Case Of LS Research Articles

PCN189 RENAL CELL CANCER IN CHILE: STUDYING THE EFFECTS OF FINANCIAL-RISK POOLING TO FACILITATE COVERAGE DECISIONS.

Renal Cell Cancer (RCC) represents 90% of malignant renal tumors. In Chile, drugs for advanced RCC are not covered by private insurers, chemotherapy is not a standard treatment, and out-of-pocket expenditure is common in patients who can afford expensive therapies. This study aims to identify treatment costs of RCC from Early to Late Stages (ES and LS) and to estimate the costs of including innovative therapies in LS for the population of a private insurer. A comprehensive direct-costs study focused on ES and LS, and the estimation of incorporating innovation drugs for LS was carried-out. International recommendations were retrieved and validated by local expert; local epidemiology, sub-groups per-stage, histological classification were examined. By designing clinical pathways, costs-drivers were identified, quantified and cost. For LS RCC, nephrectomy, tyrosine-kinase inhibitors and immunomodulators were included as alternatives. Seventeen cases were found in LS; 30% in ES, 75% in 0-1 ECOG status, and 85% present clear-cells histology. Current ES cost-per-month distributed among all ES and LS “Confirmed Cases” (CC) without drugs-treatment is U$D187 per-case, whereas for LS is U$D166 USD. For ECOG 0-1 susceptible of receiving first-line (1L) adjuvant therapies, a cost of U$D1,008 per-month per-case distributed among all CC was found; 54% out of them, could be eligible for second-line (2L) treatments at U$D1,516 per-month each distributed among CC. Incremental cost of LS, 1L, and 2L is U$D3,799 distributed among LS cases (regular procedure in local insurances); Instead, incremental cost distributed among all CC decreases until U$D2,691 (29,16% decrease). A cumulative incremental cost of 0.7 times per-month could help to gain access to high-cost medicines in LS RCC by pooling financial risk among ES and LS. This is crucial in insurance functioning. By pooling financial risk among extensive cohorts (ES and LS, and not only among LS), incremental total costs decrease in 42%.

PO-467 Unclarified cases of microsatellite instability analyses for lynch syndrome diagnostics

IntroductionLynch syndrome (LS) is an autosomal dominantly inherited form of colorectal cancer (CRC) and is implicated in 2%–4% of CRC cases. LS develops from a mutation in one allele of one of the DNA mismatch repair (MMR) genes, most commonly MLH1 and MSH2, or less frequently MSH6 and PMS2. Loss of functional MMR proteins leads to defects in DNA repair and, subsequently, high DNA microsatellite instability (MSI-High). LS diagnostics currently consists of an analysis of MMR protein expression by means of Immunohistochemistry (IHC) and a molecular analysis to detect MSI. During our 10 year experience in performing LS diagnostics we have encountered few cases where IHC and MSI analyses do not match. This study is to clarify these inconsistent molecular alterations which will contribute to our understanding of LS diagnostics.Material and methodsOf 2335 LS cases 27 (1.1%) showed discrepant IHC and MSI results. To clarify this, IHC and MSI analyses were repeated if possible with different antibodies and different MSI markers (mononucleotide instead of dinucleotide markers). Using MS-MLPA MLH1 hypermethylation, BRAF V600E mutation status and LOH of the MMR genes was analysed. Finally, germline and somatic mutations in MMR genes were analysed by using NGS. Protein modelling was also performed to visualise structural protein changes.Results and discussionsAmong these 27 cases, due to the decline of patients for further testing, 4 cases were excluded from further analyses. Of the remaining cases in 2 cases using a different antibody explained the unexpected results and in 2 cases switching from dinucleotide to mononucleotide MSI markers. In respectively 8 and 4 cases somatic and germline mutations explained the IHC and MSI results. Finally, in 2 cases protein modelling of identified mutations explained the presence of protein staining in MSI-high cases. The rest cases cannot be further studied due to the lack of tissues.ConclusionBased on these results, we have concluded: 1. Mononucleotide markers are more sensitive to detect microsatellite instability. 2. Protein modelling can explain presence of protein staining for mutations that do not cause a major conformational change. 3. Somatic sequencing is a valuable addition to Lynch syndrome diagnostics.

