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Purpose: The aim of this official guideline coordinated and published by the German Society for Gynecology and Obstetrics (DGGG) and the German Cancer Society (DKG) was to optimize the screening, diagnosis, therapy and follow-up care of breast cancer.
Methods: The process of updating the S3 guideline dating from 2012 was based on the adaptation of identified source guidelines which were combined with reviews of evidence compiled using PICO (Patients/Interventions/Control/Outcome) questions and the results of a systematic search of literature databases and the selection and evaluation of the identified literature. The interdisciplinary working groups took the identified materials as their starting point to develop recommendations and statements which were modified and graded in a structured consensus procedure.
Recommendations: Part 1 of this short version of the guideline presents recommendations for the screening, diagnosis and follow-up care of breast cancer. The importance of mammography for screening is confirmed in this updated version of the guideline and forms the basis for all screening. In addition to the conventional methods used to diagnose breast cancer, computed tomography (CT) is recommended for staging in women with a higher risk of recurrence. The follow-up concept includes suggested intervals between physical, ultrasound and mammography examinations, additional high-tech diagnostic procedures, and the determination of tumor markers for the evaluation of metastatic disease.
Background: 15-20% of all patients initially diagnosed with colorectal cancer develop metastatic disease and surgical resection remains the only potentially curative treatment available. Current 5-year survival following R0-resection of liver metastases is 28-39%, but recurrence eventually occurs in up to 70%. To date, adjuvant chemotherapy has not improved clinical outcomes significantly. The primary objective of the ongoing LICC trial (L-BLP25 In Colorectal Cancer) is to determine whether L-BLP25, an active cancer immunotherapy, extends recurrence-free survival (RFS) time over placebo in colorectal cancer patients following R0/R1 resection of hepatic metastases. L-BLP25 targets MUC1 glycoprotein, which is highly expressed in hepatic metastases from colorectal cancer. In a phase IIB trial, L-BLP25 has shown acceptable tolerability and a trend towards longer survival in patients with stage IIIB locoregional NSCLC.
Methods: This is a multinational, phase II, multicenter, randomized, double-blind, placebo-controlled trial with a sample size of 159 patients from 20 centers in 3 countries. Patients with stage IV colorectal adenocarcinoma limited to liver metastases are included. Following curative-intent complete resection of the primary tumor and of all synchronous/metachronous metastases, eligible patients are randomized 2:1 to receive either L-BLP25 or placebo. Those allocated to L-BLP25 receive a single dose of 300 mg/m2 cyclophosphamide (CP) 3 days before first L-BLP25 dose, then primary treatment with s.c. L-BLP25 930 mug once weekly for 8 weeks, followed by s.c. L-BLP25 930 mug maintenance doses at 6-week (years 1&2) and 12-week (year 3) intervals unless recurrence occurs. In the control arm, CP is replaced by saline solution and L-BLP25 by placebo. Primary endpoint is the comparison of recurrence-free survival (RFS) time between groups. Secondary endpoints are overall survival (OS) time, safety, tolerability, RFS/OS in MUC-1 positive cancers. Exploratory immune response analyses are planned. The primary endpoint will be assessed in Q3 2016. Follow-up will end Q3 2017. Interim analyses are not planned.
Discussion: The design and implementation of such a vaccination study in colorectal cancer is feasible. The study will provide recurrence-free and overall survival rates of groups in an unbiased fashion. Trial Registration EudraCT Number 2011-000218-20
Background: Neonatal manifestation of life-threatening hyperammonemic encephalopathy in urea cycle disorders (UCD) is often misdiagnosed as neonatal sepsis, resulting in significantly delayed start of specific treatment and poor outcome. The major aim of this study was to identify specific initial symptoms or signs to clinically distinguish hyperammonemic encephalopathy in neonates from neonatal sepsis in order to identify affected individuals with UCD and to start metabolic therapy without delay. Furthermore, we evaluated the impact of diagnostic delay, peak plasma ammonium (NH4+) concentration, mode of emergency treatment and transfer to a tertiary referral center on the outcome.
