Indeterminate Scores Research Articles

Role of Tomosynthesis in Determining the BI-RADS Score of Individuals with Indeterminate Mammography Results

Background: Tomosynthesis, despite its potential to produce superior images compared to mammography for Breast Imaging-Reporting and Data System (BI-RADS) scoring, has not yet been widely adopted. This is likely due to a combination of insufficient data and a scarcity of expertise in this area. Objectives: In this study, we aimed to evaluate the potential benefits of tomosynthesis for patients with indeterminate BI-RADS results from full-field digital mammography (FFDM). Specifically, we sought to determine whether this method could clarify ambiguous BI-RADS scores. Patients and Methods: This cross-sectional study involved 386 female patients, with an average age of 44.7 ± 7.9 years. The study included all patients who were admitted to a referral center for breast radiology during 2019 - 2020 and underwent both FFDM and tomosynthesis within a short interval. The purpose of performing tomosynthesis was to assess its additional benefits over FFDM. The collected data was input into SPSS version 20 for analysis. A P-value of less than 0.05 was deemed statistically significant. Results: Out of 152 patients who initially had indeterminate findings in mammography (BI-RADS score of 0), only one patient (0.7%) remained indeterminate after tomosynthesis. This implies that tomosynthesis was able to clarify the BI-RADS scores for 99.3% of patients with previously indeterminate scores. Specifically, out of these 151 patients, 81 were scored as BI-RADS 2, 45 as BI-RADS 3, 19 as BI-RADS 4, and six as BI-RADS 5. Conclusion: Tomosynthesis has the capability to clarify unclear FFDM BI-RADS scores in over 99% of cases. This suggests that it could serve as the primary supplementary imaging technique for cases with indeterminate BI-RADS scores.

Role of Tomosynthesis in Determining the BI-RADS Score of Individuals with Indeterminate Mammography Results

Background: Tomosynthesis, despite its potential to produce superior images compared to mammography for Breast Imaging-Reporting and Data System (BI-RADS) scoring, has not yet been widely adopted. This is likely due to a combination of insufficient data and a scarcity of expertise in this area. Objectives: In this study, we aimed to evaluate the potential benefits of tomosynthesis for patients with indeterminate BI-RADS results from full-field digital mammography (FFDM). Specifically, we sought to determine whether this method could clarify ambiguous BI-RADS scores. Patients and Methods: This cross-sectional study involved 386 female patients, with an average age of 44.7 ± 7.9 years. The study included all patients who were admitted to a referral center for breast radiology during 2019 - 2020 and underwent both FFDM and tomosynthesis within a short interval. The purpose of performing tomosynthesis was to assess its additional benefits over FFDM. The collected data was input into SPSS version 20 for analysis. A P-value of less than 0.05 was deemed statistically significant. Results: Out of 152 patients who initially had indeterminate findings in mammography (BI-RADS score of 0), only one patient (0.7%) remained indeterminate after tomosynthesis. This implies that tomosynthesis was able to clarify the BI-RADS scores for 99.3% of patients with previously indeterminate scores. Specifically, out of these 151 patients, 81 were scored as BI-RADS 2, 45 as BI-RADS 3, 19 as BI-RADS 4, and six as BI-RADS 5. Conclusion: Tomosynthesis has the capability to clarify unclear FFDM BI-RADS scores in over 99% of cases. This suggests that it could serve as the primary supplementary imaging technique for cases with indeterminate BI-RADS scores.

Understanding Composite-Based Structural Equation Modeling Methods From the Perspective of Regression Component Analysis

Regression component analysis (RCA) replaces the factors in a factor analysis model with weighted composites of the model’s observed variables. The weight matrix may be calculated from the factor model’s parameter estimates. Thus, RCA parameter estimates can be obtained using factor model software, but RCA composites have determinate scores, rather than the indeterminate scores of factors. Analytically, RCA equates to modeling with “regression method” factor scores, except that, while those scores will be inconsistent with the original factor model, they are strictly consistent with the RCA model. When the original factor model is strictly correct in the population and the composites in RCA are standardized, RCA parameter estimates replicate those from regression-weighted forms of partial least squares (PLS) path modeling and generalized structured component analysis (GSCA)—affirming that those methods also equate to modeling with regression method factor scores under the same conditions. Parallel measurement allows RCA to replicate both correlation weight and regression weight versions of PLS and GSCA. These results suggest that RCA and regression-weighted forms of PLS and GSCA are all consistent approaches for modeling data that conforms to a factor model. All analytical methods are described using one consistent symbol palette. Complete R syntax is provided.

