Erica Sermijn

The impact of proband mediated information dissemination in families with a BRCA1/2 gene mutation

Since the identification of the BRCA1 (17q21)1 and BRCA2 (13q12–13)2,3 genes as the major predisposition genes for hereditary breast and ovarian cancer (HBOC),4 genetic counselling and predictive testing has progressively been introduced and applied throughout the world. In many centres, the initial approach towards these families has been very cautious, mainly because of lack of prospective data on the effects of preventive measures to be proposed for mutation carriers and the uncertainty of the psychological impact of this information within these families. In the Familial Cancer Clinic of the Vrije Universiteit Brussel (VUB), Belgium, a multidisciplinary team adopted a protocol of ‘non-directive’ counselling based on the international guidelines used for Huntington families.5 Non-directiveness is a form of counselling that includes the presentation of several options without recommending a specific choice, but in the context of this study, non-directiveness is rather focused on the way the counselling team behaves towards other family members. According to this aspect of the protocol, the proband is the major and initially unique interlocutor between the family and the familial cancer team as represented by the counsellor. The proband helps in establishing the family pedigree and is informed about the various aspects of HBOC and predictive genetic testing. After a mutation is found, the relevant information and availability of predictive testing is communicated to the remainder of the family, initially through the proband and subsequently through other family members who come forward for testing. In contrast to persons affected by Huntington’s disease, several options are available to mutation carriers, which can alter their outcome. Recently, prospective data on the effectiveness of some preventive options have emerged, including the short term protection provided by preventive mastectomy compared with preventive screening.6 The availability of effective screening and prophylactic treatment makes “the right …

Cancer predisposing missense and protein truncating BARD1 mutations in non‐BRCA1 or BRCA2 breast cancer families

Fifteen years ago BRCA1 and BRCA2 were reported as high penetrant breast cancer predisposing genes. However, mutations in these genes are found in only a fraction of high risk families. BARD1 is a candidate breast cancer gene, but only a limited number of missense mutations with rather unclear pathogenic consequences have been reported.We screened 196 high risk breast cancer families for the occurrence of BARD1 variants. All genetic variants were analyzed using clinical information as well as IN SILICO predictive tools, including protein modeling. We found three candidate pathogenic mutations in seven families including a first case of a protein truncating mutation (p.Glu652fs) removing the entire second BRCT domain of BARD1. In conclusion, we provide evidence for an increased breast cancer risk associated to specific BARD1 germline mutations. However, these BARD1 mutations occur in a minority of hereditary breast cancer families. ©2010 Wiley‐Liss, Inc.

Undiagnosed and comorbid disorders in patients with presumed chronic fatigue syndrome

OBJECTIVE To assess undiagnosed and comorbid disorders in patients referred to a tertiary care center with a presumed diagnosis of chronic fatigue syndrome (CFS). METHODS Patients referred for chronic unexplained fatigue entered an integrated diagnostic pathway, including internal medicine assessment, psychodiagnostic screening, physiotherapeutic assessment and polysomnography+multiple sleep latency testing. Final diagnosis resulted from a multidisciplinary team discussion. Fukuda criteria were used for the diagnosis of CFS, DSM-IV-TR criteria for psychiatric disorders, ICSD-2 criteria for sleep disorders. RESULTS Out of 377 patients referred, 279 (74.0%) were included in the study [84.9% female; mean age 38.8years (SD 10.3)]. A diagnosis of unequivocal CFS was made in 23.3%. In 21.1%, CFS was associated with a sleep disorder and/or psychiatric disorder, not invalidating the diagnosis of CFS. A predominant sleep disorder was found in 9.7%, 19.0% had a psychiatric disorder and 20.8% a combination of both. Only 2.2% was diagnosed with a classical internal disease. In the total sample, a sleep disorder was found in 49.8%, especially obstructive sleep apnea syndrome, followed by psychophysiologic insomnia and periodic limb movement disorder. A psychiatric disorder was diagnosed in 45.2%; mostly mood and anxiety disorder. CONCLUSIONS A multidisciplinary approach to presumed CFS yields unequivocal CFS in only a minority of patients, and reveals a broad spectrum of exclusionary or comorbid conditions within the domains of sleep medicine and psychiatry. These findings favor a systematic diagnostic approach to CFS, suitable to identify a wide range of diagnostic categories that may be subject to dedicated care.

