scholarly journals Detailed Quantification of Glomerular Structural Lesions Associates with Clinical Outcomes and Transcriptomic Profiles in Nephrotic Syndrome

2021 ◽  
Author(s):  
Jeffrey B. Hodgin ◽  
Laura H. Mariani ◽  
Jarcy Zee ◽  
Q Liu ◽  
Abigail R. Smith ◽  
...  
Keyword(s):  
Nephrotic Syndrome ◽  
Disease Progression ◽  
Clinical Outcomes ◽  
Messenger Rna ◽  
Structural Changes ◽  
Classification Systems ◽  
Molecular Heterogeneity ◽  
Biologically Relevant ◽  
Current Classification ◽  
Over Time

ABSTRACTThe current classification system for focal segmental glomerulosclerosis (FSGS) and minimal change disease (MCD) does not fully capture the complex structural changes in kidney biopsies, nor the clinical and molecular heterogeneity of these diseases. The Nephrotic Syndrome Study Network (NEPTUNE) Digital Pathology Scoring System (NDPSS) was applied to 221 NEPTUNE FSGS/MCD digital kidney biopsies for glomerular scoring using 37 descriptors. The descriptor-based glomerular profiles were used to cluster patients with similar morphologic characteristics. Glomerular descriptors and patient clusters were assessed for association with time to proteinuria remission and disease progression by using adjusted Cox models, and eGFR measures over time by using linear mixed models. Messenger RNA from glomerular tissue was used to assess differentially expressed genes (DEG) between clusters and identify genes associated with individual descriptors driving cluster membership. Three clusters were identified: X (N=56), Y (N=68), and Z (N=97). Clusters Y and Z had higher probabilities of proteinuria remission (HR [95% CI]= 1.95 [0.99, 3.85] and 3.29 [1.52, 7.13], respectively), lower hazards of disease progression 0.22 [0.08, 0.57] and 0.11 [0.03, 0.45], respectively), and greater loss of eGFR over time compared with X. Cluster X had 1920 DEGs compared to Y+Z, which reflected activation of pathways of immune response and inflammation. Six individual descriptors driving the clusters individually correlated with clinical outcomes and gene expression. The NDPSS allows for characterization of FSGS/MCD patients into clinically and biologically relevant categories and uncovers histologic parameters associated with clinical outcomes and molecular signatures not included in current classification systems.TRANSLATIONAL STATEMENTFSGS and MCD are heterogeneous diseases that manifest with a variety of structural changes often not captured by conventional classification systems. This study shows that a detailed morphologic analysis and quantification of these changes allows for better representation of the structural abnormalities within each patient and for grouping patients with similar morphologic profiles into categories that are clinically and biologically relevant.

scholarly journals Trend Analysis of Clinical Outcomes in Hodgkin Lymphoma over the Last Three Decades: Report from the Nebraska Lymphoma Study Group

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1284-1284
Author(s):  
Kailash Mosalpuria ◽  
Fausto R Loberiza ◽  
R. Gregory Bociek ◽  
Matthew A. Lunning ◽  
Apar Kishor Ganti ◽  
...  
Keyword(s):  
Disease Progression ◽  
Hodgkin Lymphoma ◽  
Clinical Outcomes ◽  
Cumulative Incidence ◽  
Initial Therapy ◽  
Study Group ◽  
Related Factors ◽  
Time Periods ◽  
Lymphoma Study Group ◽  
Over Time