PD63-11 CHANGING TRENDS IN RECONSTRUCTION OF COMPLEX URETHRAL STRICTURES: FROM SKIN FLAP TO PERINEAL URETHROSTOMY

You have accessJournal of UrologyTrauma/Reconstruction/Diversion: Urethral Reconstruction (including Stricture, Diverticulum) III1 Apr 2018PD63-11 CHANGING TRENDS IN RECONSTRUCTION OF COMPLEX URETHRAL STRICTURES: FROM SKIN FLAP TO PERINEAL URETHROSTOMY Joceline Fuchs, Nabeel Shakir, Maxim McKibben, Jeremy Scott, Boyd Viers, Travis Pagliara, and Allen Morey Joceline FuchsJoceline Fuchs More articles by this author , Nabeel ShakirNabeel Shakir More articles by this author , Maxim McKibbenMaxim McKibben More articles by this author , Jeremy ScottJeremy Scott More articles by this author , Boyd ViersBoyd Viers More articles by this author , Travis PagliaraTravis Pagliara More articles by this author , and Allen MoreyAllen Morey More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2018.02.2971AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Although tissue transfer operations such as buccal mucosal graft (BMG) and penile skin flaps are commonly used for complex urethroplasty cases, outcomes for reconstruction of severe strictures can be unreliable. We report our evolving approach to reconstruction of complex strictures over the last decade. METHODS We retrospectively reviewed a large series of complex urethral reconstruction cases comparing three techniques: a) BMG, b) penile skin flap or c) perineal urethrostomy (PU) at a tertiary center (2007-2017) with ≥ 6 months follow-up. Strictures amenable to anastomotic repair were excluded. Success was defined as no need for further operative management. RESULTS Among 1129 stricture cases, 406 complex strictures were identified for this analysis (median length 4.6 cm). Reconstruction was most commonly performed using BMG urethroplasty (242/406, 59.6‰), followed by penile skin flap (85/406, 20.9‰) and PU (79/406, 19.5‰). PU use has increased steadily and significantly over the past decade, rising from 4.3‰ of case volume in 2008 to 38.7‰ of urethral reconstruction cases in 2017 (p=0.01). Over time, the proportion of complex reconstruction using BMG has remained stable, while penile skin flaps are now less commonly utilized (Figure). Over a median follow-up of 52.0 months, 18.7‰ (76/406) patients failed at a median of 13.9 months. Success rates were higher following PU (92.7‰) compared to BMG and skin flaps (76.0‰ and 78.3‰, respectively) (p<0.01) despite PU patients being older (mean age 61.4 yr), having longer strictures (5.6 cm) and more commonly having LS (20.2‰). LS patients are increasingly managed with PU in our practice, with PU performed in 58.3‰ (14/24) of complex LS cases over the last 3 years, with the exception of young men who are more likely to choose attempted repair using BMG (median age BMG 46.5 yr vs. PU 60.4 yr). CONCLUSIONS Over a decade of a urethral reconstructive practice, PU is increasingly utilized for older patients with long strictures and adverse etiology. BMG urethroplasty rates remain stable, while penile skin flap use is decreasing. Success rates of PU for these complex strictures are markedly higher than those of grafts and flaps. © 2018FiguresReferencesRelatedDetails Volume 199Issue 4SApril 2018Page: e1218 Advertisement Copyright & Permissions© 2018MetricsAuthor Information Joceline Fuchs More articles by this author Nabeel Shakir More articles by this author Maxim McKibben More articles by this author Jeremy Scott More articles by this author Boyd Viers More articles by this author Travis Pagliara More articles by this author Allen Morey More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Lymphangioma circumscriptum of the vulva: a rare case report

Lymphangioma circumscriptum (LC) is a rarely seen benign disease that involves deep dermal and subcutaneous lymphatic channels. It is seen as a group of lesions in the shape of thin-walled translucent saccules resembling frog eggs. Although the most frequently seen form of cutaneous lymphangioma is seen in the infantile period, it may occur at any age. The most common locations of these lesions are the proximal parts of extremities that contain a rich lymphatic network such as axilla, shoulder, inguinal region, and perineum. Vulvar involvement is quite rare and usually develops secondary to a radical hysterectomy, pelvic lymphadenectomy, radiotherapy, and Crohn's disease. Here, an extraordinary case of LS with an obscure cause is presented.

