Clinical and molecular predictors of very late recurrence in oestrogen receptor-positive breast cancer patients.

BACKGROUND: Risk of recurrence from primary ER+ breast cancer continues for at least 20 years. We aimed to identify clinical and molecular features associated with risk of recurrence after 10 years. METHODS: ER+ breast cancers from patients with and without recurrence were analysed with the BC360 NanoString Panel and an 87 gene targeted-exome panel. Frequency of clinical, pathologic and molecular characteristics was compared between cases (recurred between 10 and 20 years) and controls (no recurrence by 20 years) in the Very Late Recurrence (VLR) cohort. Analogous data from METABRIC were examined to confirm or refute findings. RESULTS: VLR cases had larger tumours and higher node positivity. Both VLR and METABRIC cases had higher clinical treatment score at 5 years (CTS5). There was a trend for fewer GATA3 mutations in cases in both VLR and METABRIC but no statistically significant differences in mutation frequency. Cell cycle and proliferation genes were strongly expressed in VLR cases. Immune-related genes and cell cycle inhibitors were highly expressed in controls. Neither of these changes were significant after correction for multiple testing. CONCLUSIONS: Clinicopathologic features are prognostic beyond 10 years. Conversely, molecular features, such as copy number alterations, TP53 mutations and intrinsic subtype which have early prognostic significance, have little prognostic value after 10 years.

Repeat catheter ablation after very late recurrence of atrial fibrillation after pulmonary vein isolation.

AIMS: Atrial fibrillation (AF) recurs in about one-third of patients after catheter ablation (CA), mostly in the first year. Little is known about the electrophysiological findings and the effect of re-ablation in very late AF recurrences (VLR) after more than 1 year. The aim of this study was to determine the characteristics and outcomes of the first repeat CA after VLR of AF after index CA. METHODS AND RESULTS: We analysed patients from a prospective Swiss registry that underwent a first repeat ablation procedure. Patients were stratified depending on the time to recurrence after index procedure: early recurrence (ER) for recurrences within the first year and late recurrence (LR) if the recurrence was later. The primary endpoint was freedom from AF in the first year after repeat ablation. Out of 1864 patients included in the registry, 426 patients undergoing a repeat ablation were included in the analysis (28% female, age 63 ± 9.8 years, 46% persistent AF). Two hundred and ninety-one patients (68%) were stratified in the ER group and 135 patients (32%) in the LR group. Pulmonary vein reconnections were a common finding in both groups, with 93% in the ER group compared to 86% in the LR group (P = 0.052). In the LR group, 40 of 135 patients (30%) had a recurrence of AF compared to 90 of 291 patients (31%) in the ER group (log-rank P = 0.72). CONCLUSION: There was no association between the time to recurrence of AF after initial CA and the characteristics and outcomes of the repeat procedure.

Impact of left atrial low-voltage areas during initial ablation procedures on very late recurrence of atrial fibrillation.

BACKGROUND: Very late recurrence of atrial fibrillation (VLRAF) occurring >1 year after catheter ablation may influence long-term follow-up strategies, including oral anticoagulant therapy. However, little is known about the predictors of this condition. Given that the prevalence of left atrial low-voltage areas (LVAs) is strongly associated with the recurrence of atrial tachyarrhythmias following catheter ablation, we hypothesized that VLRAF might occur more frequently in patients with LVAs at the time of initial ablation. The purpose of this study was to investigate the impact of LVAs on VLRAF. METHODS: This study included 1001 consecutive patients undergoing initial ablation procedures for AF. LVAs were defined as regions with bipolar peak-to-peak voltages of <0.50 mV on the voltage map obtained during sinus rhythm after pulmonary vein isolation. During a 1-year follow-up period, 248 patients had a late recurrence of AF (LRAF), defined as recurrence within 3-12 months after ablation. The occurrence of VLRAF was examined in 711 patients without LRAF who were followed for more than 1 year. RESULTS: A total of 711 patients who did not develop AF recurrence within 1 year and for whom clinical data were available after 1 year were analyzed. During a median follow-up of 25 (19, 37) months, VLRAF more than 1 year after the initial ablation was detected in 123 patients. On multivariate analysis, independent predictors of VLRAF were the existence of LVAs, female, left atrial diameter and early recurrence of AF. A Kaplan-Meier analysis showed that the AF-free survival rate was significantly lower in patients with LVAs than in those without LVAs within 1 year and on more than 1-year follow-up (p < .001). An additional Kaplan-Meier analysis of the incidence of VLRAF in propensity score-matched patients with and without LVAs showed that VLRAF occurred significantly more frequently in patients with LVAs (p = .003). CONCLUSIONS: LVAs during the initial AF ablation procedures have an impact on VLRAF occurrence.

