Three-tier Classification Research Articles

Stem Cell-Derived Gene Expression Scores Predict Survival and Leukemic Transformation in Myelofibrosis

Myelofibrosis (MF) is a myeloproliferative neoplasm (MPN) with survival outcomes ranging from months to years and variable risk of transformation to acute myeloid leukemia. Allogeneic bone marrow transplantation (BMT) can be curative but is associated with high treatment-related morbidity and mortality, therefore accurate risk stratification is important to guide clinical decision making in MF. Current risk prediction models use clinical and/or genomic features but do not consider the properties of the disease-driving stem cell population. Here, we use transcriptomic variation corresponding to both intra- and inter-patient heterogeneity among MF stem cells to generate novel gene expression-based scores predictive of survival and leukemic transformation in MF. To train and validate novel prognostic scores in MF, we identified 358 patients from an MPN registry at the Princess Margaret Cancer Centre (ClinicalTrials.gov Identifier: NCT02760238) from whom peripheral blood (PB) cells were collected near the date of MF diagnosis. All patients were diagnosed with either primary, post-PV, post-ET or pre-fibrotic MF with clinical follow-up of up to 12.2 years. RNA was extracted from unsorted PB mononuclear cells and RNA sequencing (RNAseq) was performed at an average depth of 50 million reads per sample. We randomly split our MF cohort into training (70%; n=250) and test sets (30%; n=108) and utilized a repeated nested cross validation approach together with statistical regression, to generate and assess the performance of models to predict survival within the training set. We tested 36,000 models derived from 36 initial MF-related genesets, ranging from stem-cell specific genesets to the whole transcriptome. The most accurate models by cross validation (median multivariable p-value = 6e-5) were produced from our retrospective identification of highly variable genes in single-cell RNAseq data derived from 82,255 Lin-CD34+ MF stem and progenitor cells across 15 patients (Psaila et al., 2020). Thus, features of intra- and inter-patient heterogeneity among MF stem and progenitor cells proved to be the most relevant for predicting survival. From these features, we derived our final model calculated as the weighted sum of gene expression across 24 genes (termed MPN24). We categorized patients with MPN24 scores above or below the training cohort median as MPN24 high or low, respectively. This model was validated in the test set, with high and low score patients experiencing 5-year survival rates of 71% [95% CI 57-88%] and 21% [95% CI 9%-52%], respectively, when censored at time of BMT (HR = 5.3 [95% CI 2.6-10.5]; p=2.1e-6) (Figure 1A). MPN24 retained independent prognostic value in multivariable analysis incorporating age, sex, DIPSS category, ECOG status, fibrosis grade, constitutional symptoms, and PB blast percentage (adjusted HR = 5.7 [95% CI 2.2-14]; p = 3e-4). Importantly, DIPSS classification remained a significant covariate, indicating that MPN24 and DIPSS capture distinct features of disease. We therefore developed a new three-tier classification scheme integrating both DIPSS and MPN24 scores (Figure 1B). Patients classified as low-, intermediate- or high-risk in this new classification scheme experienced 5-year survival rates of 88.2% [95% CI 77.9% - 99.9%], 39.3% [95% CI 19.9% - 77.7%] and 10.8% [95% CI 2.1% - 55.8%], respectively (likelihood ratio test p = 1e-8). Finally, from the MPN24 genes we derived a 13 gene subscore (MPN13) predictive of leukemic transformation in the training set. Patients in the test set scoring above the 80th percentile from the training set were classified as high risk and the remaining as low risk. Although total leukemic samples were limiting, MPN13 was significantly associated with risk of transformation (p=4.7e-03) with low and high-risk patients experiencing 3-year cumulative incidences of transformation of 5.2% [95% CI 0.2%-10.2%] and 28.6% [95% CI 3.1%-54.0%] respectively, after adjusting for death as a competing risk. Future studies will transfer our scores to the Nanostring platform for testing in independent cohorts. In summary, we used transcriptional variation among MF stem and progenitor cells to derive novel gene expression scores predictive of survival and leukemic transformation and developed a new integrated 3-tier model for predicting risk in MF patients. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Clinical exome-based panel testing for medically actionable secondary findings in a cohort of 383 Italian participants.