Abstract B04: Oncogenic relevance of IGF-IR and PI3K/AKT/GSK3-beta signaling in myxoid liposarcoma

Abstract Introduction: Myxoid liposarcoma (MLS) accounts for 30-35% of all LS cases and is the second most common type of liposarcoma. One third of MLS lesions will become metastatic with tumors spreading to unusual bone and soft tissue locations. Ninety percent of MLS are characterized by a specific reciprocal translocation t (12; 16) (q13; p11), leading to the pathogenic gene fusion of FUS and DDIT3. The resulting chimeric FUS-DDIT3 fusion protein is suggested to play a crucial role in MLS pathogenesis, although the specific biological function and the mechanism of action remain to be defined. Aiming at the preclinical identification of novel therapeutic options in vitro and in vivo, we investigate the functional relevance of IGF-IR and PI3K/AKT/GSK3-beta signaling in primary MLS and tumor-derived cell lines. Methods: Immunohistochemical analyses of IGF-IR and PI3K/AKT/GSK3-beta signaling effectors and modulators were performed in a comprehensive cohort of primary MLS specimens. FUS-DDIT3-dependent activation of the PI3K/AKT/GSK3-beta signaling cascade was analyzed by siRNA knockdown experiments and protein immunoblotting in vitro. Cell proliferation and FACS assays were performed in two different MLS cell lines. An in vivo tumor model was successfully established performing the chicken chorioallantoic membrane (CAM) assay. Results: In a significant subset of MLS specimens, immunohistochemical staining revealed elevated phosphorylation levels of the respective signaling components, indicating that activated IGF-IR and PI3K/AKT/GSK3-beta signaling is a frequent feature in MLS. IGF-IR inhibition significantly suppressed the PI3K/AKT/GSK3-beta downstream cascade, associated with reduced phosphorylation levels of several signaling components, impairment of MLS cell viability and induction of apoptosis in vitro and in vivo. Furthermore, siRNA-mediated knockdown of FUS-DDIT3 lead to dephosphorylation of PI3K/AKT/GSK3-beta signaling components, implying that the FUS-DDIT3 fusion protein is involved in the IGF-IR regulated signaling cascade. Conclusion: Our study emphasizes the pivotal role of IGF-IR and PI3K/AKT/GSK3-beta signaling in MLS pathogenesis and indicates its functional dependence on the characteristic FUS-DDIT3 fusion protein. Furthermore, our in vitro and in vivo results demonstrate that targeting the IGF-IR and PI3K/AKT/GSK3-beta signaling pathway might provide a specific, molecular founded therapeutic strategy in the treatment of MLS. Citation Format: Marcel Trautmann, Christian Bertling, Jasmin Menzel, Magdalene Cyra, Konrad Steinestel, Inga Grünewald, Pierre Åman, Eva Wardelmann, Sebastian Huss, Wolfgang Hartmann. Oncogenic relevance of IGF-IR and PI3K/AKT/GSK3-beta signaling in myxoid liposarcoma [abstract]. In: Proceedings of the AACR International Conference: New Frontiers in Cancer Research; 2017 Jan 18-22; Cape Town, South Africa. Philadelphia (PA): AACR; Cancer Res 2017;77(22 Suppl):Abstract nr B04.

