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Microorganisms May 2020This review aimed to systematically compare microbial profiles of peri-implantitis to those of periodontitis and healthy implants. Therefore, an electronic search in... (Review)
Review
This review aimed to systematically compare microbial profiles of peri-implantitis to those of periodontitis and healthy implants. Therefore, an electronic search in five databases was conducted. For inclusion, studies assessing the microbiome of peri-implantitis in otherwise healthy patients were considered. Literature was assessed for consistent evidence of exclusive or predominant peri-implantitis microbiota. Of 158 potentially eligible articles, data of 64 studies on 3730 samples from peri-implant sites were included in this study. Different assessment methods were described in the studies, namely bacterial culture, PCR-based assessment, hybridization techniques, pyrosequencing, and transcriptomic analyses. After analysis of 13 selected culture-dependent studies, no microbial species were found to be specific for peri-implantitis. After assessment of 28 studies using PCR-based methods and a meta-analysis on 19 studies, a higher prevalence of and (log-odds ratio 4.04 and 2.28, respectively) was detected in peri-implantitis biofilms compared with healthy implants. spp., spp. and spp. were found in all five pyrosequencing studies in healthy-, periodontitis-, and peri-implantitis samples. In conclusion, the body of evidence does not show a consistent specific profile. Future studies should focus on the assessment of sites with different diagnosis for the same patient, and investigate the complex host-biofilm interaction.
PubMed: 32369987
DOI: 10.3390/microorganisms8050661 -
European Journal of Clinical... May 2020More than 30 causative genes have been identified in familial and sporadic amyotrophic lateral sclerosis (ALS). The next-generation sequencing (NGS) is a powerful and...
BACKGROUND
More than 30 causative genes have been identified in familial and sporadic amyotrophic lateral sclerosis (ALS). The next-generation sequencing (NGS) is a powerful and groundbreaking tool to identify disease-associated variants. Despite documented advantages of NGS, its diagnostic reliability needs to be addressed in order to use this technology for specific routine diagnosis.
MATERIAL AND METHODS
Literature database was explored to identify studies comparing NGS and Sanger sequencing for the detection of variants causing ALS. We collected data about patients' characteristics, disease type and duration, NGS and Sanger properties.
RESULTS
More than 200 bibliographic references were identified, of which only 14 studies matching our inclusion criteria. Only 2 out of 14 studies compared results of NGS analysis with the Sanger sequencing. Twelve studies screened causative genes associated to ALS using NGS technologies and confirmed the identified variants with Sanger sequencing. Overall, data about more 2,000 patients were analysed. The number of genes that were investigated in each study ranged from 1 to 32, the most frequent being FUS, OPTN, SETX and VCP. NGS identified already known mutations in 21 genes, and new or rare variants in 27 genes.
CONCLUSIONS
NGS seems to be a promising tool for the diagnosis of ALS in routine clinical practice. Its advantages are represented by an increased speed and a lowest sequencing cost, but patients' counselling could be problematic due to the discovery of frequent variants of unknown significance.
Topics: Amyotrophic Lateral Sclerosis; Cell Cycle Proteins; DNA Helicases; High-Throughput Nucleotide Sequencing; Humans; Membrane Transport Proteins; Multifunctional Enzymes; RNA Helicases; RNA-Binding Protein FUS; Reproducibility of Results; Sequence Analysis, DNA; Valosin Containing Protein
PubMed: 32293029
DOI: 10.1111/eci.13228 -
Antimicrobial Agents and Chemotherapy Apr 2020In this retrospective study, whole-genome sequencing (WGS) data generated on an Ion Torrent platform was used to predict phenotypic drug resistance profiles for first-...
In this retrospective study, whole-genome sequencing (WGS) data generated on an Ion Torrent platform was used to predict phenotypic drug resistance profiles for first- and second-line drugs among Swedish clinical isolates from 2016 to 2018. The accuracy was ∼99% for all first-line drugs and 100% for four second-line drugs. Our analysis supports the introduction of WGS into routine diagnostics, which might, at least in Sweden, replace phenotypic drug susceptibility testing in the future.