Methods: Detailed information of 17 patients (born between 1994 and 2012) with confirmed diagnosis of UCD and neonatal hyperammonemic encephalopathy were collected from the original medical records.
Results: The initially suspected diagnosis was neonatal sepsis in all patients, but was not confirmed in any of them. Unlike neonatal sepsis and not previously reported blood pressure increased above the 95th percentile in 13 (81%) of UCD patients before emergency treatment was started. Respiratory alkalosis was found in 11 (65%) of UCD patients, and in 14 (81%) plasma NH4+concentrations further increased despite initiation of metabolic therapy.
Conclusion: Detection of high blood pressure could be a valuable parameter for distinguishing neonatal sepsis from neonatal manifestation of UCD. Since high blood pressure is not typical for neonatal sepsis, other reasons such as encephalopathy and especially hyperammonemic encephalopathy (caused by e.g. UCD) should be searched for immediately. However, our result that the majority of newborns with UCD initially present with high blood pressure has to be evaluated in larger patient cohorts.
Die Fundmeldungen in Band 33 von Botanik und Naturschutz in Hessen stammen von: Dirk Bönsel, Martin de Jong, Wolfgang Ehmke, Peter Emrich, Benjamin Feller, Brunhilde Göbel, Thomas Gregor, Arthur Händler, Sylvain Hodvina, Gerwin Kasperek, Egbert Korte, Ute Lange, Stefan Meyer, Hasko Friedrich Nesemann, Uwe Raabe, Bernd Sauerwein, Marco Schmidt, Christof Nikolaus Schröder, Antje Schwab, Rainer Stoodt und Michael Uebeler.
Background: Liver fibrosis in human immunodeficiency virus (HIV)-infected individuals is mostly attributable to co-infection with hepatitis B or C. The impact of other risk factors, including prolonged exposure to combined antiretroviral therapy (cART) is poorly understood. Our aim was to determine the prevalence of liver fibrosis and associated risk factors in HIV-infected individuals based on non-invasive fibrosis assessment using transient elastography (TE) and serum biomarkers (Fibrotest [FT]).
Methods: In 202 consecutive HIV-infected individuals (159 men; mean age 47 ± 9 years; 35 with hepatitis-C-virus [HCV] co-infection), TE and FT were performed. Repeat TE examinations were conducted 1 and 2 years after study inclusion.
Results: Significant liver fibrosis was present in 16% and 29% of patients, respectively, when assessed by TE (≥ 7.1 kPa) and FT (> 0.48). A combination of TE and FT predicted significant fibrosis in 8% of all patients (31% in HIV/HCV co-infected and 3% in HIV mono-infected individuals). Chronic ALT, AST and γ-GT elevation was present in 29%, 20% and 51% of all cART-exposed patients and in 19%, 8% and 45.5% of HIV mono-infected individuals. Overall, factors independently associated with significant fibrosis as assessed by TE (OR, 95% CI) were co-infection with HCV (7.29, 1.95-27.34), chronic AST (6.58, 1.30-33.25) and γ-GT (5.17, 1.56-17.08) elevation and time on dideoxynucleoside therapy (1.01, 1.00-1.02). In 68 HIV mono-infected individuals who had repeat TE examinations, TE values did not differ significantly during a median follow-up time of 24 months (median intra-patient changes at last TE examination relative to baseline: -0.2 kPa, p = 0.20).
Conclusions: Chronic elevation of liver enzymes was observed in up to 45.5% of HIV mono-infected patients on cART. However, only a small subset had significant fibrosis as predicted by TE and FT. There was no evidence for fibrosis progression during follow-up TE examinations.
Aim: To evaluate the ability of PillCamColon2 to visualize colonic segments missed by incomplete optical colonoscopy (OC) and to assess the diagnostic yield.
Methods: This prospective multicentre study included 81 patients from nine centres who underwent second-generation colon capsule endoscopy (CCE) following incomplete OC performed by an experienced gastroenterologist (> 1000 colonoscopies). Patients with stenosis were excluded. According to patient preferences, CCE was performed the following day (protocol A) after staying on clear liquids and 0.75 L Moviprep in the morning or within 30 d after new split-dose Moviprep (protocol B). Boosts consisted of 0.75 L and 0.25 L Moviprep, and phospho-soda was given as a rescue if the capsule was not excreted after seven hours.
