Re-classify Patients Research Articles

Digital PCR-based quantification of miR-181a in the cerebrospinal fluid aids patient stratification in pediatric acute lymphoblastic leukemia

Despite remarkable improvements in the survival of pediatric acute lymphoblastic leukemia (ALL), sensitive detection and clinical management of central nervous system leukemia (CNSL) are still immensely challenging. Blast cells residing in the CNS but not circulating in the cerebrospinal fluid (CSF) remain undetected by current diagnostic methods, preventing a truly risk-adapted anti-leukemic treatment in this compartment. We examined the clinical applicability of the molecular marker microRNA (miR)-181a quantified in the cell-free CSF to evaluate the level of CNS involvement and to optimize patient stratification based on CNS status. Normalized copy number of miR-181a was longitudinally profiled using droplet digital PCR, and the results were compared with the degree of leukemic involvement of the CNS. After combining cytospin- and flow cytometry (FCM) data with miR-181a expression, we could stratify previously ambiguous cases and reclassify patients into a CNS-positive/miR-significant group (mean ± SE for miR-181a copies: 3300.70 ± 809.69) bearing remarkable infiltration as well as into CNS-minimal/miR-significant and CNS-minimal/miR-minimal groups differentiating putative, clinically significant occult CNSL cases (2503.50 ± 275.89 and 744.02 ± 86.81 copies, respectively, p = 1.13 × 10–6). In summary, miR-181a expression is a promising biomarker for CNSL detection, facilitating the robust identification of patients who could benefit from intensified CNS-directed therapy.

Comparison of Prognostic Performance of 8th and 7th Edition of AJCC Staging System for Patients With Gallbladder Cancer Undergoing Curative Intent Surgery.

We compared the predictive performance of the 7th and 8th editions of the AJCC staging systems in stratifying disease-related survival outcomes in patients with GBC undergoing curative intent surgery. Patients that underwent curative intent surgery for GBC at our institution (2014 and 2021) were included in the study. Various clinico-pathological data were extracted to perform Kaplan-Meier survival analysis. A total of 240 patients were included in the study. Both, TNM-7, and TNM-8 staging systems can stratify patients into stages with statistically significant differences in disease-free and overall survival. Survival rates drop with stage progression. Using TNM-8, 8/240 (3.33%) patients were upstaged from Stage IIIB (TNM-7) to IVB (TNM-8) and 12/240 (5%) were down-staged from Stage IVB(TNM-7) to IIIB(TNM-8). Survival curves of the re-classified patients matched those of the corresponding TNM-8 stage. Additionally, there was statistically significant difference in their survival (p < 0.001) compared to their corresponding TNM-7 stage. There was no statistically significant difference in survival rates between stages IIA, IIB (TNM-8), and stage II (TNM-7). However, stage IIA had a slightly better survival than stage IIB. Though both TNM-7 and TNM-8 are useful for stratifying patients with GBC, TNM-8 has a better prognostic performance than TNM-7.

New Proposed Classification of Difficulty in Laparoscopic Cholecystectomy.

Background: Difficult laparoscopic cholecystectomy (LC) has been challenging for surgeons. Randhawa's system used operative time, complications, and conversion to define three difficulty grades. However, using fixed numbers of operative time as dividers among three groups might not be applicable universally. This study aimed to propose new classification with more flexible parameters. Methods: This retrospective cohort study was conducted with patients who underwent LC because of gallstone-related diseases between January 2017 and December 2021 at Thammasat University Hospital. The exclusion criteria were (1) emergent LC for acute cholecystitis, (2) other procedures performed in the same setting of LC, (3) incomplete information, and (4) LC converted to open cholecystectomy. Patients were categorized into three groups using Randhawa's classification. Thereafter, new classification using mean and standard deviation was applied to reclassify patients into three new groups. The comparison between two grading results was performed to prove the advantage of new classification. Results: Total of 523 patients who underwent LC were included with median age 59.3 years old and 60.8% female. By Randhawa classification, proportions of easy, difficult, and very difficult groups were 39%, 53.7%, and 7.3%, respectively. Then, the new operative-time dividers among three groups were changed from 60 and 120 minutes to mean and mean + 2SD, respectively. Reclassified three difficult groups were 38.9%, 57.1%, and 4%. The comparison demonstrated new classification as more flexible and more compatible with each individual surgeon. Conclusions: New surgeon-referenced grading system of difficult LC included surgeon's factors, not only unfavorable operative findings. This classification should be more flexible than the previous criterion-referenced one. Thai Clinical Trials Registry at https://www.thaiclinicaltrials.org with Number TCTR20220426003.

