Today, an enormous amount of data is being continuously generated in all walks of life by all kinds of devices and systems every day. A significant portion of such data is being captured, stored, ...aggregated and analyzed in a systematic way without losing its “4V” (i.e., volume, velocity, variety, and veracity) characteristics. We review major drivers of big data today as well the recent trends and established platforms that offer valuable perspectives on the information stored in large and heterogeneous data sets. Then, we present a classification of some of the most important challenges when handling big data. Based on this classification, we recommend solutions that could address the identified challenges, and in addition we highlight cross-disciplinary research directions that need further investigation in the future.
The contribution of molecular alterations in bone marrow mesenchymal stromal cells (BM-MSC) to the pathogenesis of acute myeloid leukemia (AML) is poorly understood. Thus we assessed genome-wide ...genetic, transcriptional and epigenetic alterations in BM-MSC derived from AML patients (AML BM-MSC). Whole-exome sequencing (WES) of AML BM-MSC samples from 21 patients revealed a non-specific pattern of genetic alterations in the stromal compartment. The only mutation present in AML BM-MSC at serial time points of diagnosis, complete remission and relapse was a mutation in the PLEC gene encoding for cytoskeleton key player Plectin in one AML patient. Healthy donor controls did not carry genetic alterations as determined by WES. Transcriptional profiling using RNA sequencing revealed deregulation of proteoglycans and adhesion molecules as well as cytokines in AML BM-MSC. Moreover, KEGG pathway enrichment analysis unravelled deregulated metabolic pathways and endocytosis in both transcriptional and DNA methylation signatures in AML BM-MSC. Taken together, we report molecular alterations in AML BM-MSC suggesting global changes in the AML BM microenvironment. Extended investigations of these altered niche components may contribute to the design of niche-directed therapies in AML.
In April 2013 our group published a review on predictive molecular pathology in this journal. Although only 2 years have passed many new facts and stimulating developments have happened in diagnostic ...molecular pathology rendering it worthwhile to present an up-date on this topic. A major technical improvement is certainly given by the introduction of next-generation sequencing (NGS; amplicon, whole exome, whole genome) and its application to formalin-fixed paraffin-embedded (FFPE) tissue in routine diagnostics. Based on this 'revolution' the analyses of numerous genetic alterations in parallel has become a routine approach opening the chance to characterize patients' malignant tumors much more deeply without increasing turn-around time and costs. In the near future this will open new strategies to apply 'off-label' targeted therapies, e.g. for rare tumors, otherwise resistant tumors etc. The clinically relevant genetic aberrations described in this review include mutation analyses of RAS (KRAS and NRAS), BRAF and PI3K in colorectal cancer, KIT or PDGFR alpha as well as BRAF, NRAS and KIT in malignant melanoma. Moreover, we present several recent advances in the molecular characterization of malignant lymphoma. Beside the well-known mutations in NSCLC (EGFR, ALK) a number of chromosomal aberrations (KRAS, ROS1, MET) have become relevant. Only very recently has the clinical need for analysis of BRCA1/2 come up and proven as a true challenge for routine diagnostics because of the genes' special structure and hot-spot-free mutational distribution. The genetic alterations are discussed in connection with their increasingly important role in companion diagnostics to apply targeted drugs as efficient as possible. As another aspect of the increasing number of druggable mutations, we discuss the challenges personalized therapies pose for the design of clinical studies to prove optimal efficacy particularly with respect to combination therapies of multiple targeted drugs and conventional chemotherapy. Such combinations would lead to an extremely high complexity that would hardly be manageable by applying conventional study designs for approval, e.g. by the FDA or EMA. Up-coming challenges such as the application of methylation assays and proteomic analyses on FFPE tissue will also be discussed briefly to open the door towards the ultimate goal of reading a patients' tissue as 'deeply' as possible. Although it is yet to be shown, which levels of biological information are most informative for predictive pathology, an integrated molecular characterization of tumors will likely offer the most comprehensive view for individualized therapy approaches. To optimize cancer treatment we need to understand tumor biology in much more detail on morphological, genetic, proteomic as well as epigenetic grounds. Finally, the complex challenges on the level of drug design, molecular diagnostics, and clinical trials make necessary a close collaboration among academic institutions, regulatory authorities and pharmaceutical companies.
Our knowledge about the incidence of pulmonary embolism (PE) and the performance of age adjusted D-dimers (Dd) cutoff amongst patients with lung cancer (LC) and suspected PE, remains limited. We ...retrospectively analyzed all clinically suspected patients who underwent computed tomography pulmonary angiography (CTPA) in a tertiary hospital during a 19 month period. Cancer diagnosis was established using ICD10 code. Eligible for Dd analysis were those tested up to 24 h prior to the scan. We analyzed 2549 patients (54.6% males, median age 68.8 years, IQR 57–78), 15.8% had active LC and 5.4% other cancers (oC), while 70% were scanned in the Emergency Department (ED) and the rest during hospitalization. Overall incidence of PE was 16%. LC, but not oC, increased significantly the risk for PE (OR 1.58, 95% CI 1.21–2.06). LC patients were less likely to have bilateral (aOR 0.16, 95% CI 0.07–0.4) or central PE (aOR 0.2, 95% CI 0.09–0.48). Amongst those diagnosed with PE in the ED, LC increased all-cause inhospital mortality (aOR 6.7, 95% CI 2.64–16.95). When age adjusted instead of conventional Dd cutoff was used for ruling out PE in the ED, specificity for LC patients increased (10.16% vs 3.91%) without false negative tests (negative likelihood ratio—NLR = 0). A higher cutoff of 1.13 mg/l raised specificity to 28.9%, with only one case missed (sensitivity: 97.4%, NLR: 0.09, 95% CI 0.01–0.64). LC increases the risk for PE and adversely affects prognosis. Age adjusted and probably an even higher, “LC adjusted” Dd cutoff, could increase the specificity of the test without compromising its sensitivity.
