Infection control, genetic assessment of drug resistance and drug susceptibility testing in the current management of multidrug/extensively-resistant tuberculosis (M/XDR-TB) in Europe: A tuberculosis network European Trialsgroup (TBNET) study

Aim Europe has the highest documented caseload and greatest increase in multidrug and extensively drug-resistant tuberculosis (M/XDR-TB) of all World Health Organization (WHO) regions. This survey examines how recommendations for M/XDR-TB management are being implemented. Methods TBNET is a pan-European clinical research collaboration for tuberculosis. An email survey of TBNET members collected data in relation to infection control, access to molecular tests and basic microbiology with drug sensitivity testing. Results 68/105 responses gave valid information and were from countries within the WHO European Region. Inpatient beds matched demand, but single rooms with negative pressure were only available in low incidence countries; ultraviolet decontamination was used in 5 sites, all with >10 patients with M/XDR-TB per year. Molecular tests for mutations associated with rifampicin resistance were widely available (88%), even in lower income and especially in high incidence countries. Molecular tests for other first line and second line drugs were less accessible (76 and 52% respectively). A third of physicians considered that drug susceptibility results were delayed by > 2 months. Conclusion Infection control for inpatients with M/XDR-TB remains a problem in high incidence countries. Rifampicin resistance is readily detected, but tests to plan regimens tailored to the drug susceptibilities of the strain of Mycobacterium tuberculosis are significantly delayed, allowing for further drug resistance to develop

Relationship between HER2 gene status and selected potential biological features related to trastuzumab resistance and its influence on survival of breast cancer patients undergoing trastuzumab adjuvant treatment

Agnieszka Adamczyk,1 Anna Kruczak,1 Agnieszka Harazin-Lechowska,1 Aleksandra Ambicka,1 Aleksandra Grela-Wojewoda,2 Małgorzata Domagała-Haduch,2 Anna Janecka-Widła,1 Kaja Majchrzyk,1 Anna Cichocka,1 Janusz Ryś,1 Joanna Niemiec1 1Department of Tumour Pathology, 2Department of Systemic and Generalized Malignancies, Maria Sklodowska-Curie Memorial Cancer Centre and Institute of Oncology, Cracow Branch, Cracow, Poland Background: The aim of the study was to investigate if parameters associated with human epidermal growth factor receptor type 2 (HER2) status (HER2 gene copy number, HER2/CEP17 ratio or polysomy of chromosome 17) are related to various biological features potentially responsible for trastuzumab resistance (PTEN, IGF-1R, MUC4, EGFR, HER3, HER4, and mutation status of PIK3CA) as well as their influence on survival of HER2-positive breast cancer patients treated with adjuvant chemotherapy and trastuzumab. Patients and methods: The investigated group consisted of 117 patients with invasive ductal breast cancer (T≥1, N≥0, M0) with overexpression of HER2, who underwent radical surgery between 2007 and 2014. Status of ER, PR, and HER2 expression was retrieved from patients’ files. HER2 gene copy number was investigated by fluorescence in situ hybridization using PathVysion HER-2 DNA Probe Kit II. Expression of PTEN, IGF-1R, MUC4, EGFR, HER3, and HER4 was assessed immunohistochemically on formalin-fixed paraffin-embedded tissue sections. PIK3CA mutation status was determined by qPCR analysis. Results: Overexpression of HER2 protein (IHC 3+) and ER negativity corresponded to higher HER2 copy number and HER2/CEP17 ratio (p<0.001). Tumors with polysomy were characterized by higher HER2 gene copy number but lower HER2/CEP17 ratio (p<0.026, p<0.001). Patients with tumors featuring HER3 immunonegativity or low HER2/CEP17 ratio (≤4) were characterized by 100% metastasis-free survival (p=0.018, p=0.062). Conclusion: Presence of both unfavorable factors, ie, HER3 expression and high HER2/CEP17 ratio, allowed to distinguish a group of patients with worse prognosis (p=0.001). Keywords: HER2-overexpressing breast cancer, HER2 amplification, HER2 gene copy number, HER2/CEP17 ratio, HER3 expression, trastuzuma

Signatures of post-zygotic structural genetic aberrations in the cells of histologically normal breast tissue that can predispose to sporadic breast cancer

Sporadic breast cancer (SBC) is a common disease without robust means of early risk prediction in the population. We studied 282 females with SBC, focusing on copy number aberrations in cancer-free breast tissue (uninvolved margin, UM) outside the primary tumor (PT). In total, 1162 UMs (1-14 per breast) were studied. Comparative analysis between UM(s), PT(s), and blood/skin from the same patient as a control is the core of the study design. We identified 108 patients with at least one aberrant UM, representing 38.3% of cases. Gains in gene copy number were the principal type of mutations in microscopically normal breast cells, suggesting that oncogenic activation of genes via increased gene copy number is a predominant mechanism for initiation of SBC pathogenesis. The gain of ERBB2, with overexpression of HER2 protein, was the most common aberration in normal cells. Five additional growth factor receptor genes (EGFR, FGFR1, IGF1R, LIFR, and NGFR) also showed recurrent gains, and these were occasionally present in combination with the gain of ERBB2. All the aberrations found in the normal breast cells were previously described in cancer literature, suggesting their causative, driving role in pathogenesis of SBC. We demonstrate that analysis of normal cells from cancer patients leads to identification of signatures that may increase risk of SBC and our results could influence the choice of surgical intervention to remove all predisposing cells. Early detection of copy number gains suggesting a predisposition toward cancer development, long before detectable tumors are formed, is a key to the anticipated shift into a preventive paradigm of personalized medicine for breast cancer.De 2 första författarna delar förstaförfattarskapet.</p