Abstract B05: Myxoid liposarcoma: A molecular and clinicopathological analysis by targeted next-generation sequencing and fluorescence in situ hybridization

Abstract Introduction: Myxoid liposarcoma (MLS) is the second most common type of liposarcoma, accounting for 30-35% of all LS cases. Over 90% of tumors are characterized by a reciprocal translocation t (12; 16) (q13; p11), resulting in a pathogenic gene fusion. The chimeric FUS-DDIT3 fusion protein is suggested to play a crucial role in MLS tumorigenesis and progression, although the specific biological function and the mechanism of action remain to be defined. We compiled a comprehensive cohort of 105 well-characterized MLS tissue specimens to identify actionable genetic aberrations. Methods: Targeted next-generation sequencing (NGS) using the Illumina MiSeq platform was performed to examine the mutational status of 23 cancer-related genes (covering all exons) known to be frequently mutated across various neoplasms. Furthermore, we examined the amplification/deletion status and characterized the specific chromosomal FUS-DDIT3 rearrangements by FISH and RT-PCR. A multivariate analysis was conducted to investigate the prognostic significance of mutation/amplification/deletion status. Results: Targeted next-generation sequencing drives the potential to generate comprehensive genetic information including less frequent mutated genes relevant for actionable treatments and prognostic assessment. Besides PIK3CA, six additional genes showed at least five mutations, including AKT1, CTNNB1, EGFR, ERBB2, MET and PTEN. Several oncogenic mutations were detected which have not been reported in MLS previously. We demonstrated several gene amplification/deletion events in MLS. Conclusion: Our results indicate the occurrence of mutational aberrations besides the chromosomal FUS-DDIT3 hallmark. These appear not to be related to specific subtypes of FUS-DDIT3 fusion transcripts in terms of a molecular pattern. Molecular screening for actionable mutations might represent a rational tool for the implementation of innovative targeted therapeutic approaches in MLS. To our best knowledge, this study is the most extensive one to yield a detailed map of actionable genetic aberrations across a comprehensive cohort of &amp;gt;100 well-characterized MLS tissue specimens. Moreover, it reveals several molecular alteration-specific targets for innovative therapy strategies. Citation Format: Marcel Trautmann, Arne Krüger, Birte Jeiler, Christian Bertling, Jasmin Menzel, Magdalene Cyra, Konrad Steinestel, Inga Grünewald, Pierre Åman, Eva Wardelmann, Sebastian Huss, Wolfgang Hartmann. Myxoid liposarcoma: A molecular and clinicopathological analysis by targeted next-generation sequencing and fluorescence in situ hybridization [abstract]. In: Proceedings of the AACR International Conference: New Frontiers in Cancer Research; 2017 Jan 18-22; Cape Town, South Africa. Philadelphia (PA): AACR; Cancer Res 2017;77(22 Suppl):Abstract nr B05.

The ϒ function ofL–space knots is a Legendre transform

AbstractGiven anL–space knot we show that its ϒ function is the Legendre transform of a counting function equivalent to thed–invariants of its large surgeries. The unknotting obstruction obtained for the ϒ function is, in the case ofL–space knots, contained in thed–invariants of large surgeries. Generalisations apply for connected sums ofL–space knots, which imply that the slice obstruction provided by ϒ on the subgroup of concordance generated byL–space knots is no finer than that provided by thed–invariants.

Gamma-ray binaries beyond one-zone models: an application to LS 5039

Context: Several binary systems hosting massive stars present gamma-ray emission. In most of these systems, despite detailed observational information being available, the nature and the structure of the emitter are still poorly known. Aims: We investigate the validity of the so-called one-zone approximation for the high-energy emitter in binary systems hosting a massive star. In particular, the case of LS 5039 is considered. Methods: Assuming a point-like emitter at rest, the presence of a nearby massive star, and the observed MeV and GeV fluxes as a reference, a non-thermal leptonic model is systematically applied for different locations, magnetic fields, and non-radiative losses. This allows us to identify both the emitter configurations that are most compatible with observations and inconsistencies between model predictions and the available data. Results: In the case of LS 5039, the best parameter combination is fast non-radiative cooling and a low magnetic field. However, discrepancies appear when comparing the model results at the MeV and GeV energy ranges with the observed fluxes. Predictions fail when the orbital motion is included in the analysis, because emitters and energy budgets that are too large are required. Values of X-ray and TeV fluxes that are too high are predicted in such a case, along half of the orbit. Conclusions: We show that the radiation in LS 5039 does not come from only one electron population, and the emitter is likely extended and inhomogeneous with a low magnetic field. We suggest that the emitter moves at relativistic velocities with Doppler boosting playing a significant role. Key words. Stars: high-mass, X-rays: binaries, gamma-rays: binaries

Prevalence of Lynch syndrome in a Middle Eastern population with colorectal cancer.

