Percutaneous Balloon-Expandable Stent Implantation to Treat Transverse Aortic Arch Obstruction: Medium- to Long-Term Outcomes of a Retrospective Multicenter Study.

BACKGROUND: Transverse aortic arch obstruction is a challenging lesion for which stent implantation provides a potentially important alternate therapy. The objectives were to evaluate the technical, procedural, and medium-to-long-term clinical outcomes of percutaneous stent implantation of transverse aortic arch obstruction. METHODS: This is a retrospective, multicenter study of transverse aortic arch stent implantation. Univariable and multivariable analyses were performed. RESULTS: Index catheterization included 187 stent implants in 146 patients. The median age is 14.3 years (interquartile range, 9.3-19), weight is 53 kg (30-69), and follow-up is 53 months (12-120). The most common stent design was open cell (n=90, 48%). Stents overlapped 142 arch vessels (37 carotid arteries) in 118 (81%) cases. Technical and procedural success rates were 100% and 88%, respectively. Lower weight (P=0.018), body surface area (P=0.013), and minimum-to-descending aortic diameter ratio (P<0.001) were associated with higher baseline aortic gradient. The residual gradient was inversely associated with implant and final dilation diameters (P<0.001). The combined incidence of aortic injury and stent-related complications was 14%. There were no reports of abnormal brain scans or stroke. Blood pressure cuff gradient, echocardiographic arch velocity, and hypertension rates improved within 1-year follow-up with increased antihypertensive medication use. Reintervention was reported in 60 (41%) patients at a median of 84 (22-148) months to first reintervention. On multivariable logistic regression, residual aortic gradient >10 mm Hg was associated with increased odds of reintervention at all time points when controlling for each final dilation diameter, weight, and minimum-to-descending aortic diameter ratio. CONCLUSIONS: Transverse aortic arch stent implantation has high rates of technical, procedural, and medium-to-long-term clinical success. Aortic gradient >10 mm Hg is associated with increased odds of reintervention at 1-year and most recent follow-ups. Open cell stent design was frequently used for its advantages in conformability, perfusion of arch vessels, low fracture rate, and the ability to perform effective angioplasty of side cells.

The impact of unilateral pulmonary artery stenosis on right ventricular to pulmonary arterial coupling in patients with transposition of the great arteries.

BACKGROUND: Unilateral pulmonary artery (PA) stenosis is common in the transposition of the great arteries (TGA) after arterial switch operation (ASO) but the effects on the right ventricle (RV) remain unclear. AIMS: To assess the effects of unilateral PA stenosis on RV afterload and function in pediatric patients with TGA-ASO. METHODS: In this retrospective study, eight TGA patients with unilateral PA stenosis underwent heart catheterization and cardiac magnetic resonance (CMR) imaging. RV pressures, RV afterload (arterial elastance [Ea]), PA compliance, RV contractility (end-systolic elastance [Ees]), RV-to-PA (RV-PA) coupling (Ees/Ea), and RV diastolic stiffness (end-diastolic elastance [Eed]) were analyzed and compared to normal values from the literature. RESULTS: In all TGA patients (mean age 12 ± 3 years), RV afterload (Ea) and RV pressures were increased whereas PA compliance was reduced. RV contractility (Ees) was decreased resulting in RV-PA uncoupling. RV diastolic stiffness (Eed) was increased. CMR-derived RV volumes, mass, and ejection fraction were preserved. CONCLUSION: Unilateral PA stenosis results in an increased RV afterload in TGA patients after ASO. RV remodeling and function remain within normal limits when analyzed by CMR but RV pressure-volume loop analysis shows impaired RV diastolic stiffness and RV contractility leading to RV-PA uncoupling.

The effects of percutaneous branch pulmonary artery interventions on exercise capacity, lung perfusion, and right ventricular function in biventricular CHD: a systematic review.

