Changes in expression of breast cancer tumor biomarkers between primary tumors and corresponding metastatic sites: common patterns and relationships with survival.

PURPOSE: In metastatic breast cancer, differences in expression patterns of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor-2 (HER2) between the primary tumor (PT) and metastatic site (MET) have been reported. However, there is limited understanding of the relationship of tumor subtype discordance and overall survival (OS). We evaluated patterns of ER/PR/HER2 in PTs and corresponding METs and assessed the relationship between these patterns and OS. METHODS: Patients diagnosed at our center with metastatic breast cancer (2011-2020) were included. ER/PR were stratified as < 1%/1-10%/ > 10% by immunohistochemistry and HER2 as positive/negative by immunohistochemistry/FISH. Tumor subtypes were classified as ER or PR + /HER2-, HER2+ , or triple-negative. Biomarker discordance data from PTs to METs were analyzed for expression patterns. OS was assessed. RESULTS: Of 254 patients, 41 (16.1%) had synchronous and 213 (83.9%) had metachronous METs. Category change of ER/PR/HER2 expression was observed in 56 (22.0%), 117 (40.5%), and 30 (11.8%) patients, respectively. Tumor subtype changed in 56 (22.0%) patients. We identified a difference between PT and MET from ER > 10% to ER < 1% (n = 28,16.2% p < 0.01); PR > 10% to PR < 1% (n = 54,48.2%, p < 0.001); PR > 10% to PR 1-10% (n = 18,16.1%, p < 0.001), and ER or PR+/HER2- to triple-negative (n = 19,13.0%, p = 0.03). In log-rank analysis, change from an ER or PR+/HER2- (5-year OS 88.6%) PT to a HER2+(67.5%) or triple-negative (54.6%) MET was associated with decreased survival (p < 0.01); however, in multivariate analysis, discordant biomarker expression was not associated with decreased survival (p > 0.05). CONCLUSION: Tumor expression of ER/PR/HER2 can differ between the PT and MET. Loss of ER/PR expression is common and may be related to worse survival. Routine assessment of MET tumor markers could inform prognosis and therapeutic decision-making.

Catheter ablation of typical atrial flutter improves cardiac chamber size and function.

INTRODUCTION: Cavo-tricuspid isthmus (CTI) dependent atrial flutter (AFL) is one of the most common atrial arrhythmias involving the right atrium (RA) for which radiofrequency catheter ablation has been widely used as a therapy of choice. However, there is limited data on the effect of this intervention on cardiac size and function. METHODS: A retrospective study was conducted on 468 patients who underwent ablation for CTI dependent typical AFL at a single institution between 2010 and 2019. After excluding patients with congenital or rheumatic heart disease, heart transplant recipients, or those without baseline echocardiogram, a total of 130 patients were included in the analysis. Echocardiographic data were analyzed at baseline before ablation, and at early follow-up within 1-year postablation. Follow-up echocardiographic data was available for 55 patients. RESULTS: Of the 55 patients with CTI-AFL, the mean age was 64.2 ± 14.8 years old with 14.5% (n = 8) female. The average left ventricular ejection fraction (LVEF) significantly improved on follow-up echo (40.2 ± 16.9 to 50.4 ± 14.9%, p < .0001), of which 50% of patients had an improvement in LVEF of at least 10%. There was a significant reduction in left atrial volume index (82.74 ± 28.5 to 72.96 ± 28 mL/m2 , p = .008) and RA volume index (70.62 ± 25.6 to 64.15 ± 31 mL/m2 , p = .046), and a significant improvement in left atrial reservoir strain (13.04 ± 6.8 to 19.10 ± 7.7, p < .0001). CONCLUSIONS: Patients who underwent CTI dependent AFL ablation showed an improvement in cardiac size and function at follow-up evaluation. While long-term results are still unknown, these findings indicate that restoration of sinus rhythm in patients with typical AFL is associated with improvement in atrial size and left ventricular function.

The prevalence and prognostic implications of pre-procedural hyperbilirubinemia in patients undergoing transcatheter aortic valve replacement.