Lynch syndrome (LS; hereditary nonpolyposis colorectal cancer) is a common cause of hereditary colorectal cancer (CRC). CRC is the most common cancer diagnosed among males in Saudi Arabia but to the authors' knowledge there is a lack of data regarding the prevalence of LS in patients with CRC. There currently are no clear guidelines for the selection criteria for these patients to screen for LS. A comprehensive molecular characterization was performed in a cohort of 807 CRC cases by immunohistochemical and microsatellite analysis using polymerase chain reaction. BRAF mutation screening, high CpG island methylator phenotype, and analysis for germline mutations were performed in 425 CRC samples. These were all high microsatellite instability (MSI-H) samples (91 cases), all low MSI samples (143 cases), and selected cases from the microsatellite stable group (191 cases) that met revised Bethesda guidelines. Polymerase chain reaction identified 91 MSI-H cases (11.3%) and sequencing revealed mismatch repair germline mutations in 8 CRC cases only. Of the total of 807 CRC cases, these 8 cases (0.99%) were MSI-H, met the revised Bethesda guidelines, and did not harbor BRAF mutations. The results of the current study confirmed cases of LS in approximately 1.0% of CRC samples and reflects the efficacy of screening among MSI-H cases that lack BRAF mutations. This comprehensive study from Saudi Arabia will help in implementing a universal screening/reflex testing strategy in a clinical setting in Saudi Arabia and in conducting a national screening program that benefits both patients and their relatives.

Abstract 1285: Identification of MMR gene exonic rearrangements in suspected Lynch syndrome tumors without loss of MMR expression

Abstract Lynch syndrome (LS), also called Hereditary Non-Polyposis Colorectal Cancer, the most well studied form of familial CRC, is responsible for about 3% of all CRC cases. LS-associated CRC often exhibits one or more of the following features namely early age of onset, occurrence of synchronous/metachronous tumors, presence of more than one affected family member and tumors predominantly localized to the proximal/right colon with specific clinico-pathological features such as a mucinous histology, poor differentiation and immune infiltration. LS is primarily a disease of defective MisMatch Repair (MMR) and is caused by germline mutational inactivation of any one of four major MMR genes viz. MLH1, MSH2, MSH6 and PMS2. A hallmark of LS-associated tumors is presence of ‘microsatellite instability’ (MSI), a term used to describe frequent occurrence of expanded/contracted microsatellites that arise during DNA replication and are not corrected due to defective MMR. MLH1 and MSH2 account for a majority (up to 90%) of LS cases while MSH6 and PMS2 are involved in a minor proportion. Mutational inactivation of an MMR gene almost always results in loss of corresponding protein expression in the tumor, which can be easily detected by immunohistochemistry. In the first comprehensive study from India, we analyzed MSI and determined expression status of the four MMR genes in forty eight suspected LS-associated colorectal tumor samples. Though a majority (85.4%) exhibited MSI, only 58% exhibited loss of MMR expression, a significantly low proportion compared to reports from other populations. PCR-DNA sequencing and Multiple Ligation-dependent Probe Amplification based mutation and exonic deletion/duplication screening respectively, revealed MMR gene lesions in 81% of samples exhibiting loss of corresponding MMR protein expression, including thirteen mutations and four exonic rearrangements. Seven novel mutations (four in MLH1 and three in MSH2) were identified. Surprisingly, MMR gene lesions were also detected in a significant proportion (78%) of tumor samples not exhibiting MMR expression loss. Interestingly, samples with and without MMR expression exhibited significant differences with respect to mucinous histology and instability exhibited by specific microsatellites. In addition, MMR negative samples mainly harbored MMR gene in-del or point mutations while MMR positive samples predominantly harbored MMR gene exonic rearrangements. The study has therefore revealed for the first time a significant proportion of suspected LS tumors not exhibiting loss of MMR expression despite harboring MMR gene rearrangements. More importantly, our results indicate significant differences in the biology of LS-associated colorectal tumors occurring due to missense/in-del mutations in MMR genes causing loss of expression and those that occur due to MMR gene exonic rearrangements not resulting in loss of expression. Citation Format: Murali D. Bashyam, Viswakalyan Kotapalli, Ratheesh Raman, Brijesh K. Yadav, Ajay K. Chaudhary, Swarnalata Gowrishankar, Shantveer G. Uppin, Ravikanth Kongara, Regulagadda A. Sastry, Mohana Vamsy, Sujit Patnaik, Shoba Dsouza, Devendra C. Desai, Tester Ashavaid. Identification of MMR gene exonic rearrangements in suspected Lynch syndrome tumors without loss of MMR expression. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1285. doi:10.1158/1538-7445.AM2014-1285