Inappropriate activation of the NOTCH signaling pathway, for example, by activating mutations, contributes to the pathogenesis of various human malignancies. Here, we demonstrate that aberrant ...expression of an essential NOTCH coactivator of the Mastermind-like (MAML) family provides an alternative mechanism to activate NOTCH signaling in human lymphoma cells. We detected high-level MAML2 expression in several B cell-derived lymphoma types, including classical Hodgkin lymphoma (cHL) cells, relative to normal B cells. Inhibition of MAML-protein activity by a dominant negative form of MAML or by small hairpin RNAs targeting MAML2 in cHL cells resulted in downregulation of the NOTCH target genes HES7 and HEY1, which we identified as overexpressed in cHL cells, and in reduced proliferation. Furthermore, a NOTCH gene-expression signature in cHL cells confirmed their cell-autonomous NOTCH activity. Finally, in line with the essential role of MAML proteins for assembly and activity of the NOTCH transcriptional complex (NTC), we show that MAML-derived small-peptide constructs block NOTCH activity and disrupt NTC formation in vitro. These data strongly suggest direct targeting of the NTC as treatment strategy for NOTCH-dependent malignancies.
Tailoring treatment by patient strata based on the risk of disease progression and treatment toxicity might improve outcomes of patients with posttransplant lymphoproliferative disorder (PTLD). We ...analysed the cohort of 70 patients treated in the international, multicenter phase II PTLD‐1 trial (NCT01458548) to identify such factors. Of the previously published scoring systems in PTLD, the international prognostic index (IPI), the PTLD prognostic index and the Ghobrial score were predictive for overall survival. None of the scoring systems had a considerable effect on the risk for disease progression. Age and ECOG performance status were the baseline variables with the highest prognostic impact in the different scoring systems. Baseline variables not included in the scoring systems that had an impact on overall survival and disease progression were the type of transplant and the response to rituximab at interim staging. Thoracic organ transplant recipients who did not respond to rituximab monotherapy were at particularly high risk for death from disease progression with subsequent CHOP‐based chemotherapy. Patients in complete remission after four courses of rituximab and patients in partial remission with low‐risk IPI had a low risk of disease progression. We speculate that chemotherapy might not be necessary in this patient cohort.
Analysis of the patients treated in the international, multicenter phase II PTLD‐1 trial with sequential treatment with four courses of rituximab followed by four cycles of three‐weekly CHOP suggests that tailoring treatment based on patient baseline characteristics and response to treatment at interim staging might improve outcomes of patients with posttransplant lymphoproliferative disorder even further.
Coronary artery fistulas are usually diagnosed accidentally without the presence of any symptoms. On the other hand, the combination of fistula between the left anterior descending artery (LAD) and ...pulmonary artery (PA) and severe stenosis of the LAD, as in this case report, is a potential life-threatening condition. A 72-year-old patient was treated surgically after being diagnosed with fistula between the LAD and PA, severe stenosis of the LAD, and severe pulmonary hypertension. In following paragraphs, the case of this man and significant issues regarding the development and management of coronary artery fistulas are analyzed.
Urea and electrolytes, liver function tests, C-reactive protein, ferritin, vitamin B12, and creatine phosphokinase were normal. 24 h urinary cortisol, serum cortisol, and corticotropin were normal ...and she had suppressed cortisol in response to an overnight 1 mg dexamethasone suppression test, which ruled out Cushing's syndrome. POEMS syndrome is a rare form of plasma cell dyscrasia, usually associated with osteosclerotic lesions.1 The designation POEMS was proposed by Bardwick and colleagues in 1980 as an acronym for this symptom complex, but not every patient has polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin lesions, and the acronym does not encompass every manifestation of this syndrome (appendix).1 The variability of clinical signs often makes the diagnosis of POEMS syndrome difficult. POEMS syndrome should always be considered in cases of demyelinating polyneuropathy or endocrinopathy of obscure cause.1,2 The mechanism of POEMS syndrome is not fully understood but might be related to very high concentrations of vascular endothelial growth factor (VEGF) produced by the plasma cells.3 VEGF-mediated vasculopathy and vasopermeability are thought to have a major role in its development. The so-called ivory vertebra is well described in association with metastatic cancer, lymphoma, Paget's disease, sarcoidosis, Pott's disease, and primary bony tumours.5
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