Hereditary breast cancer: from bench to bedside.

Purpose of review The proportion of breast cancers directly attributable to determinant hereditary factors is estimated to be 5–10%. A number of recent findings with regard to hereditary breast cancer should affect the criteria and scope of routine genetic testing and, soon, breast cancer therapy. Recent findings The number of genes causing genetic cancer has expanded, mostly with genes that encode proteins that function in the BRCA1/2 pathways. The risk level associated with some genes is still under investigation, but is high for specific mutations. Some mutant alleles occur frequently, some are rare. High-throughput technologies will progressively allow investigating all genes involved in genetic (breast) cancer risks in all individuals for whom this information could be relevant. This and the emerging novel treatment options specific for cancers in mutation carriers will oblige us to progressively drop all currently used selection criteria such as familial phenotype for genomic testing. A major challenge remains the effective penetration of this knowledge in the professional and lay community, the broad application and financing of this high-throughput technology, and the identification of as yet unknown breast cancer predisposition genes. Summary The assessment of breast cancer predisposition genes, previously only an optional predictive genetic test, is growing in importance as it also becomes a therapeutic predictive test.

Characterization of LEDGF/p75 Genetic Variants and Association with HIV-1 Disease Progression

Background As Lens epithelium-derived growth factor (LEDGF/p75) is an important co-factor involved in HIV-1 integration, the LEDGF/p75-IN interaction is a promising target for the new class of allosteric HIV integrase inhibitors (LEDGINs). Few data are available on the genetic variability of LEDGF/p75 and the influence on HIV disease in vivo. This study evaluated the relation between LEDGF/p75 genetic variation, mRNA expression and HIV-1 disease progression in order to guide future clinical use of LEDGINs. Methods Samples were derived from a therapy-naïve cohort at Ghent University Hospital and a Spanish long-term-non-progressor cohort. High-resolution melting curve analysis and Sanger sequencing were used to identify all single nucleotide polymorphisms (SNPs) in the coding region, flanking intronic regions and full 3′UTR of LEDGF/p75. In addition, two intronic tagSNPs were screened based on previous indication of influencing HIV disease. LEDGF/p75 mRNA was quantified in patient peripheral blood mononuclear cells (PBMC) using RT-qPCR. Results 325 samples were investigated from patients of Caucasian (n = 291) and African (n = 34) origin, including Elite (n = 49) and Viremic controllers (n = 62). 21 SNPs were identified, comprising five in the coding region and 16 in the non-coding regions and 3′UTR. The variants in the coding region were infrequent and had no major impact on protein structure according to SIFT and PolyPhen score. One intronic SNP (rs2737828) was significantly under-represented in Caucasian patients (P<0.0001) compared to healthy controls (HapMap). Two SNPs showed a non-significant trend towards association with slower disease progression but not with LEDGF/p75 expression. The observed variation in LEDGF/p75 expression was not correlated with disease progression. Conclusions LEDGF/p75 is a highly conserved protein. Two non-coding polymorphisms were identified indicating a correlation with disease outcome, but further research is needed to clarify phenotypic impact. The conserved coding region and the observed variation in LEDGF/p75 expression are important characteristics for clinical use of LEDGINs.

INVASIVE ASPERGILLOSIS IN PATIENTS WITH CIRRHOSIS, A CASE REPORT AND REVIEW OF THE LAST 10 YEARS

Abstract Background: Untreated invasive aspergillosis (IA) is lethal, yet diagnosis is often delayed. Recognising the risk factors can lead to earlier diagnosis. We present a case of an invasive pulmonary aspergillosis in a patient with cirrhosis, who had been treated with corticosteroids for 2.5 weeks for alcoholic hepatitis. He was successfully treated with liposomal amphotericin B and caspofungin (first in combination, then caspofungin monotherapy). Purpose: to evaluate the role of aspergillosis in cirrhosis Methods: A literature search on aspergillosis in cirrhosis and liver failure patients was conducted in PubMed/ Medline (2002-dec 2012), according to pre-set selection criteria. Results: 20 out of 330 articles were retrieved, representing 43 patients with cirrhosis and/or liver failure who had an aspergillosis infection. Most Aspergillus (A.) infections were due to A. fumigatus and the lungs were the most frequent organ involved (42/43). 58% of the patients used steroids and mortality was 53,5%. The most frequent used antifungal was caspofungin. Discussion: Diagnosis of IA is difficult and there might be a delay in diagnosis since cirrhosis is not recognised as one of the classical risk factors. Mortality was 53,5%, but this is lower than in previous decades. Since voriconazole is hepatotoxic, treatment with caspofungin and /or amphotericin is preferable. Conclusion: Early recognition of aspergillosis in a cirrhosis/ liver failure patient is crucial and should prompt direct treatment.