Distribution of airway smooth muscle remodelling in asthma: Relation to airway inflammation

Pathological phenotypes of asthma have been based predominantly on inflammation, rather than airway wall remodelling. Differences in the distribution of airway smooth muscle (ASM) remodelling between large and small airways may affect clinical outcomes in asthma. The aim of this study was to examine the distribution of ASM remodelling and its relation to airway inflammation. Post-mortem cases of asthma (n = 68) were categorized by the distribution of increased thickness of the ASM layer (relative to nonasthmatic controls, n = 37), into 'large only' (LO, n = 15), 'small only' (SO, n = 4) 'large/small' (LS, n = 24) or no increase (NI, n = 25). Subject characteristics, ASM and airway wall dimensions and inflammatory cell numbers were compared between groups. Apart from reduced clinical severity of asthma in NI cases (P = 0.002), subject characteristics did not distinguish asthma groups. Compared with control subjects, ASM cell number, reticular basement membrane thickness, airway wall thickness, percent muscle shortening and eosinophil number were increased (P < 0.05) in both large and small airways in LS cases and only the large airways in LO cases. Increased numbers of neutrophils were observed only in the small airways of LO cases. Distinct distributions of ASM remodelling are seen in asthma. Pathology limited to the small airways was uncommon. Increased thickness of the ASM layer was associated with airway remodelling and eosinophilia, but not neutrophilia. These data support the presence of distinct pathological phenotypes based on the site of increased ASM.

Tu1898 The Interactions Between Diet, Mucosal Proliferation and GI Cancer Risk in Rural Africans and African Americans

166 more tumors needed to be screened in the universal group compared to the reflex group. Conclusion: Reflex screening of CRC tumors for LS has similar outcomes as universal or referral strategies to identify LS. The universal group identified one additional case of LS that would have been missed by a reflex strategy, though 166 additional tumors needed to be tested. In clinical practice, a reflex testing strategy may be just as effective and less burdensome as compared to universal tumor screening to detect LS. The power to detect differences was a limitation to this study. Characteristics and outcomes of positively screened patients

Anion directed conformational diversities of an arene based hexa-amide receptor and recognition of the [F4(H2O)6]4−cluster

The TOC shows difference in binding energies between different conformers after binding with anions of different dimensionalities and conformersA,B&amp;Cshow structural diversities with anions in case ofL.

OPTICAL PHOTOMETRIC MONITORING OF LS I +61 303

Three gamma-ray binaries, namely PSR B1259–63, HESS J0632+057 and LS I +61 303, contain compact objects orbiting around massive Be stars. Around periastron passage the compact objects should produce significant changes in the structure of the Be disks due to gravitational forces and eventually by ram pressure from the putative pulsar wind. Indeed, variability in the Hα emission line has been detected in all these systems, and optical periodic variability has been detected in one of them. However, there is lack of a systematic monitoring with accurate photometry, which could be used to constrain the shape of the disk during the periastron passage. This information is important to build accurate physical models to explain the broadband spectral energy distribution of these sources. Here we present an ongoing program to monitor the optical photometry of gamma-ray binaries and show preliminary results for the case of LS I +61 303.

