Automatic Holter electrocardiogram analysis in ischaemic stroke patients to detect paroxysmal atrial fibrillation: ready to replace physicians?

BACKGROUND AND PURPOSE: The detection of paroxysmal atrial fibrillation (pAF) in patients presenting with ischaemic stroke shifts secondary stroke prevention to oral anticoagulation. In order to deal with the time- and resource-consuming manual analysis of prolonged electrocardiogram (ECG)-monitoring data, we investigated the effectiveness of pAF detection with an automated algorithm (AA) in comparison to a manual analysis with software support within the IDEAS study [study analysis (SA)]. METHODS: We used the dataset of the prospective IDEAS cohort of patients with acute ischaemic stroke/transient ischaemic attack presenting in sinus rhythm undergoing prolonged 72-h Holter ECG with central adjudication of atrial fibrillation (AF). This adjudicated diagnosis of AF was compared with a commercially available AA. Discordant results with respect to the diagnosis of pAF were resolved by an additional cardiological reference confirmation. RESULTS: Paroxysmal AF was finally diagnosed in 62 patients (5.9%) in the cohort (n = 1043). AA more often diagnosed pAF (n = 60, 5.8%) as compared with SA (n = 47, 4.5%). Due to a high sensitivity (96.8%) and negative predictive value (99.8%), AA was able to identify patients without pAF, whereas abnormal findings in AA required manual review (specificity 96%; positive predictive value 60.6%). SA exhibited a lower sensitivity (75.8%) and negative predictive value (98.5%), and showed a specificity and positive predictive value of 100%. Agreement between the two methods classified by kappa coefficient was moderate (0.591). CONCLUSION: Automated determination of 'absence of pAF' could be used to reduce the manual review workload associated with review of prolonged Holter ECG recordings.

[Personalized oncology]. / Personalisierte Onkologie.

CLINICAL ISSUE: Innovative next generation sequencing (NGS) technologies and comprehensive sequencing investigations in large patient cohorts have paved the way for very promising personalized treatment strategies based on the molecular characteristics of individual tumors. STANDARD TREATMENT: Targeted therapies, such as tyrosine kinase inhibitors, antibodies and modern immunotherapeutic approaches are well established as monotherapy and combination therapy for many hematological and oncological malignancies. TREATMENT INNOVATIONS: A plethora of innovative therapies targeting various components of intracellular signaling cascades and effective mechanisms against oncogenes as well as the availability of NGS technologies enable personalized cancer treatment based on the molecular profiles of individual tumors and genetic stratification, within clinical trials. DIAGNOSTIC WORK-UP: Comprehensive genetic approaches including cancer gene panel sequencing, whole exome, whole genome and transcriptome sequencing are carried out to a varying extent and particularly in the academic setting. PERFORMANCE: Principally, a comprehensive characterization of tumors in addition to DNA and RNA sequencing that also incorporates epigenetic, metabolomic, and proteomic alterations would be desirable. A comprehensive clinical implementation of integrative, multidimensional genetic typing is, however, currently not possible. ACHIEVEMENTS: It remains to be demonstrated whether these approaches will translate into significantly better outcomes for patients and whether they can be increasingly implemented in the routine diagnostic work-up. PRACTICAL RECOMMENDATIONS: The selection of diagnostic tools in individual cases and the extent of genomic analyses in the clinical context, need to take the availability of methods as well as the present clinical situation into account.

Automatic detection of paroxysmal atrial fibrillation in patients with ischaemic stroke: better than routine diagnostic workup?

BACKGROUND AND PURPOSE: Prolonged electrocardiogram (ECG) monitoring after ischaemic stroke increases the diagnostic yield of paroxysmal atrial fibrillation (pAF). In order to facilitate the additional workload involved in ECG analysis due to prolonged monitoring times, we investigated the effectiveness of pAF detection with an automated software algorithm (SA) in comparison to the routine staff-based analysis (RA) during standard stroke-unit care. Therefore, patients with acute ischaemic stroke or transitory ischaemic attack presenting with sinus rhythmus on the admission ECG and no history of atrial fibrillation were prospectively included. METHODS: A 24-h Holter ECG assessment was performed using either RA based on a computer-aided evaluation and subsequent review by a cardiologist or a commercially available automated SA. In the case of discordant results concerning the occurrence of pAF between the two methods, the data underwent an independent external rating. RESULTS: Of 809 prospectively enrolled patients, 580 patients fulfilled the inclusion criteria. pAF was ultimately diagnosed in 3.3% of the cohort (19 patients). SA and RA correctly diagnosed pAF in 17 patients resulting in a comparable diagnostic effectiveness of the analysis methods (sensitivity: SA 89.5% vs. RA 89.5%; specificity: SA 99.3% vs. RA 99.1%; κ, 0.686; P < 0.001; 95% confidence interval, 0.525-0.847). RA revealed clinically relevant ECG abnormalities in an additional seven patients. CONCLUSIONS: Although it should not completely replace RA, SA-based evaluation of Holter ECG reaches a high diagnostic effectiveness for the detection of pAF and can be used for a rapid and resource-saving analysis of ECG data to deal with prolonged monitoring times.