Diffusion-weighted imaging complements T2-weighted MRI for tumour response assessment in squamous anal carcinoma

ObjectivesA published tumour regression grade (TRG) score for squamous anal carcinoma treated with definitive chemoradiotherapy based on T2-weighted MRI yields a high proportion of indeterminate responses (TRG-3). We investigate whether the addition of diffusion-weighted imaging (DWI) improves tumour response assessment in the early post treatment period.Materials and methodsThis retrospective observational study included squamous anal carcinoma patients undergoing MRI before and within 3 months of completing chemoradiotherapy from 2009 to 2020. Four independent radiologists (1–20 years’ experience) scored MRI studies using a 5-point TRG system (1 = complete response; 5 = no response) based on T2-weighted sequences alone, and then after a 12-week washout period, using a 5-point DWI-TRG system based on T2-weighted and DWI. Scoring confidence was recorded on a 5-point scale (1 = low; 5 = high) for each reading and compared using the Wilcoxon test. Indeterminate scores (TRG-3) from each reading session were compared using the McNemar test. Interobserver agreement was assessed using kappa statistics.ResultsEighty-five patients were included (mean age, 59 years ± 12 [SD]; 55 women). T2-weighted TRG-3 scores from all readers combined halved from 24% (82/340) to 12% (41/340) with DWI (p < 0.001). TRG-3 scores changed most frequently (41%, 34/82) to DWI-TRG-2 (excellent response). Complete tumour response was recorded clinically in 77/85 patients (91%). Scoring confidence increased using DWI (p < 0.001), with scores of 4 or 5 in 84% (287/340). Interobserver agreement remained fair to moderate (kappa range, 0.28–0.58).ConclusionDWI complements T2-weighted MRI by reducing the number of indeterminate tumour responses (TRG-3). DWI increases radiologist’s scoring confidence.Clinical relevance statementDiffusion-weighted imaging improves T2-weighted tumour response assessment in squamous anal cancer, halving the number of indeterminate responses in the early post treatment period, and increases radiologists’ confidence.Key PointsTumour response based on T2-weighted MRI is often indeterminate in squamous anal carcinoma.Diffusion-weighted imaging alongside T2-weighted MRI halved indeterminate tumour regression grade scores assigned by four radiologists from 24 to 12%.Scoring confidence of expert and non-expert radiologists increased with the inclusion of diffusion-weighted imaging.

Flou: A Co-Compositional Attempt at Algorithmic Embodiment

My composition, Flou for solo violin, is an attempt at cocomposition between the composer and the performer at embodying otherwise unidiomatic machine-learning generated materials. The piece touches on a broader compositional problem where historically, when algorithms were used as a means in itself, composers were often faced with tensions between the algorithm, the composer, and the performer. To contextualize further, Cage, Xenakis, and Boulez each came up with their own algorithmic processes and dealt with these tensions differently. Upon scrutinizing these composers’ methods, I observe that these tensions are usually resolved by enabling agency for either side of the humans involved. As in, Boulez deviates from his algorithm to follow his compositional instincts, Cage creates indeterminate scores for performers to interpret, and Xenakis adds ‘human touches’ to his ‘incomplete’ algorithm. Considering these kinds of tensions, Flou uses an open score with only algorithmic pitch notated, which I ask to be played using an octave-lower scordatura. The open score affords the performer’s freedom to react to the instability of the scordatura in non-pitch ways, and it is this tantalizing physical attempt at trying to play the algorithmic pitch that foregrounds the performer’s bodily presence in the performance.

Temporal Artery Biopsy Debate: Positive TAB Result Prolongs Steroid Use in Giant Cell Arteritis.

A retrospective chart review garnered patient demographics, symptoms, comorbidities, and steroid treatment duration in patients undergoing TAB at a single center. Steroid treatment was compared between TAB+ and TAB - patients. One hundred seven patients undergoing TAB were included. Patients were predominantly women (70.1%) with a median age of 74 years (46 -91). Of 107 TAB results, 74 (69.2%) were negative, 23 (21.5%) were positive, and 10 (9.3%) were found to be indeterminate. In TAB+ patients, the mean erythrocyte sedimentation rate was not significantly different than TAB - patients (60.2 versus 43.7, P = 0.45), nor was the median C-reactive protein (38.8 versus 18.1, P = 0.17). Regarding steroid use, both TAB+ and TAB - patients had a similarly high rate of prebiopsy steroid initiation (82.6% versus 70.3%, P = 0.32). More TAB+ patients remained on steroids at 6 weeks (95.0% versus 57.4%, P = 0.004), 6 months (95% versus 37.7%, P < 0.001), 1 year (65.0% versus 31.1%, P = 0.024), and 18 months (50.0% versus 19.7%, P = 0.045). By 2 years, the difference no longer met significance (35.0% versus 14.8%, P = 0.12). P = 0.12). TAB positivity does seem to influence maintenance of steroids up to 18 months after biopsy.