Background: Next-generation sequencing-based genetic testing represents a great opportunity to identify hereditary predispositions to specific pathological conditions and to promptly implement health surveillance or therapeutic protocols in case of disease. The term secondary finding refers to the active search for causative variants in genes associated with medically actionable conditions. Methods: We evaluated 59 medically actionable ACMG genes using a targeted in silico analysis of clinical exome sequencing performed in 383 consecutive individuals referred to our Medical Genetics Unit. A three-tier classification system of SFs for assessing their clinical impact and supporting a decision-making process for reporting was established. Results: We identified SFs with high/moderate evidence of pathogenicity in 7.0% (27/383) of analyzed subjects. Among these, 12/27 (44.4%) were carriers of a high-risk recessive disease allele. The most represented disease domains were cancer predisposition (33.3%), cardiac disorders (16.7%), and familial hypercholesterolemia (12.5%). Conclusion: Although still debated, ensuring during NGS-based genetic testing an opportunistic screening might be valuable for personal and familial early management and surveillance of medically actionable disorders, the individual's reproductive choices, and the prevalence assessment of underestimated hereditary genetic diseases.

Videolaryngoendoscopic and Stroboscopic Evaluation in Predicting the Malignancy Risk of Vocal Fold Leukoplakia.

Background: Vocal fold leukoplakia (VFL), despite our knowledge of its etiopathogenetic factors, and the development of laryngeal visualization, remains a diagnostic and therapeutic challenge. Objective: This research aimed to explore the efficacy of clinical and morphological feature identification in videolaryngoendoscopy (VLE) using a three-tier classification, and videolaryngostroboscopy (VLS) in predicting the risk of VFL malignant transformation. Material and Methods: We examined 98 patients with VFL by flexible endoscopy under VLE and VLS. Morphological characteristics of 123 lesions including the surface, margin, and texture were assessed; then, VFL was subdivided into three types: I—flat and smooth, II—elevated and smooth, and III—rough. Based on the histopathological findings, 76 (61.79%) lesions were classified as low- and 47 (38.21%) lesions as high-grade dysplasia. Results: The inter-rater agreement between two raters evaluating the VFL in VLE was almost perfect (Cohen’s kappa = 0.826; p < 0.00; 95%CI 0.748–0.904). In ROC curve analysis, the AUC difference between Rater I and Rater II was 0.024 (0.726 vs. 0.702). In multivariate analysis, high-risk VFL was positively related to unilateral plaque localization (p = 0.003), the type III VLE classification (p = 0.013), absence of a mucosal wave (p = 0.034), and a positive history of alcohol consumption (p = 0.047). In ROC analysis, VLE had an AUC of 0.726, with a high sensitivity of 95.7% and low specificity of 40.8%. The NPV was high, at 93.9%; however, the PPV was low, at 50%. The proposed logistic regression model including features significant in multivariate analysis showed lower sensitivity (80.9% vs. 95.7%) and lower NPV (86.2% vs. 93.9%); however, the specificity and PPV were improved (73.7% vs. 40.8% and 65.5% vs. 50.0%, respectively). Conclusions: The combination of clinical history with endoscopic (plaque morphology) and stroboscopic examination (mucosal wave assessment) can fairly estimate the degree of dysplasia in VFL and thus is recommended for use in clinical settings. The findings of this study can be used to guide the decision regarding immediate biopsy or watchful waiting.

Endocytoscopic Observation of Esophageal Lesions: Our Own Experience and a Review of the Literature.

This review outlines the process of the development of the endocytoscope (EC) with reference to previously reported studies including our own. The EC is an ultra-high-magnification endoscope capable of imaging at the cellular level. The esophagus is the most suitable site for EC observation because it is amenable to vital staining. The diagnosis of esophageal lesions using EC is based on nuclear density and nuclear abnormality, allowing biopsy histology to be omitted. The observation of nuclear abnormality requires a magnification of ×600 or higher using digital technology. Several staining methods have been proposed, but single staining with toluidine blue or methylene blue is most suitable because the contrast at the border of a cancerous area can be easily identified. A three-tier classification of esophageal lesions visualized by EC is proposed: Type 1 (non-cancerous), Type 2 (endocytoscopic borderline), and Type 3 (cancerous). Since characteristic EC images reflecting pathology can be obtained from non-cancerous esophageal lesions, a modified form of classification with four additional characteristic non-cancerous EC features has also been proposed. Recently, deep-learning AI for analysis of esophageal EC images has revealed that its diagnostic accuracy is comparable to that of expert pathologists.

