No abstract

Background:Trastuzumab resistance hampers its well-known efficacy to control HER2-positive breast cancer. The involvement of PI3K/Akt pathway in this mechanism is still not definitively confirmed.Methods:We selected 155 patients treated with trastuzumab after development of metastasis or as adjuvant/neoadjuvant therapy. We performed immunohistochemistry for HER2, ER/PR, epidermal growth factor 1-receptor (EGFR), α-insulin-like growth factor 1-receptor (IGF1R), phosphatase and tensin homologue (PTEN), p110α, pAkt, pBad, pmTOR, pMAPK, MUC1, Ki67, p53 and p27; mutational analysis of PIK3CA and PTEN, and PTEN promoter hypermethylation.Results:We found 46% ER/PR-positive tumours, overexpression of EGFR (15%), α-IGF1R (25%), p110α (19%), pAkt (28%), pBad (22%), pmTOR (23%), pMAPK (24%), MUC1 (80%), PTEN loss (20%), and PTEN promoter hypermethylation (20%). PIK3CA and PTEN mutations were detected in 17% and 26% tumours, respectively. Patients receiving adjuvant trastuzumab with α-IGF1R or pBad overexpressing tumours presented shorter progression-free survival (PFS) (all P⩽0.043). Also, p110α and mTOR overexpression, liver and brain relapses implied poor overall survival (OS) (all P⩽0.041). In patients with metastatic disease, decreased PFS correlated with p110α expression (P=0.024), whereas for OS were the presence of vascular invasion and EGFR expression (P⩽0.019; Cox analysis).Conclusion:Our results support that trastuzumab resistance mechanisms are related with deregulation of PTEN/PI3K/Akt/mTOR pathway, and/or EGFR and IGF1R overexpression in a subset of HER2-positive breast carcinomas.

Nocardiosis has been believed to be caused by the members of the Nocardia asteroides complex and the Nocardia brasiliensis species. However, recent advances in genotypic identification have shown that the genus exhibits considerable taxonomic complexity and the phenotypic markers used in the past for its identification can be ambiguous. The aim of this study was to assess the species distribution of Nocardia isolates and to determine whether there are differences in pathogenicity or antimicrobial susceptibility between the different species identified. Nocardia isolates obtained over a 7 year period were retrospectively reviewed. The isolates were identified genotypically, their antibiotic susceptibility was tested and the clinical data of the 27 patients were retrieved. Eight different Nocardia species were identified: Nocardia farcinica (n59), Nocardia abscessus (n56), Nocardia cyriacigeorgica (n56), Nocardia otitidiscaviarum (n52), Nocardia nova (n51), N. nova complex (n51), Nocardia carnea (n51) and Nocardia transvalensis complex (n51). All species were susceptible to co-trimoxazole but different patterns of susceptibility to other agents were observed. All patients had active comorbidities at the time of infection. A total of 19 patients were immunosuppressed, due to human immunodeficiency virus infection, chronic corticosteroid therapy, immunosupressive therapy or haematological malignancies. Six patients displayed a Charlson comorbidity index score above 4. Global mortality was 50 % while attributable mortality was 34.6 %. Patients infected with N. farcinica -the most resistant species -had the highest Charlson index score and the highest mortality rate. Accurate identification of the species and susceptibility testing of Nocardia isolates may play an important role in diagnosis and treatment.