Nosocomial outbreak of extended-spectrum ß-lactamase-producing Enterobacter cloacae among cardiothoracic surgical patients: causes and consequences.

BACKGROUND: Enterobacteriaceae are recognized as leading pathogens of healthcare-associated infections. AIM: To report the investigation of a nosocomial outbreak of extended-spectrum ß-lactamase-producing Enterobacter cloacae affecting cardiothoracic surgery patients in a Belgian academic hospital. METHODS: Cases were defined based on epidemiological and microbiological investigations, including molecular typing using repetitive element-based polymerase chain reaction and multi-locus sequence typing. Case-control studies followed by field evaluations allowed the identification of a possible reservoir, and the retrospective assessment of human and financial consequences. FINDINGS: Over a three-month period, 42 patients were infected or colonized by CTX-M-15-producing E. cloacae strains that belonged to the same clonal lineage. Acquisition mainly occurred in the intensive care unit (N = 23) and in the cardiothoracic surgery ward (N = 16). All but one patient had, prior to acquisition, undergone a cardiothoracic surgical procedure, monitored by the same transoesophageal echocardiography (TOE) probe in the operating room. Despite negative microbiological culture results, the exclusion of the suspected probe resulted in rapid termination of the outbreak. Overall, the outbreak was associated with a high mortality rate among infected patients (40%) as well as significant costs (€266,550). CONCLUSION: The outbreak was indirectly shown to be associated with the contamination of a manually disinfected TOE probe used per-operatively during cardiothoracic surgery procedures, because withdrawal of the putative device led to rapid termination of the outbreak.

BRCA1, BRCA2 and PALB2 mutations and CHEK2 c.1100delC in different South African ethnic groups diagnosed with premenopausal and/or triple negative breast cancer.

BACKGROUND: Current knowledge of the aetiology of hereditary breast cancer in the four main South African population groups (black, coloured, Indian and white) is limited. Risk assessments in the black, coloured and Indian population groups are challenging because of restricted information regarding the underlying genetic contributions to inherited breast cancer in these populations. We focused this study on premenopausal patients (diagnosed with breast cancer before the age of 50; n = 78) and triple negative breast cancer (TNBC) patients (n = 30) from the four South African ethnic groups. The aim of this study was to determine the frequency and spectrum of germline mutations in BRCA1, BRCA2 and PALB2 and to evaluate the presence of the CHEK2 c.1100delC allele in these patients. METHODS: In total, 108 South African breast cancer patients underwent mutation screening using a Next-Generation Sequencing (NGS) approach in combination with Multiplex Ligation-dependent Probe Amplification (MLPA) to detect large rearrangements in BRCA1 and BRCA2. RESULTS: In 13 (12 %) patients a deleterious mutation in BRCA1/2 was detected, three of which were novel mutations in black patients. None of the study participants was found to have an unequivocal pathogenic mutation in PALB2. Two (white) patients tested positive for the CHEK2 c.1100delC mutation, however, one of these also carried a deleterious BRCA2 mutation. Additionally, six variants of unknown clinical significance were identified (4 in BRCA2, 2 in PALB2), all in black patients. Within the group of TNBC patients, a higher mutation frequency was obtained (23.3 %; 7/30) than in the group of patients diagnosed before the age of 50 (7.7 %; 6/78). CONCLUSION: This study highlights the importance of evaluating germline mutations in major breast cancer genes in all of the South African population groups. This NGS study shows that mutation analysis is warranted in South African patients with triple negative and/or in premenopausal breast cancer.

Hepatitis E seroprevalence in east and west Flanders, Belgium.

BACKGROUND AND STUDY AIM: Hepatitis E virus (HEV) infection is increasingly recognized as a cause of hepatitis in developed countries. The goal of this study is to provide an estimate of the seroprevalence of HEV in Belgium, more precisely in East and West Flanders, since data for this country are currently lacking. PATIENTS AND METHODS: One hundred patients presenting at the gynecological (mainly fertility center) or orthopedic clinics of our hospital were randomly selected to be tested for anti-HEV IgG antibodies using a sensitive indirect ELISA and, in the case of a borderline result, a strip immunoassay. RESULTS: The anti-HEV IgG seroprevalence was found to be 14%. CONCLUSIONS: The observed seroprevalence rate suggests that HEV infection is not an uncommon occurrence in Belgium. Comparisons with published seroprevalence data of other Western European countries should be made with caution due to differences in the analytical performance of anti-HEV IgG assays.

