Pathologic complete response of ductal carcinoma in situ to neoadjuvant systemic therapy in HER2-positive invasive breast cancer patients: a nationwide analysis.

PURPOSE: Ductal carcinoma in situ (DCIS) is present in more than half of HER2-positive invasive breast cancer (IBC). Recent studies show that DCIS accompanying HER2-positive IBC can be completely eradicated by neoadjuvant systemic therapy (NST). Our aim was to determine the percentage of pathologic complete response of the DCIS component in a nationwide cohort and to assess associated clinicopathologic variables. Furthermore, the impact on surgical treatment after NST was investigated. METHODS: Women diagnosed with HER2-positive IBC, treated with NST and surgery, between 2010 and 2020, were selected from the Netherlands Cancer Registry. Pre-NST biopsy and postoperative pathology reports were obtained from the Dutch Nationwide Pathology Databank and assessed for the presence of DCIS. Clinicopathologic factors associated with DCIS response were assessed using logistic regression analyses. RESULTS: A DCIS component was present in the pre-NST biopsy in 1403 (25.1%) of 5598 included patients. Pathologic complete response of the DCIS component was achieved in 730 patients (52.0%). Complete response of DCIS occurred more frequently in case of complete response of IBC (63.4% versus 33.8%, p < 0.001). ER-negative IBC (OR 1.79; 95%CI 1.33-2.42) and more recent years of diagnosis (2014-2016 OR 1.60; 95%CI 1.17-2.19, 2017-2019 OR 1.76; 95%CI 1.34-2.34) were associated with DCIS response. Mastectomy rates were higher in IBC+DCIS compared to IBC (53.6% versus 41.0%, p < 0.001). CONCLUSION: Pathologic complete response of DCIS occurred in 52.0% of HER2-positive IBC patients and was associated with ER-negative IBC and more recent years of diagnosis. Future studies should investigate imaging evaluation of DCIS response to improve surgical decision making.

Juvenile-onset multifocal atrial arrhythmias, atrial standstill and compound heterozygosity of genetic variants in TAF1A: sentinel event for evolving dilated cardiomyopathy-a case report.

Background: Juvenile onset of extensive atrial electromechanical failure, including atrial standstill, is a rare disease entity that may precede ventricular cardiomyopathy. Genetic variants associated with early-onset atrioventricular (AV) cardiomyopathy are increasingly recognized. Case summary: A 16-year-old patient presented with atrial brady- and tachyarrhythmias and concomitant impaired atrial electromechanical function (atrial standstill). The atrial phenotype preceded the development of a predominantly right-sided AV dilated cardiomyopathy with pronounced myocardial fibrosis. A His-bundle pacemaker was installed for high-degree AV conduction block and sinus arrest. Using familial-based whole-exome sequencing, a missense mutation and a copy number variant deletion (compound heterozygosity) of the TAF1A gene (involved in ribosomal RNA synthesis) were identified. Discussion: Juvenile onset of severe atrial electromechanical failure with atrial arrhythmias should prompt deep pheno- and genotyping and calls for vigilance for downstream cardiomyopathic deterioration.

Imaging findings for response evaluation of ductal carcinoma in situ in breast cancer patients treated with neoadjuvant systemic therapy: a systematic review and meta-analysis.

OBJECTIVES: In approximately 45% of invasive breast cancer (IBC) patients treated with neoadjuvant systemic therapy (NST), ductal carcinoma in situ (DCIS) is present. Recent studies suggest response of DCIS to NST. The aim of this systematic review and meta-analysis was to summarise and examine the current literature on imaging findings for different imaging modalities evaluating DCIS response to NST. More specifically, imaging findings of DCIS pre- and post-NST, and the effect of different pathological complete response (pCR) definitions, will be evaluated on mammography, breast MRI, and contrast-enhanced mammography (CEM). METHODS: PubMed and Embase databases were searched for studies investigating NST response of IBC, including information on DCIS. Imaging findings and response evaluation of DCIS were assessed for mammography, breast MRI, and CEM. A meta-analysis was conducted per imaging modality to calculate pooled sensitivity and specificity for detecting residual disease between pCR definition no residual invasive disease (ypT0/is) and no residual invasive or in situ disease (ypT0). RESULTS: Thirty-one studies were included. Calcifications on mammography are related to DCIS, but can persist despite complete response of DCIS. In 20 breast MRI studies, an average of 57% of residual DCIS showed enhancement. A meta-analysis of 17 breast MRI studies confirmed higher pooled sensitivity (0.86 versus 0.82) and lower pooled specificity (0.61 versus 0.68) for detection of residual disease when DCIS is considered pCR (ypT0/is). Three CEM studies suggest the potential benefit of simultaneous evaluation of calcifications and enhancement. CONCLUSIONS AND CLINICAL RELEVANCE: Calcifications on mammography can remain despite complete response of DCIS, and residual DCIS does not always show enhancement on breast MRI and CEM. Moreover, pCR definition effects diagnostic performance of breast MRI. Given the lack of evidence on imaging findings of response of the DCIS component to NST, further research is demanded. KEY POINTS: • Ductal carcinoma in situ has shown to be responsive to neoadjuvant systemic therapy, but imaging studies mainly focus on response of the invasive tumour. • The 31 included studies demonstrate that after neoadjuvant systemic therapy, calcifications on mammography can remain despite complete response of DCIS and residual DCIS does not always show enhancement on MRI and contrast-enhanced mammography. • The definition of pCR has impact on the diagnostic performance of MRI in detecting residual disease, and when DCIS is considered pCR, pooled sensitivity was slightly higher and pooled specificity slightly lower.