Topics: Drug Resistance, Multiple, Bacterial; Humans; Mycobacterium tuberculosis; Sweden; Tuberculosis; Tuberculosis, Multidrug-Resistant; Whole Genome Sequencing
PubMed: 32122893
DOI: 10.1128/AAC.02550-19 -
Viruses Jan 2020A majority of emerging infectious diseases are of zoonotic origin. Metagenomic Next-Generation Sequencing (mNGS) has been employed to identify uncommon and novel...
A majority of emerging infectious diseases are of zoonotic origin. Metagenomic Next-Generation Sequencing (mNGS) has been employed to identify uncommon and novel infectious etiologies and characterize virus diversity in human, animal, and environmental samples. Here, we systematically reviewed studies that performed viral mNGS in common livestock (cattle, small ruminants, poultry, and pigs). We identified 2481 records and 120 records were ultimately included after a first and second screening. Pigs were the most frequently studied livestock and the virus diversity found in samples from poultry was the highest. Known animal viruses, zoonotic viruses, and novel viruses were reported in available literature, demonstrating the capacity of mNGS to identify both known and novel viruses. However, the coverage of metagenomic studies was patchy, with few data on the virome of small ruminants and respiratory virome of studied livestock. Essential metadata such as age of livestock and farm types were rarely mentioned in available literature, and only 10.8% of the datasets were publicly available. Developing a deeper understanding of livestock virome is crucial for detection of potential zoonotic and animal pathogens and One Health preparedness. Metagenomic studies can provide this background but only when combined with essential metadata and following the "FAIR" (Findable, Accessible, Interoperable, and Reusable) data principles.
Topics: Animals; Cattle; Communicable Diseases, Emerging; Disease Reservoirs; Farms; Genome, Viral; High-Throughput Nucleotide Sequencing; Livestock; Metagenome; Metagenomics; One Health; RNA, Viral; Virus Diseases; Viruses; Zoonoses
PubMed: 31963174
DOI: 10.3390/v12010107 -
Cancer Treatment Reviews Feb 2020Molecular profiling of tumor derived cell free DNA (cfDNA) is gaining ground as a prognostic and predictive biomarker. However to what extent cfDNA reflects the full... (Meta-Analysis)
Meta-Analysis
Molecular profiling of tumor derived cell free DNA (cfDNA) is gaining ground as a prognostic and predictive biomarker. However to what extent cfDNA reflects the full metastatic landscape as currently determined by tumor tissue analysis remains controversial. Though technically challenging, whole exome sequencing (WES) of cfDNA enables thorough evaluation of somatic alterations. Here, we review the feasibility of WES of cfDNA and determine the sensitivity of WES-detected single nucleotide variants (SNVs) in cfDNA on individual patient data level using paired tumor tissue as reference (sharedSNVsAlltissueSNVs×100%). The pooled sensitivity was 50% (95% credible interval (CI): 29-72%). The tissue mutant allele frequency (MAF) of variants exclusively identified in tissue was significantly lower (12.5%, range: 0.5-18%) than the tissue MAF of variants identified in both tissue and cfDNA (23.9%, range: 17-38%), p = 0.004. The overall agreement (sharedSNVsAllSNVs×100%)between SNVs in cfDNA and tumor tissue was 31% (95% CI: 15-49%). The number of detected SNVs was positively correlated with circulating tumor DNA (ctDNA) fraction (p = 0.016). A sub analysis of samples with ctDNA fractions ≥ 25% improved the sensitivity to 69% (95% CI: 46-89%) and agreement to 46% (95% CI: 36-59%), suggesting that WES is mainly feasible for patients with high ctDNA fractions. Pre- and post-analytical procedures were highly variable between studies rendering comparisons problematic. In conclusion, various aspects of WES of cfDNA are largely in its investigative phase, standardization of methodologies is highly needed to bring this promising technique to its clinical potential.
