Outcome nach operativer Entfernung eines kardialen Myxoms: eine Gegenüberstellung zufällig diagnostizierter Myxome und nach Apoplex diagnostizierter Myxome

Der Großteil der Publikationen zu kardialen Myxomen sind Casereports mit beeindruckenden Befunden, nur wenige Autoren haben ihre Erfahrungen mit einer größeren Anzahl von Patienten mit Myxomen in Arbeiten veröffentlicht. Jedoch ist es bislang nicht bis ins Detail geklärt, welche Unterschiede Patienten hinsichtlich der perioperativen Variablen, der mittelfristigen Prognose und der späteren Lebensqualität aufweisen, insbesondere abhängig davon, ob die Diagnose nach einer zerebralen Tumorembolisation oder zufällig bei asymptomatischen beziehungsweise weniger spezifischen Symptomen gestellt wurde. Die vorliegende Arbeit hatte zum Ziel, nach diesen Unterschieden zu suchen und darüber hinaus zu erörtern, ob es in der Praxis Differenzen zwischen den beiden Gruppen in der kardiologischen und neurologischen Nachsorge gibt

Genomic and Transcriptomic Characteristics of Esophageal Adenocarcinoma

Simple Summary Cancer of the esophagus is a deadly disease. There are two main subtypes, adenocarcinoma and squamous cell carcinoma, with adenocarcinoma of the esophagus (EAC) being more common in Western countries. Barrett's esophagus (BE) describes a change in the esophageal surface near the stomach in response to reflux of gastric acid into the esophagus. BE increases the risk of developing EAC, and the incidence of EAC has risen dramatically over recent decades. One likely reason for the poor prognosis of EAC is based on the fact that each tumor has many genes affected by mutations, and most of these genes differ across patients, hampering the efficacy of therapies that target specific cancer driver proteins. In this review, we provide an overview of the gene mutations and gene activity changes in EAC and how these features can be used to divide patients into groups that might have different clinical characteristics. Esophageal adenocarcinoma (EAC) is a deadly disease with limited options for targeted therapy. With the help of next-generation sequencing studies over the last decade, we gained an understanding of the genomic architecture of EAC. The tumor suppressor gene TP53 is mutated in 70 to 80% of tumors followed by genomic alterations in CDKN2A, KRAS, ERBB2, ARID1A, SMAD4 and a long tail of less frequently mutated genes. EAC is characterized by a high burden of point mutations and genomic rearrangements, resulting in amplifications and deletions of genomic regions. The genomic complexity is likely hampering the efficacy of targeted therapies. Barrett's esophagus (BE), a metaplastic response of the esophagus to gastro-esophageal reflux disease, is the main risk factor for the development of EAC. Almost all EACs are derived from BE. The sequence from BE to EAC provides an opportunity to study the genomic evolution towards EAC. While the overlap of point mutations between BE and EAC within the same patient is, at times, surprisingly low, there is a correlation between the complexity of the genomic copy number profile and the development of EAC. Transcriptomic analyses separated EAC into a basal and a classical subtype, with the basal subtype showing a higher level of resistance to chemotherapy. In this review, we provide an overview of the current knowledge of the genomic and transcriptomic characteristics of EAC and their relevance for the development of the disease and patient care

Cardiac Myxomas Resembling Malignant Neoplasia: Incidentally Diagnosed vs. Cerebral Embolized Myxomas