BACKGROUND: Branch pulmonary artery stenosis is common after surgical repair in patients with biventricular CHD and often requires reinterventions. However, (long-term) effects of percutaneous branch pulmonary artery interventions on exercise capacity, right ventricular function, and lung perfusion remain unclear. This review describes the (long-term) effects of percutaneous branch pulmonary artery interventions on exercise capacity, right ventricular function, and lung perfusion following PRISMA guidelines. METHODS: We performed a systematic search in PubMed, Embase, and Cochrane including studies about right ventricular function, exercise capacity, and lung perfusion after percutaneous branch pulmonary artery interventions. Study selection, data extraction, and quality assessment were performed by two researchers independently. RESULTS: In total, 7 eligible studies with low (n = 2) and moderate (n = 5) risk of bias with in total 330 patients reported on right ventricular function (n = 1), exercise capacity (n = 2), and lung perfusion (n = 7). Exercise capacity and lung perfusion seem to improve after a percutaneous intervention for branch pulmonary artery stenosis. No conclusions about right ventricular function or remodelling, differences between balloon and stent angioplasty or specific CHD populations could be made. CONCLUSION: Although pulmonary artery interventions are frequently performed in biventricular CHD, data on relevant outcome parameters such as exercise capacity, lung perfusion, and right ventricular function are largely lacking. An increase in exercise capacity and improvement of lung perfusion to the affected lung has been described in case of mild to more severe pulmonary artery stenosis during relatively short follow-up. However, there is need for future studies to evaluate the effect of pulmonary artery interventions in various CHD populations.

Malignant phyllodes tumour with lymph node metastasis: a diagnostic conundrum resolved by next generation DNA sequencing.

A malignant neoplasm with spindle cell and chondroid differentiation in the breast, metastatic to lymph node. In this context, a metaplastic carcinoma is typically favored given the exceptional nature of lymph node metastases in malignant phyllodes tumors (MPT). However, we demonstrate pathognomonic hotspot mutations in MED12 and the promoter of the TERT gene by targeted next-generation DNA sequencing, supporting a diagnosis of MPT.

Clinicopathologic and genetic analysis of invasive breast carcinomas in women with germline CHEK2 variants.

PURPOSE: Germline pathogenic variants in checkpoint kinase 2 (CHEK2) are associated with a moderately increased risk of breast cancer (BC). The spectrum of clinicopathologic features and genetics of these tumors has not been fully established. METHODS: We characterized the histopathologic and clinicopathologic features of 44 CHEK2-associated BCs from 35 women, and assessed responses to neoadjuvant chemotherapy. A subset of cases (n = 23) was additionally analyzed using targeted next-generation DNA sequencing (NGS). RESULTS: Most (94%, 33/35) patients were heterozygous carriers for germline CHEK2 variants, and 40% had the c.1100delC allele. Two patients were homozygous, and five had additional germline pathogenic variants in ATM (2), PALB2 (1), RAD50 (1), or MUTYH (1). CHEK2-associated BCs occurred in younger women (median age 45 years, range 25-75) and were often multifocal (20%) or bilateral (11%). Most (86%, 38/44) were invasive ductal carcinomas of no special type (IDC-NST). Almost all (95%, 41/43) BCs were ER + (79% ER + HER2-, 16% ER + HER2 + , 5% ER-HER2 +), and most (69%) were luminal B. Nottingham grade, proliferation index, and results of multiparametric molecular testing were heterogeneous. Biallelic CHEK2 alteration with loss of heterozygosity was identified in most BCs (57%, 13/23) by NGS. Additional recurrent alterations included GATA3 (26%), PIK3CA (226%), CCND1 (22%), FGFR1 (22%), ERBB2 (17%), ZNF703 (17%), TP53 (9%), and PPM1D (9%), among others. Responses to neoadjuvant chemotherapy were variable, but few patients (21%, 3/14) achieved pathologic complete response. Most patients (85%) were without evidence of disease at time of study (n = 34). Five patients (15%) developed distant metastasis, and one (3%) died (mean follow-up 50 months). CONCLUSION: Almost all CHEK2-associated BCs were ER + IDC-NST, with most classified as luminal B with or without HER2 overexpression. NGS supported the luminal-like phenotype and confirmed CHEK2 as an oncogenic driver in the majority of cases. Responses to neoadjuvant chemotherapy were variable but mostly incomplete.

Neoadjuvant Trebananib plus Paclitaxel-based Chemotherapy for Stage II/III Breast Cancer in the Adaptively Randomized I-SPY2 Trial-Efficacy and Biomarker Discovery.

