chemoembolization reduces tumor bulk and hormone levels, and that it palliates the symptoms of many patients with liver-dominant neuroendocrine metastases. Beginning in December 1988, ten patients with unresectable and chemotherapy-refractory liver metastatic neuroendocrine tumors were treated with chemoembolization based on a mixture of lipiodol, mitomycin, cisplatin, epirubicin, followed by gelfoam powder and contrast media. Toxicity encountered included: upper right quadrant pain requiring narcotics, elevation of lactate dehydrogenase, alkaline phosphatase, and transaminases. One patient had liver abscess and persistent fever for 2 weeks. We obtained two complete remissions lasting 12 and 34 months and 5 partial remissions. The median survival was 22 months. Four patients had urinary elevation of 5-hydroxyindolacetic acid (5-HIAA). They showed more than a 75% decrease in urinary secretion after treatment. In a patient with transplanted liver we noticed a partial response lasting 7 months. We conclude that chemoembolization will improve the clinical condition of a significant percentage of patients with liver metastases, that future therapy of carcinoid tumors will be based on specific tumor biology and that treatment will be customized for each individual patient combining the use of cytoreductive procedures including radiofrequency ablation, laser treatment and chemoembolization.     

Transvaginal ultrasonography combined with water-contrast in the rectum in the diagnosis of rectovaginal endometriosis infiltrating the bowel

This prospective study evaluated the efficacy of transvaginal ultrasonography combined with water-contrast in the rectum (RWC-TVS) in the diagnosis of rectal infiltration in 35 women with rectovaginal endometriosis; ultrasonographic findings were compared with surgery and histology. The sensitivity of RWC-TVS in identifying rectal infiltration reaching at least the muscular layer was 100%, the specificity was 85.7%, the positive predictive value was 91.3%, and the negative predictive value was 100%. In 4 of 5 (80.0%) nodules reaching the submucosa, the depth of infiltration was underestimated by RWC-TVS. The RWC-TVS reliably determined the largest diameter of the endometriotic nodules and was well tolerated by the patients.