CYCLIC VOMITING SYNDROME: CASE REPORT AND SHORT REVIEW OF THE LITERATURE

Abstract Cyclic vomiting syndrome (CVS) is a functional disorder that is considered to be a manifestation of migraine diathesis. It is characterized by stereotypical episodes of severe nausea and vomiting lasting several hours or days, with return to baseline health between episodes. CVS is still an insufficiently known syndrome among physicians, and is therefore often misdiagnosed. Treatment focuses on the different phases of CVS, with interepisodic prophylaxis, abortive therapy in the prodromal phase of CVS, and supportive care during an acute vomiting episode. Anti-migraine medications have been effectively used for prophylaxis in many patients. We report a case of CVS successfully treated with flunarizine, a non-selective calcium antagonist.

Implementation of a multidisciplinary infectious diseases team in a tertiary hospital within an Antimicrobial Stewardship Program

Abstract Background: In January 2011, as part of an antimicrobial stewardship program the Antimicrobial Management Team (AMT) at the Ghent University Hospital initiated a multidisciplinary Infectious Diseases Team (MIT) consisting of infectious diseases physicians, clinical microbiologists, and clinical pharmacists. The aim of this study is to describe the type and acceptance rate of recommendations provided by the MIT. Method: Prospective, observational study in a tertiary care, university teaching hospital with 1062 beds in non-consecutive hospitalized adult patients, excluding intensive care units and paediatrics. Results: The MIT communicated 432 recommendations in 87 days observed. Of the 293 patients for whom a recommendation was made, the median age was 57 years (range: 16–91 years) and 169 (57·7%) were male. Skin or soft tissue infections (14%), respiratory tract infections (13%), infections without known focus (11%), abdominal infections (11%), and bone infections (8%) were most common. Recommendations were made to perform additional clinical investigation(s) [N = 137 (27%)], to adjust the dose of an antimicrobial drug [N = 42 (8%)], to stop an antimicrobial drug [N = 104 (21%)], to switch from a parenteral to an oral drug [N = 39 (8%)] or to initiate an antimicrobial drug [N = 178 (36%)], with an acceptance rate of 73·0%, 83·3%, 81·7%, 76·9%, and 84·0%, respectively. Conclusions: The MIT formulated about five recommendations a day primarily focusing on pharmacotherapy, but also on clinical investigations. In both fields, a high acceptance rate was observed.

Calciphylaxis: a rare complication in alcoholic liver disease.

Abstract Calciphylaxis, or calcific uremic arteriolopathy (CUA) is a rare but well described entity in patients with end-stage renal disease (ESRD) and/or hyperparathyroidism. CUA is characterized by systemic acute calcification of the small and intermediate dermal vasculature that can lead to epidermal ischemia, ulceration, and necrosis. Cutaneous lesions of calciphylaxis characteristically begin as tender, violaceous, livedoid discolorations. The mechanisms of disease remain poorly understood although abnormal bone and mineral metabolism and hyperparathyroidism can contribute to CUA. Therapeutic strategies are of unproven benefit and mortality remains high. Calciphylaxis has also been extremely rarely reported in patients without ESRD and/or hyperparathyroidism. We report an unusual case of calciphylaxis in a patient with alcoholic liver cirrhosis and normal renal function, without any alteration in the phosphocalcic and parathyroid hormone (PTH) metabolisms.

Disseminated Infection with Mycobacterium tilburgii in a Male Immunocompromised Patient

ABSTRACT Mycobacterium tilburgii is a nonculturable nontuberculous mycobacterium identifiable only by molecular methods. We report a case of disseminated M. tilburgii infection illustrating the importance of 16S rRNA gene sequencing to determine the responsible mycobacterial pathogen and the difficulties in tailoring antimycobacterial treatment in the absence of a culturable organism.