Topics: Bayes Theorem; Biomarkers, Tumor; Cell-Free Nucleic Acids; Circulating Tumor DNA; DNA, Neoplasm; High-Throughput Nucleotide Sequencing; Humans; Mutation; Neoplasms; Polymorphism, Single Nucleotide; Exome Sequencing
PubMed: 31874446
DOI: 10.1016/j.ctrv.2019.101951 -
Frontiers in Genetics 2019Recent advances in high-throughput experimentation have put the exploration of genome sequences at the forefront of precision medicine. In an effort to interpret the...
Recent advances in high-throughput experimentation have put the exploration of genome sequences at the forefront of precision medicine. In an effort to interpret the sequencing data, numerous computational methods have been developed for evaluating the effects of genome variants. Interestingly, despite the fact that every person has as many synonymous (sSNV) as non-synonymous single nucleotide variants, our ability to predict their effects is limited. The paucity of experimentally tested sSNV effects appears to be the limiting factor in development of such methods. Here, we summarize the details and evaluate the performance of nine existing computational methods capable of predicting sSNV effects. We used a set of and artificially variants to approximate large scale performance expectations of these tools. We note that the distribution of these variants across amino acid and codon types suggests purifying evolutionary selection retaining variants out of the set; i.e., we expect the set to be enriched for deleterious variants. Closer inspection of the relationship between the variant frequencies and the associated prediction scores identifies predictor-specific scoring thresholds of reliable effect predictions. Notably, across all predictors, the variants scoring above these thresholds were significantly more often than . which confirms our assumption that the set is enriched for deleterious variants. Finally, we find that while the methods differ in their ability to identify severe sSNV effects, no predictor appears capable of definitively recognizing subtle effects of such variants on a large scale.
PubMed: 31649718
DOI: 10.3389/fgene.2019.00914 -
BMC Cancer Oct 2019Sarcomatoid carcinoma of unknown primary (SCUP) is a rare entity of either poorly differentiated carcinoma with sarcoma-like differentiation or a true mixed lineage...
BACKGROUND
Sarcomatoid carcinoma of unknown primary (SCUP) is a rare entity of either poorly differentiated carcinoma with sarcoma-like differentiation or a true mixed lineage neoplasm. Limited data regarding clinicopathological profile and management exists.
METHODS
We retrospectively reviewed the MD Anderson Cancer of Unknown Primary database and tumor registry to identify 48 SCUP patients between 2001 and 2017. Patient characteristics, pathology, molecular diagnostics, treatments, and outcomes were obtained. Kaplan-Meier method was used to estimate overall survival (OS) and compared using log rank test.
RESULTS
Median age at diagnosis was 59 years (range 27-86). Majority of patients were female (58%) and presented with ≥3 metastatic sites (52%), commonly lymph node (50%), bone (42%), lung (27%), and liver (21%). First line treatment included chemotherapy (35%), surgery (27%), and radiation (24%). Gemcitabine and docetaxel (18%) was the most common chemotherapy regimen. Median OS for entire cohort was 11 months (95% CI: 5.6 to 16.4). Poor performance status (PS), > 1 metastatic site, elevated lactate dehydrogenase (LDH), and high neutrophil-to-lymphocyte ratio (NLR) were significantly associated with worse OS on univariate analyses. On multivariate analyses, poor PS (HR 8.7; 95%CI: 3.0-25.0; p < 0.001) and high NLR (HR 3.4; 95%CI: 1.3-8.8; p = 0.011) emerged as independent prognostic factors for OS.
CONCLUSIONS
SCUP is a rare presentation with an aggressive clinical course and limited survival. Diagnosis is difficult to make and requires careful review and synthesis of histology, immunohistochemistry, and molecular diagnostics. Chemotherapy resistance remains a challenge. Early mutational profiling is warranted, and clinical trial participation should be encouraged for this subset.