Very late recurrence of B-cell acute lymphoblastic leukemia masquerading as a pituitary tumor.

Involvement of the pituitary gland by leukemic infiltration is exceedingly rare. Here, we describe a very late recurrence of B-cell acute lymphoblastic leukemia masquerading as a pituitary tumor and review the literature for previously reported cases. Our female patient presented 13 years after completion of therapy for B-ALL with headache, amenorrhea, galactorrhea and a pituitary mass. Subsequent studies revealed recurrence of her leukemia, and the pituitary lesion resolved after induction chemotherapy. Our case highlights the importance of considering leukemic infiltrate in the differential diagnosis of pituitary mass, particularly in a patient with a history of hematologic malignancy, sparing unnecessary surgical intervention and informing endocrine evaluation. In addition, the case also highlights difficulties with characterizing this recurrence as a very late relapse or clonal evolution of the original leukemia.

Very late arrhythmia recurrences in patients with sinus rhythm within the first year after catheter ablation: The Leipzig Heart Center AF Ablation Registry.

AIMS: Arrhythmia recurrences after catheter ablation of atrial fibrillation (AF) still remain an important management issue. Recently, the APPLE score had been introduced to predict rhythm outcomes within 12 months after catheter ablation, while the simple MB-LATER score was developed for the prediction of very late recurrence of AF (VLRAF) occurring after 12 months. The aim of this study was to compare APPLE and MB-LATER scores in predicting VLRAF. METHODS AND RESULTS: The study population included arrhythmia-free patients within first 12 months after first radiofrequency catheter ablation from The Heart Center Leipzig AF Ablation Registry. The APPLE [one point for Age >65 years, Persistent AF, imPaired eGFR <60 mL/min/1.73 m2, Left atrial (LA) diameter ≥43 mm, EF <50%] and MB-LATER scores [one point for Male gender, Bundle branch block or QRS >120 ms, LA diameter ≥47 mm, AF Type (persistent AF), Early Recurrence <3 months] were calculated before and 3 months after ablation, respectively. We followed 482 patients {age 61 [interquartile range (IQR) 54-68] years, 66% males, 32% persistent AF} for median 40 (IQR 35-50) months. There were 184 patients (38.3%) with arrhythmia recurrences within 13-60 months after ablation. On multivariate analysis, APPLE [odds ratio (OR) 1.517, 95% confidence interval (CI) 1.244-1.850, P < 0.001] and MB-LATER (OR 1.437, 95% CI 1.211-1.705, P < 0.001) scores and diabetes mellitus (OR 2.214, 95% CI 1.353-3.625, P = 0.002) were significantly associated with arrhythmia recurrences. Receiver operating characteristic curve analyses demonstrated moderate prediction for both scores [area under the curve (AUC) 0.607, P < 0.001 for APPLE score, AUC 0.604, P < 0.001 for MB-LATER]. CONCLUSION: Prediction of VLRAF is similar for both APPLE and MB-LATER scores. A better score remains still a clinical unmet need.

Relationship between left ventricular diastolic dysfunction and very late recurrences after multiple procedures for atrial fibrillation ablation.

