Extended adjuvant endocrine therapy in early breast cancer: a meta-analysis of published randomized trials

Adjuvant endocrine therapy for 5 years is the standard adjuvant treatment for estrogen receptor-positive breast cancer while the benefits of extended adjuvant endocrine therapy (EAET) beyond 5 years are still controversial. That controversy prompted this meta-analysis to compare 5 years of adjuvant endocrine therapy only versus EAET. Eligible 11 randomized, controlled trials comprising 29,000 women were included. EAET showed no advantage in overall survival (OS) from all causes mortality (odds ratio [OR] = 0.98 (95% confidence interval [CI], 0.87–1.09); P = 0.67). On the other hand, compared with standard therapy, the pooled effects showed that EAET was associated with improvement in breast cancer-specific survival (OR = 0.87; 95% CI 0.79–0.96; P = 0.004), disease-free survival (DFS) (OR = 0.87; 95% CI 0.75–0.99; P = 0.002), disease recurrence (OR = 0.76; 95% CI 0.64–0.90; P = 0.001), and contralateral breast recurrence (OR = 0.74; 95% CI 0.59–0.93; P = 0.008). Improvement in DFS or disease recurrence was not shown in studies that compared 5 years of tamoxifen versus tamoxifen beyond 5 years. Subgroup analysis showed that EAET conferred more benefit for patients with positive lymph nodes. Rates of positive lymph nodes, the study size, and the median duration of follow-up were identified as variables that explained most of the demonstrated data heterogeneity. EAET should be considered as a preferred strategy for high-risk hormone-positive early breast cancer patients with positive lymph nodes; however, the benefit on OS could not be demonstrated.     

Novel 1,2,4-triazole derivatives: Design,synthesis, anticancer evaluation,molecular docking,and pharmacokinetic profiling studies

Three novel series of 1,2,4-triazole derivatives were designed and synthesized as potential adenosine A2B receptor antagonists. The design of the new compounds depended on a virtual screening of a previously constructed library of compounds targeting the human adenosine A2B protein. Spectroscopic techniques including ¹H nuclear magnetic resonance (NMR) and ¹³C NMR, and infrared and mass spectroscopy were used to confirm the structures of the synthesized compounds. The in vitro cytotoxicity evaluation was carried out against a human breast adenocarcinoma cell line (MDA-MB-231) using the MTT assay, and the obtained results were compared with doxorubicin as a reference anticancer agent. In addition, in silico studies to propose how the two most active compounds interact with the adenosine A2B receptor as a potential target were performed. Furthermore, a structure–activity relationship analysis was performed, and the pharmacokinetic profile to predict the oral bioavailability and other pharmacokinetic properties was also explained. Four of our designed derivatives showed promising cytotoxic effects against the selected cancer cell line. Compound 15 showed the highest activity with an IC₅₀ value of 3.48 µM. Also, compound 20 revealed an equipotent activity with the reference cytotoxic drug, with an IC₅₀ value of 5.95 µM. The observed IC₅₀ values were consistent with the obtained in silico docking scores. The newly designed compounds revealed promising pharmacokinetic profiles as compared with the reference marketed drug.     

Delayed Paclitaxel-trastuzumab-induced interstitial pneumonitis in breast cancer

Pneumonitis is a rare but serious complication associated with paclitaxel and/or trastuzumab treatment. We report a 51-year-old female patient with locally advanced breast cancer who presented with shortness of breath, fever, dry cough and pulmonary infiltrates. She had been treated without complications for 10 weeks with paclitaxel (Taxol®) and trastuzumab (Herceptin®) as neoadjuvant therapy, with complete clinical and pathological response. Infections and cardiomyopathy were excluded as causes of her symptoms. Bronchoscopy and biopsy were performed and a diagnosis of drug-induced interstitial pneumonitis was made. After treatment with steroids, the patient showed a significant response in less than 24 h; she was discharged home without the need for oxygen less than 48 h after therapy initiation. Although no causative association could be found between either trastuzumab or paclitaxel and this patient''s pulmonary syndrome, the potential for such toxicity should be considered, especially as paclitaxel/trastuzumab is a vey common combination therapy for breast cancer.Key Words: Paclitaxel, Trastuzumab, Interstitial pneumonitis, Drug-induced infiltrative lung disease, Breast cancer     

Prostanoids secreted by alveolar macrophages enhance ionic currents in swine tracheal submucosal gland cells

