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Ziele: Das Ziel dieser offiziellen Leitlinie, die von der Deutschen Gesellschaft für Gynäkologie und Geburtshilfe (DGGG) und der Deutschen Krebsgesellschaft (DKG) publiziert und koordiniert wurde, ist es, die Früherkennung, Diagnostik, Therapie und Nachsorge des Mammakarzinoms zu optimieren.
Methoden: Der Aktualisierungsprozess der S3-Leitlinie aus 2012 basierte zum einen auf der Adaptation identifizierter Quellleitlinien und zum anderen auf Evidenzübersichten, die nach Entwicklung von PICO-(Patients/Interventions/Control/Outcome-)Fragen, systematischer Recherche in Literaturdatenbanken sowie Selektion und Bewertung der gefundenen Literatur angefertigt wurden. In den interdisziplinären Arbeitsgruppen wurden auf dieser Grundlage Vorschläge für Empfehlungen und Statements erarbeitet, die im Rahmen von strukturierten Konsensusverfahren modifiziert und graduiert wurden.
Empfehlungen: Der Teil 1 dieser Kurzversion der Leitlinie zeigt Empfehlungen zur Früherkennung, Diagnostik und Nachsorge des Mammakarzinoms: Der Stellenwert des Mammografie-Screenings wird in der aktualisierten Leitlinienversion bestätigt und bildet damit die Grundlage der Früherkennung. Neben den konventionellen Methoden der Karzinomdiagnostik wird die Computertomografie (CT) zum Staging bei höherem Rückfallrisiko empfohlen. Die Nachsorgekonzepte beinhalten Untersuchungsintervalle für die körperliche Untersuchung, Ultraschall und Mammografie, während weiterführende Gerätediagnostik und Tumormarkerbestimmungen bei der metastasierten Erkrankung Anwendung finden.
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.
Downstream effects of plectin mutations in epidermolysis bullosa simplex with muscular dystrophy
(2016)
Mutations of the human plectin gene (PLEC) on chromosome 8q24 cause autosomal recessive epidermolysis bullosa simplex with muscular dystrophy (EBS-MD). In the present study we analyzed the downstream effects of PLEC mutations on plectin protein expression and localization, the structure of the extrasarcomeric desmin cytoskeleton, protein aggregate formation and mitochondrial distribution in skeletal muscle tissue from three EBS-MD patients.
PLEC gene analysis in a not previously reported 35-year-old EBS-MD patient with additional disease features of cardiomyopathy and malignant arrhythmias revealed novel compound heterozygous (p.(Phe755del) and p.(Lys1040Argfs*139)) mutations resulting in complete abolition of plectin protein expression. In contrast, the other two patients with different homozygous PLEC mutations showed preserved plectin protein expression with one only expressing rodless plectin variants, and the other markedly reduced protein levels. Analysis of skeletal muscle tissue from all three patients revealed severe disruption of the extrasarcomeric intermediate filament cytoskeleton, protein aggregates positive for desmin, syncoilin, and synemin, degenerative myofibrillar changes, and mitochondrial abnormalities comprising respiratory chain dysfunction and an altered organelle distribution and amount.
Our study demonstrates that EBS-MD causing PLEC mutations universally result in a desmin protein aggregate myopathy phenotype despite marked differences in individual plectin protein expression patterns. Since plectin is the key cytolinker protein that regulates the structural and functional organization of desmin filaments, the defective anchorage and spacing of assembled desmin filaments is the key pathogenetic event that triggers the formation of desmin protein aggregates as well as secondary mitochondrial pathology.
Background: Balloon pulmonary angioplasty is an evolving, interventional treatment option for inoperable patients with chronic thromboembolic pulmonary hypertension (CTEPH). Pulmonary hypertension at rest as well as exercise capacity is considered to be relevant outcome parameters. The aim of the present study was to determine whether measurement of pulmonary hemodynamics during exercise before and six months after balloon pulmonary angioplasty have an added value.
Methods: From March 2014 to July 2018, 172 consecutive patients underwent balloon pulmonary angioplasty. Of these, 64 consecutive patients with inoperable CTEPH underwent a comprehensive diagnostic workup that included right heart catheterization at rest and during exercise before balloon pulmonary angioplasty treatments and six months after the last intervention.