Topics: Adult; Aged; Aged, 80 and over; Biomarkers, Tumor; Carcinosarcoma; Combined Modality Therapy; Drug Resistance, Neoplasm; Female; Follow-Up Studies; High-Throughput Nucleotide Sequencing; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Molecular Targeted Therapy; Neoplasms, Unknown Primary; Prognosis; Prospective Studies; Rare Diseases; Retrospective Studies; Survival Rate; Treatment Outcome
PubMed: 31623602
DOI: 10.1186/s12885-019-6155-6 -
Cancer Medicine Oct 2019Small cell lung cancer (SCLC) is a highly invasive and lethal neuroendocrine tumor. Antiangiogenic drugs have been reported in the treatment of SCLC. We aimed to provide... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Small cell lung cancer (SCLC) is a highly invasive and lethal neuroendocrine tumor. Antiangiogenic drugs have been reported in the treatment of SCLC. We aimed to provide a comprehensive evaluation of the impact of angiogenic inhibitors on SCLC survival using network meta-analysis.
METHODS
The impact of five angiogenesis inhibitors, that is, vandetanib (Van), bevacizumab (Bev), Rh-endostatin (End), sunitinib (Sun), and thalidomide (Tha), on progression-free survival (PFS) and overall survival (OS) was evaluated by conducting a network meta-analysis. RNA sequencing data were downloaded from publicly available databases.
RESULTS
Nine phase II and III randomized controlled trials (RCTs), that involved 1599 participants, that investigated angiogenesis inhibitors in the treatment of SCLC were included in this meta-analysis. Sun and Bev achieved better PFS than Tha (Bev VS. Tha, HR = 0.88, 95% CI: 0.79-0.98, Sun VS. Tha, HR = 0.80, 95% CI: 0.65-1.00). Moreover, Sun and Bev were superior to placebo in terms of PFS (Bev VS. Placebo, HR = 0.89, 95%CI: 0.81-0.97, Sun VS. Placebo, HR = 0.81, 95% CI: 0.66-1.00). Based on this study, we found no significant difference of OS of SCLC. The angiogenesis pathway and expression of target genes were globally deactivated in SCLC tissue.
CONCLUSION
Results of this network meta-analysis indicate that the PFS outcome of SCLC with Sun or Bev drugs is superior to that of Tha. The improved therapeutic impact of angiogenesis inhibitors on SCLC needs more evidence, such as long-term observation in clinical trials, to be validated.
Topics: Angiogenesis Inhibitors; Gene Expression Regulation, Neoplastic; Humans; Lung Neoplasms; RNA-Seq; Randomized Controlled Trials as Topic; Small Cell Lung Carcinoma
PubMed: 31433125
DOI: 10.1002/cam4.2462 -
Journal of Clinical Immunology Aug 2019As the application of next generation sequencing (NGS) is moving to earlier stages in the diagnostic pipeline for primary immunodeficiencies (PIDs), re-evaluation of its...
BACKGROUND
As the application of next generation sequencing (NGS) is moving to earlier stages in the diagnostic pipeline for primary immunodeficiencies (PIDs), re-evaluation of its effectiveness is required. The aim of this study is to systematically review the diagnostic yield of NGS in PIDs.
METHODS
PubMed and Embase databases were searched for relevant studies. Studies were eligible when describing the use of NGS in patients that had previously been diagnosed with PID on clinical and/or laboratory findings. Relevant data on study characteristics, technological performance and diagnostic yield were extracted.
