Lynch Syndrome Improving Diagnostics and Surveillance

Lynch syndrome is the most common hereditary predisposition for colorectal cancer and accounts for 2-3% of all colorectal cancer cases. In addition, these patients are also at increased risk of developing extracolonic cancers, especially endometrial cancer in women. Since surveillance programs can significantly reduce morbidity and mortality in individuals with Lynch syndrome, identification of these individuals is of great importance. In chapter 3, two prediction models for Lynch syndrome were evaluated and one of those models, the PREMM5 model, was improved by adding the location of colorectal cancer as a new variable. In chapter 4 and 5 we showed that routine molecular screening for Lynch syndrome in colorectal cancer patients and endometrial cancer patients up to 70 years of age is cost-effective. In chapter 6, no Lynch syndrome patients were identified by screening for Lynch syndrome among all advanced adenomas in the population based CRC screening program. Therefore, routine screening of all adenomas is probably not effective. In chapter 7 and 8 a functional assay to classify variants of unknown significance in the mismatch repair genes was evaluated and 26 variants in MLH1, MSH2 and MSH6 were analyzed. In most cases the classification was in line with clinical data, prediction programs and results of other functional assays. Although the cancer risk in Lynch syndrome patients is highly dependent on the gene involved, all patients are currently offered the same surveillance. Therefore, chapter 9 evaluates the yield of colonoscopy surveillance in MLH1, MSH2, MSH6 and PMS2 mutation carriers. Finally, chapter 10 discusses the results of this thesis in perspective of the current guidelines and clinical practice

Al2O3 Surface Passivation Characterized on Hydrophobic and Hydrophilic c-Si by a Combination of QSSPC, CV, XPS and FTIR

Abstract In this work, the influence of the c-Si surface finishing (hydrophobic/hydrophilic) prior to the deposition of the Al2O3 passivation layer on the passivation quality is investigated. The samples are characterized by a combination of Quasi-Steady-State-PhotoConductance (QSSPC) Capacity-Conductance (CV), X-ray Photoelectron Spectroscopy (XPS) and Fourier Transformed InfraRed (FTIR) measurements. Furthermore, FTIR measurements are used to determine the thickness of interfacial SiOx layer

Robustness for a single railway line: Analytical and simulation methods

[EN] Railway scheduling has been a significant issue in the railway industry. Over the last few years, numerous approaches and tools have been developed to compute railway scheduling. However, robust solutions are necessary to absorb short disruptions. In this paper, we present the robustness problem from the point of view of railway operators and we propose analytical and simulation methods to measure robustness in a single railway line. In the analytical approach, we have developed some formulas to measure robustness based on the study of railway line infrastructure topology and buffer times. In the simulation approach, we have developed a software tool to assess the robustness for a given schedule. These methods have been inserted in MOM (More information can be found at the MOM web page http://www.dsic.upv.es/users/ia/gps/MOM), which is a project in collaboration with the Spanish Railway Infrastructure Manager (ADIF). © 2012 Elsevier Ltd. All rights reserved.This work has been partially supported by the research project TIN2010-20976-C02-01 (Min. de Economia y Competitividad, Spain) and project PIRSES-GA-2011-294931 (FP7-PEOPLE-2011-IRSES).Salido Gregorio, MA.; Barber Sanchís, F.; Ingolotti Hetter, LP. (2012). Robustness for a single railway line: Analytical and simulation methods. Expert Systems with Applications. 39(18):13305-13327. https://doi.org/10.1016/j.eswa.2012.05.071S1330513327391

Posterior lung herniation after a coughing spell: a case report

Lung hernias are rare, occurring most commonly after trauma or surgery. Spontaneous lung hernias are even rarer and have only been reported as occurring anteriorly. We present a 72-year-old male who developed a spontaneous posterior lung hernia after a severe coughing episode. We describe the evaluation and surgical management of this unusual condition and provide a brief review of the literature

Suspected Lynch syndrome associated MSH6 variants: A functional assay to determine their pathogenicity

Lynch syndrome (LS) is a hereditary cancer predisposition caused by inactivating mutations in DNA mismatch repair (MMR) genes. Mutations in the MSH6 DNA MMR gene account for approximately 18% of LS cases. Many LS-associated sequence variants are nonsense and frameshift mutations that clearly abrogate MMR activity. However, missense mutations whose functional implications are unclear are also frequently seen in suspected-LS patients. To conclusively diagnose LS and enroll patients in appropriate surveillance programs to reduce morbidity as well as mortality, the functional consequences of these variants of uncertain clinical significance (VUS) must be defined. We present an oligonucleotide-directed mutagenesis screen for the identification of pathogenic MSH6 VUS. In the screen, the MSH6 variant of interest is introduced into mouse embryonic stem cells by site-directed mutagenesis. Subsequent selection for MMR-deficient cells using the DNA damaging agent 6-thioguanine (6TG) allows the identification of MMR abrogating VUS because solely MMR-deficient cells survive 6TG exposure. We demonstrate the efficacy of the genetic screen, investigate the phenotype of 26 MSH6 VUS and compare our screening results to clinical data from suspected-LS patients carrying these variant alleles

Evaluation of current prediction models for Lynch syndrome: updating the PREMM5 model to identify PMS2 mutation carriers

