Discordant Subgroups Research Articles

Combining the GP's assessment and the PHQ-9 questionnaire leads to more reliable and clinically relevant diagnoses in primary care.

Screening questionnaires are not sufficient to improve diagnostic quality of depression in primary care. The additional consideration of the general practitioner's (GP's) assessment could improve the accuracy of depression diagnosis. The aim of this study was to examine whether the GP rating supports a reliable depression diagnosis indicated by the PHQ-9 over a period of three months. We performed a secondary data analysis from a previous study. PHQ-9 scores of primary care patients were collected at the time of recruitment (t1) and during a follow-up 3 months later (t2). At t1 GPs independently made a subjective assessment whether they considered the patient depressive (yes/no). Two corresponding groups with concordant and discordant PHQ-9 and GP ratings at t1 were defined. Reliability of the PHQ-9 results at t1 and t2 was assessed within these groups and within the entire sample by Cohen's Kappa, Pearson's correlation coefficient and Bland-Altman plots. 364 consecutive patients from 12 practices in the region of Upper Bavaria/Germany participated in this longitudinal study. 279 patients (76.6%) sent back the questionnaire at t2. Concordance of GP rating and PHQ-9 at t1 led to higher replicability of PHQ-9 results between t1 and t2. The reliability of PHQ-9 was higher in the concordant subgroup (κ = 0.507) compared to the discordant subgroup (κ = 0.211) (p = 0.064). The Bland-Altman Plot showed that the deviation of PHQ-9 scores at t1 and t2 decreased by about 15% in the concordant subgroup. Pearson's correlation coefficient between PHQ-9 scores at t1 and t2 increased significantly if the GP rating was concordant with the PHQ-9 at t1 (r = 0.671) compared to the discordant subgroup (r = 0.462) (p = 0.044). The combination of PHQ-9 and GP rating might improve diagnostic decision making regarding depression in general practices. PHQ-9 positive results might be more reliable and accurate, when a concordant GP rating is considered.

Concordance of the treatment patterns for major depressive disorders between the Canadian Network for Mood and Anxiety Treatments (CANMAT) algorithm and real-world practice in China.

Background: Antidepressant (AD) algorithm is an important tool to support treatment decision-making and improve management of major depressive disorder (MDD). However, little is known about its concordance with real-world practice. This study aimed to assess the concordance between the longitudinal treatment patterns and AD algorithm recommended by a clinical practice guideline in China. Methods: Data were obtained from the electronic medical records of Shanghai Mental Health Center (SMHC), one of the largest mental health institutions in China. We examined the concordance between clinical practice and the Canadian Network for Mood and Anxiety Treatments (CANMAT) algorithm among a cohort composed of 19,955 MDD patients. The longitudinal characteristics of treatment regimen and duration were described to identify the specific inconsistencies. Demographics and health utilizations of the algorithm-concordant and -discordant subgroups with optimized treatment were measured separately. Results: The overall proportion of algorithm-concordant treatment significantly increased from 84.45% to 86.03% during the year of 2015–2017. Among the patients who received recommended first-line drugs with subsequent optimized treatment (n = 2977), the concordance proportion was 27.24%. Mirtazapine and trazodone were the most used drugs for adjunctive strategy. Inadequate or extended duration before optimized treatment are common inconsistency. The median length of follow-up for algorithm-concordant (n = 811) and algorithm-discordant patients (n = 2166) were 153 days (Q1-Q3 = 79–328) and 368 days (Q1-Q3 = 181–577) respectively, and the average number of clinical visits per person-year was 13.07 and 13.08 respectively. Conclusion: Gap existed between clinical practice and AD algorithm. Improved access to evidence-based treatment is required, especially for optimized strategies during outpatient follow-up.

Comparison of CT volumetry versus nuclear renography for predicting remaining kidney function after uninephrectomy in living kidney donors

Computed tomography (CT) and nuclear renography are used to determine kidney procurement in living kidney donors (LKDs). The present study investigated which modality better predicts kidney function after donation. This study included 835 LKDs and they were divided into two subgroups based on whether the left–right dominance of kidney volume was concordant with kidney function (concordant group) or not (discordant group). The predictive value for post-donation kidney function between the two imaging modalities was compared at 1 month, 6 months, and > 1 year in total cohort, concordant, and discordant groups. Split kidney function (SKF) measured by both modalities showed significant correlation with each other at baseline. SKFs of remaining kidney measured using both modalities before donation showed significant correlation with eGFR (estimated glomerular filtration rate) after donation in the total cohort group and two subgroups, respectively. CT volumetry was superior to nuclear renography for predicting post-donation kidney function in the total cohort group and both subgroups. In the discordant subgroup, a higher tendency of kidney function recovery was observed when kidney procurement was determined based on CT volumetry. In conclusion, CT volumetry is preferred when determining procurement strategy especially when discordance is found between the two imaging modalities.

T2/FLAIR Abnormity Could be the Sign of Glioblastoma Dissemination.