BACKGROUND: With improvements in the treatment of Hodgkin lymphoma (HL) over time, we hypothesized a reduction in disease progression, and an increase in progression-free (PFS) and overall survival (OS) over the past 3 decades. METHODS: This is a retrospective study that included previously untreated HL patients reported to the Nebraska Lymphoma Study Group between 1983 and 2012. To analyze trends in outcomes, we divided the cohort into 3 time periods of 10 years each (1983-1992, 1993-2002, 2003-2012) to represent early (E), middle (M) and late (L) time periods. Patient, disease, and treatment-related factors as well as clinical outcomes (cumulative incidence of progression, PFS and OS) were compared according to time period. Multivariate analyses (MVA) were performed using Cox regression to adjust for significant covariates. RESULTS: In this retrospective review, 528 patients were identified during the study period: E (n=120), M (n=208), L (n=200). Patients in the more recent cohort (L) were more likely to be younger (p=0.008), have better performance score (p<0.001), have more sites of nodal involvement (p=0.05) and were more likely to receive ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) or Stanford V (mechlorethamine, doxorubicin, vinblastine, vincristine, bleomycin, etoposide, prednisone) as initial therapy (p<0.0001). In univariate analysis, there was a decrease in the 5-year cumulative incidence rate of disease progression over time (E=27% vs M=22% vs L=21%), and an increase in the 5-year probability of PFS (E=58% vs M=66% vs L=74%, p=0.004) and 5-year OS (E=67% vs M=80% vs L=85%, p=0.001). In MVA, improvement in the cumulative incidence of disease progression, PFS and OS over time was mainly driven by prognostic patient-related (age, sex) and treatment-related factors (type of chemotherapy regimen). Independent predictors of shorter PFS included age ≥45 y and male gender (Hazard Ratio [HR] 2.00 [95% CI 1.52-2.62, p<0.001] and 1.43 [1.09-1.87, p<0.01], respectively), while patients who received ABVD and Stanford V regimens as initial therapy experienced improved PFS (HR 0.39 [0.23-0.65, p<0.001] and 0.42 [0.28-0.64, p<0.001], respectively versus MOPP-like regimens). For OS, patients who were ≥45 y and males were more at risk of death (HR 4.34 [3.08-6.08, p<0.001] and 1.73 [1.26-2.37, p<0.001], respectively) while patients who received ABVD and Stanford V regimens as initial therapy were less likely to die (HR 0.36 [0.19-0.69, p <0.01] and 0.39 [0.23-0.65, p<0.001], respectively compared to MOPP-like regimens). Similarly, in MVA, a decrease in risk of progression was noted for patients who received ABVD and Stanford V regimens (HR 0.36 [0.19-0.69, p<0.01] and 0.39 [0.23-0.65, p<0.001], respectively) compared to MOPP-like regimens, while increased for patients who were ≥45 y and male (HR 4.33 [3.08-6.08, p<0.001] and 1.73 [1.26-3.37, p<0.001], respectively). CONCLUSIONS: Changes in upfront treatment regimens for HL over the last 3 decades have resulted in significant improvement in PFS and OS, and modest improvement in the risk for progression. Disclosures No relevant conflicts of interest to declare.

scholarly journals Thematic Reclassifications and Emerging Sciences

2021 ◽  
Author(s):  
Raphaël Sandoz
Keyword(s):  
Classification Systems ◽  
Coherent System ◽  
Historical Evolution ◽  
Thematic Structure ◽  
Over Time

AbstractOver time, various thematic classifications have been put forward to organize science into a coherent system of specialized areas of research. From an analysis of the historical evolution of the criteria used to distinguish the sciences from one another, I propose in this paper a quadripartite typology for the different thematic classification systems propounded by scholars throughout the centuries. Basically, I argue that the criteria used to differentiate the sciences have been alternately drawn from their respective subject matters, kinds of knowledge, methods and aims. Then, I show that several reclassifications occurred in the thematic structure of science. Finally, I argue that such changes in the structure of learning displaced the modalities of contact between the objects, knowledge, methods and aims of the various branches of science, with the result of outlining reshaped intellectual territories conducive to the emergence of new areas of research.

scholarly journals Longitudinal and multi-tissue molecular diagnostics track somatic BRCA2 reversion mutations that correct the open reading frame of germline alteration upon clinical relapse

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Shelly Sorrells ◽  
Kelly E. McKinnon ◽  
Ashleigh McBratney ◽  
Christopher Sumey
Keyword(s):  
Disease Progression ◽  
Parp Inhibitor ◽  
Acquired Resistance ◽  
Open Reading Frame ◽  
Genomic Testing ◽  
Clinical Relapse ◽  
Resistance Mutations ◽  
Reading Frame ◽  
Germline Alteration ◽  
Over Time

AbstractBRCA-mutant cancers often develop therapeutic resistance through several mechanisms. Here, we report a case of pathogenic germline BRCA2-driven breast cancer monitored for disease progression and acquired resistance using longitudinal multi-tissue genomic testing. Briefly, genomic testing was performed throughout the course of disease on tumor tissue from multiple sites, circulating tumor DNA from blood plasma, and matched normal tissue. Genomic analyses identified actionable variants for targeted therapies, as well as emerging resistance mutations over time. Two unique BRCA2 somatic alterations (p.N255fs and p.D252fs) were identified upon resistance to PARP inhibitor and platinum treatment, respectively. Both alterations restored the open reading frame of the original germline alteration, likely accounting for acquired resistance. This case exemplifies the evolution of multiple subclonal BRCA reversion alterations over time and demonstrates the value of longitudinal multi-tissue genomic testing for monitoring disease progression, predicting measures of response, and evaluating treatment outcomes in oncology patients.