PURPOSE: The neutralizing peptibody trebananib prevents angiopoietin-1 and angiopoietin-2 from binding with Tie2 receptors, inhibiting angiogenesis and proliferation. Trebananib was combined with paclitaxel±trastuzumab in the I-SPY2 breast cancer trial. PATIENTS AND METHODS: I-SPY2, a phase II neoadjuvant trial, adaptively randomizes patients with high-risk, early-stage breast cancer to one of several experimental therapies or control based on receptor subtypes as defined by hormone receptor (HR) and HER2 status and MammaPrint risk (MP1, MP2). The primary endpoint is pathologic complete response (pCR). A therapy "graduates" if/when it achieves 85% Bayesian probability of success in a phase III trial within a given subtype. Patients received weekly paclitaxel (plus trastuzumab if HER2-positive) without (control) or with weekly intravenous trebananib, followed by doxorubicin/cyclophosphamide and surgery. Pathway-specific biomarkers were assessed for response prediction. RESULTS: There were 134 participants randomized to trebananib and 133 to control. Although trebananib did not graduate in any signature [phase III probabilities: Hazard ratio (HR)-negative (78%), HR-negative/HER2-positive (74%), HR-negative/HER2-negative (77%), and MP2 (79%)], it demonstrated high probability of superior pCR rates over control (92%-99%) among these subtypes. Trebananib improved 3-year event-free survival (HR 0.67), with no significant increase in adverse events. Activation levels of the Tie2 receptor and downstream signaling partners predicted trebananib response in HER2-positive disease; high expression of a CD8 T-cell gene signature predicted response in HR-negative/HER2-negative disease. CONCLUSIONS: The angiopoietin (Ang)/Tie2 axis inhibitor trebananib combined with standard neoadjuvant therapy increased estimated pCR rates across HR-negative and MP2 subtypes, with probabilities of superiority >90%. Further study of Ang/Tie2 receptor axis inhibitors in validated, biomarker-predicted sensitive subtypes is warranted.

Right ventricular to pulmonary arterial coupling in patients with repaired tetralogy of Fallot: a case series.

Background: In repaired tetralogy of Fallot (ToF) patients with residual right ventricular (RV) outflow tract obstructions (RVOTO), risk stratification and timing of re-interventions are based on RVOTO gradients. However, this might be insufficient to prevent RV dysfunction. Instead, assessment of RV to pulmonary arterial (RV-PA) coupling allows integrated assessment of RV function in relationship to its afterload and could be of additional value in clinical decision-making. Case summary: Two patients with repaired ToF and residual RVOTO without pulmonary regurgitation underwent right heart catheterization (RHC) and cardiac magnetic resonance imaging. We determined RV end-systolic elastance (Ees), arterial elastance (Ea) and RV-PA coupling (Ees/Ea) using single-beat RV pressure-volume analysis. Patient 1 was asymptomatic despite severely increased RV pressures and a left pulmonary artery (LPA) stenosis (invasive gradient 20 mmHg). Right ventricular volumes and function were preserved. The Ea and Ees were increased but RV-PA coupling was relatively maintained. Of interest, RV end-diastolic pressure and RV diastolic stiffness were increased. After LPA plasty, RV function was preserved during long-term follow-up. Patient 2 was symptomatic despite mildly elevated RV pressures and a supravalvular RV-PA conduit stenosis (invasive gradient 30 mmHg). The RV showed severe RV dilatation and dysfunction. The Ea was increased but Ees was decreased leading to RV-PA uncoupling. Despite balloon angioplasty, RV function was unchanged during long-term follow-up. Discussion: Development of RV dysfunction might be insufficiently predicted by RVOTO severity in patients with repaired ToF. Assessment of RV remodelling and function in relationship to its afterload might help to optimize risk stratification.

Solid-Basaloid Adenoid Cystic Carcinoma of the Breast: An Aggressive Subtype Enriched for Notch Pathway and Chromatin Modifier Mutations With MYB Overexpression.