Revision to the musculoskeletal domain of the BILAG-2004 index to incorporate ultrasound findings.

To improve the definitions of inflammatory arthritis within the musculoskeletal (MSK) domain of the BILAG-2004 index by incorporating imaging findings and clinical features predictive of response to treatment. The BILAG MSK Subcommittee proposed revisions to the BILAG-2004 index definitions of inflammatory arthritis, based on review of evidence in two recent studies. Data from these studies were pooled and analysed to determine the impact of the proposed changes on the severity grading of inflammatory arthritis. The revised definition for severe inflammatory arthritis includes definition of 'basic activities of daily living'. For moderate inflammatory arthritis, it now includes synovitis, defined by either observed joint swelling or MSK US evidence of inflammation in joints and surrounding structures. For mild inflammatory arthritis, the definition now includes reference to symmetrical distribution of affected joints and guidance on how US may help re-classify patients as moderate or no inflammatory arthritis. Data from two recent SLE trials were analysed (219 patients). A total of 119 (54.3%) were graded as having mild inflammatory arthritis (BILAG-2004 Grade C). Of these, 53 (44.5%) had evidence of joint inflammation (synovitis or tenosynovitis) on US. Applying the new definition increased the number of patients classified as moderate inflammatory arthritis from 72 (32.9%) to 125 (57.1%), while patients with normal US (n = 66/119) could be recategorized as BILAG-2004 Grade D (inactive disease). Proposed changes to the definitions of inflammatory arthritis in the BILAG-2004 index will result in more accurate classification of patients who are more or less likely to respond to treatment.

Use of Lipoprotein(a) to improve diagnosis and management in clinical familial hypercholesterolemia

Background and aimsLipoprotein(a) (Lp(a)) is an LDL-like particle whose plasma levels are largely genetically determined. The impact of measuring Lp(a) in patients with clinical familial hypercholesterolemia (FH) referred for genetic testing is largely unknown. We set out to evaluate the contribution of (genetically estimated) Lp(a) in a large nation-wide referral population of clinical FH. MethodsIn 1504 patients referred for FH genotyping, we used an LPA genetic instrument (rs10455872 and rs3798220) as a proxy for plasma Lp(a) levels. The genetic Lp(a) proxy was used to correct LDL-cholesterol and reclassify patients with clinical FH based on Dutch Lipid Criteria Network (DLCN) scoring. Finally, we used estimated Lp(a) levels to reclassify ASCVD risk using the SCORE and SMART risk scores. ResultsLPA SNPs were more prevalent among mutation-negative compared with mutation-positive patients (296/1280 (23.1%) vs 35/224 (15.6%), p = 0.016). Among patients with genetically defined high Lp(a) levels, 9% were reclassified to the DLCN category ‘unlikely FH’ using Lp(a)-corrected LDL-cholesterol (LDL-Ccor) and all but one of these patients indeed carried no FH variant. Furthermore, elevated Lp(a) reclassified predicted ASCVD risk into a higher category in up to 18% of patients. ConclusionsIn patients referred for FH molecular testing, we show that taking into account (genetically estimated) Lp(a) levels not only results in reclassification of probability of genetic FH, but also has an impact on individual cardiovascular risk evaluation. However, to avoid missing the diagnosis of an FH variant, clear thresholds for the use of Lp(a)-cholesterol adjusted LDL-cholesterol levels in patients referred for genetic testing of FH must be established.

18F-FDG PET/CT improves diagnostic certainty in native and prosthetic valve Infective Endocarditis over the modified Duke Criteria

BackgroundInternational guidance recognizes the shortcomings of the modified Duke Criteria (mDC) in diagnosing infective endocarditis (IE) when transoesophageal echocardiography (TOE) is equivocal. 18F-FDG PET/CT (PET) has proven benefit in prosthetic valve endocarditis (PVE), but is restricted to extracardiac manifestations in native disease (NVE). We investigated the incremental benefit of PET over the mDC in NVE. MethodsDual-center retrospective study (2010-2018) of patients undergoing myocardial suppression PET for NVE and PVE. Cases were classified by mDC pre- and post-PET, and evaluated against discharge diagnosis. Receiver Operating Characteristic (ROC) analysis and net reclassification index (NRI) assessed diagnostic performance. Valve standardized uptake value (SUV) was recorded. Results69/88 PET studies were evaluated across 668 patients. At discharge, 20/32 had confirmed NVE, 22/37 PVE, and 19/69 patients required surgery. PET accurately re-classified patients from possible, to definite or rejected (NRI: NVE 0.89; PVE 0.90), with significant incremental benefit in both NVE (AUC 0.883 vs 0.750) and PVE (0.877 vs 0.633). Sensitivity and specificity were 75% and 92% in NVE; 87% and 86% in PVE. Duration of antibiotics and C-reactive Protein level did not impact performance. No diagnostic SUV cut-off was identified. ConclusionPET improves diagnostic certainty when combined with mDC in NVE and PVE.