PurposeNewly emerged or constantly enlarged contrast-enhancing (CE) lesions were the necessary signs for the diagnosis of glioblastoma (GBM) progression. This study aimed to investigate whether the T2-weighted-Fluid-Attenuated Inversion Recovery (T2/FLAIR) abnormal transformation could predict and assess progression for GBMs, especially for tumor dissemination.MethodsA consecutive cohort of 246 GBM patients with regular follow-up and sufficient radiological data was included in this study. The series of T2/FLAIR and T1CE images were retrospectively reviewed. The patients were separated into T2/FLAIR and T1CE discordant and accordant subgroups based on the initial progression images.ResultsA total of 170 qualified patients were finally analyzed. The incidence of discordant T2/FLAIR and T1CE images was 25.9% (44/170). The median time-span of T2/FLAIR indicated tumor progression was 119.5 days (ranging from 57 days-unreached) prior to T1CE. Nearly half of patients (20/44, 45.5%) in the discordant subgroup suffered from tumor dissemination, substantially higher than accordant patients (23/126, 20.6%, p < 0.001). The median time to progression (TTP), post-progression survival (PPS), and overall survival (OS) were not statistically different (all p > 0.05) between discordant and accordant patients.ConclusionsT2/FLAIR abnormity could be the sign of GBM progression, especially for newly emerged lesions disseminating from the primary cavity. Physicians should cast more attention on the dynamic change of T2/FLAIR images, which might be of great significance for progression assessment and subsequent clinical decision-making.

Discordance Between Histopathologic Grading and Dual-Tracer PET/CT Findings in Metastatic NETs and Outcome of 177Lu-DOTATATE PRRT: Does InVivo Molecular PET Perform Better from the Viewpoint of Prediction of Tumor Biology?

Discordance between histopathologic grading and dual-tracer PET/CT (68Ga-DOTATATE and 18F-FDG) findings in neuroendocrine tumors (NETs), though not typical, can be encountered in real-world scenarios. The aim of this study was to assess patients with discordance between World Health Organization (WHO) 2017 grade-predicted molecular PET/CT imaging and the actual dual-tracer PET/CT findings (by exploring their histopathologic, immunohistochemical, and molecular imaging characteristics), with a view toward identifying the prognostic determinants affecting outcome in a peptide receptor radionuclide therapy setup. Methods: Thirty-six patients with histopathologically proven inoperable, locally advanced or metastatic NETs, referred for peptide receptor radionuclide therapy, were included in this study. The cohort was divided into 2 broad population groups: those with discordance (between WHO 2017 grade-predicted molecular imaging and the dual-tracer PET/CT findings) and control (showing both 18F-FDG and 68Ga-DOTATATE uptake). The cohort was divided on the basis of dual-tracer PET/CT into 3 groups: metabolically inactive (non-18F-FDG-avid) and somatostatin receptor (SSTR)-expressing tumors, metabolically active (18F-FDG-avid) and non-68Ga-DOTATATE-concentrating (non-SSTR-expressing) tumors, and matched imaging characteristics with the WHO 2017 grading system (showing both 18F-FDG- and 68Ga-DOTATATE-concentrating disease) for statistical analysis. Descriptive statistics were used to analyze categoric data; multivariate analysis was used to assess the correlation between different variables with progression-free survival (PFS) and overall survival (OS). Kaplan-Meier curves were used for survival analysis to calculate median survival and to analyze survival on the basis of WHO 2017 grading and dual-tracer PET. Cox proportional hazards regression analysis was used to determine predictors of survival (OS and PFS). Results: Of the 36-patient cohort, 24 (66.7%) showed discordance and 12 (33.3%) were in the control group. Among those showing discordance: 14 (38.9%) had metabolically inactive and SSTR-expressing disease and the remaining 10 (27.8%) had 18F-FDG-concentrating and non-SSTR-expressing disease. Among those in the control group, 12 (33.3%) had intermediate-grade NETs and showed matched (68Ga-DOTATATE- and 18F-FDG-concentrating lesions) disease. Multivariate analysis in patients with discordant findings showed a significant correlation of dual-tracer PET with OS, whereas no significant correlation could be established between WHO grade and OS in the discordant subgroups. No significant correlation could be appreciated between PFS and either dual-tracer PET or WHO grading. The Kaplan-Meier analysis and Cox analysis showed dual-tracer PET/CT imaging to be a significant prognostic determinant and predictor of outcome, respectively. Conclusion: In NET patients with discordance between the 2 parameters, dual-tracer PET/CT with 18F-FDG and 68Ga-DOTATATE performed better than WHO grading, differentiation status, and immunohistochemistry in prognosticating and predicting outcome.

PSMA PET Validates Higher Rates of Metastatic Disease for European Association of Urology Biochemical Recurrence Risk Groups: An International Multicenter Study.