Real World Application of Chemotherapy Response Score in High Grade Serous Cancer of the Ovary

Background: High grade serous cancers (HGSC) of gynecological origin can be treated with neoadjuvant chemotherapy (NACT) and subsequent interval debulking surgery (IDS) when upfront surgery is not feasible. Chemotherapy response score (CRS) was proposed to evaluate on pathological specimens at IDS the response to NACT. Objective: We aim to assess survival outcomes stratified by CRS in HGSC patients and to explore interaction with residual disease (RD) after surgery. Methods: We identified all consecutive patients with HGSC at advanced stage (FIGO III–IV) that underwent NACT and IDS. We collected baseline data as well as survival data such as disease-free survival (DFS) and overall survival (OS). CRS was assessed on adnexal and omental specimens based on a three-tier classification. We conducted multivariate cox regression analyses of CRS classifications (CRS 1 vs 2 vs 3, CRS 1+2 vs 3 and CRS 1 vs 2+3) using RD as covariate. Results: We enrolled 47 patients with a median follow-up of 25 months (IQR: 11–78). RD after IDS failed to correlate with DFS (p = 0.73) and OS (p = 0.93). Adnexal CRS 2 (HR 0.4; 95% CI 0.2–1.0; p = 0.05) and CRS 3 (HR 0.30; 95% CI 0.11–0.65; p = 0.04) correlated with longer DFS. Moreover, CRS 2 (HR 0.12; 95% CI 0.04–0.33; p &lt; 0.01) and CRS 3 (HR 0.06; 95% CI 0.02–0.20; p &lt; 0.01) on adnexal specimens were significantly associated with improved OS. Neither the omental three-tier nor the two-tier classifications correlated with DFS and OS. Conclusions: CRS classification is apparently a simple and reproducible method. In our study the adnexal three-tier system correlate with DFS and OS independently from RD at IDS. Further studies are needed to clarify the clinical role of CRS classification.

Prognostic Significance of Three-Tiered World Health Organization Classification of Phyllodes Tumor and Correlation to Singapore General Hospital Nomogram.

Phyllodes tumors (PTs) are categorized by the World Health Organization (WHO) as benign, borderline, and malignant. Singapore General Hospital (SGH) nomogram is a recurrence risk assessment tool for PT, which uses cytologic atypia, mitosis, stromal overgrowth, and the surgical margin status. We studied the prognostic significance of WHO classification and its correlation to the SGH nomogram. We identified 270 consecutive cases of PT (195 benign, 49 borderline, 26 malignant). Follow-up was available on 246 cases (mean follow-up of 51 months). The recurrence rates were 2% (4 of 176) for benign, 4% (2 of 46) for borderline, and 25% (6 of 24) for malignant (log-rank test P < .0001 for recurrence-free survival). Only five patients with malignant PT experienced distant recurrence. Stromal overgrowth was an independent predictor of recurrence-free survival on multivariable analysis. The mean nomogram scores for benign, borderline, and malignant PT were 20, 20.3, and 32, respectively. The higher than expected score for benign PT was due to positive margins in 39% of cases. The WHO three-tiered classification of PT is prognostic. Despite positive margin status, most benign PTs do not recur. Other features of the nomogram help in determining recurrence but are also used for WHO classification.

Breaking the link: Film pedagogy and drug policy in the United Kingdom

Fifty-one years ago the UK government passed the Misuse of Drugs Act, establishing the three-tier drugs classification system that remains largely unchanged to this day. Since that time, representations of drugs and drug users in the media have fuelled (if not entirely fabricated) moral panics to which political actors are happy to respond, rather than engaging with more evidence-based yet publicly controversial solutions. The result is a link between drug policy and media representation that is characterized by ‘moral panic’ public outrage and knee-jerk government responses that are resistant to scientific evidence and the testimony of drug users. This article focuses on the ways in which some filmmakers have developed practices that aim to undermine the dominant hegemonic representation of drugs and drug users through airing discourses that are grounded in harm reduction, rather than criminality. We highlight the ways in which harm reduction discourses can be represented to verify and justify normalized policy positions centred on crime and punishment, or can be promoted through a selection of pedagogical filmmaking strategies that facilitate the testimony of drug users. We argue that certain filmmaking strategies confer possibilities for breaking the link between harmful drugs policy and simplified media representations of drugs and drug users.