Adenoid cystic carcinoma (AdCC) is a rare triple-negative breast cancer analogous to its extramammary counterparts. Diagnosis of the more aggressive solid-basaloid variant of AdCC (SB-AdCC) can be challenging due to poorly defined histopathologic and molecular features. We characterized 22 invasive and in situ basaloid carcinomas by morphology, immunohistochemistry, genetics, and MYB status using multiple platforms and assessed clinical behavior and neoadjuvant chemotherapy responses. After consensus review, 16/22 cases were classified as SB-AdCC. All SB-AdCC had predominantly solid growth and at least focal myxohyaline stroma and were immune-poor. Eosinophilic squamoid cells (69%, 11/16) and basement membrane-like secretions (69%, 11/16) were common, and intercalated ducts (31%, 5/16) were less frequent. SB-AdCC typically expressed SOX10 (100%, 16/16) and luminal markers (100%, 16/16 CK7; 88%, 14/16 CD117; 93%, 13/14 CAM5.2). SMA (40%, 6/15) expression was less common, and SMM (27%, 3/11), GATA3 (20%, 3/15), and p63 (25%, 4/16) were mostly negative. MYB protein and/or MYB RNA overexpression was universal in evaluable cases (13/13), with RNA in situ hybridization (10/10) more reliable than immunohistochemistry (10/11, plus 4 excisions inconclusive). Fluorescence in situ hybridization and/or next-generation sequencing identified MYB rearrangements (20%, 3/15) and amplifications/copy gains (60%, 9/15) but no MYB::NFIB fusions. SB-AdCC often had aberrations in Notch pathway (60%, including 40% NOTCH1 and 20% NOTCH2) and/or chromatin modifier (60%, including 33% CREBBP) genes, with relatively infrequent TP53 mutations (27%). Unclassified invasive basaloid carcinomas lacking described histologic features of SB-AdCC (n = 4) and basaloid ductal carcinoma in situ (n = 2) showed similar immunoprofiles and genetics as SB-AdCC, including Notch aberrations and MYB overexpression with MYB rearrangements/amplifications. Overall, nodal (22%) and distant (33%) metastases were common, and 23% of patients died of disease (mean follow-up, 35 months; n = 22). Responses were poor in all 7 neoadjuvant chemotherapy-treated patients, without any achieving pathologic complete response. The data highlight the histopathologic spectrum of basaloid carcinomas including SB-AdCC and reveal shared genetics and MYB activation, which can be diagnostically useful. Aggressive behavior and poor treatment responses emphasize a need for additional treatment approaches.

Genetic and Immunohistochemical Profiling of Mammary Hidradenoma and Comparison to Mucoepidermoid Carcinoma.

Mucoepidermoid carcinoma (MEC) is exceedingly rare in the breast, with <45 cases reported in the literature. Although estrogen receptor/progesterone receptor/human epidermal growth factor 2 triple-negative, MEC is characterized as a special subtype of breast carcinoma with significantly better prognosis than conventional basal-type tumors. Cutaneous hidradenoma (HA) is considered a benign adnexal neoplasm showing histomorphologic overlap with MEC. Rare cases of HA have also been reported in the breast, but these are relatively uncharacterized. In this study, we examined the clinicopathologic, immunohistochemical (IHC), and genetic features of 8 breast HAs, in comparison to 3 mammary MECs. All cases were positive for MAML2 break-apart fluorescence in situ hybridization. Eight cases demonstrated a CRTC1::MAML2 fusion, and one MEC harbored a CRTC3::MAML2 fusion; the latter is a novel finding in the breast. Mutational burden was very low, with only one HA exhibiting a MAP3K1 pathogenic alteration. By IHC, both MEC and HA demonstrated cell type-dependent expression of high- and low-molecular-weight keratins and p63, as well as negative to low-positive estrogen receptor and androgen receptor. Smooth muscle myosin and calponin highlighted an in situ component in the 3 cases of MEC; expression of these myoepithelial markers was negative in HAs. Additional distinguishing characteristics included the growth pattern and tumor architecture, the presence of glandular/luminal cells in HA, and overall higher IHC expression of SOX10, S100 protein, MUC4, and mammaglobin in MEC. Morphologic findings were also compared to a series of 27 cutaneous nonmammary HAs. Mucinous and glandular/luminal cells were identified in significantly more mammary HAs than nonmammary lesions. The findings provide insight into the pathogenesis of MAML2-rearranged neoplasms of the breast, underscore the overlapping genetic features of MEC and HA, and highlight similarities to their extramammary counterparts.

Comparison of Four-Dimensional Flow MRI, Two-Dimensional Phase-Contrast MRI and Echocardiography in Transposition of the Great Arteries.