Clinicopathological significance of indoleamine 2,3-dioxygenase 1 expression in colorectal cancer.

BACKGROUND: Indoleamine 2,3-dioxygenase 1 (IDO1) is a tryptophan-catabolising enzyme that induces immune tolerance by modulating T-cell responses. Carcinomas may create an immunosuppressive state via IDO1 expression. Here we examined a possible contribution of IDO1 on this phenomenon and investigated whether IDO1 has prognostic value in colorectal cancer (CRC). METHODS: IDO1 expression was investigated by quantitative PCR and western blotting in three colon cancer cell lines, in basal state and after interferon (IFN)-γ stimulation. Semi-quantitative immunohistochemistry was used to evaluate IDO1 expression in 265 pT1-4N0-2Mx-staged CRCs. Results were related to clinical variables and correlated with amounts of CD3(+) and CD8(+) T lymphocytes, which were quantitatively evaluated using image analysis. RESULTS: In vitro expression of IDO1 depended on IFN-γ stimulation. Higher IDO1 expression at the tumour invasion front was an independent adverse prognostic factor in pT1-4N1Mx-staged CRC. It was associated with overall survival (P=0.001) and with metachronous metastases (P=0.018). IDO1 expression was not associated with the presence of CD3(+) or CD8(+) T lymphocytes. CONCLUSION: Higher IDO1 expression at the tumour invasion front is involved in CRC progression and correlates with impaired clinical outcome, suggesting that IDO1 is an independent prognostic indicator for CRC.

An integrative genomics screen uncovers ncRNA T-UCR functions in neuroblastoma tumours.

Different classes of non-coding RNAs, including microRNAs, have recently been implicated in the process of tumourigenesis. In this study, we examined the expression and putative functions of a novel class of non-coding RNAs known as transcribed ultraconserved regions (T-UCRs) in neuroblastoma. Genome-wide expression profiling revealed correlations between specific T-UCR expression levels and important clinicogenetic parameters such as MYCN amplification status. A functional genomics approach based on the integration of multi-level transcriptome data was adapted to gain insights into T-UCR functions. Assignments of T-UCRs to cellular processes such as TP53 response, differentiation and proliferation were verified using various cellular model systems. For the first time, our results define a T-UCR expression landscape in neuroblastoma and suggest widespread T-UCR involvement in diverse cellular processes that are deregulated in the process of tumourigenesis.

Escape from p53-mediated tumor surveillance in neuroblastoma: switching off the p14(ARF)-MDM2-p53 axis.

A primary failsafe program against unrestrained proliferation and oncogenesis is provided by the p53 tumor suppressor protein, inactivation of which is considered as a hallmark of cancer. Intriguingly, mutations of the TP53 gene are rarely encountered in neuroblastoma tumors, suggesting that alternative p53-inactivating lesions account for escape from p53 control in this childhood malignancy. Several recent studies have shed light on the mechanisms by which neuroblastoma cells circumvent the p53-driven antitumor barrier. We review here these mechanisms for evasion of p53-mediated growth control and conclude that deregulation of the p14(ARF)-MDM2-p53 axis seems to be the principal mode of p53 inactivation in neuroblastoma, opening new perspectives for targeted therapeutic intervention.

Astrocyte elevated gene-1 contributes to the pathogenesis of neuroblastoma.

Neuroblastoma, derived from neural crest progenitor cells, is the most common extracranial solid tumor of childhood. Astrocyte elevated gene-1 (AEG-1) is a primary mediator of tumor progression and metastasis in several human cancers. In this study, we investigated the potential contribution of AEG-1 in human neuroblastoma pathogenesis. AEG-1 expression was significantly elevated in neuroblastoma patient-derived samples and neuroblastoma cell lines as compared with normal peripheral nerve tissues, normal astrocytes and immortalized melanocytes. Knockdown of AEG-1 by small interfering RNA reduced the tumorigenic properties of highly aggressive neuroblastoma cells. Conversely, over-expression of AEG-1 enhanced proliferation and expression of the transformed state in less aggressive neuroblastoma cells through activation of the phosphatidylinositol 3-kinase-Akt-signaling pathway and stabilization of MYCN. These provocative results indicate that AEG-1 may play a crucial role in the pathogenesis of neuroblastoma and could represent a potential target for therapeutic intervention.