Pan-cancer integrative analysis of whole-genome De novo somatic point mutations reveals 17 cancer types

BackgroundThe advent of high throughput sequencing has enabled researchers to systematically evaluate the genetic variations in cancer, identifying many cancer-associated genes. Although cancers in the same tissue are widely categorized in the same group, they demonstrate many differences concerning their mutational profiles. Hence, there is no definitive treatment for most cancer types. This reveals the importance of developing new pipelines to identify cancer-associated genes accurately and re-classify patients with similar mutational profiles. Classification of cancer patients with similar mutational profiles may help discover subtypes of cancer patients who might benefit from specific treatment types.ResultsIn this study, we propose a new machine learning pipeline to identify protein-coding genes mutated in many samples to identify cancer subtypes. We apply our pipeline to 12,270 samples collected from the international cancer genome consortium, covering 19 cancer types. As a result, we identify 17 different cancer subtypes. Comprehensive phenotypic and genotypic analysis indicates distinguishable properties, including unique cancer-related signaling pathways.ConclusionsThis new subtyping approach offers a novel opportunity for cancer drug development based on the mutational profile of patients. Additionally, we analyze the mutational signatures for samples in each subtype, which provides important insight into their active molecular mechanisms. Some of the pathways we identified in most subtypes, including the cell cycle and the Axon guidance pathways, are frequently observed in cancer disease. Interestingly, we also identified several mutated genes and different rates of mutation in multiple cancer subtypes. In addition, our study on “gene-motif” suggests the importance of considering both the context of the mutations and mutational processes in identifying cancer-associated genes. The source codes for our proposed clustering pipeline and analysis are publicly available at: https://github.com/bcb-sut/Pan-Cancer.

Effect of heparin treatment on pulmonary embolism and in-hospital death in unvaccinated COVID-19 patients without overt deep vein thrombosis

BackgroundPulmonary embolism (PE) without overt deep vein thrombosis (DVT) was common in hospitalized coronavirus-induced disease (COVID)-19 patients and represented a diagnostic, prognostic, and therapeutic challenge. The aim of this study was to analyze the prognostic role of PE on mortality and the preventive effect of heparin on PE and mortality in unvaccinated COVID-19 patients without overt DVT.MethodsData from 401 unvaccinated patients (age 68 ± 13 years, 33% females) consecutively admitted to the intensive care unit or the medical ward were included in a retrospective longitudinal study. PE was documented by computed tomography scan and DVT by compressive venous ultrasound. The effect of PE diagnosis and any heparin use on in-hospital death (primary outcome) was analyzed by a classical survival model. The preventive effect of heparin on either PE diagnosis or in-hospital death (secondary outcome) was analyzed by a multi-state model after having reclassified patients who started heparin after PE diagnosis as not treated.ResultsMedian follow-up time was 8 days (range 1–40 days). PE cumulative incidence and in-hospital mortality were 27% and 20%, respectively. PE was predicted by increased D-dimer levels and COVID-19 severity. Independent predictors of in-hospital death were age (hazards ratio (HR) 1.05, 95% confidence interval (CI) 1.03–1.08, p < 0.001), body mass index (HR 0.93, 95% CI 0.89–0.98, p = 0.004), COVID-19 severity (severe versus mild/moderate HR 3.67, 95% CI 1.30–10.4, p = 0.014, critical versus mild/moderate HR 12.1, 95% CI 4.57–32.2, p < 0.001), active neoplasia (HR 2.58, 95% CI 1.48–4.50, p < 0.001), chronic obstructive pulmonary disease (HR 2.47; 95% CI 1.15–5.27, p = 0.020), respiratory rate (HR 1.06, 95% CI 1.02–1.11, p = 0.008), heart rate (HR 1.03, 95% CI 1.01–1.04, p < 0.001), and any heparin treatment (HR 0.35, 95% CI 0.18–0.67, p = 0.001). In the multi-state model, preventive heparin at prophylactic or intermediate/therapeutic dose, compared with no treatment, reduced PE risk and in-hospital death, but it did not influence mortality of patients with a PE diagnosis.ConclusionsPE was common during the first waves pandemic in unvaccinated patients, but it was not a negative prognostic factor for in-hospital death. Heparin treatment at any dose prevented mortality independently of PE diagnosis, D-dimer levels, and disease severity.