The Impact of Tumor Regression on Prognosis After Neoadjuvant Chemoradiotherapy in Surgically Treated Esophageal Adenocarcinoma.

The 5-year survival for patients with esophageal carcinoma remains poor despite neoadjuvant therapy and surgery. The eighth American Joint Committee on Cancer (AJCC) staging, based on the neoadjuvant treatedTNM(ypTNM) stage of the resection specimen, is used for prognosis. Tumor characteristics such as tumor grade, subtype of adenocarcinoma, and tumor regression scores are not included in this classification. This study aimed to determine the impact of these tumor characteristics on overall survival (OS) and disease-free survival (DFS). This retrospective cohort study included 228 patients with esophageal adenocarcinoma. Tumor regression was determined by the Mandard tumor regression (MTR) score. Subtype and grade of adenocarcinoma were confirmed using either the preoperative biopsy or residual tumor tissue after surgery. The MTR was modified to a three-tier classification. The study classified MTR 1 and 2 in one group as a "major response," with MTR 4 and 5 classified in one group as a "minimal response." The median follow-up period was 2.1 years. Combining MTR with AJCC staging did not improve the prognostic value for the prediction of OS. However, the multivariate analysis showed that the prognostic value of AJCC staging for DFS was improved by adding the three-tiered MTR (odds ratio for MTR4+5: 2.46; 95 % confidence interval, 1.07-5.67). Grade or subtype correlated with neither OS nor DFS in the univariate analyses and did not improve the prognostic value of the AJCC staging. Neither adenocarcinoma subtype nor grade influenced OS or DFS. However, the eighth AJCC staging combined with a three-tier MTR provided a better prognostic tool for DFS in esophageal adenocarcinoma treated with esophagectomy after neoadjuvant chemoradiotherapy.

Vocal Fold Leukoplakia: Which of the Classifications of White Light and Narrow Band Imaging Most Accurately Predicts Laryngeal Cancer Transformation? Proposition for a Diagnostic Algorithm.

Simple SummaryThe management of Vocal Fold Leukoplakia, especially distinguishing malignant leukoplakia and early glottic carcinoma from benign lesions pose a challenge for laryngologists. In this two-center study we have attempted to select the most accurate classification for predicting low- and high-risk Vocal Fold Leukoplakia in White Light Imaging and Narrow Band Imaging and to establish a diagnostic algorithm with a timely referral for treatment. We have shown that both the plaque image and the microvascular pattern on the leukoplakia periphery are critical in the diagnosis of high-risk Vocal Fold Leukoplakia. The proposed algorithm combines both imaging techniques to show the added value of Narrow Band Imaging and indicates the solution for non-users.The management of Vocal Fold Leukoplakia (VFL) remains problematic. There is no consensus on the indications or the timing for surgery. The objective was to select the most accurate classification for predicting low- and high-risk VFL in White Light Imaging (WLI) and Narrow Band Imaging (NBI) and to establish a diagnostic algorithm with a timely referral for treatment. A total of 259 VFL patients were included in the study; 186 lesions were classified as low-grade and 110 as high-grade dysplasia. The results of WLI acc. to the two-tier and the three-tier Chen 2019 classifications and NBI classifications: ELS, Ni 2011, and Ni 2019 with different cut-off points were compared with the pathological examination (HP). In WLI, the greatest agreement was obtained between type 3 of the three-tier classification and high-grade dysplasia (accuracy, specificity, and PPV: 80.4%, 92.0%, and 81.5%, respectively). Assessing VFL periphery in NBI, cut-off point 5 (Ni 2011 type V) demonstrated a higher accuracy, specificity, and PPV than 4 (83.1%, 93.6%, 85.5% and 77.4%, 74.9%, and 65.4%, respectively). In NBI, we observed higher accuracy, sensitivity, and PPV (84.1%, 93.0%, 85.2% vs. 80.7%, 81.3% and 71.3%, respectively) for cut-off point 5 (Ni 2019 type V and VI) in comparison to the cut-off point 4 group (type IV, V, and VI) (80.7%, 81.3%, 71.3%, respectively), and a higher kappa value (0.68 vs. 0.58) was obtained. We have shown that both the plaque image and the microvascular pattern on the leukoplakia periphery are critical in the diagnosis of high-risk VFL. The most accurate predictor of VFL malignant transformation in WLI is type 3 according to the Chen 2019 classification, while in NBI type V and VI according to the Ni 2019 classification.