Myocardial Scar Detection Using High-Resolution Free-Breathing 3D Dark-Blood and Standard Breath-Holding 2D Bright-Blood Late Gadolinium Enhancement MRI: A Comparison of Observer Confidence.

OBJECTIVE: To compare observer confidence for myocardial scar detection using 3 different late gadolinium enhancement (LGE) data sets by 2 observers with different levels of experience. MATERIALS AND METHODS: Forty-one consecutive patients, who were referred for 3D dark-blood LGE MRI before implantable cardioverter-defibrillator implantation or ablation therapy and who underwent 2D bright-blood LGE MRI within a time frame of 3 months, were prospectively included. From all 3D dark-blood LGE data sets, a stack of 2D short-axis slices was reconstructed. All acquired LGE data sets were anonymized and randomized and evaluated by 2 independent observers with different levels of experience in cardiovascular imaging (beginner and expert). Confidence in detection of ischemic scar, nonischemic scar, papillary muscle scar, and right ventricular scar for each LGE data set was scored using a using a 3-point Likert scale (1 = low, 2 = medium, or 3 = high). Observer confidence scores were compared using the Friedman omnibus test and Wilcoxon signed-rank post hoc test. RESULTS: For the beginner observer, a significant difference in confidence regarding ischemic scar detection was observed in favor of reconstructed 2D dark-blood LGE compared with standard 2D bright-blood LGE (p = 0.030) while for the expert observer, no significant difference was found (p = 0.166). Similarly, for right ventricular scar detection, a significant difference in confidence was observed in favor of reconstructed 2D dark-blood LGE compared with standard 2D bright-blood LGE (p = 0.006) while for the expert observer, no significant difference was found (p = 0.662). Although not significantly different for other areas of interest, 3D dark-blood LGE and its derived 2D dark-blood LGE data set showed a tendency to score higher for all areas of interest at both experience levels. CONCLUSIONS: The combination of dark-blood LGE contrast and high isotropic voxels may contribute to increased observer confidence in myocardial scar detection, independent of observer's experience level but in particular for beginner observers.

High-resolution structural-functional substrate-trigger characterization: Future roadmap for catheter ablation of ventricular tachycardia.

Introduction: Patients with ventricular tachyarrhythmias (VT) are at high risk of sudden cardiac death. When appropriate, catheter ablation is modestly effective, with relatively high VT recurrence and complication rates. Personalized models that incorporate imaging and computational approaches have advanced VT management. However, 3D patient-specific functional electrical information is typically not considered. We hypothesize that incorporating non-invasive 3D electrical and structural characterization in a patient-specific model improves VT-substrate recognition and ablation targeting. Materials and methods: In a 53-year-old male with ischemic cardiomyopathy and recurrent monomorphic VT, we built a structural-functional model based on high-resolution 3D late-gadolinium enhancement (LGE) cardiac magnetic resonance imaging (3D-LGE CMR), multi-detector computed tomography (CT), and electrocardiographic imaging (ECGI). Invasive data from high-density contact and pace mapping obtained during endocardial VT-substrate modification were also incorporated. The integrated 3D electro-anatomic model was analyzed off-line. Results: Merging the invasive voltage maps and 3D-LGE CMR endocardial geometry led to a mean Euclidean node-to-node distance of 5 ± 2 mm. Inferolateral and apical areas of low bipolar voltage (<1.5 mV) were associated with high 3D-LGE CMR signal intensity (>0.4) and with higher transmurality of fibrosis. Areas of functional conduction delay or block (evoked delayed potentials, EDPs) were in close proximity to 3D-LGE CMR-derived heterogeneous tissue corridors. ECGI pinpointed the epicardial VT exit at ∼10 mm from the endocardial site of origin, both juxtaposed to the distal ends of two heterogeneous tissue corridors in the inferobasal left ventricle. Radiofrequency ablation at the entrances of these corridors, eliminating all EDPs, and at the VT site of origin rendered the patient non-inducible and arrhythmia-free until the present day (20 months follow-up). Off-line analysis in our model uncovered dynamic electrical instability of the LV inferolateral heterogeneous scar region which set the stage for an evolving VT circuit. Discussion and conclusion: We developed a personalized 3D model that integrates high-resolution structural and electrical information and allows the investigation of their dynamic interaction during arrhythmia formation. This model enhances our mechanistic understanding of scar-related VT and provides an advanced, non-invasive roadmap for catheter ablation.