Until recently, no prediction models for Lynch syndrome (LS) had been validated for PMS2 mutation carriers. We aimed to evaluate MMRpredict and PREMM5 in a clinical cohort and for PMS2 mutation carriers specifically. In a retrospective, clinic-based cohort we calculated predictions for LS according to MMRpredict and PREMM5. The area under the operator receiving characteristic curve (AU

Gynecological surveillance and surgery outcomes in Dutch Lynch syndrome carriers

Simple SummaryFemale Lynch syndrome (LS) carriers have an increased risk to develop endometrial and ovarian cancer. In the Netherlands, carriers are therefore advised annual gynecological surveillance and eventually, risk-reducing surgery. Global gynecological LS surveillance guidelines are scarce and based on limited evidence. These are, however, warranted to offer accurate surveillance. To provide more insight into surveillance outcomes, this study assessed outcomes of gynecological surveillance and risk-reducing surgery in 164 LS carriers diagnosed in our center, with a median follow-up of 5.6 years per carrier. Although most surveillance visits happened within an advised timeframe, we observed large variability in how gynecological surveillance visits were performed. This finding stresses the need for development of clear and evidence-based guidelines. Endometrial cancers identified at surveillance were all found in early stage, mostly symptomatic, questioning surveillance benefit. Large, prospective studies should assess to what extent current LS surveillance programs contribute to early detection of gynecological tumors.Lynch syndrome (LS) is caused by pathogenic germline variants in DNA mismatch repair (MMR) genes, predisposing female carriers for endometrial cancer (EC) and ovarian cancer (OC). Since gynecological LS surveillance guidelines are based on little evidence, we assessed its outcomes. Data regarding gynecological tumors, surveillance, and (risk-reducing) surgery were collected from female LS carriers diagnosed in our center since 1993. Of 505 female carriers, 104 had a gynecological malignancy prior to genetic LS diagnosis. Of 264 carriers eligible for gynecological management, 164 carriers gave informed consent and had available surveillance data: 38 MLH1, 25 MSH2, 82 MSH6, and 19 PMS2 carriers (median follow-up 5.6 years). Surveillance intervals were within advised time in >80%. Transvaginal ultrasound, endometrial sampling, and CA125 measurements were performed in 76.8%, 35.9%, and 40.6%, respectively. Four symptomatic ECs, one symptomatic OC, and one asymptomatic EC were diagnosed. Endometrial hyperplasia was found in eight carriers, of whom three were symptomatic. Risk-reducing surgery was performed in 73 (45.5%) carriers (median age 51 years), revealing two asymptomatic ECs. All ECs were diagnosed in FIGO I. Gynecological management in LS carriers varied largely, stressing the need for uniform, evidence-based guidelines. Most ECs presented early and symptomatically, questioning the surveillance benefit in its current form.Hereditary cancer genetic

Rijkswaterstaat:Guardian of the Dutch Delta

Founded in 1798, Rijkswaterstaat, the Dutch government’s agency for infrastructural works, brought flood security, navigable waterways and highways to the Netherlands. It is an iconic institution within Dutch society, best known for its ‘battle against the water’. The Zuiderzee Works (1920–1968) and the Delta Works (1954–1997) brought worldwide acclaim. This chapter tells the story of a humble semi-military organization that developed into a formidable institution of civil engineers with a strong technocratic mission mystique. It also recounts the institutional crisis the agency experienced in the 1970s–1990s when it was too slow to adapt to major sociocultural and political changes. To ride the waves of change, it eventually developed several proactive adaptation strategies and reinvented its mission mystique in managerial terms. Adaptation to climate change now presents another key challenge, for which Rijkswaterstaat will have to develop a new ‘social license to operate’

Raloxifene augmentation in men and women with a schizophrenia spectrum disorder:A study protocol

Although acute psychotic symptoms are often reduced by antipsychotic treatment, many patients with schizophrenia are impaired in daily functioning due to the persistence of negative and cognitive symptoms. Raloxifene, a Selective Estrogen Receptor Modulator (SERM) has been shown to be an effective adjunctive treatment in schizophrenia. Yet, there is a paucity in evidence for raloxifene efficacy in men and premenopausal women. We report the design of a study that aims to replicate earlier findings concerning the efficacy of raloxifene augmentation in reducing persisting symptoms and cognitive impairment in postmenopausal women, and to extend these findings to a male and peri/premenopausal population of patients with schizophrenia. The study is a multisite, placebo-controlled, double-blind, randomised clinical trial in approximately 110 adult men and women with schizophrenia. Participants are randomised 1:1 to adjunctive raloxifene 120 mg or placebo daily during 12 weeks. The treatment phase includes measurements at three time points (week 0, 6 and 12), followed by a follow-up period of two years. The primary outcome measure is change in symptom severity, as measured with the Positive and Negative Syndrome Scale (PANSS), and cognition, as measured with the Brief Assessment of Cognition in Schizophrenia (BACS). Secondary outcome measures include social functioning and quality of life. Genetic, hormonal and inflammatory biomarkers are measured to assess potential associations with treatment effects. If it becomes apparent that raloxifene reduces psychotic symptoms and/or improves cognition, social functioning and/or quality of life as compared to placebo, implementation of raloxifene in clinical psychiatric practice can be considered

Evaluation of current prediction models for Lynch syndrome: updating the PREMM5 model to identify PMS2 mutation carriers

Analysis and support of clinical decision makin