Implementation of tumor testing for lynch syndrome in endometrial cancers at a large academic medical center

ObjectivesLynch syndrome (LS) is a hereditary condition that increases the risk for endometrial and other cancers. Recognizing women at risk for LS based on personal/family history is burdensome and imprecise. Tumor testing using microsatellite instability (MSI) testing and immunohistochemistry (IHC) for mismatch repair protein expression can be an effective strategy for identifying potential LS in patients presenting with colorectal or endometrial cancer. Here we describe our experience implementing a screening program for endometrial cancers. MethodsEndometrial cancers diagnosed ≤50years or those with suspicious personal history or histopathologic features were screened with MSI/IHC, June 2009–June 2011. Criteria were later (July 2011–July 2012) expanded to patients diagnosed <60years, or at any age with suspicious features, and finally (after August 2012) universal screening was implemented. Screening techniques began with both MSI and IHC for every tumor, and later converted to IHC for two proteins, and MLH1 promoter methylation analysis when indicated. A genetic counselor contacted patients directly to offer genetic counseling appointments. ResultsTwo hundred and forty-five endometrial cancers (average age, 57years) were screened. Sixty-two patients (25%) had abnormal results, and 42 patients were referred for genetic counseling. Of the 42 patients, 34 underwent genetic counseling, 28 pursued genetic testing, and 11 were diagnosed with LS. When age and pathology criteria were used, 27 eligible cases were overlooked for screening and 3 cases of LS were found only because a clinician requested screening. ConclusionsUniversal screening of endometrial cancers for LS is practical and successfully implemented with collaboration among genetic counselors, gynecologic oncologists, and pathologists.

A Case of Endocarditis Caused by Lactococcus garvieae and Suggested Methods for Identification

Lactococcus garvieae is a Gram-positive coccus that has morphological and biochemical similarities to enterococci. L. garvieae strains rare human pathogens, with only a few cases reported in the literature, mainly as a cause of infective endocarditis. L. garvieae is well known as a fish pathogen, and in some of the reported cases, the patients had a history of contact with raw fish. Some of the reported endocarditis patients had valvular damage as a predisposing condition. We report a case of L. garvieae endocarditis in a patient with no history of contact with raw fish and with history of valvular repair in an unaffected heart valve.

Impact of the orbital uncertainties on the timing of pulsars in binary systems

The detection of pulsations from an X-ray binary is an unambiguous signature of the presence of a neutron star in the system. When the pulsations are missed in the radio band, their detection at other wavelengths, like X-ray or gamma-rays, requires orbital demodulation, since the length of the observations are often comparable to, or longer than the system orbital period. The detailed knowledge of the orbital parameters of binary systems plays a crucial role in the detection of the spin period of pulsars, since any uncertainty in their determination translates into a loss in the coherence of the signal during the demodulation process. In this paper, we present an analytical study aimed at unveiling how the uncertainties in the orbital parameters might impact on periodicity searches. We find a correlation between the power of the signal in the demodulated arrival time series and the uncertainty in each of the orbital parameters. This correlation is also a function of the pulsar frequency. We test our analytical results with numerical simulations, finding good agreement between them. Finally, we apply our study to the cases of LS 5039 and LS I +61 303 and consider the current level of uncertainties in the orbital parameters of these systems and their impact on a possible detection of a hosted pulsar. We also discuss the possible appearance of a sideband ambiguity in real data. The latter can occur when, due to the use of uncertain orbital parameters, the power of a putative pulsar is distributed in frequencies lying nearby the pulsar period. Even if the appearance of a sideband is already a signature of a pulsar component, it may introduce an ambiguity in the determination of its period. We present here a method to solve the sideband issue.