Results: Improvements in pulmonary hemodynamics at rest and during exercise, in quality of life, and in exercise capacity were observed six months after balloon pulmonary angioplasty: WHO functional class improved in 78% of patients. The mean pulmonary arterial pressure (mPAP) at rest was reduced from 41 ± 9 to 31 ± 9 mmHg (p < 0.0001). The mPAP/cardiac output slope decreased after balloon pulmonary angioplasty (11.2 ± 25.6 WU to 7.7 ± 4.1 WU; p < 0.0001), and correlated with N-terminal fragment of pro-brain natriuretic peptide (p = 0.035) and 6-minute walking distance (p = 0.01).
Conclusions: Exercise right heart catheterization provides valuable information on the changes of pulmonary hemodynamics after balloon pulmonary angioplasty in inoperable CTEPH patients that are not obtainable by measuring resting hemodynamics.
Traditional chinese medicine and herbal hepatotoxicity: a tabular compilation of reported cases
(2015)
Traditional Chinese Medicine (TCM) with its focus on herbal use became popular worldwide. Treatment was perceived as safe, with neglect of rare adverse reactions including liver injury. To compile worldwide cases of liver injury by herbal TCM, we undertook a selective literature search in the PubMed database and searched for the items Traditional Chinese Medicine, TCM, Traditional Asian Medicine, and Traditional Oriental Medicine, also combined with the terms herbal hepatotoxicity or herb induced liver injury. The search focused primarily on English-language case reports, case series, and clinical reviews. We identified reported hepatotoxicity cases in 77 relevant publications with 57 different herbs and herbal mixtures of TCM, which were further analyzed for causality by the Council for International Organizations of Medical Sciences (CIOMS) scale, positive reexposure test results, or both. Causality was established for 28/57 different herbs or herbal mixtures, Bai Xian Pi, Bo He, Ci Wu Jia, Chuan Lian Zi, Da Huang, Gan Cao, Ge Gen, Ho Shou Wu, Huang Qin, Hwang Geun Cho, Ji Gu Cao, Ji Xue Cao, Jin Bu Huan, Jue Ming Zi, Jiguja, Kudzu, Ling Yang Qing Fei Keli, Lu Cha, Rhen Shen, Ma Huang, Shou Wu Pian, Shan Chi, Shen Min, Syo Saiko To, Xiao Chai Hu Tang, Yin Chen Hao, Zexie, and Zhen Chu Cao. In conclusion, this compilation of liver injury cases establishes causality for 28/57 different TCM herbs and herbal mixtures, aiding diagnosis for physicians who care for patients with liver disease possibly related to herbal TCM.
Causality assessment of suspected drug induced liver injury (DILI) and herb induced liver injury (HILI) is hampered by the lack of a standardized approach to be used by attending physicians and at various subsequent evaluating levels. The aim of this review was to analyze the suitability of the liver specific Council for International Organizations of Medical Sciences (CIOMS) scale as a standard tool for causality assessment in DILI and HILI cases. PubMed database was searched for the following terms: drug induced liver injury; herb induced liver injury; DILI causality assessment; and HILI causality assessment. The strength of the CIOMS lies in its potential as a standardized scale for DILI and HILI causality assessment. Other advantages include its liver specificity and its validation for hepatotoxicity with excellent sensitivity, specificity and predictive validity, based on cases with a positive reexposure test. This scale allows prospective collection of all relevant data required for a valid causality assessment. It does not require expert knowledge in hepatotoxicity and its results may subsequently be refined. Weaknesses of the CIOMS scale include the limited exclusion of alternative causes and qualitatively graded risk factors. In conclusion, CIOMS appears to be suitable as a standard scale for attending physicians, regulatory agencies, expert panels and other scientists to provide a standardized, reproducible causality assessment in suspected DILI and HILI cases, applicable primarily at all assessing levels involved.
Background and aim. In the fall of 2013, the US Centers for Disease Control and Prevention (CDC) published a preliminary report on a cluster of liver disease cases that emerged in Hawaii in the summer 2013. This report claimed a temporal association as sufficient evidence that OxyELITE Pro (OEP), a dietary supplement (DS) mainly for weight loss, was the cause of this mysterious cluster. However, the presented data were inconsistent and required a thorough reanalysis.
Material and methods. To further investigate the cause(s) of this cluster, we critically evaluated redacted raw clinical data of the cluster patients, as the CDC report received tremendous publicity in local and nationwide newspapers and television. This attention put regulators and physicians from the medical center in Honolulu that reported the cluster, under enormous pressure to succeed, risking biased evaluations and hasty conclusions.