Although very late recurrences (VLRs) (first recurrence >12 months after the last catheter ablation) of atrial fibrillation (AF) after multiple catheter ablation procedures are rare, it remains a critical issue. The risk factors for VLRs remain largely unclear. From December 2011 to April 2014, 253 patients underwent an initial catheter ablation. Of the 253 patients, 21 had AF recurrences within 1 year after the last catheter ablation. The study was conducted in the remaining 232 patients. Left ventricular diastolic dysfunction (LVDD) was assessed by echocardiography using composite categories with tissue Doppler imaging and left atrial volume measurements, i.e., a septal e' < 8 cm/s, lateral e' < 10 cm/s, and left atrium volume index (LAV/body surface area) (LAVI) ≥34 mL/m2. LVDD was observed in 40 patients. Sinus rhythm was preserved in 220 patients after multiple catheter procedures, and 12 had VLRs. The clinical factors possibly related to VLRs were examined, and a multivariate regression analysis showed that LVDD was the only independent risk factor for VLRs (hazard ratio: 10.31, 95% confidence interval: 2.78-38.18, P < 0.0001). LVDD at baseline is a risk factor for a VLR after multiple catheter ablation procedures for AF.

Incidence and risk factors for very late recurrence of atrial fibrillation after radiofrequency catheter ablation.

AIMS: Although several prognostic factors for atrial fibrillation (AF) recurrence after catheter ablation (CA) have been reported, predictors of very late recurrence (VLR; initial recurrence >12 months after ablation) remain unidentified. This study investigated clinical variables predictive of VLR after CA for AF. METHODS AND RESULTS: This retrospective single-centre cohort study evaluated data from 1016 consecutive drug-refractory AF patients who underwent single CA for AF from July 2004 to May 2010. After excluding 324 patients with a short follow-up period (<1 year) and 300 patients with recurrence within a year of CA, 392 patients were included. Study subjects were divided into two groups on the basis of VLR presence. Preoperative clinical variables were evaluated as predictors of VLR using the Cox proportional hazards model. The annual rate of VLR was 7.6% after single CA. Univariate analysis revealed that hypertension [hazard ratio (HR) 1.77, 95% confidence interval (CI) 0.93-3.37, P = 0.08], obesity (HR 1.84, 95% CI 0.98-3.45, P = 0.06), long-standing persistent AF (HR 2.35, 95% CI 1.08-5.11, P = 0.03), and abnormally high preoperative C-reactive protein (CRP) levels >0.5 mg/dL (HR 4.28, 95% CI 2.03-9.03, P < 0.0001) were associated with VLR. In the multivariate model, only abnormally high preoperative CRP level was an independent predictor of VLR (HR 4.9, 95% CI 2.3-10.7, P < 0.0001). CONCLUSION: Even after a year without AF, VLR occurred annually in 7.6% cases. Continued vigilance for VLR after CA is clinically desirable, especially for patients with abnormally high preoperative CRP levels.

ABO Blood Groups as a Disease Marker to Predict Atrial Fibrillation Recurrence after Catheter Ablation.

Chronic inflammation harbors a vulnerable substrate for atrial fibrillation (AF) recurrence after catheter ablation. However, whether the ABO blood types are associated with AF recurrence after catheter ablation is unknown. A total of 2106 AF patients (1552 men, 554 women) who underwent catheter ablation were enrolled retrospectively. The patients were separated into two groups according to the ABO blood types, the O-type (n = 910, 43.21%) and the non-O-type groups (A, B, or AB type) (n = 1196, 56.79%). The clinical characteristics, AF recurrence, and risk predictors were investigated. The non-O type blood group had a higher incidence of diabetes mellitus (11.90 vs. 9.03%, p = 0.035), larger left atrial diameters (39.43 ± 6.74 vs. 38.20 ± 6.47, p = 0.007), and decreased left ventricular ejection fractions (56.01 ± 7.33 vs. 58.65 ± 6.34, p = 0.044) than the O-type blood group. In the non-paroxysmal AF (non-PAF) patients, the non-O-type blood groups have significantly higher incidences of very late recurrence (67.46 vs. 32.54%, p = 0.045) than those in the O-type blood group. The multivariate analysis revealed the non-O blood group (odd ratio 1.40, p = 0.022) and amiodarone (odd ratio 1.44, p = 0.013) were independent predictors for very late recurrence in the non-PAF patients after catheter ablation, which could be applied as a useful disease marker. This work highlighted the potential link between the ABO blood types and inflammatory activities that contribute to the pathogenic development of AF. The presence of surface antigens on cardiomyocytes or blood cells in patients with different ABO blood types will have an impactful role in risk stratification for AF prognosis after catheter ablation. Further prospective studies are warranted to prove the translational benefits of the ABO blood types for the patients receiving catheter ablation.