Pulmonary artery (PA) stenosis is a common complication after the arterial switch operation (ASO) for transposition of the great arteries (TGA). Four-dimensional flow (4D flow) CMR provides the ability to quantify flow within an entire volume instead of a single plane. The aim of this study was to compare PA maximum velocities and stroke volumes between 4D flow CMR, two-dimensional phase-contrast (2D PCMR) and echocardiography. A prospective study including TGA patients after ASO was performed between December 2018 and October 2020. All patients underwent echocardiography and CMR, including 2D PCMR and 4D flow CMR. Maximum velocities and stroke volumes were measured in the main, right, and left PA (MPA, LPA, and RPA, respectively). A total of 39 patients aged 20 ± 8 years were included. Maximum velocities in the MPA, LPA, and RPA measured by 4D flow CMR were significantly higher compared to 2D PCMR (p < 0.001 for all). PA assessment by echocardiography was not possible in the majority of patients. 4D flow CMR maximum velocity measurements were consistently higher than those by 2D PCMR with a mean difference of 65 cm/s for the MPA, and 77 cm/s for both the RPA and LPA. Stroke volumes showed good agreement between 4D flow CMR and 2D PCMR. Maximum velocities in the PAs after ASO for TGA are consistently lower by 2D PCMR, while echocardiography only allows for PA assessment in a minority of cases. Stroke volumes showed good agreement between 4D flow CMR and 2D PCMR.

Low-grade fibromyxoid sarcoma of the breast: genetic characterization and immunohistochemical comparison to morphologic mimics.

Spindle cell lesions of the breast elicit a specific, relatively limited differential diagnosis, and accurate classification often requires careful morphologic evaluation and immunohistochemical workup. Low-grade fibromyxoid sarcoma (LGFMS) is a rare malignant fibroblastic tumor with deceptively bland spindle cell morphology. Involvement of the breast is exceedingly rare. We examined the clinicopathologic and molecular characteristics of three cases of breast/axillary LGFMS. In addition, we interrogated the immunohistochemical expression of MUC4, a commonly used marker of LGFMS, in other breast spindle cell lesions. LGFMS presented in women at 23, 33, and 59 years of age. Tumor size ranged from 0.9 to 4.7 cm. Microscopically, they were circumscribed nodular masses composed of bland spindle cells with fibromyxoid stroma. Immunohistochemically, tumors were diffusely positive for MUC4 and negative for keratin, CD34, S100 protein, and nuclear beta-catenin. Fluorescence in-situ hybridization demonstrated FUS (n = 2) or EWSR1 (n = 1) rearrangements. Next-generation sequencing identified FUS::CREB3L2 and EWSR1::CREB3L1 fusions. MUC4 immunohistochemistry performed on 162 additional breast lesions demonstrated only weak and limited expression in a subset of cases of fibromatosis (10/20, ≤30% staining), scar (5/9, ≤10%), metaplastic carcinoma (4/23, ≤5%), and phyllodes tumor (3/74, ≤10%). MUC4 was entirely negative in cases of pseudoangiomatous stromal hyperplasia (n = 9), myofibroblastoma (n = 6), periductal stromal tumor (n = 3), and cellular/juvenile fibroadenoma (n = 21). LGFMS can rarely occur in the breast and should be considered in the differential diagnosis of breast spindle cell lesions. Strong and diffuse MUC4 expression is highly specific in this histologic context. Detection of an FUS or EWSR1 rearrangement can confirm the diagnosis.

Triple-Negative Apocrine Carcinomas: Toward a Unified Group With Shared Molecular Features and Clinical Behavior.