We examined the effect of substances released by swine alveolar macrophages (AMs) on ionic currents in airway submucosal gland cells (SGCs). AMs obtained by lavage were activated by 24-h zymosan exposure (0.1 mg/ml). Supernatant was collected and used to stimulate short-circuit current changes (DeltaI(SC)) in SGC monolayers in Ussing chambers. Dexamethasone (1 microM) or indomethacin (5 muM) during zymosan exposure of AMs reduced or abolished the supernatant-induced DeltaI(SC). Zymosan exposure induced a 5-fold increase in cyclooxygenase (COX)-2 but not COX-1 protein levels in AMs. Prostaglandin E(2) (PGE(2)) concentration in the supernatant from zymosan-activated AMs was 550 +/- 10 nM (n = 3) compared with 28 +/- 3 nM for unstimulated AMs (n = 3). PGE(2), applied serosally, induced DeltaI(SC) with an EC(50) of 15.5 +/- 1.3 nM (n = 4) and 3.6 +/- 1.8 microM (n = 3) when applied apically. Four types of endoprostanoid receptors (EP(1-4)) were detected in SGCs using Western blot. PGE(2)-induced DeltaI(SC) were inhibited by AH6809 (6-isopropoxy-9-oxoxanthene-2-carboxylic acid) but not by SC19220 (8-chloro-dibenzo[b,f][1,4]oxazepine-10(11H)-carboxylic acid, 2-acetylhydrazide), suggesting that endoprostanoid (EP)(2) but not EP(1) receptors were activated by PGE(2). Pretreatment of SGCs with supernatant from zymosan-activated AMs, PGE(2), or forskolin enhanced the sensitivity to acetylcholine (ACh)-induced DeltaI(SC). PGE(2)-induced DeltaI(SC) were blocked by charybdotoxin (ChTX), chromanol 293B, or glibenclamide. ACh-induced DeltaI(SC) were only blocked by ChTX or glibenclamide. None of these blockers altered PGE(2) pretreatment-induced sensitization of ACh-induced DeltaI(SC). These results demonstrate that prostanoids released from activated AMs directly increase cystic fibrosis transmembrane conductance regulator and K(+) channel activity. ACh-induced DeltaI(SC) are also enhanced due to enhanced activation of Ca(2+)-activated K(+) channels (K(Ca)).     

Unravelling the antifungal and antiprotozoal activities and LC-MS/MS quantification of steroidal saponins isolated from Panicum turgidum

Bioassay-guided investigation of Panicum turgidum extract resulted in the identification of seven steroidal saponins (Turgidosterones 1–7). They were evaluated for their in vitro antifungal, antileishmanial, and antitrypanosomal activities. Turgidosterone 6 was the most active antifungal against Candida albicans and Candida neoformans (IC₅₀ values of 2.84 and 1.08 μg mL⁻¹, respectively). Turgidosterones 4–7 displayed antileishmanial activity against Leishmania donovani promastigotes with IC₅₀ values ranging from 4.95 to 8.03 μg mL⁻¹ and against Leishmania donovani amastigote/THP with IC₅₀ values range of 4.50–9.29 μg mL⁻¹. Activity against Trypanosoma brucei was also observed for Turgidosterones 4–7 with an IC₅₀ values range of 1.26–3.77 μg mL⁻¹. Turgidosterones 1–3 did not display any activity against the tested pathogens. The study of structure–activity relationships of the isolated saponins indicated that the antifungal, antileishmanial, and antitrypanosomal activities are markedly affected by the presence of spirostane-type saponins and the elongation of the sugar residue at C-3. To quantitatively determine the most abundant active ingredient in Panicum turgidum extract, a single run, sensitive, and highly selective liquid chromatography-tandem mass spectrometry (LC-MS/MS) method has been applied under positive and negative modes. The obtained results showed that compound 5 was the most abundant (95.93 ± 1.10 mg per gram of dry Panicum turgidum extract), followed by 6 (52.51 ± 1.05 mg gm⁻¹), 4 (32.71 ± 0.48 mg gm⁻¹), and 7 (13.19 ± 0.50 mg gm⁻¹). Docking of these saponins against the Candida albicans oxidoreductases and Leishmania infantum trypanothione reductase active sites revealed their potential to effectively bind with a number of key residues in both receptor targets.

Bioassay-guided investigation of Panicum turgidum extract resulted in the identification of seven steroidal saponins (Turgidosterones 1–7).     

Survey of utilization of multidisciplinary management tumor boards in Arab countries

Multidisciplinary management (MDM) of cancer patients provides better care and is recommended by all authorities and published guidelines. There is very little documentation of MDM practices in low and middle income countries. A survey of 338 practicing oncology specialists from various Arab countries was conducted at four major pan-Arab oncology conferences in the first half of 2010. While 72% of respondents reported having an MDM tumor board, only 49% reported that their tumor boards met on a weekly basis. Of those who do not have a tumor board, 57% attend a tumor board meeting at another hospital within their country. 60% of respondents attend tumor board meetings to seek group opinion and help in the management of their patients. 93% of physicians surveyed agreed that tumor boards should be mandatory. The vast majority of physicians agreed that in the absence of all specialties, "mini tumor boards" should be organized between available specialists at all hospitals that treat cancer patients.     

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Weitere Untersuchungen über Spontantumoren bei wilden Ratten. Noch ein Fall von Epitheliom des Vormagens durch einen neuen Parasiten hervorgerufen

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