scholarly journals One‐year clinically important deterioration and long‐term clinical course in Japanese patients with COPD: a multicenter observational cohort study

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Yuki Abe ◽  
Masaru Suzuki ◽  
Hironi Makita ◽  
Hirokazu Kimura ◽  
Kaoruko Shimizu ◽  
...  
Keyword(s):  
Cohort Study ◽  
Disease Progression ◽  
Clinical Outcomes ◽  
Japanese Patients ◽  
Drop Out ◽  
Chronic Obstructive ◽  
First Year ◽  
Severe Exacerbation ◽  
Clinically Important Deterioration

Abstract Background Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease with a complex progression of many clinical presentations, and clinically important deterioration (CID) has been proposed in the Western studies as a composite endpoint of disease progression. The aim of this study was to investigate the relationships between 1-year CID and the following long-term clinical outcomes in Japanese patients with COPD who have been reported to have different characteristics compared to the Westerners. Methods Among Japanese patients with COPD enrolled in the Hokkaido COPD cohort study, 259 patients who did not drop out within the first year were analyzed in this study. Two definitions of CID were used. Definition 1 comprised ≥ 100 mL decrease in forced expiratory volume in 1 s (FEV1), ≥ 4-unit increase in St George’s Respiratory Questionnaire (SGRQ) score from baseline, or moderate or severe exacerbation. For Definition 2, the thresholds for the FEV1 and SGRQ score components were doubled. The presence of CID was evaluated within the first year from enrollment, and analyzed the association of the presence of CID with following 4-year risk of exacerbations and 9-year mortality. Results Patients with CID using Definition 1, but not any single CID component, during the first year had a significantly worse mortality compared with those without CID. Patients with CID using Definition 2 showed a similar trend on mortality, and had a shorter exacerbation-free survival compared with those without CID. Conclusions Adoption of CID is a beneficial and useful way for the assessment of long-term disease progression and clinical outcomes even in Japanese population with COPD. The definition of CID might be optimized according to the characteristics of COPD population and the observation period for CID.

Computational Studies of Magnesium and Strontium Substitution in Hydroxyapatite

2012 ◽  
Vol 529-530 ◽  
pp. 123-128 ◽  
Author(s):  
Flora E. Imrie ◽  
Marta Corno ◽  
Piero Ugliengo ◽  
Iain R. Gibson
Keyword(s):  
Density Functional ◽  
Structural Changes ◽  
Harmonic Approximation ◽  
Site Preference ◽  
Ionic Radii ◽  
Biologically Relevant ◽  
Site Preferences ◽  
Mechanical Approach ◽  
Quantum Mechanical Approach ◽  
Mg Substitution

The properties of hydroxyapatite can be improved by substitution of biologically relevant ions, such as magnesium (Mg) and strontium (Sr), into its structure. Previous work in the literature has not reached agreement as to site preferences in these substitutions, and there are suggestions that these may change with differing levels of substitution. The current work adopted a quantum mechanical approach based on density functional theory using the CRYSTAL09 code to investigate the structural changes relating to, and site preferences of, magnesium and strontium substitution (to 10 mol%) in hydroxyapatites and also to predict the corresponding vibrational spectra in the harmonic approximation. The structures underwent full geometrical optimisation within the P63 space group, indicating an energetic site preference for the Ca (2) site in the case of Mg substitution, and the Ca (1) site in the case of Sr. Shrinkage of the unit cell was observed in the case of Mg substitution, and expansion in the case of Sr substitution, in agreement with the corresponding ionic radii. Thermodynamic properties of the structures obtained from the harmonic vibrational frequency calculations confirmed that the structures were minima on the potential energy surface. Isotopic substitutions indicated that the main contribution of Sr and Mg to vibrational modes is at frequencies < 400 cm-1.

NCOG-18. RELATIONSHIP BETWEEN RANO-PRO WORKING GROUP STANDARDIZED PRIORITY CONSTRUCTS AND DISEASE PROGRESSION AMONG MALIGNANT GLIOMA PATIENTS AS MEASURED THROUGH CLINICAL OUTCOMES ASSESSMENTS

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi155-vi156
Author(s):  
Elizabeth Vera ◽  
Tito Mendoza ◽  
Alvina Acquaye ◽  
Nicole Briceno ◽  
Anna Choi ◽  
...  
Keyword(s):  
Malignant Glioma ◽  
Disease Progression ◽  
Clinical Outcomes ◽  
Stable Disease ◽  
Working Group ◽  
Karnofsky Performance Status ◽  
Clinical Care ◽  
Self Care ◽  
Work Activity ◽  
Core Symptoms