Abstract 2808: cfDNA multi-omics profiling and tissue of origin predictions in cancers of unknown primary

Abstract Cancers of Unknown Primary (CUP) comprise a heterogeneous group of metastatic cancers where the primary site is undetectable. It accounts for 2% of all new UK cancer diagnoses and is the 6th leading cause of cancer death. Favourable subsets of CUP exist, based on clinico-pathological features, and although these patients have improved clinical outcomes, they make up only 20% of patients with CUP. The evolution of molecular profiling and tissue-of-origin (TOO) classifiers has the potential to transform diagnosis and management of patients with CUP. Reliable molecular profiling requires good quality and quantity tumour tissue material, often scarce in patients with CUP. Liquid biopsies offer an alternative, minimally invasive approach. We developed a novel cell-free DNA (cfDNA)-based multi-omics assay combining methylation profiling with mutation and copy number alterations (CNA) detection, to enable TOO prediction and biomarker discovery to aid treatment stratification. Methods: Two novel library preparation methods were applied to 41 CUP cfDNA samples, 80 non-cancer controls and 80 cfDNA samples from known tumour types (breast, lung, colorectal cancer): 1) Targeted (641 gene panel) next generation sequencing (NGS); 2) A multiplex genome-wide methylation capture assay (T7-MBDSeq). Both sequencing outputs can estimate CNA. Cancer Genome Interpreter (CGI) was used to evaluate the potential actionability of molecular alterations detected. A novel TOO classifier, generated utilising in silico dilution mixture sets derived from The Cancer Genome Atlas (TCGA) methylation data, demonstrated an AUROC of 0.96 across 15 different cancer groups. This was applied to cfDNA methylation data from known tumour types to test performance accuracy and subsequently applied to CUP cfDNA samples. Results: Multi-omics profiling from cfDNA was completed for 34/41 patients with CUP. cfDNA mutation profiling and estimated CNA analysis so far revealed &amp;gt;350 alterations across 225 genes. 17/34 (50%) of patients harboured potentially actionable alterations by CGI and, where performed, 68% of tumour mutations were concordant in the cfDNA. cfDNA methylation profiling revealed tumour-specific methylation changes in breast, lung and colorectal cancers. Our preliminary TOO classifier performance in these tumour types had an overall sensitivity and specificity of 85% and 98%, respectively. In patients with CUP, a predicted TOO was made in 26/41 (63%) patients and for 6 patients, where a subsequent primary tumour diagnosis was made, the TOO prediction was correct. Conclusions: cfDNA multi-omics profiling revealed potential therapeutic benefit in 77% of this retrospective CUP cohort and illustrates the potential to re-classify patients to primary tumour types where alternative therapies may improve clinical outcomes. Further multi-omics cfDNA profiling of the CUP cohort and validation in known primary cancer types are ongoing. Citation Format: Alicia-Marie Conway, Alexandra Clipson, Francesca Chemi, Simon Pearce, Katarzyna Kamieniecka, Saba Ferdous, Sophie Richardson, Elaine Kilgour, Matthew G. Krebs, Alastair Kerr, Dominic Rothwell, Natalie Cook, Caroline Dive. cfDNA multi-omics profiling and tissue of origin predictions in cancers of unknown primary [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2808.

Invasive exercise hemodynamics predict survival in patients with clinical heart failure irrespective of left ventricular systolic function