RESULTS
Fourteen studies were eligible for data extraction. Six studies described patient populations from specific PID subcategories. The remaining studies included patients with unsorted PIDs. The studies were based on populations from Italy, Iran, Turkey, Thailand, the Netherlands, Norway, Saudi Arabia, Sweden, the UK, and the USA. Eight studies used an array-based targeted gene panel, four used WES in combination with a PID filter, and two used both techniques. The mean reported reading depth ranged from 98 to 1337 times. Five studies described the sensitivity of the applied techniques, ranging from 83 to 100%, whereas specificity ranged from 45 to 99.9%. The percentage of patients who were genetically diagnosed ranged from 15 to 79%. Several studies described clinical implications of the genetic findings.
DISCUSSION
NGS has the ability to contribute significantly to the identification of molecular mechanisms in PID patients. The diagnostic yield highly depends on population and on the technical circumstances under which NGS is employed. Further research is needed to determine the exact diagnostic yield and clinical implications of NGS in patients with PID.
Topics: Genetic Association Studies; Genetic Predisposition to Disease; Genetic Testing; High-Throughput Nucleotide Sequencing; Humans; Primary Immunodeficiency Diseases; Reproducibility of Results
PubMed: 31250335
DOI: 10.1007/s10875-019-00656-x -
Annals of Oncology : Official Journal... Aug 2019Cancers with a defective DNA mismatch repair (dMMR) system contain thousands of mutations most frequently located in monomorphic microsatellites and are thereby defined...
ESMO recommendations on microsatellite instability testing for immunotherapy in cancer, and its relationship with PD-1/PD-L1 expression and tumour mutational burden: a systematic review-based approach.
BACKGROUND
Cancers with a defective DNA mismatch repair (dMMR) system contain thousands of mutations most frequently located in monomorphic microsatellites and are thereby defined as having microsatellite instability (MSI). Therefore, MSI is a marker of dMMR. MSI/dMMR can be identified using immunohistochemistry to detect loss of MMR proteins and/or molecular tests to show microsatellite alterations. Together with tumour mutational burden (TMB) and PD-1/PD-L1 expression, it plays a role as a predictive biomarker for immunotherapy.
METHODS
To define best practices to implement the detection of dMMR tumours in clinical practice, the ESMO Translational Research and Precision Medicine Working Group launched a collaborative project, based on a systematic review-approach, to generate consensus recommendations on the: (i) definitions related to the concept of MSI/dMMR; (ii) methods of MSI/dMMR testing and (iii) relationships between MSI, TMB and PD-1/PD-L1 expression.
RESULTS
The MSI-related definitions, for which a consensus frame-work was used to establish definitions, included: 'microsatellites', 'MSI', 'DNA mismatch repair' and 'features of MSI tumour'. This consensus also provides recommendations on MSI testing; immunohistochemistry for the mismatch repair proteins MLH1, MSH2, MSH6 and PMS2 represents the first action to assess MSI/dMMR (consensus with strong agreement); the second method of MSI/dMMR testing is represented by polymerase chain reaction (PCR)-based assessment of microsatellite alterations using five microsatellite markers including at least BAT-25 and BAT-26 (strong agreement). Next-generation sequencing, coupling MSI and TMB analysis, may represent a decisive tool for selecting patients for immunotherapy, for common or rare cancers not belonging to the spectrum of Lynch syndrome (very strong agreement). The relationships between MSI, TMB and PD-1/PD-L1 expression are complex, and differ according to tumour types.
CONCLUSIONS
This ESMO initiative is a response to the urgent questions raised by the growing success of immunotherapy and provides also important insights on the relationships between MSI, TMB and PD-1/PD-L1.
Topics: Antineoplastic Agents, Immunological; B7-H1 Antigen; Biomarkers, Tumor; DNA Mismatch Repair; DNA Mutational Analysis; European Union; Genetic Testing; High-Throughput Nucleotide Sequencing; Humans; Immunohistochemistry; Medical Oncology; Microsatellite Instability; Mutation; Neoplasms; Patient Selection; Practice Guidelines as Topic; Programmed Cell Death 1 Receptor; Societies, Medical
PubMed: 31056702
DOI: 10.1093/annonc/mdz116