Added Value of Magnetic Resonance Over Computed Tomography in Distinguishing Nonneoplastic Complex Thymic Cysts From Malignant Cystic Thymic Neoplasms.

The aim of the study was to evaluate cystic thymic masses by using computed tomography (CT) and magnetic resonance (MR) scoring systems to differentiate nonneoplastic thymic cysts from cystic thymic neoplasms. This retrospective multisite study included adult patients who underwent CT and MR imaging of the chest between 2007 and 2020 with any of the following impressions on cross-sectional imaging studies: "thymic mass with cystic component," "unilocular or multilocular cystic thymic lesion," "complex thymic cyst," "thymic cyst with hemorrhage." Two blinded radiologists reviewed and recorded specific imaging features as well as overall impressions on both CT and MR using a Likert scale scoring system. Data were analyzed, and diagnostic accuracy of CT and MR was compared using areas under the receiver operating characteristic curves (AUC). Fifty-six patients were included, of which 45 (80%) had benign masses. Total of 21 patients (38%) had indeterminate scores on CT of which 3 (14%) were malignant, while only 6 (11%) had indeterminate scores on MR and 1 was malignant. Magnetic resonance scoring system (AUC, 0.95) performed better than CT scoring system (AUC, 0.86) in distinguishing benign versus malignant lesions (P = 0.06). Lack of enhancement within the mass was completely predictive of benign etiology (P < 0.001). Wall thickness of an enhancing cyst was predictive of malignancy, with AUC 0.93. Magnetic resonance yielded higher specificity allowing a larger number of lesions to be confidently assigned a benign diagnosis. This could help in averting unnecessary follow-up, biopsies, or surgery. The authors recommend follow-up imaging with MR for prevascular masses, even those appearing "solid" on CT.

The Correlation between Fetuin-A Levels And Nafld Fibrosis Score (NFS)

Abstract. Fetuin-A is a plasma glycoprotein expressed in the liver. Fatty liver accumulation because changing fetuin-A expression leads to nonalcoholic fatty liver disease (NAFLD). The benefits of serum fetuin-A as a predictor of fibrosis biomarkers in NAFLD patients remain unclear. Non-invasive scoring system predicting fibrosis among patients with NAFLD is the NAFLD fibrosis score (NFS). Objective. This study aims to find the correlation between circulating fetuin-A levels and NFS in NAFLD patients. Methods. Eighty subjects (male, 52; female, 26) followed this cross-sectional study. NAFLD is diagnosed with an abdominal ultrasound. The serum levels of fetuin-A measured by ELISA. NFS is used to identify the probability of fibrosis in subjects. The correlation between Fetuin-A levels and NFS was determined using Pearson correlation tests. A p-value &lt; 0.05 was significant. Results. There was significant difference in fetuin-A levels (p &lt; 0.001) between NAFLD degree I (421.71 pg/mL), NAFLD degree II (494.88 pg/mL), and NAFLD degree III (692 pg/mL). The NFS low probability score in 46 subjects and NFS indeterminate score in 34 subjects. Serum concentrations of fetuin-A correlate significantly with NFS (r = 0.478, p &lt; 0.001). Conclusion. There is a positive correlation between serum levels of fetuin-A and NFS.

A220 THE IMPACT OF DIABETES AND AGE ON PERFORMANCE OF NON-INVASIVE SERUM-BASED TESTS FOR PREDICTION OF ADVANCED FIBROSIS IN BIOPSY-PROVEN NAFLD