The European Association of Urology (EAU) prostate cancer guidelines panel recommends risk groups for biochemical recurrence (BCR) of prostate cancer to identify men at high risk of progression or metastatic disease. The rapidly growing availability of PSMA-directed PET imaging will impact prostate cancer staging. We determined the rates of local and metastatic disease in BCR and biochemical persistence (BCP) of prostate cancer stratified by EAU BCR risk groups and BCP. Methods: Patients with BCR or BCP were enrolled under the same prospective clinical trial protocol conducted at 3 sites (n = 1,777 [91%]: UCLA, n = 662 [NCT02940262]; University of California San Francisco, n = 508 [NCT03353740]; University of Michigan, n = 607 [NCT03396874]); 183 patients with BCP from the Universities of Essen, Bologna, and Munich were included retrospectively. Patients with BCR had to have sufficient data to determine the EAU risk score. Multivariate, binomial logistic regression models were applied to assess independent predictors of M1 disease. Results: In total, 1,960 patients were included. Post-radical prostatectomy EAU BCR low-risk, EAU BCR high-risk, and BCP groups yielded distant metastatic (M1) detection in 43 of 176 (24%), 342 of 931 (37%), and 154 of 386 (40%) patients. For postradiotherapy EAU BCR low-risk and EAU BCR high-risk groups, the M1 detection rate was 113 of 309 (37%) and 110 of 158 (70%), respectively. BCP, high-risk BCR, and higher levels of serum prostate-specific antigen were significantly associated with PSMA PET M1 disease in multivariate regression analysis. PSMA PET revealed no disease in 25% and locoregional-only disease in 33% of patients with post-radical prostatectomy or postradiotherapy EAU BCR high risk. Conclusion: Our findings support the new EAU classification; EAU BCR high-risk groups have higher rates of metastatic disease on PSMA PET than do the low-risk groups. Discordant subgroups, including metastatic disease in low-risk patients and no disease in high-risk patients, warrant inclusion of PSMA PET stage to refine risk assessment.

Multimorbidity and achievement of treatment goals among patients with type 2 diabetes: a primary care, real-world study

BackgroundType 2 diabetes (T2D), with its prevalence and disability-causing nature, is a challenge for primary health care. Most patients with T2D are multimorbid, i.e. have one or more long-term diseases in addition to T2D. Multimorbidity may play a role in the achievement of T2D treatment targets, but is still not fully understood. The aims of the present cross-sectional, register-based study were to evaluate the prevalence and the most common patterns of multimorbidity among patients with T2D; and to study the potential associations between multimorbidity and treatment goal achievement, including measurements of glycosylated haemoglobin A1c (HbA1c), low-density lipoprotein (LDL) and systolic blood pressure (sBP).MethodsThe study population consisted of 4545 primary care patients who received a T2D diagnosis between January 2011 and July 2019 in Rovaniemi Health Centre, Finland. Data on seven long-term concordant (T2D-related) diseases, eight long-term discordant (non-T2D-related) diseases, potential confounders (age, sex, body mass index, prescribed medication), and the outcomes studied were collected from patients’ records. Logistic regression models with odds ratios (ORs) and 95 % confidence intervals (CIs) were assessed to determine the associations between multimorbidity and the achievement of treatment targets.ResultsAltogether, 93 % of the patients had one or more diseases in addition to T2D, i.e. were considered multimorbid. Furthermore, 21 % had only concordant disease(s) (Concordant subgroup), 8 % had only discordant disease(s) (Discordant subgroup) and 64 % had both (Concordant and discordant subgroup). As either single diseases or in combination with others, hypertension, musculoskeletal (MS) disease and hyperlipidaemia were the most prevalent multimorbidity patterns. Being multimorbid in general (OR 1.32, CI 1.01–1.70) and belonging to the Concordant (OR 1.45, CI 1.08–1.95) and Concordant and discordant (OR 1.31, CI 1.00–1.72) subgroups was associated with achievement of the HbA1c treatment target. Belonging to the Concordant and discordant subgroup was related to meeting the LDL treatment target (OR 1.31, CI 1.00–1.72).ConclusionsMultimorbidity, including cardiovascular risk and the musculoskeletal disease burden, was extremely prevalent among the T2D patients who consulted primary health care. Primary care clinicians should survey the possible co-existence of long-term diseases among T2D patients to help maintain adequate treatment of T2D.

A latent class analysis of parent-child discrepancies in reports of peer victimization: Associations to child sexual abuse status and psychological adjustment.

Researchers face an important challenge when assessing peer victimization in children, since self-reports are often discrepant with parent-reports. A latent class analysis identified patterns of response to items assessing peer victimization, which were either divergent or convergent between the parent and the child. Classes were then compared on the child sexual abuse status and on various behavioral and social outcomes. Participants were 720 school-aged child victims of sexual abuse and a comparison group of 173 nonvictims and their caregivers. We identified two discordant subgroups (self-identified and parent-identified) and two concordant groups (nonvictims and concordant victims of peer victimization). Compared to children of the comparison group, sexually abused children were five times more likely to be identified as targets of peer victimization solely by their parent than the contrary. Sexually abused children with concordant reports of peer victimization showed the poorest adjustment on all studied outcomes assessed 6 months later. Children who discounted experiencing peer victimization while their parent reported it were also at risk of maladjustment. Results underscore the importance of supplementing self-reports with other available sources of information, especially in young and vulnerable populations who may be inclined to discount their victimization experiences.

Aortic valve area using computed tomography-derived correction factor to improve the validity of left ventricular outflow tract measurements.