Abstract Funding Acknowledgements Type of funding sources: None. Introduction When aiming to stratify heart failure patients for mortality risk, exercise stress testing has proven to be relevant in specific populations of heart failure patients, but is not universally applied. Analysis of left ventricular systolic function (LVEF) remains the cornerstone for stratifying heart failure patients for prognosis and clinical treatment. The aim of the present study is to investigate the prognostic capabilities of invasive exercise testing in a real-world cohort of suspected heart failure patients in whom non-cardiac causes of dyspnea were excluded. Methods We retrospectively analyzed survival of patients who underwent right heart catheterization at rest and during exercise between 2007 to 2017 for dyspnea and expected heart failure. Pulmonary capillary wedge pressure (PCWP) at rest and the PCWP response to exercise, expressed as the ratio of PCWP at peak exercise to workload normalized to body weight [PCWL (mmHg/W/kg)], were determined. Mortality data was deducted from the official German death registry. Results A total of 682 patients [aged 64.1 ± 12 years, 269 (39.2%) women] were included. Based on LVEF, 515 patients (76.4%) had sustained LVEF ≥50%, 71 patients (10.5%) had heart failure with mildly-impaired LVEF (40-49%) and 88 patients (13.1%) had heart failure with reduced LVEF (≤40%). Absolute LVEF was not associated with all-cause mortality (HR 0.995; 95% CI 0.99-1.00; p=0.231). While increases in PCWP at rest an PCWL during exercise were both associated with death, the discriminative properties of pressure measurements derived during exercise were superior in ROC-analysis (AUC 0.637 for PCWP and AUC 0.728 for PCWL, p&amp;lt;0.001) Exercise hemodynamics and systolic function were next used to re-classify patients in four groups based on normal vs. impaired LVEF (≥/&amp;lt; 50%) and response to exercise (PCWL≥/&amp;lt;25.5 mmHg/W/kg for normal LVEF and PCWL≥/&amp;lt;34.7 mmHg/W/kg for impaired LVEF). In multivariate models adjusted for pertinent baseline parameters, patients with pathological response to exercise carried a 2.0-fold (with sustained LVEF, 95% CI 1.17-3.52, p=0.011) to 3.2-fold (with impaired LVEF, 95% CI 1.83-5.91, p&amp;lt;0.001) increased risk for death. Patients with impaired LVEF but featuring a normal response to exercise did not carry an increased risk for death (HR 1.117, 95% CI 0.453-2.757, p=0.810). Discussion: In patients with clinical heart failure, invasive exercise testing improves the prediction of mortality. Subjects with a normal response to exercise have a relatively low mortality irrespective of systolic function.

Dramatic Reduction of Distant Pancreatic Metastases Using Local Light Activation of Verteporfin with Nab-Paclitaxel.

Despite substantial drug development efforts, pancreatic adenocarcinoma (PDAC) remains a difficult disease to treat, and surgical resection is the only potentially curative option. Unfortunately, 80% of patients are ineligible for surgery due to the presence of invasive disease and/or distant metastases at the time of diagnosis. Treatment strategies geared towards reclassifying these patients as surgical candidates by reducing metastatic burden represents the most promising approach to improve long-term survival. We describe a photodynamic therapy (PDT) based approach that, in combination with the first-line chemotherapeutic nab-paclitaxel, effectively addresses distant metastases in three separate orthotopic PDAC models in immunodeficient mice. In addition to effectively controlling local tumor growth, PDT plus nab-paclitaxel primes the tumor to elicit systemic effects and reduce or abrogate metastases. This combination dramatically inhibits (up to 100%) the eventual development of metastases in models of early stage PDAC, and completely eliminates metastasis in 55% of animals with already established distant disease in late-stage models. Our findings suggest that this light activation process initiates local biological and/or physiological changes within the tumor microenvironment that can be leveraged to treat both localized and distant disease, and potentially reclassify patients with previously inoperable disease as surgical candidates.

Re-classification of uterine cervical cancer cases treated with radical hysterectomy based on the 2018 FIGO staging system

ObjectiveWe re-classified patients with stage IB–II disease (based on the 2008 system) and compared the outcomes with those obtained after using the 2018 International Federation of Gynecology and Obstetrics (FIGO) staging system. Materials and methodsWe reviewed the data of 154 patients with cervical cancer who underwent radical hysterectomy at our hospital during 2006–2016. Pathological, histological, and radiographic data were used to re-classify the cases based on the 2018 FIGO system. We compared these outcomes to those obtained after using the 2008 FIGO assignments. Overall survival (OS) was calculated from primary therapy initiation until death or the last follow-up examination. ResultsThe histological types were squamous cell carcinoma (108 cases) and others (46 cases). The 2008 FIGO system assignments were stage IB1, IB2, IIA1, IIA2, and IIB (87, 27, seven, five, and 28 patients, respectively). The new 2018 FIGO system assignments were stage IB1, IB2, IB3, IIA1, IIA2, IIB, and IIIC1 (52, 26, 16, six, three, 21, and 30 patients, respectively). Re-classification to stage IIIC1 disease was observed for previously assigned stage IB1, IB2, IIA1, IIA2, and IIB cases (10, seven, two, two, and nine cases, respectively). The median OS durations based on the 2018 FIGO system were 71.7, 61.1, and 62.3 months for patients with stage IB1, IB2, and IB3 (p = 0.04) disease, respectively. The new stage IB3/IIA2/IIB cases had longer OS than the old stage IB2/IIA2/IIB cases. A positive computed tomography (CT) finding of nodal involvement was observed in 37% of cases with pathological confirmation of pelvic lymph node (LN) involvement. Using CT to identify pelvic LN metastasis had a sensitivity of 37% and specificity of 93%. ConclusionThe 2018 FIGO staging system for cervical cancer after radical hysterectomy showed a better ability to differentiate survival outcomes. However, the image evaluation method should be reconsidered.