Very late orbital recurrence of choroidal melanoma four decades post enucleation.

Orbital recurrence of malignant choroidal melanoma is quite uncommon, occurring in about 3% of patients undergoing enucleation for large tumors. Orbital recurrences after more than 10 years from enucleation are even rarer. In literature, only few reports described orbital recurrence that occurred between 10 and 40 years after primary diagnosis. Herein we report a very late choroidal melanoma recurrence, 40 years post enucleation, of a 52 year-old female who had undergone left enucleation at the age of 12. She presented to our clinic for consultation in 2017, complaining of difficulty to contain the prosthesis, as well as, presence of small pigmented palpable nodules inferiorly in her anophthalmic socket. The patient was not aware of the medical condition which had lead to the enucleation. We requested her medical reports and detailed history through her family. We realized after reviewing her charts 40 years back, that her enucleation was due to malignant choroidal melanoma (CMM). Full screening was performed. After magnetic resonance imaging (MRI), that showed the presence of nodular masses in the anophthalmic socket, an excisional biopsy was performed. Histopathology confirmed the diagnosis of CMM (epithelioid and spindle cell type), supporting the hypothesis that residual melanoma cells may remain clinically dormant for long periods, even for decades. A literature review was performed in order to review similar cases and to understand and discuss multiple factors, which may explain this extremely delayed recurrence. To the best of our knowledge, this is the third case to be reported in the literature.

Evaluation of predictive scores for late and very late recurrence after cryoballoon-based ablation of atrial fibrillation.

PURPOSE: Studies on predictive scores for very late recurrence (VLR) (recurrence later than 12 months) after second-generation cryoballoon-based pulmonary vein isolation (CB2-PVI) are sparse. We aimed to evaluate the frequency of late recurrence (LR) (later than 3 months) and VLR, and to validate predictive scores for LR and VLR after initial CB2-PVI. METHODS: A total of 288 patients undergoing initial CB2-PVI (66 ± 11 years, 46% paroxysmal) were retrospectively enrolled in the LR cohort. In the VLR cohort, 83 patients with recurrence within 3-12 months or with < 12-month follow-up were excluded. The predictive scores of arrhythmia recurrence were assessed, including the APPLE, DR-FLASH, PLAAF, BASE-AF2, ATLAS, SCALE-CryoAF, and MB-LATER scores. RESULTS: During a mean follow-up of 15.3 ± 7.1 months, 188 of 288 (65.2%) patients remained in sinus rhythm without any recurrences. Thirty-two of 205 (15.6%) patients experienced VLR after a mean of 16.6 ± 5.6 months. Comparing the predictive values of these specific scores, the MB-LATER score showed a reliable trend toward greater risk of both LR and VLR (area under the curve in LR; 0.632, 0.637, 0.632, 0.637, 0.604, 0.725, and 0.691 (p = ns), VLR; 0.612, 0.636, 0.644, 0.586, 0.541, 0.633, and 0.680 (p = 0.038, vs. BASE-AF2, respectively)). Kaplan-Meier analysis estimated patients with higher MB-LATER scores which had favorable outcomes (24-month freedom from LR; 26.0% vs. 56.7%, p < 0.0001, VLR; 53.4% vs. 82.1%, p = 0.013). CONCLUSION: The MB-LATER score provided more reliable predictive value for both LR and VLR. Patients with higher MB-LATER scores may benefit from more intensive long-term follow-up.

Persistent left atrial remodeling after catheter ablation for non-paroxysmal atrial fibrillation is associated with very late recurrence.