Given the inherent inaccuracies stemming from the assumption that the left ventricular outflow tract (LVOT) is circular, this study aimed to improve the accuracy of transthoracic echocardiography (TTE)-based aortic valve area (AVA) calculation using continuity equation (CE) by introducing a correction factor (CF) derived from multidetector computed tomography angiography (MDCTA) images and validate it in aortic stenosis (AS) patients. This retrospective study used MDCTA images of 400 patients for modeling and 403 TTE dataset for validation. Echocardiographic parasternal long-axis view was modeled using MDCTA, and LVOT diameter (D1) was measured. Direct planimetry of LVOT area was performed and subsequently converted into a theoretical circle. The assumed circle (D2) diameter was derived, and D2/D1 was calculated and termed as the CF. The CF was 1.13, and it improved the agreement between MDCTA- and TTE-derived LVOT areas and correlation between AVA and peak velocity, mean pressure gradient, and velocity ratio. In discordant subgroups of severe AS, the CF reclassified patients to moderate AS in 40% in the low flow (LF), low gradient (LG), and low ejection fraction (EF) group; 53% in the LF, LG, and normal EF group; and 68% in the LF, high gradient, and normal EF group. CF of 1.13 derived from MDCTA improved the accuracy of TTE-derived LVOT area and AVA and improved correlation with hemodynamic variables in AS patients. Reclassification of AS patients using CF may have clinical applicability for patient selection for early intervention.

A higher glycemic response to oral glucose is associated with higher plasma apolipoprotein C3 independently of BMI in healthy twins

Background and aimsPlasma apolipoprotein C3 (ApoC3) is associated with higher plasma triglyceride and type 2 diabetes incidence. We evaluated whether body mass index (BMI) or glucose metabolism were associated with ApoC3 in healthy monozygotic (MZ) twins. Methods and ResultsForty-seven MZ twin-pairs (20 man, 27 women), aged 23–42 years, were divided in subgroups according to discordance or concordance for (a) BMI (within-pair difference (Δ) in BMI≥3.0 or<3.0 kg/m2), or (b) 2-h glucose iAUC, during oral glucose tolerance test (ΔGlucose iAUC ≥97.5 or<97.5 mmol × 120 minutes). Within these discordant or concordant subgroups, we tested (Wilcoxon signed-rank test) co-twin differences in ApoC3, adiposity measures, insulin-resistance and beta-cell function indices, and plasma and lipoprotein lipids.In BMI-Discordant (p = 0.92) or BMI-Concordant (p = 0.99) subgroups, ApoC3 did not differ between leaner and heavier co-twins. In the Glucose–Discordant subgroup, ApoC3 was significantly higher in twins with higher Glucose iAUC than in their co-twins with the lower Glucose iAUC (10.03 ± 0.78 vs. 8.48 ± 0.52 mg/dl; M ± SE; p = 0.032). Co-twins with higher Glucose iAUC also had higher waist circumference, body fat percentage, liver fat content, worse insulin-sensitivity and beta-cell function and higher cholesterol and triglyceride in plasma VLDL, IDL, and LDL. In Glucose–Concordant twin-pairs, no significant differences were observed in the explored variables. In all twin-pairs, ΔApoC3 correlated with Δ in lipids and glucose metabolism variables, the closest relationship being between ΔApoC3 and ΔVLDL triglyceride (r = 0.74, p < 0.0001). ConclusionsWhile ApoC3 was not related to acquired differences in BMI, it associated with early dysregulation of glucose metabolism independently of obesity and genetic background.

"My Family Wants Something Different": Discordance in Perceived Personal and Family Treatment Preference and Its Association With Do-Not-Resuscitate Order Placement.

Patients make treatment decisions based not only on what they want, but what they think their families want. Discordance in such perceived preferences may therefore pose challenges for advance care planning. This study examines discordance in preference for life-extending care versus comfort-focused care and its association with do-not-resuscitate (DNR) order placement. One hundred eighty-nine patients with advanced cancers refractory to at least one chemotherapy regimen were enrolled in a multisite observational study. In structured interviews, patients reported their preference for treatment maximizing either life extension or comfort; patients also indicated their perception of their families' preference. DNR placement was reported by patients and verified using medical records. Approximately 23% of patients (n = 43) perceived discordance between their preference and their families' preference. Patients who perceived discordance were less likely to have completed a DNR compared with those who perceived concordance, even after controlling for relevant confounds (odds ratio = .35; P = .02). Subgroups of discordance and concordance showed varying DNR placement rates (χ2, 19.95; P < .001). DNR placement rate was lowest among discordant subgroups, where there was either a personal (26.7%; four of 15) or family preference for comfort care (28.6%; eight of 28), followed by patients who perceived concordance for wanting life-extending care (34.5%; 29 of 84) and by patients who perceived concordance in wanting comfort-focused care (66.1%; 41 of 62). Many patients may perceive discordance between personal and family treatment preferences, posing impediments to advance care planning. Such patients may benefit from additional decision support.