Preoperative hyperbilirubinemia is associated with increased mortality and morbidity after cardiac surgery. However, this clinical significance is unclear with transcatheter aortic valve replacement (TAVR) procedures. The aims of this study were to determine the prevalence and prognostic implications of preoperative elevations of serum total bilirubin on TAVR outcomes. In 611 consecutive patients who underwent an elective TAVR procedure, 576 patients had recorded serum total bilirubin levels. Hyperbilirubinemia was defined as any value of serum total bilirubin ≥ 1.2 mg/dL obtained within 30-days prior to the TAVR procedure. The primary composite endpoint was post-TAVR all-cause in-hospital mortality or stroke. The overall prevalence of hyperbilirubinemia was 10% (n = 58). There were no patients with a prespecified diagnosis of liver cirrhosis. Pre-TAVR hyperbilirubinemia compared to normal bilirubin level was more common in younger (78 ± 10 vs. 82 ± 8 years old, p < 0.001) males (15 vs. 6%, p < 0.001), with history of pacemaker or ICD (33 vs. 18%, p = 0.005), congestive heart failure New York Heart Association class IV within 2 weeks from TAVR (35 vs. 14%, p < 0.001), severe tricuspid regurgitation (14 vs. 4%, p < 0.001), and atrial fibrillation or flutter (60 vs. 40%, p = 0.004, respectively). Pre-TAVR hyperbilirubinemia was independently associated with an increased post-TAVR in-hospital mortality (7 vs. 2% in normal bilirubin, p = 0.03), stroke (5 vs. 1%, p = 0.019, respectively), and a composite endpoint of death or stroke (12 vs. 3%, p < 0.001). Preoperative hyperbilirubinemia in patients undergoing TAVR is more prevalent than previously considered with multifactorial causes. Hyperbilirubinemia is independently associated with an increased post-TAVR in-hospital mortality and stroke.

Absence of electrocardiographic left ventricular hypertrophy in patients undergoing Transcatheter aortic valve replacement is associated with increased mortality.

BACKGROUND: We examined the association between the absence ECG LVH and all-cause mortality in patients with severe AS undergoing TAVR. METHODS: We conducted a retrospective single center study on 399 TAVR patients from 2012 to 2016. ECGs were reviewed for LVH diagnosed by Sokolow-Lyon's voltage criteria. All patients met echocardiographic criteria for LVH. Logistic regression was used to examine the association between ECG LVH and covariates. Survival analysis was performed using Cox regression analysis and Kaplan Meier curves. RESULTS: Patients without ECG LVH were younger (81.0 ± 8.4 vs. 84.0 ± 7.7 years, p = 0.001) with a higher BMI (29.3 ± 7.0 vs. 27.1 ± 5.6 kg/m2, p = 0.006) and lower FEV1 (65.6 ± 22.8 vs. 74.1 ± 21.6%, p = 0.002). In multivariable analysis, increased BMI and decreased FEV1 remained predictive of the absence of ECG LVH. Over a mean follow-up time of 32 (± 17.0) months, the 5-year cumulative survival was 79% in the ECG LVH group and 58% in the group without ECG LVH (p = 0.039). Absence of ECG LVH remained predictive of all-cause mortality (HR 1.56, 95% CI 1.01-2.59, p = 0.045) in multivariable Cox regression analysis. When patients were grouped by comorbidities, patients with the highest mortality were those with increased BMI or decreased FEV1. CONCLUSIONS: Absence of LVH by ECG criteria in patients with severe AS undergoing TAVR was associated with increased all-cause mortality. Routinely performed, noninvasive and inexpensive ECG may aid in identification of high-risk patients that may not benefit from TAVR and warrant further evaluation of underlying comorbidities.

Attainment of Guideline-Directed Medical Treatment in Stable Ischemic Heart Disease Patients With and Without Chronic Kidney Disease.