Combining MGMT promoter pyrosequencing and protein expression to optimize prognosis stratification in glioblastoma.

Pyrosequencing (PSQ) represents the golden standard for MGMT promoter status determination. Binary interpretation of results based on the threshold from the average of several CpGs tested would neglect the existence of the “gray zone”. How to define the gray zone and reclassify patients in this subgroup remains to be elucidated. A consecutive cohort of 312 primary glioblastoma patients were enrolled. CpGs 74‐81 in the promoter region of MGMT were tested by PSQ and the protein expression was assessed by immunohistochemistry (IHC). Receiver operating characteristic curves were constructed to calculate the area under the curves (AUC). Kaplan‐Meier plots were used to estimate the survival rate of patients compared by the log‐rank test. The optimal threshold of each individual CpG differed from 5% to 11%. Patients could be separated into the hypomethylated subgroup (all CpGs tested below the corresponding optimal thresholds, n = 126, 40.4%), hypermethylated subgroup (all CpGs tested above the corresponding optimal thresholds, n = 108, 34.6%), and the gray zone subgroup (remaining patients, n = 78, 25.0%). Patients in the gray zone harbored an intermediate prognosis. The IHC score instead of the average methylation levels could successfully predict the prognosis for the gray zone (AUC for overall survival, 0.653 and 0.519, respectively). Combining PSQ and IHC significantly improved the efficiency of survival prediction (AUC: 0.662, 0.648, and 0.720 for PSQ, IHC, and combined, respectively). Immunohistochemistry is a robust method to predict prognosis for patients in the gray zone defined by PSQ. Combining PSQ and IHC could significantly improve the predictive ability for clinical outcomes.

Integrated multi-omics approaches to improve classification of chronic kidney disease.

Chronic kidney diseases (CKDs) are currently classified according to their clinical features, associated comorbidities and pattern of injury on biopsy. Even within a given classification, considerable variation exists in disease presentation, progression and response to therapy, highlighting heterogeneity in the underlying biological mechanisms. As a result, patients and clinicians experience uncertainty when considering optimal treatment approaches and risk projection. Technological advances now enable large-scale datasets, including DNA and RNA sequence data, proteomics and metabolomics data, to be captured from individuals and groups of patients along the genotype-phenotype continuum of CKD. The ability to combine these high-dimensional datasets, in which the number of variables exceeds the number of clinical outcome observations, using computational approaches such as machine learning, provides an opportunity to re-classify patients into molecularly defined subgroups that better reflect underlying disease mechanisms. Patients with CKD are uniquely poised to benefit from these integrative, multi-omics approaches since the kidney biopsy, blood and urine samples used to generate these different types of molecular data are frequently obtained during routine clinical care. The ultimate goal of developing an integrated molecular classification is to improve diagnostic classification, risk stratification and assignment of molecular, disease-specific therapies to improve the care of patients with CKD.

Comparison of early warning scores in patients with COPD exacerbation: DECAF and NEWS score

BackgroundThe National Early Warning Score 2 (NEWS2) includes two oxygen saturation scales; the second adjusts target saturations to 88%–92% for those with hypercapnic respiratory failure. Using this second scale in...

Abstract 5382: A DNMT3A-independent hypomethylator phenotype is a unifying epigenetic signature of AML with good risk cytogenetics