Results: Seventy-four patients were analysed (51% of them in group A; 49% in group B). Bowel cleansing was adequate in 67% of cases, and CCE could visualize colonic segments missed by incomplete colonoscopy in 90% of patients under protocol A and 97% of patients under protocol B (P = 0.35, n.s.). Significant polyps including adenocarcinoma were detected in 24% of cases. Detection rates for all polyps and significant polyps per patient were similar in both protocols. Polyps were found predominantly in the right colon (86%) in segments that were not reached by OC. Extracolonic findings - such as reflux esophagitis, suspected Barrett esophagus, upper GI-bleeding, gastric polyps, gastric erosions and angiectasia - were detected in eight patients. PillCamColon2 capsule was retained in the ileum of one patient (1.4%) without symptoms and removed during an uneventful resection for unknown Crohn’s disease that was diagnosed as the cause of anemia, which was the indication for colonoscopy. CCE was well tolerated. One patient suffered from self-limiting vomiting after consuming the phospho-soda.
Conclusion: Second-generation CCE using a low-volume preparation is useful after incomplete OC, and it allows for the detection of additional relevant findings, but cleansing efficiency could be improved.
Als abschließende Glieder regressiver Sedimentationsphasen treten im westlichen Wiehengebirge innerhalb oberjurassischer Sand-, Mergel- und Tonstein-Wechselfolgen "Bröckeltonsteine" auf, die sich durch große Mächtigkeit (bis über 10 m), homogene schluffig-tonige Textur, auffallend grobpolyedrische Struktur, glänzende, mit etwa 20°–40° Grad geneigte Gleitflächen ("Slickensides") und domartige, einander randlich durchschneidende Aufwölbungs-Strukturen von 1,5 - 3 m horizontaler Ausdehnung auszeichnen. Die in semiariden bis subhumiden Überflutungs- Landschaften gebildeten Sedimente wurden synsedimentär durch Peloturbation beeinflusst. Dies erklärt die teilweise extrem große Mächtigkeit der vertischen Merkmale. Mikromorphologisch zeigt das Material deutlich ausgeprägte Bioturbations-Merkmale sowie Stress-Kutane. Erhöhte Temperaturen durch die Aktivität eines Plutons in der Kreide-Zeit scheinen eine Smektit-zu-Illit-Umwandlung und eine diagenetische Kornvergrößerung bewirkt zu haben. Im Verlauf der synsedimentären Bodenbildung kam es zu einer deutlichen Kompaktierung, sodass Groß-Dinosaurier über die Flächen hinweg schreiten konnten, ohne tiefer als etwa 5 cm einzusinken. Im Quartär dürfte es zu teilweise intensiver Eisen-Umverteilung, zum Eindringen von Ton in Spalten sowie zur Freilegung der bereits im Jura präformierten Polyeder ("Bröckel") gekommen sein.
Die Bewertung der Nitrataustragsgefährdung (NAG) landwirtschaftlich genutzter Flächen in Wasserschutzgebieten (WSG) erfolgte bislang auf Basis bodenkundlicher Kartierungen und wurde seit 1996 nach einem im Staatsanzeiger für das Land Hessen veröffentlichten Merkblatt des ehemaligen Hessischen Landesamtes für Bodenforschung im Rahmen der Muster-Wasserschutzgebietsverordnung geregelt (HLfB 1996, HMUJFG 1996). Infolge der Verfügbarkeit hochauflösender Bodendaten in Form der „Bodenflächendaten 1: 5.000, landwirtschaftliche Nutzfläche“ (BFD5L) wird die Ermittlung der Nitrataustragsgefährdung landwirtschaftlich genutzter Flächen neu geregelt. Die BFD5L liefert Auswertungen der Bodenschätzungsdaten zur Feldkapazität des Wurzelraums sowie weiterer relevanter Parameter, die zur Bewertung der Nitrataustragsgefährdung herangezogen werden können.