BACKGROUND: Stable ischemic heart disease (SIHD) is prevalent in patients with chronic kidney disease (CKD); however, whether guideline-directed medical therapy (GDMT) is adequately implemented in patients with SIHD and CKD is unknown. HYPOTHESIS: Use of GDMT and achievement of treatment targets would be higher in SIHD patients without CKD than in patients with CKD. METHODS: This was a retrospective study of 563 consecutive patients with SIHD (mean age 67.8 years, 84% Caucasians, 40% females). CKD was defined as an estimated glomerular filtration rate (eGFR) of < 60 mL/min/1.73m2 using the four-variable MDRD Study equation. We examined the likelihood of achieving GDMT targets (prescription of high-intensity statins, antiplatelet agents, renin-angiotensin-aldosterone system inhibitors (RAASi), and low-density lipoprotein cholesterol levels < 70 mg/dL, blood pressure < 140/90 mmHg, and hemoglobin A1C < 7% if diabetes) in patients with (n = 166) and without CKD (n = 397). RESULTS: Compared with the non-CKD group, CKD patients were significantly older (72 vs 66 years; p < 0.001), more commonly female (49 vs 36%; p = 0.002), had a higher prevalence of diabetes (46 vs 34%; p = 0.004), and left ventricular systolic ejection fraction (LVEF) < 40% (23 vs. 10%, p < 0.001). All GDMT goals were achieved in 26% and 24% of patients with and without CKD, respectively (p = 0.712). There were no between-group differences in achieving individual GDMT goals with the exception of RAASi (CKD vs non-CKD: adjusted risk ratio 0.73, 95% CI 0.62-0.87; p < 0.001). CONCLUSIONS: Attainment of GDMT goals in SIHD patients with CKD was similar to patients without CKD, with the exception of lower rates of RAASi use in the CKD group.

The Assessment of Cough in a Sarcoidosis Clinic Using a Validated instrument and a Visual Analog Scale.

PURPOSE: Cough is a common symptom of pulmonary sarcoidosis. We analyzed the severity of cough and factors associated with cough in a university sarcoidosis clinic cohort. METHODS: Consecutive patients completed the Leicester Cough Questionnaire (LCQ) and a cough visual analog scale (VAS). Clinical and demographic data were collected. Means of the LCQ were analyzed in patients who had multiple visits in terms of constant variables (e.g., race, sex). RESULTS: 355 patients completed the LCQ and VAS at 874 visits. Cough was significantly worse in blacks than whites as determined by the LCQ-mean (16.5 ± 2.6 vs. 17.8 ± 3.0, p < 0.001) and VAS-mean (3.8 ± 3.0 vs. 2.0 ± 2.6, p < 0.0001). Cough was worse in women than men as measured by the VAS-mean (2.7 ± 2.9 vs. 2.2 ± 2.7, p = 0.002), one of the LCQ-mean domains (LCQ-Social-mean 5.4 ± 0.9 vs. 5.2 ± 1.0, p = 0.03), but not the total LCQ-mean score. Cough was not significantly different by either measure in terms of smoking status, age, or spirometric parameter (FVC % predicted, FEV1 % predicted, FEV1/FVC). In a multivariable linear regression analysis, cough was significantly worse in blacks than whites and in pulmonary sarcoidosis than non-pulmonary sarcoidosis with both cough measures, in women than men for the VAS only, and not for spirometric parameters, Scadding stage, or age. The LCQ and VAS were strongly correlated. CONCLUSIONS: In a large university outpatient sarcoidosis cohort, cough was worse in blacks than whites. Cough was not statistically significantly different in terms of age, spirometric measures, Scadding stage, or smoking status. The LCQ correlated strongly with a visual analog scale for cough.

Heart transplantation: advances in expanding the donor pool and xenotransplantation.

Approximately 65 million adults globally have heart failure, and the prevalence is expected to increase substantially with ageing populations. Despite advances in pharmacological and device therapy of heart failure, long-term morbidity and mortality remain high. Many patients progress to advanced heart failure and develop persistently severe symptoms. Heart transplantation remains the gold-standard therapy to improve the quality of life, functional status and survival of these patients. However, there is a large imbalance between the supply of organs and the demand for heart transplants. Therefore, expanding the donor pool is essential to reduce mortality while on the waiting list and improve clinical outcomes in this patient population. A shift has occurred to consider the use of organs from donors with hepatitis C virus, HIV or SARS-CoV-2 infection. Other advances in this field have also expanded the donor pool, including opt-out donation policies, organ donation after circulatory death and xenotransplantation. We provide a comprehensive overview of these various novel strategies, provide objective data on their safety and efficacy, and discuss some of the unresolved issues and controversies of each approach.