Abstract Recognizing the importance of clinical outcomes assessments (COA), the RANO-PRO Working Group recommends inclusion of core symptoms/functions in clinical care/research for malignant glioma patients. This study evaluated the association between the recommended symptoms (pain, perceived cognition, seizures, aphasia, treatment-specific symptoms) and functions (physical: weakness, walking; and role/social: work, usual activities) and disease progression in these patients. MDASI-Brain Tumor and EQ-5D-3L scores, Karnofsky Performance Status (KPS), and Neurologic Function Score (NFS) were evaluated in relation to disease progression by chi-square tests, independent- and paired-samples t-tests, adjusted for multiple comparisons. Our sample included 336 patients with malignant glioma; 82% white, 64% male, median age=52 (21-79). Imaging study revealed disease progression for 46% of patients. All symptoms except seizures and difficulty concentrating were worse in the group whose imaging showed disease progression versus stable disease, as well as the functions of walking, work, activity, and self-care (0.8 &lt; difference &lt; 1.8). Patients with disease progression were 4 times more likely to have a poor KPS (≤ 80) and worse NFS. Among patients with disease progression (n=112), all symptoms, except seizures, worsened from first assessment to time of progression. Up to 22% of patients reported worsening mobility, self-care, and usual activity; 46% and 35% had worsened KPS and NFS, respectively. Seven symptoms and functions were each individually reported by at least 10% of patients as having worsened the most. Worsening of symptoms and functions was not observed among patients with stable disease, except in difficulty understanding. Identified core symptoms/functions worsen at the time of progression demonstrating the relationship between priority constructs and a traditional tumor response measure while highlighting the importance of longitudinal collection of COA. The pattern of worsening was observed via both patient- and clinician-reported outcomes, emphasizing the utility of COA in clinical care and clinical trials.

scholarly journals Learning longitudinal patterns and identifying subtypes of pediatric Crohn disease treated with infliximab via trajectory cluster analysis of electronic health records

2021 ◽  
Author(s):  
Andrew Chen ◽  
Ronen Stein ◽  
Robert N. Baldassano ◽  
Jing Huang
Keyword(s):  
Electronic Health Records ◽  
Disease Activity ◽  
Crohn Disease ◽  
Cross Sectional ◽  
Health Records ◽  
Disease Evolution ◽  
Current Classification ◽  
Electronic Health ◽  
Over Time

ABSTRACTBackgroundThe current classification of pediatric CD is mainly based on cross-sectional data. The objective of this study is to identify subgroups of pediatric CD through trajectory cluster analysis of disease activity using data from electronic health records.MethodsWe conducted a retrospective study of pediatric CD patients who had been treated with infliximab. The evolution of disease over time was described using trajectory analysis of longitudinal data of C-Reactive Protein (CRP). Patterns of disease evolution were extracted through functional principal components analysis and subgroups were identified based on those patterns using the Gaussian mixture model. We compared patient characteristics, a biomarker for disease activity, received treatments, and long-term surgical outcomes across subgroups.ResultsWe identified four subgroups of pediatric CD patients with differential relapse-and-remission risk profiles. They had significantly different disease phenotype (p < 0.001), CRP (p < 0.001) and calprotectin (p = 0.037) at diagnosis, with increasing percentage of inflammatory phenotype and declining CRP and fecal calprotectin levels from Subgroup 1 through 4. The risk of colorectal surgery within 10 years after diagnosis was significantly different between groups (p < 0.001). We did not find statistical significance in gender or age at diagnosis across subgroups, but the BMI z-score was slightly smaller in subgroup 1 (p =0.055).ConclusionsReadily available longitudinal data from electronic health records can be leveraged to provide a deeper characterization of pediatric Crohn disease. The identified subgroups captured novel forms of variation in pediatric Crohn disease that were not explained by baseline measurements and treatment information.SummaryThe current classification of pediatric Crohn disease mainly relies on cross-sectional data, e.g., the Paris classification. However, the phenotypic classification may evolve over time after diagnosis. Our study utilized longitudinal measures from the electronic health records and stratified pediatric Crohn disease patients with differential relapse-and-remission risk profiles based on patterns of disease evolution. We found trajectories of well-maintained low disease activity were associated with less severe disease at baseline, early initiation of infliximab treatment, and lower risk of surgery within 10 years of diagnosis, but the difference was not fully explained by phenotype at diagnosis.

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