Results. We noted pervasive bias in the documentation, conclusions, and public statements, also poor quality of case management. Among the cases we reviewed, many causes unrelated to any DS were evident, including decompensated liver cirrhosis, acute liver failure by acetaminophen overdose, acute cholecystitis with gallstones, resolving acute hepatitis B, acute HSV and VZV hepatitis, hepatitis E suspected after consumption of wild hog meat, and hepatotoxicity by acetaminophen or ibuprofen. Causality assessments based on the updated CIOMS scale confirmed the lack of evidence for any DS including OEP as culprit for the cluster.
Conclusions. Thus, the Hawaii liver disease cluster is now best explained by various liver diseases rather than any DS, including OEP.
Background. Spontaneous reports of herb induced liver injury (HILI) represent a major regulatory issue, and it is in the interest of pharmacovigilance to identify and quantify previously unrecognized adverse reactions and to confirm or refute false positive signals of safety concerns. In a total of 13 spontaneous cases, liver disease has initially been attributed to the use of Pelargonium sidoides (PS), a plant from the South African region. Water/ethanol extracts derived from its roots are available as registered herbal drugs for the treatment of upper respiratory tract infections including acute bronchitis. Objectives. The present study examines whether and to what extent treatment by PS was associated with the risk of liver injury in these spontaneous cases. Study design: Overall, 13 spontaneous cases with primarily suspected PS hepatotoxicity were included in the study. Their data were submitted to a thorough clinical evaluation that included the use of the original and updated scale of CIOMS (Council for International Organizations of Medical Sciences) to assess causality levels. These scales are liver specific, validated for liver toxicity, structured and quantitative.
Results. None of the 13 spontaneous cases of liver disease generated a positive signal of safety concern, since causality for PS could not be established on the basis of the applied CIOMS scales in any of the assessed patients. Confounding variables included comedication with synthetic drugs, major comorbidities, low data quality, lack of appropriate consideration of differential diagnoses, and multiple alternative diagnoses. Among these were liver injury due to comedication, acute pancreatitis and cholangitis, acute cholecystitis, hepatic involvement following lung contusion, hepatitis in the course of virus and bacterial infections, ANA positive autoimmune hepatitis, and other preexisting liver diseases. In the course of the case assessments and under pharmacovigilance aspects, data and interpretation deficits became evident. Possible improvements include appropriate data quality of cases in spontaneous reports, case assessment by skilled specialists, use of a validated liver specific causality assessment method, and inclusion only of confirmed cases into the final regulatory case database.
Conclusions. This study shows lack of hepatotoxicity by PS in all 13 spontaneous cases as opposed to initial judgment that suggested a toxic potential of PS. Major shortcomings emerged in the pharmacovigilance section that require urgent improvements.
The diagnosis of drug induced liver injury (DILI) is based primarily on the exclusion of alternative causes. To assess the frequency of alternative causes in initially suspected DILI cases, we searched the Medline database with the following terms: drug hepatotoxicity, drug induced liver injury, and hepatotoxic drugs. For each term, we used the first 100 publications. We reviewed references, selected those reports relevant to our study, and retrieved finally 15 publications related to DILI and alternative causes. A total of 2,906 cases of initially assumed DILI were analyzed in these 15 publications, with diagnoses missed in 14% of the cases due to overt alternative causes. In another 11%, the diagnosis of DILI could not be established because of confounding variables. Alternative diagnoses included hepatitis B, C, and E, CMV, EBV, ischemic hepatitis, autoimmune hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis, hemochromatosis, Wilson’s disease, Gilbert’s syndrome, fatty liver, non alcoholic steatohepatitis, alcoholic liver diseases, cardiac and thyroid causes, rhabdomyolysis, polymyositis, postictal state, tumors, lymphomas, chlamydial and HIV infections. Causality assessment methods applied in these 15 publications were the CIOMS (Council for International Organizations of Medical Sciences) scale alone (n = 5) or combined with the Maria and Victorino (MV) scale (n = 1), the DILIN (Drug-Induced Liver Injury Network) method (n = 4), or the Naranjo scale (n = 1); the qualitative CIOMS method alone (n = 3) or combined with the MV scale (n = 1). In conclusion, alternative diagnoses are common in primarily suspected DILI cases and should be excluded early in future cases, requiring a thorough clinical and causality assessment.