Abstract Background Non-alcoholic fatty liver disease (NAFLD) is now a leading cause of end-stage liver disease. Advanced stage F3-4 fibrosis predicts liver-related mortality in NAFLD patients. Simple non-invasive serum-based tests (NIT) for F3-4 are limited by indeterminate scores, necessitating secondary tests or liver biopsy. Diagnostic NIT cut-offs may vary in NAFLD patients with diabetes mellitus (DM) and the elderly. Identifying appropriate thresholds in populations in which these tests can be applied will reduce indeterminates and facilitate their broader use. Aims The aim of this study was to assess the impact of DM status and age on the performance of NIT for prediction of advanced fibrosis in patients with biopsy-proven NAFLD. Methods Patients presenting to two Canadian tertiary care centers between 2010–2018 for liver biopsy to diagnose NAFLD were included in this study. NIT including NFS, FIB4, BARD, AST-to-platelet ratio index (APRI), and AST to ALT ratio (AST/ALT) were calculated for each patient using validated cut-offs. Results 457 patients were included in this study. Mean age was 48.8±12.9 years, 56% male, mean BMI 32.3 ± 6.7kg/m2, 69% with DM, and F3-4 prevalence 48%. Indeterminate rates for NIT were generally higher for older patients, with or without DM (27–49% and 37–52%, vs. 33–42% and 20–37%, respectively). FIB-4 and NFS both had high specificity &amp;gt;0.9 in DM patients &amp;lt;60 years (Table 1). There were no differences in AUROC for individual NITs between patients with and without DM, and those &amp;lt; 60 vs. ≥ 60, nor between individual NIT within these groups. Conclusions DM status and age, ≥ 60 vs. &amp;lt; 60, do not appear to have a significant impact on diagnostic performance of serum-based NIT in our cohort. Older patients had higher indeterminate results and reduced specificity, but T2DM status and age did not appear to have an impact on rate of misclassified patients. Serum-based NIT thresholds need to be optimized for older patients to reduce indeterminates and improve specificity. Funding Agencies None

Determination of "indeterminate score" measurements in lean nonalcoholic fatty liver disease patients from western Saudi Arabia.

BACKGROUNDNoninvasive measures to estimate liver fibrosis in lieu of biopsy in nonalcoholic liver disease (NAFLD) can broadly differentiate high vs low degrees of condition extent. However, an “indeterminate score” necessitates further clinical investigation and biopsy becomes essential, highlighting the need for identification of other noninvasive factors with accuracy for this midlevel extent and its prognosis. Lean NAFLD cases are of particular interest regarding this issue, as they present as otherwise healthy, and will benefit greatly from the less invasive assessment.AIMTo estimate the agreement of two noninvasive assessment tools in lean NAFLD patients, and assess factors related to indeterminate scores.METHODSUltrasound-diagnosed NAFLD patients, without sign of other chronic liver disease (n = 1262), were enrolled from a tertiary private medical centre between 2016-2019. After grouping by body mass index (obese, overweight, and lean), each participant underwent FibroScan. NAFLD fibrosis score (NFS) was used for subclassification (lower, higher, and indeterminate). No patient underwent liver biopsy. The kappa statistic was used to assess inter-rater agreement between the three groups on liver fibrosis degree assessed via FibroScan and NFS. Indeterminate score among the three groups was assessed to identify factors that predict its determination. RESULTSThe NAFLD study cohort was composed of lean (159/1262, 12.6%), overweight (365/1262, 29%) and obese (737/1262, 58.4%) individuals. The lean patients were significantly younger (49.95 ± 15.3 years, P < 0.05), with higher serum high density lipoprotein (52.56 ± 16.27 mg/dL, P < 0.001) and lower prevalences of type 2 diabetes mellitus, hypertension and hyperlipidaemia. All groups showed a predominance of lower fibrosis degree. The lean NAFLD patients showed a significantly lower NFS (P < 0.001). Degree of agreement between FibroScan and NFS was fair between the lean and obese NAFLD categories, and moderate in the overweight category. NFS was predictive of indeterminate score. Age was a factor among all the body mass index (BMI) categories; other associated factors, but with less strength, were serum alanine aminotransferase in the overweight category and BMI in the obese category.CONCLUSIONLean NAFLD patients showed lower degree and prevalence of liver fibrosis by NFS; however, follow-up biopsy is still needed.

MRI-based (MAST) score accurately identifies patients with NASH and significant fibrosis