The clinical picture of cachexia: a mosaic of different parameters (experience of 503 patients).

BACKGROUND: Despite our growing knowledge about the pathomechanisms of cancer cachexia, a whole clinical picture of the cachectic patient is still missing. Our objective was to evaluate the clinical characteristics in cancer patients with and without cachexia to get the whole picture of a cachectic patient. METHODS: Cancer patients of the University Clinic "Klinikum rechts der Isar" with gastrointestinal, gynecological, hematopoietic, lung and some other tumors were offered the possibility to take part in the treatment concept including a nutrition intervention and an individual training program according to their capability. We now report on the first 503 patients at the time of inclusion in the program between March 2011 and October 2015. We described clinical characteristics such as physical activity, quality of life, clinical dates and food intake. RESULTS: Of 503 patients with cancer, 131 patients (26.0%) were identified as cachectic, 369 (73.4%) as non-cachectic. The change in cachexia were 23% reduced capacity performance (108 Watt for non-cachectic-patients and 83 Watt for cachectic patients) and 12% reduced relative performance (1.53 Watt/kg for non-cachectic and 1.34 Watt/kg for cachectic patients) in ergometry test. 75.6% of non-cachectic and 54.3% of cachectic patients still received curative treatment. CONCLUSION: Cancer cachectic patients have multiple symptoms such as anemia, impaired kidney function and impaired liver function with elements of mild cholestasis, lower performance and a poorer quality of life in the EORTC questionnaire. Our study reveals biochemical and clinical specific features of cancer cachectic patients.

Mutant KIT as imatinib-sensitive target in metastatic sinonasal carcinoma.

Background: Sinonasal carcinomas (SNCs) comprise various rare tumor types that are characterized by marked histologic diversity and largely unknown molecular profiles, yet share an overall poor prognosis owing to an aggressive clinical course and frequent late-stage diagnosis. The lack of effective systemic therapies for locally advanced or metastatic SNC poses a major challenge to therapeutic decision making for individual patients. We here aimed to identify actionable genetic alterations in a patient with metastatic SNC whose tumor, despite all diagnostic efforts, could not be assigned to any known SNC category and was refractory to multimodal therapy. Patients and methods: We used whole-exome and transcriptome sequencing to identify a KIT exon 11 mutation (c.1733_1735del, p.D579del) as potentially druggable target in this patient and carried out cancer hotspot panel sequencing to detect secondary resistance-conferring mutations in KIT. Furthermore, as a step towards clinical exploitation of the recently described signatures of mutational processes in cancer genomes, we established and applied a novel bioinformatics algorithm that enables supervised analysis of the mutational catalogs of individual tumors. Results: Molecularly guided treatment with imatinib in analogy to the management of gastrointestinal stromal tumor (GIST) resulted in a dramatic and durable response with remission of nearly all tumor manifestations, indicating a dominant driver function of mutant KIT in this tumor. KIT dependency was further validated by a secondary KIT exon 17 mutation (c.2459_2462delATTCinsG, p.D820_S821delinsG) that was detected upon tumor progression after 10 months of imatinib treatment and provided a rationale for salvage therapy with regorafenib, which has activity against KIT exon 11/17 mutant GIST. Conclusions: These observations highlight the potential of unbiased genomic profiling for uncovering the vulnerabilities of individual malignancies, particularly in rare and unclassifiable tumors, and underscore that KIT exon 11 mutations represent tractable therapeutic targets across different histologies.

Cooperation of BRAF(F595L) and mutant HRAS in histiocytic sarcoma provides new insights into oncogenic BRAF signaling.