Abstract CT140: Circulating tumor cells as a tool to guide first line therapy in metastatic breast cancer: subgroup analyses of the STIC CTC Phase III utility trial

Abstract Background: Endocrine therapy (ET) is the preferred 1st line therapy in ER+ HER2- metastatic breast cancer (MBC) patients, but not all benefit from such strategy for which predictive biomarkers are lacking. Prior studies showed that circulating tumor cells (CTC) count is the strongest prognostic factor beyond PS in that population. The STIC CTC trial (NCT01710605) assessed whether CTC count could drive the choice between frontline ET or chemotherapy (CT, with or without ET maintenance). Methods: For this multicenter phase 3 non-inferiority trial, main inclusion criteria were: ER+ HER2- MBC with no prior therapy, PS≤2, no contra-indication to ET or CT, informed consent. Patients were randomized 1:1 between clinically-driven choice (single agent ET if clinicallow, CT if clinicalhigh, as decided by physician based on clinical factors, blinded to CTC results) or a CTC-driven choice [ET if CTClow (&amp;lt;5 CTCs/7.5mL), CT if CTChigh (≥5 CTCs/7.5mL)]. The primary objective was treatment efficacy ([PFS hazard ratio (HR)], non-inferiority being established if the upper bound of the PFS HR 2-sided 90%CI is &amp;lt;1.25; secondary objectives included subgroup analyses (CTC status, patient characteristics) and OS. Results: In this trial, 778 patients were randomized between both strategies. Of all patients, 71.0%, 26.6% and 2.4% were considered as endocrine-sensitive, with secondary or with primary endocrine resistance, respectively. In both arms (clinically- and CTC-driven), prognostic evaluation by physician/CTCs and allocated treatments were as follows: (i) clinicallow/CTClow 46.5% and 48.6% of patients, all treated with ET. (ii) clinicalhigh/CTChigh 14.0% and 13.0%, all treated with CT. (iii) clinicallow/CTChigh 26.1% and 24.2%, treated with ET or CT respectively. (iv) clinicalhigh/CTClow 13.4% and 14.0%, treated with CT or ET respectively. CTC-driven strategy met the primary endpoint, yielding a non-inferior PFS (median: 17 months; 95%CI [15.4-20.3] vs 18 months 95%CI[13.9-23.3]). In the 2 discordant subgroups, preplanned analyses showed the following results: in the clinicallow/CTChigh subgroup, patients treated with CT had a significantly longer PFS than those treated with ET (15.6 months, 95%CI [12.2-22.7] vs 10.5 months, 95%CI [7.3-15.4], log rank p=0.002). In the clinicalhigh/CTClow subgroup, patients treated with CT had a non-significant PFS advantage over patients treated with ET. Pooling these two subgroups of patients (N=292) with discordant treatment recommendations (depending on clinician or CTC count standpoint), an exploratory analysis showed that patients treated with CT frontline had significantly longer PFS (HR=0.66; 95%CI [0.51-0.85]) and OS (HR=0.65; 95%CI [0.43-0.98]); 2-year OS were 82.9% versus 74.7% in patients treated with CT (±maintenance ET) or ET, respectively. Conclusion: This trial demonstrates the utility of CTC count to select 1st line therapy in ER+ HER2- MBC patients, especially in those for whom single agent ET is the recommended therapy based on clinical factors. With this modern prognostic biomarker, the STIC CTC trial is the first one to identify potential ER+ HER2- MBC patients who might derive more benefit from frontline CT followed by maintenance ET than from frontline ET, challenging current standards. Funding: French Ministry of Health (PSTIC 2011); Menarini SB; Institut Curie. Citation Format: Francois-Clement Bidard, William Jacot, Sylvain Dureau, Etienne Brain, Thomas Bachelot, Hugues Bourgeois, Anthony Goncalves, Sylvain Ladoire, Herve Naman, Florence Dalenc, Joseph Gligorov, Marc Espie, Christelle Levy, Jean-Marc Ferrero, Delphine Loirat, Paul Cottu, Veronique Dieras, Marie-Emmanuelle Legrier, Frederique Berger, Catherine Alix-Panabieres, Jean-Yves Pierga. Circulating tumor cells as a tool to guide first line therapy in metastatic breast cancer: subgroup analyses of the STIC CTC Phase III utility trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT140.

Abstract GS3-07: Clinical utility of circulating tumor cell count as a tool to chose between first line hormone therapy and chemotherapy for ER+ HER2- metastatic breast cancer: Results of the phase III STIC CTC trial