Simplified identification of Lynch syndrome: A prospective, multicenter study

BackgroundRecommended strategies to screen for Lynch syndrome in colorectal cancer are not applied in daily practice and most of Lynch cases remain undiagnosed. AimsWe investigated in routine conditions a strategy that uses simplified clinical criteria plus detection of MisMatch Repair deficiency in tumours to identify Lynch carriers. MethodsColorectal cancer patients that met at least one of three clinical criteria were included: (1) colorectal cancer before 50 years, (2) personal history of colorectal or endometrial cancer, (3) first-degree relative history of colorectal or endometrial cancer. All tumours underwent an MisMatch Repair test combining microsatellite instability analysis and MisMatch Repair immunohistochemistry. Patients with an MisMatch Repair-deficient tumour were offered germline testing. ResultsOf the 307 patients fulfilling the clinical criteria, 46 (15%) had a MisMatch Repair-deficient tumour. Amongst them 27 were identified as Lynch carriers (20 with germline mutation: 12 MLH1, 7 MSH2, 1 MSH6; 7 highly suspected cases despite failure of genetic testing). The simplified clinical criteria selected a population whose MisMatch Repair-deficient status was highly predictive (59%) of Lynch syndrome. ConclusionThis bio-clinical strategy based on simplified clinical criteria combined with an MisMatch Repair test efficiently detected LS cases and is easy to use in clinical practice, outside expert centres.

Direct wind accretion and jet launch in binary systems

In this paper we study the wind accretion onto a rotating black hole in the close binary system harboring a young massive star. It is shown that the angular momentum of the accreted stellar wind material is not sufficient for the formation of an accretion disk. On the other hand, in the considered conditions the Blanford-Znajek mechanism can be activated, thus powerful jets can be launched in the direction of the rotation axis of the black hole. Importantly, no observational signatures of accretion, as typically seen from the thermal X-ray emission from the accretion disks, are expected in the suggested scenario. Here, properties of the generated jet are studied numerically in the framework of a 2D general relativity magnetohydrodynamical approach. Due to the accumulation of the magnetic flux at the black hole horizon, the jet power is expected to be modulated on a sub-second time-scale. Although the intervals between jet active phases depend on the magnetic flux escape from the black hole horizon (which can be modeled self-consistently only using a 3D code), a general estimate of the averaged jet power is obtained. It is expected that for the black hole rotation, expected in stellar binary system (the dimensionless rotation parameter a=0.5), approximately 10% of the accreted rest energy can be channeled into the jets. In the specific case of the gamma-ray binary system LS 5039, the obtained jet luminosity can be responsible for the observed GeV radiation if one invokes Doppler boosting, which can enhanced the apparent flux from the system.

On the binary nature of the γ-ray sources AGL J2241+4454 (= MWC 656) and HESS J0632+057 (= MWC 148)

We present optical spectroscopy of MWC 656 and MWC 148, the proposed optical counterparts of the gamma-ray sources AGL J2241+4454 and HESS J0632+0 57, respectively. The main parameters of the Halpha emission line (EW, FWHM and centroid velocity) in these stars are modulated on the proposed orbital periods of 60.37 and 321 days, respectively. These modulations are likely produced by the resonant interaction of the Be discs with compact stars in eccentric orbits. We also present radial velocity curves of the optical stars folded on the above periods and obtain the first orbital elements of the two gamma-ray sources thus confirming their binary nature. Our orbital solution support eccentricities e~0.4 and 0.83+-0.08 for MWC 656 and MWC 148, respectively. Further, our orbital elements imply that the X-ray outbursts in HESS J0632+057/MWC 148 are delayed ~0.3 orbital phases after periastron passage, similarly to the case of LS I +61 303. In addition, the optical photometric light curve maxima in AGL J2241+4454/MWC 656 occur ~0.25 phases passed periastron, similar to what is seen in LS I +61 303. We also find that the orbital eccentricity is correlated with orbital period for the known gamma-ray binaries. This is explained by the fact that small stellar separations are required for the efficient triggering of VHE radiation. Another correlation between the EW of Halpha and orbital period is also observed, similarly to the case of Be/X-ray binaries. These correlations are useful to provide estimates of the key orbital parameters Porb and e from the Halpha line in future Be gamma-ray binary candidates.