Triple-negative apocrine carcinomas (TNACs) are rare breast tumors with limited studies evaluating their molecular characteristics and clinical behavior. We performed a histologic, immunohistochemical, genetic, and clinicopathologic assessment of 42 invasive TNACs (1 with a focal spindle cell component) from 41 patients, 2 pure apocrine ductal carcinomas in situ (A-DCIS), and 1 A-DCIS associated with spindle cell metaplastic carcinoma (SCMBC). All TNACs had characteristic apocrine morphology and expressed androgen receptor (42/42), gross cystic disease fluid protein 15 (24/24), and CK5/6 (16/16). GATA3 was positive in most cases (16/18, 89%), and SOX10 was negative (0/22). TRPS1 was weakly expressed in a minority of tumors (3/14, 21%). Most TNACs had low Ki67 proliferation (≤10% in 67%, 26/39), with a median index of 10%. Levels of tumor infiltrating lymphocytes were low (≤10% in 93%, 39/42, and 15% in 7%, 3/42). Eighteen percent of TNACs presented with axillary nodal metastasis (7/38). No patients treated with neoadjuvant chemotherapy achieved pathologic complete response (0%, 0/10). Nearly all patients with TNAC (97%, n = 32) were without evidence of disease at the time of study (mean follow-up of 62 months). Seventeen invasive TNACs and 10 A-DCIS (7 with paired invasive TNAC) were profiled by targeted capture-based next-generation DNA sequencing. Pathogenic mutations in phosphatidylinositol 3-kinase pathway genes PIK3CA (53%) and/or PIK3R1 (53%) were identified in all TNACs (100%), including 4 (24%) with comutated PTEN. Ras-MAPK pathway genes, including NF1 (24%), and TP53 were mutated in 6 tumors each (35%). All A-DCIS shared mutations, such as phosphatidylinositol 3-kinase aberrations and copy number alterations with paired invasive TNACs or SCMBC, and a subset of invasive carcinomas showed additional mutations in tumor suppressors (NF1, TP53, ARID2, and CDKN2A). Divergent genetic profiles between A-DCIS and invasive carcinoma were identified in 1 case. In summary, our findings support TNAC as a morphologically, immunohistochemically, and genetically homogeneous subgroup of triple-negative breast carcinomas and suggest overall favorable clinical behavior.

Association of Residual Ductal Carcinoma In Situ With Breast Cancer Recurrence in the Neoadjuvant I-SPY2 Trial.

Importance: Pathologic complete response (pCR) after neoadjuvant chemotherapy (NAC) in breast cancer strongly correlates with overall survival and has become the standard end point in neoadjuvant trials. However, there is controversy regarding whether the definition of pCR should exclude or permit the presence of residual ductal carcinoma in situ (DCIS). Objective: To examine the association of residual DCIS in surgical specimens after neoadjuvant chemotherapy for breast cancer with survival end points to inform standards for the assessment of pathologic complete response. Design, Setting, and Participants: The study team analyzed the association of residual DCIS after NAC with 3-year event-free survival (EFS), distant recurrence-free survival (DRFS), and local-regional recurrence (LRR) in the I-SPY2 trial, an adaptive neoadjuvant platform trial for patients with breast cancer at high risk of recurrence. This is a retrospective analysis of clinical specimens and data from the ongoing I-SPY2 adaptive platform trial of novel therapeutics on a background of standard of care for early breast cancer. I-SPY2 participants are adult women diagnosed with stage II/III breast cancer at high risk of recurrence. Interventions: Participants were randomized to receive taxane and anthracycline-based neoadjuvant therapy with or without 1 of 10 investigational agents, followed by definitive surgery. Main Outcomes and Measures: The presence of DCIS and EFS, DRFS, and LRR. Results: The study team identified 933 I-SPY2 participants (aged 24 to 77 years) with complete pathology and follow-up data. Median follow-up time was 3.9 years; 337 participants (36%) had no residual invasive disease (residual cancer burden 0, or pCR). Of the 337 participants with pCR, 70 (21%) had residual DCIS, which varied significantly by tumor-receptor subtype; residual DCIS was present in 8.5% of triple negative tumors, 15.6% of hormone-receptor positive tumors, and 36.6% of ERBB2-positive tumors. Among those participants with pCR, there was no significant difference in EFS, DRFS, or LRR based on presence or absence of residual DCIS. Conclusions and Relevance: The analysis supports the definition of pCR as the absence of invasive disease after NAC regardless of the presence or absence of DCIS. Trial Registration: ClinicalTrials.gov Identifier NCT01042379.

Standardizing Pathologic Evaluation of Breast Carcinoma After Neoadjuvant Chemotherapy.