Histopathological validation of semi-automated myocardial scar quantification techniques for dark-blood late gadolinium enhancement magnetic resonance imaging.

AIMS: To evaluate the performance of various semi-automated techniques for quantification of myocardial infarct size on both conventional bright-blood and novel dark-blood late gadolinium enhancement (LGE) images using histopathology as reference standard. METHODS AND RESULTS: In 13 Yorkshire pigs, reperfused myocardial infarction was experimentally induced. At 7 weeks post-infarction, both bright-blood and dark-blood LGE imaging were performed on a 1.5 T magnetic resonance scanner. Following magnetic resonance imaging (MRI), the animals were sacrificed, and histopathology was obtained. The percentage of infarcted myocardium was assessed per slice using various semi-automated scar quantification techniques, including the signal threshold vs. reference mean (STRM, using 3 to 8 SDs as threshold) and full-width at half-maximum (FWHM) methods, as well as manual contouring, for both LGE methods. Infarct size obtained by histopathology was used as reference. In total, 24 paired LGE MRI slices and histopathology samples were available for analysis. For both bright-blood and dark-blood LGE, the STRM method with a threshold of 5 SDs led to the best agreement to histopathology without significant bias (-0.23%, 95% CI [-2.99, 2.52%], P = 0.862 and -0.20%, 95% CI [-2.12, 1.72%], P = 0.831, respectively). Manual contouring significantly underestimated infarct size on bright-blood LGE (-1.57%, 95% CI [-2.96, -0.18%], P = 0.029), while manual contouring on dark-blood LGE outperformed semi-automated quantification and demonstrated the most accurate quantification in this study (-0.03%, 95% CI [-0.22, 0.16%], P = 0.760). CONCLUSION: The signal threshold vs. reference mean method with a threshold of 5 SDs demonstrated the most accurate semi-automated quantification of infarcted myocardium, without significant bias compared to histopathology, for both conventional bright-blood and novel dark-blood LGE.

Histopathological Validation of Dark-Blood Late Gadolinium Enhancement MRI Without Additional Magnetization Preparation.

BACKGROUND: Conventional bright-blood late gadolinium enhancement (LGE) cardiac magnetic resonance imaging (MRI) often suffers from poor scar-to-blood contrast due to the bright blood pool adjacent to the enhanced scar tissue. Recently, a dark-blood LGE method was developed which increases scar-to-blood contrast without using additional magnetization preparation. PURPOSE: We aim to histopathologically validate this dark-blood LGE method in a porcine animal model with induced myocardial infarction (MI). STUDY TYPE: Prospective. ANIMAL MODEL: Thirteen female Yorkshire pigs. FIELD STRENGTH/SEQUENCE: 1.5 T, two-dimensional phase-sensitive inversion-recovery radiofrequency-spoiled turbo field-echo. ASSESSMENT: MI was experimentally induced by transient coronary artery occlusion. At 1-week and 7-week post-infarction, in-vivo cardiac MRI was performed including conventional bright-blood and novel dark-blood LGE. Following the second MRI examination, the animals were sacrificed, and histopathology was obtained. Matching LGE slices and histopathology samples were selected based on anatomical landmarks. Independent observers, while blinded to other data, manually delineated the endocardial, epicardial, and infarct borders on either LGE images or histopathology samples. The percentage of infarcted left-ventricular myocardium was calculated for both LGE methods on a per-slice basis, and compared with histopathology as reference standard. Contrast-to-noise ratios were calculated for both LGE methods at 1-week and 7-week post-infarction. STATISTICAL TESTS: Pearson's correlation coefficient and paired-sample t-tests were used. Significance was set at P < 0.05. RESULTS: A combined total of 24 matched LGE and histopathology slices were available for histopathological validation. Dark-blood LGE demonstrated a high level of agreement compared to histopathology with no significant bias (-0.03%, P = 0.75). In contrast, bright-blood LGE showed a significant bias of -1.57% (P = 0.03) with larger 95% limits of agreement than dark-blood LGE. Image analysis demonstrated significantly higher scar-to-blood contrast for dark-blood LGE compared to bright-blood LGE, at both 1-week and 7-weeks post-infarction. DATA CONCLUSION: Dark-blood LGE without additional magnetization preparation provides superior visualization and quantification of ischemic scar compared to the current in vivo reference standard. LEVEL OF EVIDENCE: 1 TECHNICAL EFFICACY STAGE: 2.