Um die Eignung der BFD5L-Daten zur Ermittlung der Nitrataustragsgefährdung zu überprüfen, wurden in den Jahren 2009 bis 2012 bodenkundliche Vergleichskartierungen im Rahmen eines Pilotvorhabens im Wasserschutzgebiet Eschollbrücken/Pfungstadt in Südhessen, im Wassereinzugsgebiet der Quelle Meineringhausen bei Korbach, im Wasserschutzgebiet des Tiefbrunnens Spieß der Gemeinde Bad Emstal sowie im WSG Quelle Ohmes der Stadt Kirtorf durchgeführt. Ziel war es, die Umsetzungsmöglichkeiten bei der Nutzung der BFD5LDaten in organisatorischer und technischer Hinsicht zu erproben und das bisherige Verfahren zu überarbeiten (PETER & MILLER 2009, PETER & MILLER 2010a und 2010b, PETER & MILLER 2012).
Die Ergebnisse der Vergleichskartierungen zeigen, dass sich die Daten der BFD5L grundsätzlich für die Ermittlung der Nitrataustragsgefährdung in Wasserschutzgebieten eignen. Lediglich für Flächen, für die nach den bislang im System BFD5L enthaltenen Methoden keine Kennwerte abgeleitet werden können sowie für Sonderstandorte, muss die Nitrataustragsgefährdung durch bodenkundliche Geländearbeiten ermittelt werden.
Modification of SMN2 exon 7 (E7) splicing is a validated therapeutic strategy against spinal muscular atrophy (SMA). However, a target-based approach to identify small-molecule E7 splicing modifiers has not been attempted, which could reveal novel therapies with improved mechanistic insight. Here, we chose as a target the stem-loop RNA structure TSL2, which overlaps with the 5′ splicing site of E7. A small-molecule TSL2-binding compound, homocarbonyltopsentin (PK4C9), was identified that increases E7 splicing to therapeutic levels and rescues downstream molecular alterations in SMA cells. High-resolution NMR combined with molecular modelling revealed that PK4C9 binds to pentaloop conformations of TSL2 and promotes a shift to triloop conformations that display enhanced E7 splicing. Collectively, our study validates TSL2 as a target for small-molecule drug discovery in SMA, identifies a novel mechanism of action for an E7 splicing modifier, and sets a precedent for other splicing-mediated diseases where RNA structure could be similarly targeted.
The wide range of immunosuppressive therapies and protocols permits tailored planning of the initial regimen according to the immunological risk status of individual patients. Pre-transplant risk assessment can include many factors, but there is no clear consensus on which parameters to take into account, and their relative importance. In general younger patients are known to be at higher risk for acute rejection, compounded by higher rates of non-adherence in adolescents. Donor age and recipient gender do not appear to exert a meaningful effect on risk of rejection per se, but black recipient ethnicity remains a well-established risk factor even under modern immunosuppression regimens. Little difference in risk is now observed between deceased- and living-donor recipients. Immunological risk assessment has developed substantially in recent years. Cross-match testing with cytotoxic analysis has long been supplemented by flow cytometry, but development of solid-phase single-bead antigen testing of solubilized human leukocyte antigens (HLA) to detect donor-specific antibodies (DSA) permits a far more nuanced stratification of immunological risk status, including the different classes and intensities of HLA antibodies Class I and/or II, including HLA-DSA. Immunologic risk evaluation is now often based on a combination of these tests, but other assessments are becoming more widely introduced, such as measurement of non-HLA antibodies against angiotensin type 1 (AT1) receptors or T-cell ELISPOT assay of alloantigen-specific donor. Targeted densensitization protocols can improve immunological risk, notably for DSA-positive patients with negative cytotoxicity and flow cross-match. HLA mismatch remains an important and undisputed risk factor for rejection. Delayed graft function also increases the risk of subsequent acute rejection, and the early regimen can be modified in such cases. Overall, there is a shift towards planning the immunosuppressive regimen based on pre-transplant immunology testing although certain conventional risk factors retain their importance.