Abstract Background: Acute myeloid leukemia (AML) causes the most leukemia-related deaths in the United States, and has frequent mutations in epigenetic regulators, including DNMT3A, IDH, and TET2. Such aberrations have been proposed to transform the epigenetic state in cancer, often involving DNA hypomethylation, however, the genomic specificity, causes, and clinical consequences of such methylation changes in AML remain unclear. Methods: We queried genome-wide CpG methylation using The Cancer Genome Atlas (TCGA) AML samples (n=194) run on Illumina 450k arrays. We used RNA-seq data to study gene expression changes associated with hypomethylator phenotypes (HP). Analysis was done using R. Results: Genome-wide analysis of CpG sites that are highly methylated in normal blood, and variably methylated in AML (β-value standard deviation in AML &amp;gt; 0.2; average β-value in normal blood &amp;gt; 0.8) revealed two distinct HPs by hierarchical clustering: Good-risk (GR) HP which included favorable cytogenetics, and DNMT-HP, which was enriched for DNMT3A mutations. We refined DNA methylation signatures of each HP cluster by differential methylation analysis and re-classified patients accordingly. Strikingly, all patients with t(8;21), inv(16), or t(15;17) belonged to the GR-HP+ group, suggesting that a common epigenetic thread connects these otherwise disparate genetic aberrations. From a clinical perspective GR-HP+ patients were younger than GR-HP- patients, and had significantly longer overall survival (median OS, years: GR-HP+ = Not reached; GR-HP- = 1.00; P &amp;lt; 0.001). In contrast, DNMT-HP+ cases were statistically equivalent to DNMT-HP- except for an enrichment for higher WBC counts, including no difference in survival (median OS, years: DNMT-HP+ = 0.92; DNMT-HP- = 1.34; P = 0.27). From an epigenetic perspective the two HP clusters harbored distinct DNA methylation changes; although both favored hypomethylation within non-CpG islands relative to CpG islands, the enrichment was more pronounced for DNMT-HP (Odds ratio: hypomethylated CpG islands/hypomethylated non-CpG islands, GR-HP = 0.64; DNMT-HP = 0.18). Genetic analysis revealed that GR-HP+ leukemia had wild-type IDH, DNMT3A, and NPM1 genes. In contrast, DNMT-HP+ AML had significantly more FLT3, NPM1, and DNMT3A mutations compared to DNMT-HP- patients. RNA-seq revealed significant up-regulation of genes in both HP phenotypes (216, and 150 genes for GR-HP and DNMT-HP, respectively at FDR &amp;lt; 0.01 and FC &amp;gt; 2). Pathway analysis of these genes revealed enrichments for ion channels and the complement pathway in DNMT-HP, and for nervous system and developmental genes in GR-HP. Conclusions: Our data suggest that two HPs exist in AML with unique epigenetic and transcriptomic signatures. The striking association between GR-HP and different favorable cytogenetic changes suggests that a common set of epigenetic features may contribute to improved survival in these patients. Citation Format: Andrew D. Kelly, Jozef Madzo, Priyanka Madireddi, Patricia Kropf, Charly R. Good, Jaroslav Jelinek, Jean-Pierre J. Issa. A DNMT3A-independent hypomethylator phenotype is a unifying epigenetic signature of AML with good risk cytogenetics [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5382. doi:10.1158/1538-7445.AM2017-5382

Renal function estimations and dose recommendations for Gabapentin, Ibuprofen and Morphine in acute hip fracture patients

Abstract Aims Optimization of pain management is essential for fasttrack surgery and safety in acute hip fracture (AHF) patients. Kidney function determines the doses of several postoperative painkillers, but previous studies have shown the standard Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation overestimate glomerular filtration rate (GFR) in elderly and underweight patients. The optimized Cockcroft Gault (CGop) equation might be more accurate in this patient group. The study aims to (1) investigate the differences in estimated GFR (eGFR) based on CKD-EPI and CGop and (2) to simulate this impact on recommended dosing of standard painkillers in AHF patients. Methods Patients admitted with AHF from January to April 2015 were included. eGFR was calculated for each patient by CKD-EPI and CGop based on the lowest measured serum creatinine between 1 and 4 days postoperatively. CKD-classification (1–5) was performed based on both eGFR values. If patients were classified differently based on the two eGFR values, then drug dosages were simulated for Morphine, Ibuprofen and Gabapentin according to prescribing recommendations in Renbase®.Two-sided Mann–Whitney test was used to compare median values between groups. Results 176 patients (62% women) with a median age of 76 years were included. CKD-EPI (78.0mL/min/m2) estimated eGFR significantly higher compared with GGop (58.9, P &lt; 0.001). Depending on the equation used to estimate GFR, CKD ≥ 3 (eGFR &lt; 60 mL/min/m2) occurred in 23–53% all patients. Using CGop to estimate GFR resulted in CKD re-classification for 63% of all patients. Using CKD-EPI to estimate GFR resulted in significantly higher doses of Morphine, Ibuprofen and Gabapentin (P &lt; 0.0001) in re-classified patients. Conclusions GFR estimates are significantly higher when calculated by CKD-EPI compared to CGop, and this difference results in significantly higher recommended doses of painkillers in AHF patients. Future studies should include a gold standard for measuring GFR and maybe alternative biomarkers for the renal function.

Arterial stiffness and coronary artery disease.