A Boolean Dilemma: True or False Aneurysm?

A feared complication of acute myocardial infarction is the formation of a cardiac pseudoaneurysm. We report a case of a gargantuan, arrhythmogenic left-ventricular pseudoaneurysm with contradictory morphological characteristics. The integrative use of high-resolution 3-dimensional magnetic resonance imaging and computed tomography proved essential for the diagnostic discrimination and successful therapeutic intervention. (Level of Difficulty: Advanced.).

Steadily Increasing Inversion Time Improves Blood Suppression for Free-Breathing 3D Late Gadolinium Enhancement MRI With Optimized Dark-Blood Contrast.

MATERIALS AND METHODS: Fifty consecutive patients with previous cardiac arrhythmias, scheduled for high-resolution 3D LGE MRI, were prospectively enrolled between October 2017 and February 2020. Free-breathing 3D dark-blood LGE MRI with high isotropic resolution (1.6 × 1.6 × 1.6 mm) was performed using a conventional fixed TI (n = 25) or a dynamic TI (n = 25). The average increase in blood nulling TI per minute was obtained from Look-Locker scans before and after the 3D acquisition in the first fixed TI group. This average increment in TI was used as input to calculate the dynamic increment of the initial blood nulling TI value as set in the second dynamic TI group. Regions of interest were drawn in the left ventricular blood pool to assess mean signal intensity as a measure for blood pool suppression. Overall image quality, observer confidence, and scar demarcation were scored on a 3-point scale. RESULTS: Three-dimensional dark-blood LGE data sets were successfully acquired in 46/50 patients (92%). The calculated average TI increase of 2.3 ± 0.5 ms/min obtained in the first fixed TI group was incorporated in the second dynamic TI group and led to a significant decrease of 72% in the mean blood pool signal intensity compared with the fixed TI group (P < 0.001). Overall image quality (P = 0.02), observer confidence (P = 0.02), and scar demarcation (P = 0.01) significantly improved using a dynamic TI. CONCLUSIONS: A steadily increasing dynamic TI improves blood pool suppression for optimized dark-blood contrast and increases observer confidence in free-breathing 3D dark-blood LGE MRI with high isotropic resolution.

Integration of cardiac magnetic resonance imaging, electrocardiographic imaging, and coronary venous computed tomography angiography for guidance of left ventricular lead positioning.

AIMS: An appropriate left ventricular (LV) lead position is a pre-requisite for response to cardiac resynchronization therapy (CRT) and is highly patient-specific. The purpose of this study was to develop a non-invasive pre-procedural CRT-roadmap to guide LV lead placement to a coronary vein in late-activated myocardium remote from scar. METHODS AND RESULTS: Sixteen CRT candidates were prospectively included. Electrocardiographic imaging (ECGI), computed tomography angiography (CTA), and delayed enhancement cardiac magnetic resonance imaging (DE-CMR) were integrated into a 3D cardiac model (CRT-roadmap) using anatomic landmarks from CTA and DE-CMR. Electrocardiographic imaging was performed using 184 electrodes and a CT-based heart-torso geometry. Coronary venous anatomy was visualized using a designated CTA protocol. Focal scar was assessed from DE-CMR. Cardiac resynchronization therapy-roadmaps were constructed for all 16 patients [left bundle branch block: n = 6; intraventricular conduction disturbance: n = 8; narrow-QRS (ablate and pace strategy); n = 1; right bundle branch block: n = 1]. The number of coronary veins ranged between 3 and 4 per patient. The CRT-roadmaps showed no (n = 5), 1 (n = 6), or 2 (n = 5) veins per patient located outside scar in late-activated myocardium [≥50% QRS duration (QRSd)]. Final LV lead position was outside scar in late-activated myocardium in 11 out of 14 implanted patients, while a LV lead in scar was unavoidable in the remaining three patients. CONCLUSION: A non-invasive pre-implantation CRT-roadmap was feasible to develop in a case series by integration of coronary venous anatomy, myocardial-scar localization, and epicardial electrical activation patterns, anticipating on clinically relevant features.