Spatiotemporal analysis of out-of-hospital cardiac arrest in the City of Los Angeles, 2011–2019

ObjectiveThe goal of this analysis is to spatiotemporally identify and categorize areas in a large urban city according to Out-of-Hospital Cardiac Arrest (OHCA) rates and No Bystander CPR (NBCPR) risk levels. Study Area and ParticipantsThe study comprised all cardiac arrests within the administrative geographic boundary of the City of Los Angeles. The final sample included 15,904 cases that were geolocated within 985 census tracts. Main Outcomes and MeasuresThe primary outcome was stratification of census tracts into risk levels of OHCA and NBCPR by observed spatiotemporal patterns. ResultsOf 985 census tracts in the analytical sample, 182 census tracts (18.5%) were identified as having higher risk of OHCA and NBCPR. This assessment resulted in 129 census tracts in Tier 3 (moderate risk), 36 in Tier 2 (moderate-high risk), and 17 in Tier 1 (highest risk). Census tracts in Tiers 2 and 3 had higher amounts incident OHCA, while those in tier 1 had more OHCA events with NBCPR. These areas were largely contiguous and located in the Central and South areas of Los Angeles. ConclusionsUsing a novel three-tiered neighborhood risk classification tool, specific neighborhoods have been identified in the second largest city in the U.S. with consistently high or accelerating rates of OHCA and low bystander CPR. Further study of bystander response and community-based public health campaigns are needed in these communities.

An indicator-based integrated methodology for evaluating sustainability in transportation systems using multivariate statistics and fuzzy logic

PurposeThe purpose of this paper is to quantify and evaluate transport sustainability from an integrated perspective. It is argued that transportation systems being interdisciplinary and complex, the integrated approach towards quantification and evaluation would present its sustainability goals’ attainment in a much better way.Design/methodology/approachThe proposed integrated methodology is divided into five major steps that are sub-divided. It adopts a three-tier classification system i.e. pillar, sub-division and indicator. In total, 116 sustainable transportation indicators (STIs) were classified into 10 subdivisions corresponding to three sustainability pillars. The weighting and aggregation of STIs were done using a combination of a statistical tool called principal component analysis/factor analysis, a machine learning tool called fuzzy logic and equal weighting method. The final output that the proposed integrated methodology generates is a new composite index called the integrated sustainable transportation index (IIST).FindingsTo check the credibility of the proposed integrated methodology, it was applied to 26 states and the National Capital Territory (NCT) of Delhi, India. Based on the computed IIST, 27 study zones were ranked and mapped. The results showed that while Tamil Nadu (0.643), Telangana (0.574) and Maharashtra (0.564) were the best-performing states, Goa (0.347), Chhattisgarh (0.436) and Meghalaya (0.439) were the worst-performing states, as far as the relative transportation sustainability is concerned.Practical implicationsThe proposed integrated methodology could be useful for transportation evaluators, planners and policymakers who can recognize, track and improve the strengths and overcome the weaknesses within a transportation system.Originality/valueThe novelty of this research work is that it uses a multi-stage multi-tool approach to quantify and evaluate transport sustainability that minimizes the demerits of single-stage individual tools while maximizing their merits.

Comparison of Ki-67 Labeling Index Patterns of Diffuse Large B-Cell Lymphomas and Burkitt Lymphomas Using Image Analysis: A Multicenter Study.