Diagnostic Value of Aortic Valve Calcification Levels in the Assessment of Low-Gradient Aortic Stenosis.

BACKGROUND: In patients with low-gradient aortic stenosis (AS) and low transvalvular flow, dobutamine stress echocardiography (DSE) is recommended to determine AS severity, whereas the degree of aortic valve calcification (AVC) supposedly correlates with AS severity according to current European and American guidelines. OBJECTIVES: The purpose of this study was to assess the relationship between AVC and AS severity as determined using echocardiography and DSE in patients with aortic valve area <1 cm2 and peak aortic valve velocity <4.0 m/s. METHODS: All patients underwent DSE to determine AS severity and multislice computed tomography to quantify AVC. Receiver-operating characteristics curve analysis was used to assess the diagnostic value of AVC for AS severity grading as determined using echocardiography and DSE in men and women. RESULTS: A total of 214 patients were included. Median age was 78 years (25th-75th percentile: 71-84 years) and 25% were women. Left ventricular ejection fraction was reduced (<50%) in 197 (92.1%) patients. Severe AS was diagnosed in 106 patients (49.5%). Moderate AS was diagnosed in 108 patients (50.5%; in 77 based on resting transthoracic echocardiography, in 31 confirmed using DSE). AVC score was high (≥2,000 for men or ≥1,200 for women) in 47 (44.3%) patients with severe AS and in 47 (43.5%) patients with moderate AS. AVC sensitivity was 44.3%, specificity was 56.5%, and positive and negative predictive values for severe AS were 50.0% and 50.8%, respectively. Area under the receiver-operating characteristics curve was 0.508 for men and 0.524 for women. CONCLUSIONS: Multi-slice computed tomography-derived AVC scores showed poor discrimination between grades of AS severity using DSE and cannot replace DSE in the diagnostic work-up of low-gradient severe AS.

Long-Term Outcomes of Permanent Pacemaker Implantation in Bicaval Heart Transplant Recipients.

BACKGROUND: Permanent pacemakers (PPMs) may be necessary in up to 10% of patients after heart transplantation (HT). OBJECTIVES: The purpose of this study was to evaluate long-term outcomes and clinical courses of heart transplant recipients who received PPM. METHODS: All patients who required PPM after bicaval HT at Columbia University between January 2005 and December 2021 were included. Cases were compared to matched heart transplant recipients by age, sex, and year of transplantation. Patient and device characteristics including complications and device interrogations were reviewed. Outcomes of re-transplantation or graft failure/death were compared between groups. RESULTS: Of 1,082 heart transplant recipients, 41 (3.8%) received PPMs. The median time from transplantation to PPM was 118 days (IQR: 18-920 days). The most common indications were sinus node dysfunction (60%, n = 25) and atrioventricular (AV) nodal disease (41.5%, n = 17). Post-implantation complications included pocket hematoma (n = 3), lead under-sensing (n = 2), and pocket infection requiring explant (n = 1). Rates of death and re-transplantation at 10 years post-HT were similar between groups. In multivariable analysis, after adjustment for mechanical circulatory support, pretransplantation amiodarone use, donor ischemic time and age, only older donor age was associated with increased risk of PPM implantation (P = 0.03). There was a significant decrease in PPM placement after 2018 (1.2% vs 4.4%, P = 0.02), largely driven by a decline in early PPM placement. There were no differences in mortality or need for re-transplantation between groups. CONCLUSIONS: PPMs are implanted after HT for sinus and atrioventricular node dysfunctions with low incidence of device-related complications. Our study shows a decrease in PPM implantation after 2018, likely attributable to expectant management in the early postoperative period.

Frequency of Atrial Arrhythmia in Hospitalized Patients With COVID-19.