Abstract Background: In ER+ HER2- metastatic breast cancer (MBC) patients, the clinical choice between 1st line hormone therapy (HT, the recommended option) or chemotherapy (CT) is based on the absence of “visceral crisis” or adverse prognostic factors, with no proven/objective criteria. In that context, STIC CTC (NCT01710605) was set up as a strategy trial to test whether circulating tumor cells (CTC) count could help customize the choice between 1st line HT or CT. Methods: For this multicenter phase 3 non-inferiority trial, the main inclusion criteria were: ER+ HER2- MBC with no prior therapy, PS≤2, no contra-indication to HT or CT and informed consent. The a priori treatment choice (HT or CT) and CTC count (CellSearch®) were obtained in all patients prior to randomization. Patients were randomized 1:1 between clinically-driven choice (CTC count not disclosed, HT or CT administered as decided a priori), or a CTC-driven choice (HT if &amp;lt;5 CTC/7.5ml, CT if ≥5 CTC/7.5ml). The primary objective was treatment efficacy (PFS hazard ratio), non-inferiority being established if the upper bound of the PFS HR 2-sided 90%CI is ≤1.25; secondary objectives included subgroup analyses (CTC status, patient characteristics) and OS. Results: 761 MBC patients were randomized between 02/2012 and 08/2016. Baseline characteristics: 7.8% of patients had a PS=2, 24.1% had a de novo metastatic disease; 63.3% received prior adjuvant HT and 49.9% prior adjuvant CT; 31.3% had ≥3 metastatic sites. A priori treatments (HT or CT) and CTC count (&amp;lt; or ≥5 CTC/7.5ml) were well balanced between the two arms. After randomization, in the clinically-driven arm, N=267 (72.4%) patients received HT and N=102 (27.6%) CT (as decided a priori). In the CTC-driven arm: (1) the a priori choice of HT was confirmed by a low CTC count in N=181 (67.5%) of patients, while N=87 (32.5%) were switched to CT due to a high CTC count; (2) the a priori choice of CT was confirmed by high CTC count in only N=48 (48%) patients, while N=52 (52%) were switched to HT. The primary endpoint was met, PFS being not inferior in the CTC-driven arm (HR=0.98, 90%CI=[0.84–1.13]). Analyses focusing on discordant subgroups showed that for patients with a priori choice of HT but with high CTC count (leading to a switch to CT in the CTC-arm), PFS was significantly longer in the CTC-driven arm than in the standard arm (HR=0.67, 95%CI=[0.49–0.92]; p=0.01), with a non-significant trend toward longer OS (HR=0.68, 95%CI=[0.44–1.07]; p=0.09). Inversely, for patients with a priori choice of CT but with low CTC count (i.e. de-escalation to HT in the CTC arm), PFS was not statistically different between the two arms. Conclusion: This trial demonstrates the clinical utility of CTC count as an objective decision tool when considering 1st line therapy in ER+ HER2- MBC. In most patients, CTC count did confirm the a priori clinical choice; however, trial results show that in discrepant cases, CTC count may be trusted for either escalating (i.e. considering CT in patients if high CTC count) or de-escalating (i.e. considering HT in patients if low CTC count) 1st line therapy. Funding: French National Cancer Institute; Menarini Silicon Biosystems. Citation Format: Bidard F-C, Jacot W, Dureau S, Brain E, Bachelot T, Bourgeois H, Goncalves A, Ladoire S, Naman H, Dalenc F, Gligorov J, Espie M, Levy C, Ferrero J-M, Loirat D, Cottu P, Dieras V, Simondi C, Berger F, Alix-Panabieres C, Pierga J-Y. Clinical utility of circulating tumor cell count as a tool to chose between first line hormone therapy and chemotherapy for ER+ HER2- metastatic breast cancer: Results of the phase III STIC CTC trial [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr GS3-07.

P16 and HPV-DNA Tests Discordance in Human Papilloma Virus (HPV)-Associated Oropharyngeal Cancer: Results From a Case-matched Study

HPV-associated oropharyngeal cancer (OPC) has been associated with improved prognosis compared to HPV-negative OPC. Concomitant HPV DNA and p16 testing has been shown to improve sensitivity and specificity; however, the prognostic significance of discordant testing (i.e., p16+/HPV DNA or p16-/HPV DNA+) in OPC patients has not been quantitatively studied due to inadequate sample sizes. We aim to determine whether there is a prognostic significance for discordant p16/HPV-DNA test results for OPC patients receiving curative intent radiation treatment. A case-control study design was used to retrospectively analyze 136 patients with pathologically proven oropharyngeal cancer (OPC) treated with curative intent radiation therapy at our institution between the years 2005 and 2012. HPV DNA status was evaluated using in-situ hybridization (ISH) methods, and p16 status was identified via immunohistochemistry (IHC). Two subgroups were identified: concordant (p16+/HPV DNA+) and discordant (p16+/HPV DNA- or p16-/HPV DNA+) subgroups, with the former serving as control. Characteristics including sex, age at diagnosis, ethnicity, smoking status, cancer stage, and treatment modality were identified. Kaplan-Meier survival analysis and univariate Cox proportional hazard analysis were performed. Patient characteristics, including age, sex, smoking status, stage, pathological grade, tumor subsite within oropharynx, treatment modality, and follow-up duration were well-matched between the concordant and discordant subgroups. Survival analysis failed to show any statistically significant difference between the concordant and discordant subgroups in terms of overall survival, local, locoregional, or distant control. The discordant subgroup was comprised entirely of p16+/HPV DNA- patients; no patients in the discordant subgroup were found to be p16-/HPV DNA+. Univariate analysis demonstrated statistically significant correlation between overall survival and N-category in the discordant group (P = .024 by Effect Wald Test), in contrast to the concordant group (P = .18). This study suggests that HPV test discordance is not correlated with differential treatment outcomes as compared to HPV test concordance. p16 testing by IHC has been previously shown to be more sensitive and specific than HPV DNA testing by ISH. This study further validates this observation and suggests that p16 may be used as a standalone test in the diagnosis of HPV in HNC patients.