Diffuse large B-cell lymphoma (DLBCL) is the most common high-grade B-cell lymphoma found in Korea; it manifests with a variety of cellular morphologies and a high proliferation index. It is difficult to differentiate between DLBCL and Burkitt lymphoma (BL) based on immunohistochemistry, histology, and Epstein-Barr virus infection status owing to the overlap in findings. In this study, we performed comparative morphometric analysis to understand the proportional difference in Ki-67 staining between DLBCL and BL. We analyzed Ki-67-stained slides of 103 DLBCLs and 29 BLs that were pathologically confirmed using a three-tier classification system (negative, 1+, 2+, and 3+) to compare Ki-67 expression between BL and activated B-cell and germinal center B-cell subtypes of DLBCL and DLBCL with high proliferation indices (>90% of 2+ and 3+ cells). Patients with DLBCL were older than those with BL (62.1 versus 51.0 years). The number and proportion of negative cells (passenger and true negative cells) were significantly lower in BLs than those in DLBCLs (337.4, 5.9% versus 690.3, 12.4%). The number and proportion of 3+ cells were significantly higher in BLs than those in DLBCLs (5213.6, 96.3% versus 3132.4, 62.0%). BLs and DLBCLs with a high proliferation index showed similar results as those between BLs and overall DLBCLs. We were able to differentiate BLs and DLBCLs with 98.1% sensitivity and 100.0% specificity using an optimal cut-off of 97.9% of 2+/3+ Ki-67-positive cells. Thus, the Ki-67 labeling index may be a good differential biomarker for DLBCLs and BLs.

Osseous morphology of the medial epicondyle: an anatomoradiological study with potential clinical implications

The cubital tunnel is limited anteriorly by the medial epicondyle (ME), laterally by the medial collateral ligament, and superiorly by Osborne's fascia and the cubital tunnel retinaculum. Previous studies were mostly dedicated to the roof of the cubital tunnel, in the way that the study of the groove for ulnar nerve and ME anatomy is relatively scarce in the literature. We sought to describe the radiological anatomy of the groove for ulnar nerve and ME in healthy volunteers with multiplanar computed tomography (CT). We analyzed 3D CT images of 30 healthy volunteers (mean age 39years, range 18-66years). Nine variables were measured from the right elbow, including sizes, areas and angles in two different planes (coronal and axial). Mean ME width and length were 17.3 ± 3.5mm and 31.7 ± 4.5mm, respectively. According to categorical correlation studies, ME width (X) was deemed the most representative morphological characteristic because of the positive correlation to five other different anatomical measurements. A three-tiered anatomical classification was proposed based on data distribution. Large individual variation is found in the shape of ME, both in coronal and axial planes. The knowledge of individual osseous morphology is of great value potentially contributing to the surgical decision-making in patients affected by cubital tunnel syndrome.

Windowing petrogenesis of continental flood basalts through mineralogical investigations: a case study from the Eastern Deccan Volcanic Province

Evaluation of the petrogenetic history of continental flood basalt using mineral–chemical data has been sparingly used for several flood basalt provinces of the world. For the Deccan flood basalts, such attempts are still rudimentary. The present contribution highlights several facets of petrogenesis of the Eastern Deccan Volcanic Province using details of constituent phases including glass. The present-study area around Khandwa (21°49′N, 76°21′E) indicates the presence of three distinct lava flows, which were identified on the basis of physical volcanological features based on a three-tier classification. Moreover, the occasional presence of chilled dykes and feeder dykes has been documented. The lava succession rests above (apparent) cumulate gabbro basement. The lava flows, in general, are characterized by dominant pyroxene (mostly augite, locally pigeonite) and plagioclase, opaque (magnetite and ilmenite) and glass, whereas olivine is rare. Both of these principal mineral phases (namely, plagioclase and pyroxene) occur both as phenocrysts and groundmass, while opaque phases occur only as groundmass. Pyroxene and plagioclase are generally zoned due to the changing milieu of crystallization conditions. Pyroxene thermometry data show the equilibration temperature range of 1050–1300 °C. Except for two samples of Flow II and one sample of chilled zone, the pyroxene thermometry data are broadly similar to that obtained from magnetite–ilmenite thermometry. As expected, deduced glass thermometric data reveal a relatively higher temperature. Crystallization history of parental magma was quantitatively modeled using Petrolog 3 software. The results indicate that the parental magma underwent both equilibrium and fractional crystallization (for example initially crystallized olivine reacted with ambient liquid to give rise to pyroxene). Phenocrystal and groundmass plagioclase and pyroxene show distinct patterns of compositional zoning corresponding to fluctuating physical parameters within the magma. Some of the glass [especially from the chilled dyke, feeder dyke, and Upper Colonnade Zone (UCZ) of flow II and flow III] represents ‘higher magnitude pressure ambience’ (fossilized glass) which is distinct from ‘surficial glass’ caused by equilibrium quenching. The glass and pyroxene compositions (using tectonic discrimination diagrams) suggest a non-orogenic continental setting of the parent magma. It is concluded that the studied Deccan volcanism shows a complex interplay of repeated pulses of magma ascent, fluctuation of crystallization condition, effervescence, and local magma mixing.