Background: Cardiac myxomas (CM) are the most common primary cardiac tumors in adults. They are usually benign; however, malignant changes are known to occur but are extremely rare. Embolization is a common complication of cardiac myxomas and can cause neurological deficits before their surgical removal. The current study analyzed the outcomes after operative myxoma excision in patients, with and without cerebral embolic events prior to excision. Methods: All 66 consecutive patients who underwent a surgical excision of CM between 2005 and 2019 at our department were analyzed retrospectively. Patients with (n = 14) and without (n = 52) preoperative strokes caused by cerebral tumor embolization were compared. Results: The mean age was 58.4 ± 12.7 years in the stroke group (SG) and 62.8 ± 11.7 years in the non-stroke group (N-SG) (p = 0.226). Gender (35.7% vs. 61.5% female; p = 0.084) did not differ significantly, and comorbidities were comparable in both groups. The left hemisphere in the territory of the middle cerebral artery was affected by preoperative cerebral infarction most commonly (28.6%). The time from diagnosis to cardiac surgery procedure was 7 (3–24) days in the SG and 23 (5–55) days in the N-SG (p = 0.120). Cardiac myxomas were localized in the left atrium in both groups more frequently (SG: 92.9% vs. N-SG: 78.8%; p = 0.436). In the SG, 57.1% of CM had a non-solid surface, were localized in the left heart, and had a pedunculated attachment away from the fossa ovalis. In the N-SG, 92.3% of CM did not meet all these criteria (p p = 0.538). The operation times (192.5 (139.3–244.5) min vs. 215.5 (184.5–273.3) min; p = 0.046) and the cross-clamp times (54.5 (33.3–86.5) min vs. 78.5 (55–106.8) min; p = 0.035) were significantly shorter in the SG. Only in the N-SG were reconstructions of the endocardium with bovine pericardium required after resection (51.9% vs 0%; p p = 0.007). Patients in the N-SG required significantly shorter ICU care after surgery (p = 0.020). Other postoperative courses did not differ significantly. After tumor removal, 1.9% of the N-SG suffered their first stroke and 14.3% of the SG had a cerebral re-infarction (p = 0.111). The 30-day mortality rates were 1.9% in the N-SG and 7.1% in the SG (p = 0.382). In one case in the N-SG, a tumor recurrence was diagnosed. The Kaplan–Meiercurves showed a significantly better long-term prognosis for patients in the N-SG (p = 0.043). Conclusions: After the surgical removal of CM, the outcome is compromised if preoperative cerebral embolization occurs. Surgical treatment is therefore indicated as soon as possible, especially when CM have a non-solid surface, are localized in the left heart, and have a pedunculated attachment away from the fossa ovalis

A rice Serine/Threonine receptor-like kinase regulates arbuscular mycorrhizal symbiosis at the peri-arbuscular membrane

In terrestrial ecosystems most plant species live in mutualistic symbioses with nutrient-delivering arbuscular mycorrhizal (AM) fungi. Establishment of AM symbioses includes transient, intracellular formation of fungal feeding structures, the arbuscules. A plant-derived peri-arbuscular membrane (PAM) surrounds the arbuscules, mediating reciprocal nutrient exchange. Signaling at the PAM must be well coordinated to achieve this dynamic cellular intimacy. Here, we identify the PAM-specific Arbuscular Receptor-like Kinase 1 (ARK1) from maize and rice to condition sustained AM symbiosis. Mutation of rice ARK1 causes a significant reduction in vesicles, the fungal storage structures, and a concomitant reduction in overall root colonization by the AM fungus Rhizophagus irregularis. Arbuscules, although less frequent in the ark1 mutant, are morphologically normal. Co-cultivation with wild-type plants restores vesicle and spore formation, suggesting ARK1 function is required for the completion of the fungal life-cycle, thereby defining a functional stage, post arbuscule development

A rice Serine/Threonine receptor-like kinase regulates arbuscular mycorrhizal symbiosis at the peri-arbuscular membrane.

In terrestrial ecosystems most plant species live in mutualistic symbioses with nutrient-delivering arbuscular mycorrhizal (AM) fungi. Establishment of AM symbioses includes transient, intracellular formation of fungal feeding structures, the arbuscules. A plant-derived peri-arbuscular membrane (PAM) surrounds the arbuscules, mediating reciprocal nutrient exchange. Signaling at the PAM must be well coordinated to achieve this dynamic cellular intimacy. Here, we identify the PAM-specific Arbuscular Receptor-like Kinase 1 (ARK1) from maize and rice to condition sustained AM symbiosis. Mutation of rice ARK1 causes a significant reduction in vesicles, the fungal storage structures, and a concomitant reduction in overall root colonization by the AM fungus Rhizophagus irregularis. Arbuscules, although less frequent in the ark1 mutant, are morphologically normal. Co-cultivation with wild-type plants restores vesicle and spore formation, suggesting ARK1 function is required for the completion of the fungal life-cycle, thereby defining a functional stage, post arbuscule development.Marie Curie FP7-PEOPLE-2013-IEF Grant number 629887 Gatsby Charitable Foundation RG60824 Isaac Newton Trust RG7410

Immune responses against shared antigens are common in esophago-gastric cancer and can be enhanced using CD40-activated B cells