First imaging results of an intraindividual comparison of 11C-acetate and 18F-fluorocholine PET/CT in patients with prostate cancer at early biochemical first or second relapse after prostatectomy or radiotherapy

(18)F-Fluorocholine (FCH) and (11)C-acetate (ACE) PET are widely used for detection of recurrent prostate cancer (PC). We present the first results of a comparative, prospective PET/CT study of both tracers evaluated in the same patients presenting with recurrence and low PSA to compare the diagnostic information provided by the two tracers. The study group comprised 23 patients studied for a rising PSA level after radical prostatectomy (RP, 7 patients, PSA ≤ 3 ng/ml), curative radiotherapy (RT, 7 patients, PSA ≤ 5 ng/ml) or RP and salvage RT (9 patients, PSA ≤ 5 ng/ml). Both FCH and ACE PET/CT scans were performed in a random sequence a median of 4 days (range 0 to 11 days) apart. FCH PET/CT was started at injection (307 ± 16 MBq) with a 10-min dynamic acquisition of the prostate bed, followed by a whole-body PET scan and late (45 min) imaging of the pelvis. ACE PET/CT was performed as a double whole-body PET scan starting 5 and 22 min after injection (994 ± 72 MBq), and a late view (45 min) of the prostate bed. PET/CT scans were blindly reviewed by two independent pairs of two experienced nuclear medicine physicians, discordant subgroup results being discussed to reach a consensus for positive, negative end equivocal results. PET results were concordant in 88 out of 92 local, regional and distant findings (Cohen's kappa 0.929). In particular, results were concordant in all patients concerning local status, bone metastases and distant findings. Lymph-node results were concordant in 19 patients and different in 4 patients. On a per-patient basis results were concordant in 22 of 23 patients (14 positive, 5 negative and 3 equivocal). In only one patient was ACE PET/CT positive for nodal metastases while FCH PET/CT was overall negative; interestingly, the ACE-positive and FCH-negative lymph nodes became positive in a second FCH PET/CT scan performed a few months later. Overall, ACE and FCH PET/CT showed excellent concordance, on both a per-lesion and a per-patient basis, suggesting that both tracers perform equally for recurrent prostate cancer staging.

Do robotic prostatectomy positive surgical margins occur in the same location as extraprostatic extension?

Positive surgical margins (PSMs) may reflect incomplete surgical resection, while extraprostatic extension (EPE) could suggest that complete tumor resection is more difficult. This study evaluated cases with both EPE and PSMs in robotic-assisted radical prostatectomy (RARP) specimens to determine the respective locations of each. A single institutional retrospective review of RARP performed between 2007 and 2009 was conducted to identify cases with both EPE and PSM. Prostates were entirely submitted and processed in whole mount format. All locations of EPE and PSM were recorded as was the size of the largest focus of EPE and PSM. About 8.5 % (112/1,315) of RARP had both EPE and PSM. Analysis of cases with concurrent EPE and PSM revealed that EPE occurred most commonly in the mid-gland, particularly in the posterolateral mid-prostate. In contrast, PSM was most frequent at the base (bladder neck), specifically the anterior base. 51.8 % of the cases had EPE and PSM in discordant locations, 19.6 % had EPE and PSM in the same location, and 28.6 % had areas of EPE and PSM both in the same location as well as in different locations. Cases with both concordant and discordant locations of EPE and PSM had significantly more high-risk features including higher tumor volume, more frequent positive nodes, and more frequent Gleason score ≥ 8 compared to concordant or discordant subgroups. PSMs frequently did not occur in the same location as EPE. A better understanding of where EPE and PSMs occur may help guide surgical technique to decrease residual tumor.

Biomarker-Based Ovarian Carcinoma Typing: A Histologic Investigation in the Ovarian Tumor Tissue Analysis Consortium

Ovarian carcinoma is composed of five major histologic types, which associate with outcome and predict therapeutic response. Our aim was to evaluate histologic type assessments across the centers participating in the Ovarian Tumor Tissue Analysis (OTTA) consortium using an immunohistochemical (IHC) prediction model. Tissue microarrays (TMA) and clinical data were available for 524 pathologically confirmed ovarian carcinomas. Centralized IHC was conducted for ARID1A, CDKN2A, DKK1, HNF1B, MDM2, PGR, TP53, TFF3, VIM, and WT1, and three histologic type assessments were compared: the original pathologic type, an IHC-based calculated type (termed TB_COSPv2), and a WT1-assisted TMA core review. The concordance between TB_COSPv2 type and original type was 73%. Applying WT1-assisted core review, the remaining 27% discordant cases subdivided into unclassifiable (6%), TB_COSPv2 error (6%), and original type error (15%). The largest discordant subgroup was classified as endometrioid carcinoma by original type and as high-grade serous carcinoma (HGSC) by TB_COSPv2. When TB_COSPv2 classification was used, the difference in overall survival of endometrioid carcinoma compared with HGSC became significant [RR 0.60; 95% confidence interval (CI), 0.37-0.93; P = 0.021], consistent with previous reports. In addition, 71 cases with unclear original type could be histologically classified by TB_COSPv2. Research cohorts, particularly those across different centers within consortia, show significant variability in original histologic type diagnosis. Our IHC-based reclassification produced more homogeneous types with respect to outcome than original type. Biomarker-based classification of ovarian carcinomas is feasible, improves comparability of results across research studies, and can reclassify cases which lack reliable original pathology.