There is growing evidence that COVID-19 can cause cardiovascular complications. However, there are limited data on the characteristics and importance of atrial arrhythmia (AA) in patients hospitalized with COVID-19. Data from 1,029 patients diagnosed with of COVID-19 and admitted to Columbia University Medical Center between March 1, 2020 and April 15, 2020 were analyzed. The diagnosis of AA was confirmed by 12 lead electrocardiographic recordings, 24-hour telemetry recordings and implantable device interrogations. Patients' history, biomarkers and hospital course were reviewed. Outcomes that were assessed were intubation, discharge and mortality. Of 1,029 patients reviewed, 82 (8%) were diagnosed with AA in whom 46 (56%) were new-onset AA 16 (20%) recurrent paroxysmal and 20 (24%) were chronic persistent AA. Sixty-five percent of the patients diagnosed with AA (n=53) died. Patients diagnosed with AA had significantly higher mortality compared with those without AA (65% vs 21%; p < 0.001). Predictors of mortality were older age (Odds Ratio (OR)=1.12, [95% Confidence Interval (CI), 1.04 to 1.22]); male gender (OR=6.4 [95% CI, 1.3 to 32]); azithromycin use (OR=13.4 [95% CI, 2.14 to 84]); and higher D-dimer levels (OR=2.8 [95% CI, 1.1 to 7.3]). In conclusion, patients diagnosed with AA had 3.1 times significant increase in mortality rate versus patients without diagnosis of AA in COVID-19 patients. Older age, male gender, azithromycin use and higher baseline D-dimer levels were predictors of mortality.

Papilloma diagnosed on core biopsies has a low upgrade rate.

CONTEXT: Surgical excision of benign intraductal papillomas (IDP) diagnosed on core needle biopsy (CNB) remains controversial. OBJECTIVE: To examine the upgrade rate of IDPs diagnosed at core needle biopsy to carcinoma at surgical excision. DESIGN: We identified 188 consecutive IDPs diagnosed at CNB from 2011 to 2016 with subsequent surgical excision. Radiologic, clinical, and histologic features were evaluated and correlated with upgrade rate at surgical excision. RESULTS: Two of the 188 IDPs (1.1%) were upgraded to ductal carcinoma in situ or invasive carcinoma at excision. Features associated with upgrade rate include patient age (P = .03), largest size of papilloma on a single core at CNB (P = .04), and the presence of additional masses noted at ultrasound (P = .03). CONCLUSIONS: Our study demonstrated a low 1.1% upgrade rate of surgically excised benign, concordant papillomas with no atypia or concurrent ipsilateral malignancy originally diagnosed on core biopsy. This data suggests that observation may be appropriate for radiologic-pathologic concordant benign IDPs diagnosed at CNB.

Short-Term Reproducibility of Masked Hypertension Among Adults Without Office Hypertension.

The 2017 American College of Cardiology/American Heart Association blood pressure (BP) Hypertension Clinical Practice Guidelines recommends ambulatory BP monitoring to detect masked hypertension. Data on the short-term reproducibility of masked hypertension are scarce. The IDH study (Improving the Detection of Hypertension) enrolled 408 adults not taking antihypertensive medication from 2011 to 2013. Office BP and 24-hour ambulatory BP monitoring were performed on 2 occasions, a median of 29 days apart. After excluding participants with office hypertension (mean systolic BP ≥130 mm Hg or diastolic BP ≥80 mm Hg), the analytical sample included 254 participants. Using the κ statistic, we evaluated the reproducibility of masked awake hypertension (awake systolic/diastolic BP ≥130/80 mm Hg) defined by the 2017 BP guideline thresholds, as well as masked 24-hour (24-hour systolic/diastolic BP ≥125/75 mm Hg), masked asleep (asleep systolic/diastolic BP ≥110/65 mm Hg), and any masked hypertension (high awake, 24-hour, and asleep BP). The mean (SD) age of participants was 38.0 (12.3) years and 65.7% were female. Based on the first and second ambulatory BP recordings, 24.0% and 26.4% of participants, respectively, had masked awake hypertension. The κ statistic (95% CI) was 0.50 (0.38-0.62) for masked awake, 0.57 (0.46-0.69) for masked 24-hour, 0.57 (0.47-0.68) for masked asleep, and 0.58 (0.47-0.68) for any masked hypertension. Clinicians should consider the moderate short-term reproducibility of masked hypertension when interpreting the results from a single ambulatory BP recording.

Quantifying the relationship between symptoms at presentation and the prognosis of sarcoidosis.