Among the large population of patients with non-alcoholic fatty liver disease (NAFLD), identifying those with fibrotic non-alcoholic steatohepatitis (Fibro-NASH) is a clinical priority, as these patients are at the highest risk of disease progression and will benefit most from pharmacologic treatment. MRI-based proton density fat fraction (MRI-PDFF) and MR elastography (MRE) can risk-stratify patients with NAFLD by assessing steatosis and fibrosis, respectively. We developed a highly specific MRI-based score to identify patients with Fibro-NASH. This analysis included derivation (n= 103) and validation (n= 244) cohorts of patients who underwent MRI, liver biopsy, transient elastography, and laboratory testing for NAFLD from 2016-2020 in 2 tertiary care centers. To identify Fibro-NASH, a formula was developed based on MRI-PDFF, MRE, and a third variable with highest balanced accuracy per logistic regression. The MRI-aspartate aminotransferase (MAST) score was created and compared to NAFLD fibrosis (NFS), Fibrosis-4 (FIB-4), and FibroScan-aspartate aminotransferase (FAST) scores. The MAST score demonstrated high performance and discrimination in the validation cohort (AUC 0.93; 95% CI 0.88-0.97). In the validation cohorts, the 90% specificity cut-off of 0.242 corresponded to a sensitivity of 75.0%, positive predictive value (PPV) of 50.0% and negative predictive value (NPV) of 96.5%, whereas the 90% sensitivity cut-off of 0.165 corresponded to a specificity of 72.2%, PPV of 29.4%, and NPV of 98.1%. Compared to NFS and FIB-4, MAST resulted in fewer patients having indeterminate scores and an overall higher AUC. Compared to FAST, MAST exhibited a higher AUC and overall better discrimination. The MAST score is an accurate, MRI-serum-based score that outperforms previous scores in non-invasively identifying patients at higher risk of Fibro-NASH. Identifying patients with non-alcoholic steatohepatitis and significant fibrosis - who need treatment and are at risk of clinical liver-related outcomes - is a clinical priority. We developed a more accurate score using MRI-based technologies and a laboratory blood test (aspartate aminotransferase) that outperforms previous non-invasive scores for the identification of patients at higher risk of liver disease progression.

Medications and risk of motor vehicle collision responsibility in British Columbia, Canada: a population-based case-control study

Many medications impair driving skills yet their influence on collision risk remains uncertain. We aimed to systematically investigate the risk of collision responsibility associated with common classes of prescription medications. In this population-based case-control study we analysed linked driving and health records in British Columbia, Canada from Jan 1, 1997, to Dec 31, 2016. The study cohort included all drivers involved in an incident collision (defined as first collision after 3 collision-free years) that resulted in a police report. We scored police collision reports and classified drivers as responsible for the collision (cases) or not responsible (controls); drivers with indeterminate scores were excluded. We used logistic regression to determine odds of collision responsibility in drivers with current prescriptions for medications of interest versus drivers without prescriptions. To explore whether risk of collision responsibility was related to medication effect or driver factors, we compared risk in current medication users versus past users. To study whether drivers developed tolerance to medication effects, we compared risk in new (first 30 days of a prescription) versus established users. During the study period, 4 906 925 drivers had their driving licence linked to health records; of these drivers, 747 662 unique drivers were involved in 837 919 incident collisions between Jan 1, 2000, and Dec 31, 2016. 382 685 drivers responsible for the collision (cases) and 332 259 drivers not responsible (controls) were included in the final analysis; 122 975 drivers with indeterminate responsibility were excluded. We found increased risk of collision responsibility in drivers prescribed sedating antipsychotics (adjusted odds ratio [aOR] 1·35 [98·75% CI 1·25-1·46]), long-acting benzodiazepines (aOR 1·30 [1·22-1·38]), short-acting benzodiazepines (aOR 1·25 [1·20-1·31]), and high-potency opioids (aOR 1·24 [1·17-1·30]). Among medications used for medical indications, the highest risk was seen in drivers prescribed neurological medications: cholinergic drugs (aOR 1·83 [1·39-2·40]), anticholinergic agents for Parkinson's disease (aOR 1·45 [1·08-1·96]), dopaminergic agents (aOR 1·20 [1·04-1·38]), and anticonvulsants (aOR 1·20 [1·14-1·26]). People currently taking benzodiazepines, non-sedating antidepressants, high-potency opioids, and anticonvulsants had increased risk compared with past users, and we did not find increased risk in new compared with established users of these drugs. Drivers prescribed benzodiazepines or high-potency opioids are at increased risk of being responsible for collisions and this risk does not decrease over time. Several other classes of medications are associated with increased risk, but this association might be independent of medication effect. These findings can guide medication warnings and prescription choices and inform public education campaigns targeting impaired driving. Canadian Institutes of Health Research.