Standardization of pleural effusion-based tumor mutation burden (TMB) estimation using capture-based targeted sequencing

BackgroundTumor mutation burden (TMB) has received considerable attention as a potential predictive biomarker for response to anticancer treatment with immune checkpoint inhibitors (ICIs), and has been increasingly incorporated into clinical practice. Currently, TMB is often determined with tissue biopsies using whole-exome sequencing (WES) or panel-based targeted sequencing. Meanwhile, liquid biopsies such as blood are actively investigated as alternative media, although there is currently no report of the performance of targeted sequencing in assessing TMB using pleural effusion (PE) specimens.MethodsThirty-two patients diagnosed with advanced non-small cell lung cancer (NSCLC) with associated PE were prospectively enrolled (NCT 03546452). Cell-free DNA (cfDNA) from the supernatant of PE was subjected to both WES and capture-based targeted sequencing using various commercially-available panels.ResultsAll five panels assessed in this study demonstrated a good correlation with WES-derived TMB, with correlation coefficients ranging from 0.68–0.81. Two- and three-tier classification systems built on the TMB estimates achieved respective concordance rates of 74% and 63% between classifications based on WES- and panel-derived TMB levels.ConclusionsThis study provides real-world evidence that all panels assessed in this study can be used for TMB evaluation based on PE samples. We also demonstrated that PE can serve as an alternative medium for TMB evaluation. To the best of our knowledge, this is the first study evaluating the potential of PE samples for TMB estimation, thereby providing a basis for establishing future standard protocols.

Key histopathologic features in idiopathic noncirrhotic portal hypertension: an interobserver agreement study and proposal for diagnostic criteria.

Histologic features of idiopathic noncirrhotic portal hypertension (INCPH), loosely termed as obliterative portal venopathy (OPV), are heterogenous, often subtle, and overlap with other entities. To this date, no consensus histopathologic diagnostic criteria have been established for INCPH. For these reasons, rendering a reproducible consensus histologic diagnosis of OPV on a liver biopsy may often be challenging even for experienced hepatopathologists. We report herein a two-phase interobserver agreement study on the diagnosis of OPV and assessed the relative value of histologic features in 104 liver biopsies in distinguishing between INCPH and non-INCPH with the goal to obtain a consensus on specific practical diagnostic criteria. Six hepatopathologists blinded to clinical information and original pathologic diagnosis reviewed internet-based case study sets with high-resolution whole-slide images. The initial interobserver agreement on OPV was expectedly low, but significantly improved (moderate agreement in most categories) upon adopting a consensus view recognizing portal vein sclerosis as the only strong independent histologic predictor for INCPH, and that contrary to the conventional view, aberrant portal/periportal vessels does not significantly contribute to the positive assignment of OPV status. We propose a three-tiered classification with diagnostic criteria to facilitate the histologic assignment of OPV status for the evaluation of INCPH. Furthermore, we have validated the performance of the proposed criteria either based on histology alone or coupled with clinicopathologic correlation. This classification may aid in practical histologic assessment of liver biopsies with or without portal hypertension and help to improve diagnostic consistency and accuracy.

A three-tier road condition classification system using a spiking neural network model

Road surface anomaly detection and classification based on crowd-sourced smart phone sensor data has become an important area of research over the last decade due to its potential benefits to road maintenance. Previous studies focused on paved roads in which anomaly classification were modelled as single-staged events mostly using machine learning and threshold-based methods. Little or no attention has been paid to road type classification and anomaly detection and classification on unpaved roads, which constitute a larger percentage of roads in the developing world. In this paper, road condition classification is approached as a multi-tier activity, comprising of models for road type classification, anomaly classification models for paved roads as well as unpaved roads using a novel Spiking Neural Network (SNN) learning model. To demonstrate the viability of the proposed system, road condition data for the various tasks were collected via an Android Application developed by the authors from which statistical features were extracted and used to train and evaluate the models. Experimental results showed that the proposed SNN model yielded significantly higher classification performance when compared to a Support Vector Machine (SVM) and Multilayer Perceptron (MLP) trained and tested using the collected datasets and classification models reported in existing studies.