Background Specific immune response is a hallmark of cancer immunotherapy and shared tumor-associated antigens (TAAs) are important targets. Recent advances using combined cellular therapy against multiple TAAs renewed the interest in this class of antigens. Our study aims to determine the role of TAAs in esophago-gastric adenocarcinoma (EGA).Methods RNA expression was assessed by NanoString in tumor samples of 41 treatment-naïve EGA patients. Endogenous T cell and antibody responses against the 10 most relevant TAAs were determined by FluoroSpot and protein-bound bead assays. Digital image analysis was used to evaluate the correlation of TAAs and T-cell abundance. T-cell receptor sequencing, in vitro expansion with autologous CD40-activated B cells (CD40Bs) and in vitro cytotoxicity assays were applied to determine specific expansion, clonality and cytotoxic activity of expanded T cells.Results 68.3% of patients expressed ≥5 TAAs simultaneously with coregulated clusters, which were similar to data from The Cancer Genome Atlas (n=505). Endogenous cellular or humoral responses against ≥1 TAA were detectable in 75.0% and 53.7% of patients, respectively. We found a correlation of T-cell abundance and the expression of TAAs and genes related to antigen presentation. TAA-specific T-cell responses were polyclonal, could be induced or enhanced using autologous CD40Bs and were cytotoxic in vitro. Despite the frequent expression of TAAs co-occurrence with immune responses was rare.Conclusions We identified the most relevant TAAs in EGA for monitoring of clinical trials and as therapeutic targets. Antigen-escape rather than missing immune response should be considered as mechanism underlying immunotherapy resistance of EGA

Transcriptional consequences of genomic structural aberrations in breast cancer.

Using a long-span, paired-end deep sequencing strategy, we have comprehensively identified cancer genome rearrangements in eight breast cancer genomes. Herein, we show that 40%-54% of these structural genomic rearrangements result in different forms of fusion transcripts and that 44% are potentially translated. We find that single segmental tandem duplication spanning several genes is a major source of the fusion gene transcripts in both cell lines and primary tumors involving adjacent genes placed in the reverse-order position by the duplication event. Certain other structural mutations, however, tend to attenuate gene expression. From these candidate gene fusions, we have found a fusion transcript (RPS6KB1-VMP1) recurrently expressed in ∼30% of breast cancers associated with potential clinical consequences. This gene fusion is caused by tandem duplication on 17q23 and appears to be an indicator of local genomic instability altering the expression of oncogenic components such as MIR21 and RPS6KB1

Comprehensive long-span paired-end-tag mapping reveals characteristic patterns of structural variations in epithelial cancer genomes

Somatic genome rearrangements are thought to play important roles in cancer development. We optimized a long-span paired-end-tag (PET) sequencing approach using 10-Kb genomic DNA inserts to study human genome structural variations (SVs). The use of a 10-Kb insert size allows the identification of breakpoints within repetitive or homology-containing regions of a few kilobases in size and results in a higher physical coverage compared with small insert libraries with the same sequencing effort. We have applied this approach to comprehensively characterize the SVs of 15 cancer and two noncancer genomes and used a filtering approach to strongly enrich for somatic SVs in the cancer genomes. Our analyses revealed that most inversions, deletions, and insertions are germ-line SVs, whereas tandem duplications, unpaired inversions, interchromosomal translocations, and complex rearrangements are over-represented among somatic rearrangements in cancer genomes. We demonstrate that the quantitative and connective nature of DNA–PET data is precise in delineating the genealogy of complex rearrangement events, we observe signatures that are compatible with breakage-fusion-bridge cycles, and we discover that large duplications are among the initial rearrangements that trigger genome instability for extensive amplification in epithelial cancers

A common variant mapping to <i>CACNA1A </i>is associated with susceptibility to exfoliation syndrome

Author manuscript available from PMC http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4605818/Exfoliation syndrome (XFS) is the most common recognizable cause of open-angle glaucoma worldwide. To better understand the etiology of XFS, we conducted a genome-wide association study (GWAS) of 1,484 cases and 1,188 controls from Japan and followed up the most significant findings in a further 6,901 cases and 20,727 controls from 17 countries across 6 continents. We discovered a genome-wide significant association between a new locus (CACNA1A rs4926244) and increased susceptibility to XFS (odds ratio (OR) = 1.16, P = 3.36 × 10−11). Although we also confirmed overwhelming association at the LOXL1 locus, the key SNP marker (LOXL1 rs4886776) demonstrated allelic reversal depending on the ancestry group (Japanese: ORA allele = 9.87, P = 2.13 × 10−217; non-Japanese: ORA allele = 0.49, P = 2.35 × 10−31). Our findings represent the first genetic locus outside of LOXL1 surpassing genome-wide significance for XFS and provide insight into the biology and pathogenesis of the disease