Distinction Between Hypertrophic Lichen Planus and Squamous Cell Carcinoma Requires Clinicopathologic Correlation in Difficult Cases

Distinguishing hypertrophic lichen planus (HLP) and squamous cell carcinoma (SCC) can be diagnostically challenging because of overlapping clinical and histopathological features. This study characterizes histopathological features in HLP and SCC, assessing their utility in diagnosing atypical squamous proliferations. We compared 12 histopathological features of 15 HLP and 11 SCC biopsies from the lower extremities. We then reviewed 16 cases that were diagnosed as atypical squamous proliferations with differential diagnoses of HLP versus SCC. Clinical follow-up allowed for retrospective categorization of these difficult cases as HLP or SCC. HLP showed significant differences in hyperorthokeratosis (P = 0.04), wedge-shaped hypergranulosis (P = 0.0033), and irregular psoriasiform hyperplasia (P = 0.004), whereas parakeratosis (P = 0.001), solar elastosis (P = 0.001), deep extension (P = 0.02), and perforating elastic fibers (P = 0.0001) were significant for SCC. A scoring system based on these significant differences was devised to aid the classification of difficult cases. 56% of the difficult cases received an "indeterminate" score. A score favoring HLP had a sensitivity of 44% and a specificity of 71%. Although significant differences were identified between cases of definitive HLP and SCC, these histopathological features were unable to distinguish difficult cases, highlighting the need for clinicopathological correlation in patients with atypical squamous proliferations of the lower extremities. Many difficult cases had histologic features that could not be evaluated because of the superficial nature of the biopsy. Therefore, obtaining a deep wedge or punch biopsy may facilitate a diagnosis in cases with a differential diagnosis of HLP and SCC.

Post-treatment FDG PET-CT in head and neck carcinoma: comparative analysis of 4 qualitative interpretative criteria in a large patient cohort

There is no consensus regarding optimal interpretative criteria (IC) for Fluorine-18 fluorodeoxyglucose (FDG) Positron Emission Tomography – Computed Tomography (PET-CT) response assessment following (chemo)radiotherapy (CRT) for head and neck squamous cell carcinoma (HNSCC). The aim was to compare accuracy of IC (NI-RADS, Porceddu, Hopkins, Deauville) for predicting loco-regional control and progression free survival (PFS). All patients with histologically confirmed HNSCC treated at a specialist cancer centre with curative-intent non-surgical treatment who underwent baseline and response assessment FDG PET-CT between August 2008 and May 2017 were included. Metabolic response was assessed using 4 different IC harmonised into 4-point scales (complete response, indeterminate, partial response, progressive disease). IC performance metrics (sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), accuracy) were compared. Kaplan-Meier and Cox proportional hazards regression analyses were performed for survival analysis. 562 patients were included (397 oropharynx, 53 hypopharynx, 48 larynx, 64 other/unknown primary). 420 patients (75%) received CRT and 142 (25%) had radiotherapy alone. Median follow-up was 26 months (range 3–148). 156 patients (28%) progressed during follow-up. All IC were accurate for prediction of primary tumour (mean NPV 85.0% (84.6–85.3), PPV 85.0% (82.5–92.3), accuracy 84.9% (84.2–86.0)) and nodal outcome (mean NPV 85.6% (84.1–86.6), PPV 94.7% (93.8–95.1), accuracy 86.8% (85.6–88.0)). Number of indeterminate scores for NI-RADS, Porceddu, Deauville and Hopkins were 91, 25, 20, 13 and 55, 70, 18 and 3 for primary tumour and nodes respectively. PPV was significantly reduced for indeterminate uptake across all IC (mean PPV primary tumour 36%, nodes 48%). Survival analyses showed significant differences in PFS between response categories classified by each of the four IC (p <0.001). All four IC have similar diagnostic performance characteristics although Porceddu and Deauville scores offered the best trade off of minimising indeterminate outcomes whilst maintaining a high NPV.

Analysis of the Prevalence of Microsatellite Instability in Prostate Cancer and Response to Immune Checkpoint Blockade