BACKGROUND: Although it is the general consensus that sarcoidosis patients who present with sarcoidosis-related symptoms have a worse outcome than patients whose disease is detected incidentally without symptoms, this premise has not been rigorously examined. METHODS: Consecutive patients followed longitudinally at one US university sarcoidosis clinic were questioned concerning the onset and description of sarcoidosis-related symptoms at disease presentation. The patients were classified into those with no sarcoidosis-related symptoms at presentation (NSP group) and those with symptoms at presentation (SP group). The following outcomes were examined in the NSP and SP groups: most recent spirometry, organ involvement, need for sarcoidosis therapy, most recent health related quality of life (HRQOL) as measured by the Sarcoidosis Assessment Tool (SAT), most recent chest imaging Scadding stage results. RESULTS: 660 sarcoidosis patients were analyzed, with 175 in the NSP group and 485 in the SP group. Compared to the NSP group, the SP group had a more frequent requirement for any sarcoidosis treatment, corticosteroid treatment, and non-corticosteroid treatment at some time and within the most recent year of follow up (at least 50% more than the NP group with strong statistical differences with p values all 0.01 or less). In addition, the SP group had significantly more organ involvement (p < 0.001) and several worse SAT domains (p < 0.022) than the NP group. There were no differences between the groups in terms of final spirometry or development of Scadding stage 4 chest radiographs. These findings held even after adjusting for age, sex, race, and time between presentation and the most recent follow-up visit using a multivariable logistic regression framework. CONCLUSIONS: In our sarcoidosis cohort, compared to the absence of symptoms at presentation, the presence of symptoms was associated with a greater need for treatment, more organ involvement, and worse HRQOL.

The DYT6 Dystonia Protein THAP1 Regulates Myelination within the Oligodendrocyte Lineage.

The childhood-onset motor disorder DYT6 dystonia is caused by loss-of-function mutations in the transcription factor THAP1, but the neurodevelopmental processes in which THAP1 participates are unknown. We find that THAP1 is essential for the timing of myelination initiation during CNS maturation. Conditional deletion of THAP1 in the CNS retards maturation of the oligodendrocyte (OL) lineage, delaying myelination and causing persistent motor deficits. The CNS myelination defect results from a cell-autonomous requirement for THAP1 in the OL lineage and is recapitulated in developmental assays performed on OL progenitor cells purified from Thap1 null mice. Loss of THAP1 function disrupts a core set of OL maturation genes and reduces the DNA occupancy of YY1, a transcription factor required for OL maturation. These studies establish a role for THAP1 transcriptional regulation at the inception of myelination and implicate abnormal timing of myelination in the pathogenesis of childhood-onset dystonia.

TorsinA hypofunction causes abnormal twisting movements and sensorimotor circuit neurodegeneration.

Lack of a preclinical model of primary dystonia that exhibits dystonic-like twisting movements has stymied identification of the cellular and molecular underpinnings of the disease. The classical familial form of primary dystonia is caused by the DYT1 (ΔE) mutation in TOR1A, which encodes torsinA, AAA⁺ ATPase resident in the lumen of the endoplasmic reticular/nuclear envelope. Here, we found that conditional deletion of Tor1a in the CNS (nestin-Cre Tor1a(flox/-)) or isolated CNS expression of DYT1 mutant torsinA (nestin-Cre Tor1a(flox/ΔE)) causes striking abnormal twisting movements. These animals developed perinuclear accumulation of ubiquitin and the E3 ubiquitin ligase HRD1 in discrete sensorimotor regions, followed by neurodegeneration that was substantially milder in nestin-Cre Tor1a(flox/ΔE) compared with nestin-Cre Tor1a(flox/-) animals. Similar to the neurodevelopmental onset of DYT1 dystonia in humans, the behavioral and histopathological abnormalities emerged and became fixed during CNS maturation in the murine models. Our results establish a genetic model of primary dystonia that is overtly symptomatic, and link torsinA hypofunction to neurodegeneration and abnormal twisting movements. These findings provide a cellular and molecular framework for how impaired torsinA function selectively disrupts neural circuits and raise the possibility that discrete foci of neurodegeneration may contribute to the pathogenesis of DYT1 dystonia.