Favorable clinical efficacy of cytotoxic chemotherapy in patients with progressive desmoid tumors: a retrospective real-world study.

BACKGROUND: The real-world evidence about the efficacy of cytotoxic chemotherapy in desmoid tumors is still limited. We investigated the efficacy of chemotherapy in the treatment of recurrent or progressive desmoid tumors. METHODS: The patients with desmoid tumors who had received cytotoxic chemotherapy between November 2007 and June 2020 in two tertiary hospitals in Korea were reviewed. RESULTS: A total of 25 patients were included in the analysis. The most common primary tumor site was the intra-abdominal or pelvic cavity (56%), followed by the trunk and abdominal wall (24%), extremities (16%), and head and neck (4%). Sixty percent of the patients had familial adenomatous polyposis and 76% received doxorubicin plus dacarbazine. The objective response rate and disease control rate was 64% (95% confidence interval [CI]: 40.7-82.8) and 96% (95% CI: 77.2-99.9), respectively. With the median follow-up time of 55 months (95% CI: 41.0-68.2), the 3-year PFS rate was 65% (95% CI: 41.1-80.5), and the 3-year OS rate was 89% (95% CI: 63.8-97.3). Grade 3 or 4 hematologic adverse events were reported in 14 patients, all of which were manageable. CONCLUSION: Our real-world evidence suggests that doxorubicin-based cytotoxic chemotherapy can be an effective treatment option for recurrent and progressive desmoid tumors with respect to favorable clinical outcomes.

Clinical Activity of TGF-ß Inhibitor Vactosertib in Combination with Imatinib in Desmoid Tumors: A Multicenter Phase Ib/II Study.

PURPOSE: The study was to determine the activity and safety of the TGF-ß inhibitor vactosertib in combination with imatinib in patients with desmoid tumors. PATIENTS AND METHODS: In this investigator-initiated, open-label, multicenter, phase Ib/II trial, patients with desmoid tumors not amenable to locoregional therapies (surgery and/or radiotherapy) or with disease progression following at least one treatment were enrolled. Participants were administered 400 mg imatinib daily in combination with vactosertib (5 days on and 2 days off, twice a day) every 28 days. In phase Ib, the vactosertib dose was set at 100 mg (level -1) and 200 mg (level 1) to determine the recommended phase II dose (RP2D). Phase II assessed the efficacy, with the primary endpoint being progression-free rate (PFR) at 16 weeks. RESULTS: No dose-limiting toxicities were observed during phase Ib; therefore RP2D was defined at doses of 400 mg imatinib daily in combination with 200 mg vactosertib. Of the 27 patients evaluated, 7 (25.9%) achieved a confirmed partial response and 19 (70.4%) were stable. The PFR at 16 weeks and 1 year were 96.3% and 81.0%, respectively. Most toxicities were mild to moderate myalgia (n = 10, 37%), anemia (n = 10, 37%), and nausea (n = 9, 33.3%). Common grade 3 to 4 toxicities included neutropenia (n = 6, 22.2%) and anemia (n = 5, 18.5%). CONCLUSIONS: The vactosertib and imatinib combination was well tolerated, with promising clinical activity in patients with progressive, locally advanced desmoid tumors. This is the first study investigating a novel target agent, a TGF-ß inhibitor, in this rare and difficult-to-treat desmoid tumor.

21-gene expression assay and clinical outcomes of premenopausal patients with hormone receptor-positive breast cancer.

The prognostic role of the recurrence score (RS) based on the 21-gene expression assay in premenopausal women is not well delineated, and we investigated the association of outcomes and the RS in premenopausal patients who had 21-gene expression assay at Asan Medical Center, Seoul, Korea, between June 2005 and July 2018. Invasive breast cancer-free survival (IBCFS) by STEEP version 2.0 was compared according to the RS and clinical risk factors. A total of 554 patients were included in our study and 116 patients (20.9%) had age <40 years, 238 patients (43.0%) had luminal B subtype (Ki67 ≥ 20%), and 83 patients (15.0%) had RS >25. All patients received adjuvant tamoxifen ± chemotherapy. Overall, patients with RS >25 showed trend toward worse IBCFS from multivariable analysis (adjusted HR 1.89 [95% CI: 0.95-3.73], P = .069). When comparing outcomes according to age and luminal subtypes, patients with luminal B subtype and age <40 years (n = 60) showed significantly worse outcomes compared to the others (luminal A or luminal B + age ≥40 years, n = 494; adjusted HR 2.95 [95% CI: 1.49-5.82], log-rank P < .001). Among patients with luminal B subtype and age <40 years, there was no significant association observed between IBCFS and the RS (log-rank P = .51). In conclusion, while RS >25 showed association with poor outcomes in premenopausal women, it may have less prognostic significance among those with luminal B subtype and age <40 years.