The anti-programmed cell death protein 1 (PD-1) antibody pembrolizumab is approved by the US Food and Drug Administration for the treatment of microsatellite instability-high (MSI-H) or mismatch repair-deficient (dMMR) solid tumors, but the prevalence of MSI-H/dMMR prostate cancer and the clinical utility of immune checkpoint blockade in this disease subset are unknown. To define the prevalence of MSI-H/dMMR prostate cancer and the clinical benefit of anti-PD-1/programmed cell death 1 ligand 1 (PD-L1) therapy in this molecularly defined population. In this case series, 1551 tumors from 1346 patients with prostate cancer undergoing treatment at Memorial Sloan Kettering Cancer Center were prospectively analyzed using a targeted sequencing assay from January 1, 2015, through January 31, 2018. Patients had a diagnosis of prostate cancer and consented to tumor molecular profiling when a tumor biopsy was planned or archival tissue was available. For each patient, clinical outcomes were reported, with follow-up until May 31, 2018. Tumor mutation burden and MSIsensor score, a quantitative measure of MSI, were calculated. Mutational signature analysis and immunohistochemistry for MMR protein expression were performed in select cases. Among the 1033 patients who had adequate tumor quality for MSIsensor analysis (mean [SD] age, 65.6 [9.3] years), 32 (3.1%) had MSI-H/dMMR prostate cancer. Twenty-three of 1033 patients (2.2%) had tumors with high MSIsensor scores, and an additional 9 had indeterminate scores with evidence of dMMR. Seven of the 32 MSI-H/dMMR patients (21.9%) had a pathogenic germline mutation in a Lynch syndrome-associated gene. Six patients had more than 1 tumor analyzed, 2 of whom displayed an acquired MSI-H phenotype later in their disease course. Eleven patients with MSI-H/dMMR castration-resistant prostate cancer received anti-PD-1/PD-L1 therapy. Six of these (54.5%) had a greater than 50% decline in prostate-specific antigen levels, 4 of whom had radiographic responses. As of May 2018, 5 of the 6 responders (5 of 11 total [45.5%]) were still on therapy for as long as 89 weeks. The MSI-H/dMMR molecular phenotype is uncommon yet therapeutically meaningful in prostate cancer and can be somatically acquired during disease evolution. Given the potential for durable responses to anti-PD-1/PD-L1 therapy, these findings support the use of prospective tumor sequencing to screen all patients with advanced prostate cancer for MSI-H/dMMR. Because not all patients with the MSI-H/dMMR phenotype respond, further studies should explore mechanisms of resistance.

Primary Mediastinal B-Cell Lymphoma: Evaluation of Clinicopathologic Diagnosis Compared to Gene Expression Based Diagnosis in a Clinical Trial with CD30+ B-Cell Lymphomas

Primary Mediastinal B-Cell Lymphoma: Evaluation of Clinicopathologic Diagnosis Compared to Gene Expression Based Diagnosis in a Clinical Trial with CD30+ B-Cell Lymphomas

Degree of Estimated Fibrosis in Asymptomatic Subjects With Non-Alcoholic Fatty Liver Disease Correlates With Higher Cardiovascular Risk

Introduction: Our aim is to assess the estimated 10-year atherosclerotic cardiovascular (ASCVD) risk scores in patients with NAFLD according to the degree of estimated fibrosis by Non-alcoholic fatty liver disease (NAFLD) fibrosis score (NFS). Methods: Cross-sectional observational study from a single center in Mexico conducted as a case control analysis in asymptomatic outpatients. NAFLD cases were defined by a positive ultrasound. Estimated 10-year ASCVD risk was calculated with the 2013 American College of Cardiology and the American Heart Association (2013 ACC/AHA) risk equation, Framingham risk score for coronary heart disease (FRS-CHD). High ASCVD risk was defined according to standardized cutoff points: for 2013 ACC/AHA (>= 7.5%) and Framingham (> =20%). NFS was stratified according to the following cut-off points into three groups with progressive degree of fibrosis (<-1.455: F0-F2, >=-1.455-≤ 0.675: indeterminate score, >0.675: F3-F4 fibrosis). Results: We included data from 141 patients with NAFLD by ultrasound and 354 healthy controls. 62% were males, BMI of 25.9 (SD ± 3.9) Kg/m2, 45 (SD ± 11.5) years old. We previously excluded patients with significant alcohol consumption (defined by >30 gr/day in men, >20 g/day in women). NAFLD vs. controls patients had higher mean cardiovascular risk assesed by FRS and 2013 ACC/AHA with 7.1 vs 4.1%(p=0.05) and 5.7 vs 4.4% (p=0.05), respectively, additionally a selected cutoff point for FRS (=>10%) showed a strong association with NAFLD [OR = 5.05 (95% CI 2.1 - 11.9, p < 0.01)]. Global 10-year ASCVD risk was in the case group: for ACC/AHA 5.8% (CI: 95% 4.6-6.9), FRS-CHD 7.2% (CI: 95% 6.1-8.2). Higher degree of fibrosis by NFS correlated with higher FRS risk with a median of 3.5 (RIQ 1.3-7.5), 3.9 (RIQ 2.0-5.7), 8.7 (RIQ 5.3-13.1), for NFS cut-off points F0-F2, indeterminate score, F3-F4 fibrosis, respectively (p < 0.01). High cardiovascular risk estimated for FRS was strongly associated with F3-F4 fibrosis [OR = 9.8 (95% CI 1.17 - 81, p=0.011)]. Total NFS and FRS scores showed correlation with a spearman's Rho of 0.49, (p < 0.001).Figure: Comparison between estimated 10-year risk by Framingham score and NAFLD fibrosis score in patients with ultrasonographic fatty liver disease (n=141).Conclusion: NAFLD patients have higher ASCVD risk than healthy subjects. Higher estimated fibrosis by NAFLD score correlated with higher 10-year ASCVD risk in asymptomatic patients with ultrasonographic fatty liver disease. Presence of higher estimated NFS in fatty liver disease should prompt cardiovascular risk assessment and intervention.