CONTEXT.­: Neoadjuvant systemic therapy refers to the use of systemic agent(s) for malignancy prior to surgical treatment and has recently emerged as an option for most breast cancer patients eligible for adjuvant systemic therapy. Consequently, treated breast carcinomas have become routine specimens in pathology practices. A standard protocol has not yet been universally adopted for the evaluation and reporting of these specimens. The American Joint Committee on Cancer staging system recognizes the challenges in staging breast carcinomas after neoadjuvant treatment and provides important data points but does not currently provide detailed guidance in estimating the residual tumor burden in the breast and lymph nodes. The Residual Cancer Burden system is the only Web-based system that quantifies treatment response as a continuous variable using residual tumor burden in the breast and the lymph nodes. OBJECTIVE.­: To provide clarifications and guidance for evaluation and reporting of postneoadjuvant breast specimens, discuss issues with the current staging and reporting systems, and provide specific suggestions for future modifications to the American Joint Committee on Cancer system and the Residual Cancer Burden calculator. DATA SOURCES.­: English-language literature on the subject and the data from the I-SPY 2, a multicenter, adaptive randomization phase 2 neoadjuvant platform trial for early-stage, high-risk breast cancer patients. CONCLUSIONS.­: This article highlights challenges in the pathologic evaluation and reporting of treated breast carcinomas and provides recommendations and clarifications for pathologists and clinicians. It also provides specific recommendations for staging and discusses future directions.

Genetic and immunohistochemical profiling of small cell and large cell neuroendocrine carcinomas of the breast.

Neuroendocrine carcinomas (NEC) of the breast are exceedingly rare tumors, which are classified in the WHO system as small cell (SCNEC) and large cell (LCNEC) carcinoma based on indistinguishable features from their lung counterparts. In contrast to lung and enteropancreatic NEC, the genomics of breast NEC have not been well-characterized. In this study, we examined the clinicopathologic, immunohistochemical, and genetic features of 13 breast NEC (7 SCNEC, 4 LCNEC, 2 NEC with ambiguous small versus large cell morphology [ANEC]). Co-alterations of TP53 and RB1 were identified in 86% (6/7) SCNEC, 100% (2/2) ANEC, and 50% (2/4) LCNEC. The one SCNEC without TP53/RB1 alteration had other p53 pathway aberrations (MDM2 and MDM4 amplification) and was immunohistochemically RB negative. PIK3CA/PTEN pathway alterations and ZNF703 amplifications were each identified in 46% (6/13) NEC. Two tumors (1 SCNEC, 1 LCNEC) were CDH1 mutated. By immunohistochemistry, 100% SCNEC (6/6) and ANEC (2/2) and 50% (2/4) LCNEC (83% NEC) showed RB loss, compared to 0% (0/8) grade 3 neuroendocrine tumors (NET) (p < 0.001) and 38% (36/95) grade 3 invasive ductal carcinomas of no special type (IDC-NST) (p = 0.004). NEC were also more often p53 aberrant (60% vs 0%, p = 0.013), ER negative (69% vs 0%, p = 0.005), and GATA3 negative (67% vs 0%, p = 0.013) than grade 3 NET. Two mixed NEC had IDC-NST components, and 69% (9/13) of tumors were associated with carcinoma in situ (6 neuroendocrine DCIS, 2 non-neuroendocrine DCIS, 1 non-neuroendocrine LCIS). NEC and IDC-NST components of mixed tumors were clonally related and immunophenotypically distinct, lacking ER and GATA3 expression in NEC relative to IDC-NST, with RB loss only in NEC of one ANEC. The findings provide insight into the pathogenesis of breast NEC, underscore their classification as a distinct tumor type, and highlight genetic similarities to extramammary NEC, including highly prevalent p53/RB pathway aberrations in SCNEC.

Troubled Judging of Bronchus Compression Due to Contrast-Filled Balloon in Three-Dimensional Rotational Angiography.

Three-dimensional rotational angiography (3DRA) is a suitable technique to detect the risk of left main bronchus (LMB) compression during left pulmonary artery (LPA) stenting in partial cavopulmonary connection and total cavopulmonary connection (TCPC). We report on a case of a 4-year-old boy with hypoplastic left heart syndrome and TCPC in which 3DRA and bronchoscopy gave conflicting information on airway patency during balloon interrogation. The balloon with high contrast concentration created a severe artifact impeding visibility of the LMB. Simultaneous flexible bronchoscopy revealed an unobstructed LMB. Repeated 3DRAs with lower contrast concentration had no artifact and showed a patent airway in accordance with the bronchoscopy. Conventional LPA stenting was performed without indication for stent ovalization. The benefit of low contrast concentration in the interrogation balloon was demonstrated in a second case of an 11-year-old boy with TCPC. The margins of the LPA and LMB were clearly visible without blank-out artifact. Oval stent procedure was necessary to prevent LMB compression. When 3DRA is used for vessel-airway interrogation, the balloon contrast concentration should be low in order to avoid artifacts. When in doubt, simultaneous flexible bronchoscopy can overcome the dilemma in airway judgment.