Clinical Outcomes of Intracardiac Echocardiography-Guided Contrast Agent-Free Cryoballoon Ablation in Atrial Fibrillation Patients With Renal Insufficiency.

BACKGROUND AND OBJECTIVES: Previous studies have reported an association between impaired renal function and poor outcomes after radiofrequency catheter ablation in patients with atrial fibrillation (AF). However, outcomes of cryoballoon ablation (CBA) in patients with renal insufficiency are not fully elucidated. This study aimed to compare outcomes of CBA in AF patients with chronic kidney disease (CKD) versus those without CKD and to assess changes in renal function over 12 months following CBA. METHODS: A total of 839 patients (65.1% with non-paroxysmal AF [PAF]) who underwent de novo CBA were prospectively enrolled. We divided patients into two groups based on creatinine clearance rate (CCr) and performed intracardiac echocardiography (ICE)-guided contrast agent-free CBA. RESULTS: In comparison with patients without CKD (CCr >50, n=722), those with CKD (CCr ≤50, n=117) were older and predominantly female, had a lower body mass index, and showed a higher prevalence of heart failure and hypertension. Mean CHA2DS2-VAS score was significantly higher in CKD group than in non-CKD group. Procedure-related complications were not significantly different between two groups. During a mean follow-up period of 25.4±11.9 months, clinical recurrence occurred in 182 patients (21.7%) and not significantly different between two groups. In multivariate analysis, non-PAF and left atrial size were independent predictors of AF recurrence. CCr levels significantly improved over 12 months after CBA in CKD group. CONCLUSIONS: ICE-guided contrast-agent-free CBA showed comparable long-term clinical outcomes without increasing procedure-related complications and improvement of renal function over 12 months following CBA in AF patients with CKD.

Pembrolizumab Plus Chemotherapy Followed by Pembrolizumab in Patients With Early Triple-Negative Breast Cancer: A Secondary Analysis of a Randomized Clinical Trial.