The current traditional risk scores are not sufficient to predict the full incidence of cardiovascular disease. In this brief review, we discuss the pathophysiological mechanisms through which arterial stiffness affects cardiac function and the additive value of markers of arterial stiffness, to detect the presence of coronary artery disease (CAD) and predict adverse outcome in these patients. Arterial stiffness causes early arrival of wave reflections in systole instead of diastole and, thus, increases systolic afterload and reduces diastolic coronary perfusion pressure. Abnormal collagen turnover, cytokines, and metalloproteinase activity are common biochemical links between vascular and myocardial stiffness. Pulse wave velocity, augmentation index, and central pressures measured by simple noninvasive methods are related to atheromatic plaque vulnerability, incidence, severity, and extent of CAD. Recent meta-analyses have shown the additive value of markers of arterial stiffness, and particularly of pulse wave velocity, to detect CAD, predict cardiovascular events, and reclassify patients to a higher cardiovascular risk. Studies assessing whether reduction of arterial stiffness is associated with improved prognosis are lacking. Markers of arterial stiffness are useful tools to identify early atherosclerosis and adverse clinical outcomes in young adults and individuals with a modest risk factor profile. Assessing arterial stiffness may facilitate cardiovascular risk stratification beyond traditional risk scores.

Variability of oxygenation in possible hepatopulmonary syndrome: effects of requiring two abnormal arterial blood gas results for diagnosis.

Hepatopulmonary syndrome (HPS) affects 10-32 % of patients with cirrhosis and is defined by liver abnormalities, intrapulmonary vascular dilatations (IPVDs), and abnormal oxygenation. However, published criteria for abnormal oxygenation are inconsistent. We sought to evaluate variation in oxygenation over time and to compare various diagnostic criteria for validity, based on their diagnostic stability over time and ability to identify patients with clinically relevant findings. We retrospectively analyzed oxygenation and diffusion capacity in patients with liver abnormalities and IPVDs who had ≥ 2 arterial blood gases (ABGs) at the University of Toronto or Universite de Montreal. We compared the performance of nine possible oxygenation criteria for HPS and for each explored whether validity improved when requiring two consecutive abnormal ABGs on different days. Mean PaO2 was 68.4 mmHg and annual within-patient coefficient of variation 6.3 % (58 patients). Applying published criteria, 8.6-15.5 % of patients initially diagnosed with HPS no longer met the criterion for HPS on a subsequent ABG (re-classified). Requiring two consecutive abnormal ABGs on different days: (1) reduced the proportion of re-classified patients (9/9 criteria); (2) identified patients with more rapid progression in hypoxemia and greater difference in rate of progression between HPS and non-HPS (7/9 criteria); and (3) identified patients with lower diffusion and a larger difference in diffusion between HPS and non-HPS (8/9 criteria). Oxygenation is variable in this population, and requiring two abnormal results might reduce misdiagnosis and better differentiate patients with and without HPS according to clinically relevant markers of disease.

ATRX mRNA expression combined with IDH1/2 mutational status and Ki-67 expression refines the molecular classification of astrocytic tumors: evidence from the whole transcriptome sequencing of 169 samples samples.

Astrocytic tumors are the most common primary brain tumors in adults. ATRX mutations have been identified in gliomas and are correlated with its loss of expression, which causes alternative lengthening of telomeres (ALT) leading to genomic instability. In this study, we aimed to explore the role of ATRX mRNA expression alteration in the progression and subclassification of astrocytic tumors and examine its impact on clinical outcome. We investigated ATRX mRNA expression and its association with IDH1 and IDH2 mutations in 169 adult astrocytic tumors using whole transcriptome sequencing. In our cohort, low ATRX mRNA expression was detected in 68% of astrocytomas, 50% of anaplastic astrocytomas and 41.6% of glioblastomas. Low ATRX expression closely overlapped with mutations in IDH1/2 (P<0.0001) in astrocytic tumors across WHO grades II-IV. Significant association between low ATRX expression and longer overall survival was identified in our cohort (P<0.01). ATRX combined with IDH1/2 and Ki-67 was used to re-classify patients with astrocytic tumors: group A1 containing IDH1/2 mutations and low ATRX expression predicted a better prognostic outcome, whereas group A3 carrying wild-type IDH1/2 and high Ki-67 expression had the shortest overall survival; IDH-mutant tumors with low ATRX expression and IDH-wild-type tumors with high Ki-67 expression were grouped into group A2. In summary, our results showed that ATRX in cooperation with IDH1/2 and Ki-67 defines three subgroups of astrocytic tumors regardless of the conventional WHO grades consensus. The molecular stratification in astrocytic tumors may aid in treatment strategy selection, therapeutic trial design, and clinical prognosis evaluation.