Hypertensive response to exercise in adult patients with repaired aortic coarctation.

OBJECTIVE: The clinical and prognostic implications of a hypertensive response to exercise after repair of coarctation of the aorta (CoA) remain controversial. We aimed to determine the prevalence of a hypertensive response to exercise, identify factors associated with peak exercise systolic blood pressure (SBP) and explore the association of peak exercise SBP with resting blood pressure and cardiovascular events during follow-up. METHODS: From the Dutch national CONgenital CORvitia (CONCOR) registry, adults with repaired CoA who underwent exercise stress testing were included. A hypertensive response to exercise was defined as a peak exercise SBP ≥210 mm Hg in men and ≥190 mm Hg in women. Cardiovascular events consisted of coronary artery disease, stroke, aortic complications and cardiovascular death. RESULTS: Of the original cohort of 920 adults with repaired CoA, 675 patients (median age 24 years (range 16-72 years)) underwent exercise stress testing. Of these, 299 patients (44%) had a hypertensive response to exercise. Mean follow-up duration was 10.1 years. Male sex, absence of a bicuspid aortic valve and elevated resting SBP were independently associated with increased peak exercise SBP. Peak exercise SBP was positively predictive of office SBP (ß=0.11, p<0.001) and 24-hour SBP (ß=0.05, p=0.03) at follow-up, despite correction for baseline SBP. During follow-up, 100 patients (15%) developed at least 1 cardiovascular event. Peak exercise SBP was not significantly associated with the occurrence of cardiovascular events (HR 0.994 (95% CI 0.987 to 1.001), p=0.11). CONCLUSIONS: A hypertensive response to exercise was present in nearly half of the patients in this large, prospective cohort of adults with repaired CoA. Risk factors for increased peak exercise SBP were male sex, absence of a bicuspid aortic valve and elevated resting SBP. Increased peak exercise SBP independently predicted hypertension at follow-up. These results support close follow-up of patients with a hypertensive response to exercise to ensure timely diagnosis and treatment of future hypertension.

Cardiovascular Morbidity and Mortality in Adult Patients With Repaired Aortic Coarctation.

Background The long-term burden of cardiovascular disease after repair of coarctation of the aorta (CoA) has not been elucidated. We aimed to determine the incidence of and risk factors for cardiovascular events in adult patients with repaired CoA. Additionally, mortality rates were compared between adults with repaired CoA and the general population. Methods and Results Using the Dutch Congenital Corvitia (CONCOR) registry, patients aged ≥16 years with previous surgical or transcatheter CoA repair from 5 tertiary referral centers were included. Cardiovascular events were recorded, comprising coronary artery disease, stroke/transient ischemic attack, aortic complications, arrhythmias, heart failure hospitalizations, endocarditis, and cardiovascular death. In total, 920 patients (median age, 24 years [range 16-74 years]) were included. After a mean follow-up of 9.3±5.1 years, 191 patients (21%) experienced at least 1 cardiovascular event. A total of 270 cardiovascular events occurred, of which aortic complications and arrhythmias were most frequent. Older age at initial CoA repair (hazard ratio [HR], 1.017; 95% CI, 1.000-1.033 [P=0.048]) and elevated left ventricular mass index (HR, 1.009; 95% CI, 1.005-1.013 [P<0.001]) were independently associated with an increased risk of cardiovascular events. The mortality rate was 3.3 times higher than expected based on an age- and sex-matched cohort from the Dutch general population (standardized mortality ratio, 3.3; 95% CI, 2.3-4.4 [P<0.001]). Conclusions This large, prospective cohort of adults with repaired CoA showed a high burden of cardiovascular events, particularly aortic complications and arrhythmias, during long-term follow-up. Older age at initial CoA repair and elevated left ventricular mass index were independent risk factors for the occurrence of cardiovascular events. Mortality was 3.3-fold higher compared with the general population. These results advocate stringent follow-up after CoA repair and emphasize the need for improved preventive strategies.