Clinical implications of discordance between low-density lipoprotein cholesterol and particle number

The amount of cholesterol per low-density lipoprotein (LDL) particle is variable and related in part to particle size, with smaller particles carrying less cholesterol. This variability causes concentrations of LDL cholesterol (LDL-C) and LDL particles (LDL-P) to be discordant in many individuals. LDL-P measured by nuclear magnetic resonance spectroscopy, calculated LDL-C, and carotid intima-media thickness (IMT) were assessed at baseline in the Multi-Ethnic Study of Atherosclerosis, a community-based cohort of 6814 persons free of clinical cardiovascular disease (CVD) at entry and followed for CVD events (n = 319 during 5.5-year follow-up). Discordance, defined as values of LDL-P and LDL-C differing by ≥ 12 percentile units to give equal-sized concordant and discordant subgroups, was related to CVD events and to carotid IMT in models predicting outcomes for a 1 SD difference in LDL-C or LDL-P, adjusted for age, gender, and race. LDL-C and LDL-P were associated with incident CVD overall: hazard ratios (HR 1.20, 95% CI [CI] 1.08-1.34; and 1.32, 95% CI 1.19-1.47, respectively, but for those with discordant levels, only LDL-P was associated with incident CVD (HR 1.45, 95% CI 1.19-1.78; LDL-C HR 1.07, 95% CI 0.88-1.30). IMT also tracked with LDL-P rather than LDL-C, ie, adjusted mean IMT of 958, 932, and 917 microm in the LDL-P > LDL-C discordant, concordant, and LDL-P < LDL-C discordant subgroups, respectively, with the difference persisting after adjustment for LDL-C (P = .002) but not LDL-P (P = .60). For individuals with discordant LDL-C and LDL-P levels, the LDL-attributable atherosclerotic risk is better indicated by LDL-P.

Clinician-rated functioning and patient-rated quality of life in schizophrenia: Implications of their correspondence for psychopathology and side effects

Past studies have found inconsistent associations between subjective and objective measures of quality of life (QOL) in schizophrenia. We hypothesized that this may be due to heterogeneity in the demographic and/or clinical variables inherent in the samples and we investigated this possibility. We stratified the patients according to a descriptive measure of correspondence between self-reported QOL and clinician-rated functioning. We then examined whether heterogeneous patterns existed among the subgroups in terms of demographic variables, symptom severity, associations between self-reported and clinician-rated psychopathology and associations between side effects, QOL and functioning. The subgroups significantly differed with respect to clinician-rated positive symptoms (F=3.075, p<.05), subjective symptoms (somatization, F=5.768, p<.01; obsessive-compulsive, F=3.885, p<.05; interpersonal sensitivity, F=8.278, p<.001; depression, F=9.368, p<.001; anxiety, F=6.909, p<.01; hostility, F=7.787, p<.01; phobic anxiety, F=9.551, p<.001; paranoia, F=5.304, p<.01; psychoticism, F=5.071, p<.01) and in- and outpatient ratio (Chi(2)=11.58, p<.01). Only the subgroup with relatively good correspondence between clinician-rated functioning and self-reported QOL showed significant low to moderate associations between the aforementioned measures and side effects. In addition, they showed similar levels of significant associations between the positive and subjective symptoms. In contrast, other discordant subgroups lacked overall associations between side effects, functioning and QOL as well as between subjective and objective measures of psychopathology. Low to moderate levels of correspondence between subjective QOL and objective functioning were partly supportive of the independence of the constructs. Insight is likely to be a mediating variable of the correspondence between self-report and clinician-rated measures and should be considered in studies using self-report measures.

Cluster Analysis and Clinical Asthma Phenotypes

Heterogeneity in asthma expression is multidimensional, including variability in clinical, physiologic, and pathologic parameters. Classification requires consideration of these disparate domains in a unified model. To explore the application of a multivariate mathematical technique, k-means cluster analysis, for identifying distinct phenotypic groups. We performed k-means cluster analysis in three independent asthma populations. Clusters of a population managed in primary care (n = 184) with predominantly mild to moderate disease, were compared with a refractory asthma population managed in secondary care (n = 187). We then compared differences in asthma outcomes (exacerbation frequency and change in corticosteroid dose at 12 mo) between clusters in a third population of 68 subjects with predominantly refractory asthma, clustered at entry into a randomized trial comparing a strategy of minimizing eosinophilic inflammation (inflammation-guided strategy) with standard care. Two clusters (early-onset atopic and obese, noneosinophilic) were common to both asthma populations. Two clusters characterized by marked discordance between symptom expression and eosinophilic airway inflammation (early-onset symptom predominant and late-onset inflammation predominant) were specific to refractory asthma. Inflammation-guided management was superior for both discordant subgroups leading to a reduction in exacerbation frequency in the inflammation-predominant cluster (3.53 [SD, 1.18] vs. 0.38 [SD, 0.13] exacerbation/patient/yr, P = 0.002) and a dose reduction of inhaled corticosteroid in the symptom-predominant cluster (mean difference, 1,829 mug beclomethasone equivalent/d [95% confidence interval, 307-3,349 mug]; P = 0.02). Cluster analysis offers a novel multidimensional approach for identifying asthma phenotypes that exhibit differences in clinical response to treatment algorithms.