A case of acute myeloid leukemia (AML) with an unreported combination of chromosomal abnormalities: gain of isochromosome 5p, tetrasomy 8 and unbalanced translocation der(19)t(17;19)(q23;p13)

BACKGROUND: Acute myeloid leukemia (AML) comprises a spectrum of myeloid malignancies which are often associated with distinct chromosomal abnormalities, and the analysis of such abnormalities provides us with important information for disease classification, treatment selection and prognosis. Some chromosomal abnormalities albeit recurrent are rare such as tetrasomy 8 or isochromosome 5p. In addition, erratic chromosomal rearrangements may occur in AML, sometimes unbalanced and also accompanied by other abnormalities. Knowledge on the contribution of rare abnormalities to AML disease, progression and prognosis is limited. Here we report a unique case of acute monoblastic leukemia with gain of i(5)(p10), tetrasomy 8, an unbalanced translocation der(19)t(17;19)(q23;p13.3) and mutated NPM1. RESULTS: Bone marrow cells were examined by conventional karyotyping, fluorescence in situ hybridization (FISH) and mutation analysis at diagnosis and follow-up. At diagnosis we detected trisomy 8, an unbalanced translocation der(19)t(17;19)(q23;p13.3) and mutated NPM1. During the course of the disease we observed clonal evolution with gain of i(5)(p10), tetrasomy 8 and eventually duplication of der(19)t(17;19)(q23;p13.3). By using the der(19)t(17;19) as clonal marker, we found that i(5)(p10) and tetrasomy 8 were secondary genetic events and that tetrasomy 8 had clonally evolved from trisomy 8. CONCLUSIONS: This case of acute monoblastic leukemia presents a combination of rare chromosomal abnormalities including the unbalanced translocation der(19)t(17;19)(q23;p13.3), hitherto un-reported in AML. In addition, our case supports the hypothesis of a step-wise clonal evolution from trisomy 8 to tetrasomy 8 in AML. Reporting and collecting data of rare chromosomal abnormalities will add information to AML disease, progression and prognosis, and may eventually translate to improved patient management

Anastrozole versus tamoxifen for the prevention of locoregional and contralateral breast cancer in postmenopausal women with locally excised ductal carcinoma in situ (IBIS-II DCIS): a double-blind, randomised controlled trial

Background Third-generation aromatase inhibitors are more effective than tamoxifen for preventing recurrence in postmenopausal women with hormone-receptor-positive invasive breast cancer. However, it is not known whether anastrozole is more effective than tamoxifen for women with hormone-receptor-positive ductal carcinoma in situ (DCIS). Here, we compare the efficacy of anastrozole with that of tamoxifen in postmenopausal women with hormone-receptor-positive DCIS. Methods In a double-blind, multicentre, randomised placebo-controlled trial, we recruited women who had been diagnosed with locally excised, hormone-receptor-positive DCIS. Eligible women were randomly assigned in a 1:1 ratio by central computer allocation to receive 1 mg oral anastrozole or 20 mg oral tamoxifen every day for 5 years. Randomisation was stratified by major centre or hub and was done in blocks (six, eight, or ten). All trial personnel, participants, and clinicians were masked to treatment allocation and only the trial statistician had access to treatment allocation. The primary endpoint was all recurrence, including recurrent DCIS and new contralateral tumours. All analyses were done on a modified intention-to-treat basis (in all women who were randomised and did not revoke consent for their data to be included) and proportional hazard models were used to compute hazard ratios and corresponding confidence intervals. This trial is registered at the ISRCTN registry, number ISRCTN37546358. Results Between March 3, 2003, and Feb 8, 2012, we enrolled 2980 postmenopausal women from 236 centres in 14 countries and randomly assigned them to receive anastrozole (1449 analysed) or tamoxifen (1489 analysed). Median follow-up was 7·2 years (IQR 5·6–8·9), and 144 breast cancer recurrences were recorded. We noted no statistically significant difference in overall recurrence (67 recurrences for anastrozole vs 77 for tamoxifen; HR 0·89 [95% CI 0·64–1·23]). The non-inferiority of anastrozole was established (upper 95% CI <1·25), but its superiority to tamoxifen was not (p=0·49). A total of 69 deaths were recorded (33 for anastrozole vs 36 for tamoxifen; HR 0·93 [95% CI 0·58–1·50], p=0·78), and no specific cause was more common in one group than the other. The number of women reporting any adverse event was similar between anastrozole (1323 women, 91%) and tamoxifen (1379 women, 93%); the side-effect profiles of the two drugs differed, with more fractures, musculoskeletal events, hypercholesterolaemia, and strokes with anastrozole and more muscle spasm, gynaecological cancers and symptoms, vasomotor symptoms, and deep vein thromboses with tamoxifen. Conclusions No clear efficacy differences were seen between the two treatments. Anastrozole offers another treatment option for postmenopausal women with hormone-receptor-positive DCIS, which may be be more appropriate for some women with contraindications for tamoxifen. Longer follow-up will be necessary to fully evaluate treatment differences

Nonantimicrobial actions of macrolides:Overview and perspectives for future development

Macrolides are among the most widely prescribed broad spectrum antibacterials, particularly for respiratory infections. It is now recognized that these drugs, in particular azithromycin, also exert time-dependent immunomodulatory actions that contribute to their therapeutic benefit in both infectious and other chronic inflammatory diseases. Their increased chronic use in airway inflammation and, more recently, of azithromycin in COVID-19, however, has led to a rise in bacterial resistance. An additional crucial aspect of chronic airway inflammation, such as chronic obstructive pulmonary disease, as well as other inflammatory disorders, is the loss of epithelial barrier protection against pathogens and pollutants. In recent years, azithromycin has been shown with time to enhance the barrier properties of airway epithelial cells, an action that makes an important contribution to its therapeutic efficacy. In this article, we review the background and evidence for various immunomodulatory and time-dependent actions of macrolides on inflammatory processes and on the epithelium and highlight novel nonantibacterial macrolides that are being studied for immunomodulatory and barrier-strengthening properties to circumvent the risk of bacterial resistance that occurs with macrolide antibacterials. We also briefly review the clinical effects of macrolides in respiratory and other inflammatory diseases associated with epithelial injury and propose that the beneficial epithelial effects of nonantibacterial azithromycin derivatives in chronic inflammation, even given prophylactically, are likely to gain increasing attention in the future. SIGNIFICANCE STATEMENT: Based on its immunomodulatory properties and ability to enhance the protective role of the lung epithelium against pathogens, azithromycin has proven superior to other macrolides in treating chronic respiratory inflammation. A nonantibiotic azithromycin derivative is likely to offer prophylactic benefits against inflammation and epithelial damage of differing causes while preserving the use of macrolides as antibiotics.European Innovation Counci