Discovery and validation of a colorectal cancer classifier in a new blood test with improved performance for high-risk subjects

BackgroundThe aim was to improve upon an existing blood-based colorectal cancer (CRC) test directed to high-risk symptomatic patients, by developing a new CRC classifier to be used with a new test embodiment. The new test uses a robust assay format—electrochemiluminescence immunoassays—to quantify protein concentrations. The aim was achieved by building and validating a CRC classifier using concentration measures from a large sample set representing a true intent-to-test (ITT) symptomatic population.Methods4435 patient samples were drawn from the Endoscopy II sample set. Samples were collected at seven hospitals across Denmark between 2010 and 2012 from subjects with symptoms of colorectal neoplasia. Colonoscopies revealed the presence or absence of CRC. 27 blood plasma proteins were selected as candidate biomarkers based on previous studies. Multiplexed electrochemiluminescence assays were used to measure the concentrations of these 27 proteins in all 4435 samples. 3066 patients were randomly assigned to the Discovery set, in which machine learning was used to build candidate classifiers. Some classifiers were refined by allowing up to a 25% indeterminate score range. The classifier with the best Discovery set performance was successfully validated in the separate Validation set, consisting of 1336 samples.ResultsThe final classifier was a logistic regression using ten predictors: eight proteins (A1AG, CEA, CO9, DPPIV, MIF, PKM2, SAA, TFRC), age, and gender. In validation, the indeterminate rate of the new panel was 23.2%, sensitivity/specificity was 0.80/0.83, PPV was 36.5%, and NPV was 97.1%.ConclusionsThe validated classifier serves as the basis of a new blood-based CRC test for symptomatic patients. The improved performance, resulting from robust concentration measures across a large sample set mirroring the ITT population, renders the new test the best available for this population. Results from a test using this classifier can help assess symptomatic patients’ CRC risk, increase their colonoscopy compliance, and manage next steps in their care.

A Gene Expression Panel is Accurate for Diagnosis and Monitoring Treatment of Eosinophilic Esophagitis in Adults.

Objective:Eosinophilic esophagitis (EoE) can be difficult to diagnose. We aimed to evaluate whether a gene expression score could differentiate adult EoE cases from non-EoE controls and to determine whether scores normalized after treatment for EoE.Methods:We analyzed prospectively collected esophageal biopsies from EoE patients (diagnosed as per consensus guidelines and after a proton pump inhibitor trial) and non-EoE controls. Gene expression for a previously constructed 94 gene panel was quantified for a single RNA-later preserved biopsy. For diagnosis, a summary expression score and the area under the receiver operating characteristic curve (AUC) were calculated. For treatment response (defined as <15 eosinophils per high-power field), pretreatment and posttreatment EoE samples were compared.Results:For 91 EoE cases and 174 controls, gene scores for EoE cases were lower than non-EoE controls (mean 198 vs. 420; P<0.001), with an AUC of 0.927. A score ≤263 yielded a positive predictive value=91% a score ≥349 yielded a negative predictive value=90% only 12% of subjects had an indeterminate score (264–348) by this classification scheme. For the 89 EoE cases with paired pretreatment and posttreatment samples, overall gene scores improved after treatment from 199 to 343 (P<0.001). This normalization was seen only in cases with histological response (202 vs. 425; P<0.001); scores were unchanged in non-responders (189 vs. 226; P=0.25).Conclusions:A gene expression score has high diagnostic utility for distinguishing EoE patients from non-EoE controls in adults and can be used in clinical algorithms. Because it is highly responsive to treatment, the test could be used to monitor disease status.

Understanding Indeterminate Music through Performance: Cage's Solo for Piano

AbstractThis article demonstrates how performance may further understanding of – and offer new perspectives on – indeterminate music, and in particular the ways in which performers realize the indeterminate aspects of the scores. Cage's Solo for Piano (1957–8), one of the most celebrated indeterminate scores, is used as the model for such an approach. The close involvement that performers have with the score and the music over what is often a prolonged period of time leads to a particular kind of understanding, different from that of non-performers, which, when articulated, can offer valuable insights. After a brief outline of the score, the article begins by discussing the performances of other pianists, notably David Tudor. It then examines in detail the author's own approach to making a realization, discussing the implications of such an approach from both practical and aesthetic perspectives.