BACKGROUND: This study aimed to evaluate the association between left atrial (LA) structural remodeling and very late recurrence [VLR; initial recurrence >12 months after catheter ablation (CA)] after successful CA for non-paroxysmal atrial fibrillation (AF). METHODS: We retrospectively evaluated 63 patients who underwent initial, single ablation for drug-refractory persistent or long-standing persistent AF and those who had no recurrence in the first year after CA. We followed patients for a mean of 3.2±1.5 years and divided them into VLR and no-recurrence (NR) groups. Before and 3 months after ablation, all patients were subjected to 64-slice multidetector computed tomography scanning to estimate LA volume, including maximum and minimum volume during the cardiac cycle (LAMaxV and LAMinV, respectively), and the LA emptying fraction. RESULTS: VLR occurred in 21 patients. The reduction rate of LAMaxV after CA was significantly larger in the NR group than in the VLR group (25±19% vs. 5±18%, p=0.0002). Receiver operating characteristic analysis was performed to determine the best cut-off values in the prediction of VLR. The highest area-under curve was obtained with post-CA LAMinV [0.828 (95% confidence interval, 0.712-0.912), p<0.0001], with a best cut-off value of 44mL (sensitivity 81.0%, specificity 81.0%). CONCLUSIONS: Persistent LA structural remodeling after initially successful CA for non-paroxysmal AF may be an important risk factor for VLR.

Recurrence after "long-term success" in catheter ablation of paroxysmal atrial fibrillation.

BACKGROUND: The latest guidelines define "long-term success" as freedom from atrial arrhythmia recurrence more than 36 months after procedures without any antiarrhythmic drug therapy. OBJECTIVE: The purpose of this study was to investigate the clinical outcomes and procedural findings in patients with recurrence beyond "long-term success." METHODS: Among patients who underwent pulmonary vein (PV) antrum isolation for drug-refractory symptomatic paroxysmal atrial fibrillation (AF), 37 in whom recurrent arrhythmias were observed during annual follow-up after "long-term success" and who underwent repeat procedures for recurrent arrhythmias were included in the study. RESULTS: The time from the latest procedure to recurrence was a median of 61 ([25th, 75th percentiles]: [51-77.5]) months. Recurrent arrhythmia type was paroxysmal in 22 patients (59.5%) and persistent in 15 (40.5%). Recurrent arrhythmias were atrial tachycardia (AT) in 13 patients (35.1%), including 8 with AT unrelated to PVs. Repeat procedures were performed a median of 2.0 [1.0-4.0] months after identifying recurrent episodes. Recovered PV conduction was found in 29 patients (78.4%) and non-PV foci in 4 (10.8%). Freedom from recurrence 1 year after repeat procedures was 63.3%. Seven patients (18.9%) underwent further repeat procedures a median of 7.0 [2.0-28.0] months after repeat procedures and had no PV reconnections. In total, AF/AT unrelated to PVs was present in 24 patients (64.9%). In contrast, arrhythmias related to PVs were observed in 2 patients (5.4%) during a total of 46 repeat procedures after "long-term success." CONCLUSION: Although PV reconnections were commonly found even after "long-term success," AF/AT unrelated to PVs was assumed to be present in the majority of this population.

Very long-term outcome after initially successful catheter ablation of atrial fibrillation.

BACKGROUND: The ablation of atrial fibrillation (AF) using pulmonary vein isolation is indicated when patients do not respond favorably to medical therapy. Successful procedures are accomplished in the majority of patients, but the outcome after many years of follow-up after ablation is unknown. OBJECTIVE: To describe the long-term recurrence rate and pattern of AF after successful ablation. METHODS: A prospectively identified cohort of 445 patients who demonstrated freedom from AF for at least 1 year postablation (single procedure in 391 [87.9%]) was followed for 66.0 ± 34.0 months. Patients were seen at least annually as outpatients and underwent regular electrocardiographic monitoring. RESULTS: At 40.7 ± 27.0 months postablation, 97 (21.8%) patients experienced at least 1 episode of recurrent AF. The vast majority of events were symptomatic, and no serious clinical events were associated with AF recurrence (eg, stroke). There was a steady attrition rate reaching 16.3% and 29.8% at 5 and 10 years, respectively. In 29 patients (29.5%) of the patients, recurrences were self-limited; the remainder required either medical therapy or repeat ablation. By multivariate analysis, persistent AF (hazard ratio 3.08; P < .0001) and hypertension (hazard ratio 1.08; P = .009) were independent risk factors for the recurrence of AF. The presence of both factors placed the patient at high risk of recurrence: 37.6% at 5 years and 68.8% at 10 years. CONCLUSIONS: Over the decade after a successful ablation of AF, most patients continue to demonstrate freedom from AF. At the highest risk of very late recurrence is the subset of patients with hypertension and prior persistent AF.