Activating BRAF mutations, in particular V600E/K, drive many cancers and are considered mutually exclusive with mutant RAS, whereas inactivating BRAF mutations in the D(594)F(595)G(596) motif cooperate with RAS via paradoxical MEK/ERK activation. Due to the increasing use of comprehensive tumor genomic profiling, many non-V600 BRAF mutations are being detected whose functional consequences and therapeutic actionability are often unknown. We investigated an atypical BRAF mutation, F595L, which was identified along with mutant HRAS in histiocytic sarcoma and also occurs in epithelial cancers, melanoma and neuroblastoma, and determined its interaction with mutant RAS. Unlike other DFG motif mutants, BRAF(F595L) is a gain-of-function variant with intermediate activity that does not act paradoxically, but nevertheless cooperates with mutant RAS to promote oncogenic signaling, which is efficiently blocked by pan-RAF and MEK inhibitors. Mutation data from patients and cell lines show that BRAF(F595L), as well as other intermediate-activity BRAF mutations, frequently coincide with mutant RAS in various cancers. These data define a distinct class of activating BRAF mutations, extend the spectrum of patients with systemic histiocytoses and other malignancies who are candidates for therapeutic blockade of the RAF-MEK-ERK pathway and underscore the value of comprehensive genomic testing for uncovering the vulnerabilities of individual tumors.

Clinical predictors to identify paroxysmal atrial fibrillation after ischaemic stroke.

BACKGROUND AND PURPOSE: Detection of paroxysmal atrial fibrillation (pAF) after an ischaemic cerebrovascular event is of imminent interest, because oral anticoagulation as a highly effective secondary preventive treatment is available. Whereas permanent atrial fibrillation (AF) can be detected during routine electrocardiogram (ECG), longer detection duration will detect more pAF but might be resource consuming. The current study tried to identify clinical predictors for pAF detected during long-term Holter ECG and clinical follow-up. METHODS: Patients with acute ischaemic stroke were prospectively investigated with an intensified algorithm to detect pAF (7-day Holter ECG, follow-up investigations after 90 days and 1 year). RESULTS: Two hundred and eighty-one patients were included, 44 of whom had to be excluded since they presented with permanent AF and another 13 patients had to be excluded due to other causes leaving 224 patients (mean age 68.5 years, 58.5% male). Twenty-nine (12.9%) patients could be identified to have pAF during prolonged Holter monitoring, an additional 13 (5.8%) after follow-up investigations. Multivariate analysis identified advanced age [odds ratio (OR) 1.05, 95% confidence interval (CI) 1.01-1.08] as well as clinical symptoms >24 h (OR 5.17, 95% CI 1.73-15.48) and a history of coronary artery disease (OR 3.14, 95% CI 1.35-7.28) to be predictive for the detection of pAF. CONCLUSIONS: In acute stroke patients with advanced age, history of coronary artery disease and clinical symptoms >24 h, a prolonged Holter ECG monitoring and follow-up is warranted to identify pAF. This could increase the detection rate of patients requiring anticoagulation and may be able to reduce the risk of recurrent stroke in the case of successful anticoagulation of these patients.

Synthesis of novel MMT/acyl-protected nucleo alanine monomers for the preparation of DNA/alanyl-PNA chimeras.

Alanyl-peptide nucleic acid (alanyl-PNA)/DNA chimeras are oligomers envisaged to be beneficial in efficient DNA diagnostics based on an improved molecular beacon concept. A synthesis of alanyl-PNA/DNA chimera can be based on the solid phase assembly of the oligomer with mixed oligonucleotide/peptide backbone under DNA synthesis conditions, in which the nucleotides are introduced as phosphoramidites, whereas the nucleo amino acids make use of the acid labile monomethoxytrityl (MMT) group for temporary protection of the alpha-amino groups and acyl protecting groups for the exocyclic amino functions of the nucleobases. In this work, we realized for the first time the synthesis of all four MMT/acyl-protected nucleo alanines, achieved by deprotection/reprotection of the newly synthesized Boc/acyl intermediates, useful monomers for the obtainment of (alanyl-PNA)/DNA chimeras by conditions fully compatible with the standard phosphoramidite DNA synthesis strategy.

Unilateral dilation of virchow-robin spaces in early childhood.

Observations of extreme unilateral widening of Virchow-Robin spaces (VRS) are rare and hitherto confined to adult, mainly old-aged patients. Magnetic resonance imaging (MRI) was performed in two unrelated boys aged 3 years with developmental coordination disorders. In one of these patients, follow-up MRI and diffusion tensor imaging (DTI) were carried out 5 years later. In both boys, MRI incidentally revealed numerous intracerebral cysts strictly confined to one hemisphere. Localization, size, shape, and signal isointensity to cerebrospinal fluid indicated unilateral marked widening of VRS. In one patient, follow-up investigation after 5 years showed unchanged dilation of VRS on MRI, but mild facial hemihypertrophy, ipsilateral to the widened VRS. DTI indicated displacement rather than disruption of fiber tracks adjacent to the dilated VRS. Unilateral widening of VRS may be detected fortuitously on neuroimaging already in early childhood.