The Canadian Bikeway Comfort and Safety (Can-BICS) Classification System: A common naming convention for cycling infrastructure.

There is no standard naming convention for cycling infrastructure across cities. Our aim was to develop a common nomenclature for cycling infrastructure in Canada, relevant to the context of public health practice. We drew on transportation engineering design guides and public health guidance to develop a bicycle facility classification system: the Canadian Bikeway Comfort and Safety (Can-BICS) classification system, a three-tiered classification scheme that groups five bicycle facilities based on safety performance and user comfort. Adopting consistent nomenclature as per the Can-BICS system will support regional and national surveillance efforts in public health, planning and sustainability.

Risk stratification for prostate cancer management: value of the Cambridge Prognostic Group classification for assessing treatment allocation

BackgroundThe five-tiered Cambridge Prognostic Group (CPG) classification is a better predictor of prostate cancer-specific mortality than the traditional three-tiered classification (low, intermediate, and high risk). We investigated radical treatment rates according to CPG in men diagnosed with non-metastatic prostate cancer in England between 2014 and 2017.MethodsPatients diagnosed with non-metastatic prostate cancer were identified from the National Prostate Cancer Audit database. Men were risk stratified according to the CPG classification. Risk ratios (RR) were estimated for undergoing radical treatment according to CPG and for receiving radiotherapy for those treated radically. Funnel plots were used to display variation in radical treatment rates across hospitals.ResultsA total of 61,999 men were included with 10,963 (17.7%) in CPG1 (lowest risk group), 13,588 (21.9%) in CPG2, 9452 (15.2%) in CPG3, 12,831 (20.7%) in CPG4, and 15,165 (24.5%) in CPG5 (highest risk group). The proportion of men receiving radical treatment increased from 11.3% in CPG1 to 78.8% in CGP4, and 73.3% in CPG5. Men in CPG3 were more likely to receive radical treatment than men in CPG2 (66.3% versus 48.4%; adjusted RR 1.44; 95% CI 1.36–1.53; P < 0.001). Radically treated men in CPG3 were also more likely to receive radiotherapy than men in CPG2 (59.2% versus 43.9%; adjusted RR, 1.18; 95% CI 1.10–1.26). Although radical treatment rates were similar in CPG4 and CPG5 (78.8% versus 73.3%; adjusted RR 1.01; 95% CI 0.98–1.04), more men in CPG5 had radiotherapy than men in CPG4 (79.9% versus 59.1%, adjusted RR 1.26; 95% CI 1.12–1.40).ConclusionsThe CPG classification distributes men in five risk groups that are about equal in size. It reveals differences in treatment practices in men with intermediate-risk disease (CPG2 and CPG3) and in men with high-risk disease (CPG4 and CPGP5) that are not visible when using the traditional three-tiered risk classification.

Developing Classifications of Laryngeal Dysplasia: The Historical Basis.

During the last 60 years numerous significant attempts have been made to achieve a widely acceptable terminology and histological grading for laryngeal squamous intraepithelial lesions. While dysplasia was included in the pathology of the uterine cervix already in 1953, the term dysplasia was accepted in laryngeal pathology first after the Toronto Centennial Conference on Laryngeal Cancer in 1974. In 1963 Kleinsasser proposed a three-tier classification, and in 1971 Kambic and Lenart proposed a four-tier classification. Since then, four editions of the World Health Organisation (WHO) classification have been proposed (1978, 1991, 2005 and 2017). Several terms such as squamous intraepithelial neoplasia (SIN) and laryngeal intraepithelial neoplasia (LIN) are now being abandoned and replaced by squamous intraepithelial lesions (SIL). The essential change between the 2005 and 2017 WHO classifications is the attempt to induce a simplification from a four- to a two-tier system. The current WHO classification (2017) thus recommends the use of a two-tier system with reasonably clear histopathological criteria for the two groups: low-grade and high-grade dysplasia. Problems with interobserver variability apart, subjectivities and uncertainties remain, but to a lesser degree. Ongoing and additional molecular studies may help to clarify underlying events that will increase our understanding and possibly can facilitate our attempts to obtain an even better classification. The classification needs to be easier for the general pathologist to perform and easier for the clinician to interpret. These two objectives are equally important to provide each patient the best personalised treatment available for squamous intraepithelial lesions.