Importance: In the phase 3 KEYNOTE-522 study, addition of pembrolizumab to neoadjuvant chemotherapy followed by adjuvant pembrolizumab significantly increased pathologic complete response (pCR) and event-free survival (EFS) vs neoadjuvant chemotherapy in patients with early triple-negative breast cancer. Objective: To evaluate efficacy and safety outcomes for patients enrolled in East/Southeast Asia (Asia) in KEYNOTE-522. Design, Setting, and Participants: KEYNOTE-522, a multicenter, double-blind, randomized clinical trial, enrolled 1174 patients between March 7, 2017, and September 13, 2018. For interim EFS and overall survival (OS) analyses (data cutoff, March 23, 2021), median follow-up was 39.8 months (range, 30.4-46.9 months) for pembrolizumab plus chemotherapy and 40.8 months (range, 30.1-46.9 months) for placebo plus chemotherapy. Data cutoff for pCR analysis was September 24, 2018. This secondary analysis included adults enrolled in Asia with newly diagnosed, previously untreated, nonmetastatic triple-negative breast cancer (tumor stage T1c and nodal stage N1-2 or tumor stage T2-4 and nodal stage N0-2) and Eastern Cooperative Oncology Group performance status of 0 to 1, regardless of programmed cell death ligand 1 (PD-L1) status. Intervention: Patients were randomized 2:1 to 4 cycles of pembrolizumab (200 mg every 3 weeks) or placebo plus carboplatin and paclitaxel and another 4 cycles of pembrolizumab or placebo plus doxorubicin or epirubicin and cyclophosphamide before surgery. After definitive surgery, patients received pembrolizumab or placebo every 3 weeks for 9 cycles or until recurrence or unacceptable toxic effects. Main Outcomes and Measures: The main outcome was pCR (no evidence of primary tumor after neoadjuvant therapy or carcinoma in situ after neoadjuvant therapy and no regional lymph node involvement after neoadjuvant therapy) at the time of definitive surgery and EFS. Results: A total of 216 of 1174 randomized patients (all female; median [range] age, 46.0 [24.0-71.0] years) were from Korea, Japan, Taiwan, and Singapore (136 in the pembrolizumab plus chemotherapy group and 80 in the placebo plus chemotherapy group). Of these patients, 104 (76.5%) in the pembrolizumab plus chemotherapy group and 60 (75.0%) in the placebo plus chemotherapy group had a tumor PD-L1 combined positive score of 1 or greater. Pathologic complete response was 58.7% (95% CI, 46.7%-69.9%) with pembrolizumab plus chemotherapy and 40.0% (95% CI, 26.4%-54.8%) with placebo plus chemotherapy; benefit was observed regardless of PD-L1 status. Thirteen patients (9.6%) in the pembrolizumab plus chemotherapy group and 20 patients (25.0%) in the placebo plus chemotherapy group had EFS events (hazard ratio, 0.35; 95% CI, 0.17-0.71). The 36-month EFS rate was 91.2% (95% CI, 85.0%-94.9%) with pembrolizumab plus chemotherapy and 77.2% (95% CI, 66.3%-85.0%) with placebo plus chemotherapy. Grade 3 to 4 treatment-related adverse events occurred in 109 patients (80.1%) receiving pembrolizumab plus chemotherapy and 64 patients (81.0%) receiving placebo plus chemotherapy. Conclusions and Relevance: In this subgroup analysis of patients enrolled in Asia in KEYNOTE-522, neoadjuvant pembrolizumab plus chemotherapy followed by adjuvant pembrolizumab led to clinically meaningful improvements in pCR and EFS vs neoadjuvant chemotherapy alone. These findings support the use of neoadjuvant pembrolizumab plus chemotherapy followed by adjuvant pembrolizumab as a standard-of-care therapy for patients in Asian countries with early triple-negative breast cancer. Trial Registration: ClinicalTrials.gov Identifier: NCT03036488.

Effect of High-Intensity Rosuvastatin vs. Combination of Low-Intensity Rosuvastatin and Ezetimibe on HbA1c Levels in Patients without Diabetes: A Randomized IDEAL Trial.

There is a dearth of studies investigating whether the combination of low-intensity statins with ezetimibe can reduce the risk of diabetes in patients requiring statin therapy. Therefore, we aimed to evaluate the effects of combination therapy on the prevention of glycated hemoglobin (HbA1c) elevation in patients without diabetes. Sixty-eight patients were randomly assigned in a 1:1 ratio to receive a combination of low-intensity rosuvastatin (5 mg/day) and ezetimibe (10 mg/day) or high-intensity rosuvastatin (20 mg/day). The primary endpoint was the absolute difference in the HbA1c levels at 12 weeks. The HbA1c level showed an overall elevation of 0.11% at 12 weeks compared to that at baseline (mean ± standard deviation: 5.78 ± 0.3%, 95% confidence interval [CI]: 5.86-6.07, p = 0.044). The HbA1c levels did not differ between the groups at 12 weeks (least square mean difference: 0.001, 95% CI: 0.164-0.16, p = 0.999). Our study found that the combination of low-intensity rosuvastatin and ezetimibe did not yield significant differences in HbA1c levels compared to high-intensity rosuvastatin alone after 12 weeks in patients without diabetes. This suggests that the combination of low-intensity rosuvastatin and ezetimibe may not be an effective strategy for preventing HbA1c elevation in patients without diabetes requiring statins.

Prognostic implications of HER2 changes after neoadjuvant chemotherapy in patients with HER2-zero and HER2-low breast cancer.

BACKGROUND: The transition of human epidermal growth factor receptor 2 (HER2) status after neoadjuvant chemotherapy (NAC) in HER2-low breast cancer has not been thoroughly evaluated. Here, we evaluated the HER2 transition among HER2-zero and HER2-low breast cancer cases post-NAC and its impact on clinical outcomes. METHODS: We included 1288 patients with HER2-low or zero breast cancer who underwent NAC and surgery between 2014 and 2018 and had paired pre- and post-therapeutic HER2 status results. RESULTS: Among patients who were HER2-zero pre-NAC (n = 650), 68% and 29% were HER2-zero and HER2-low, respectively, post-NAC. Among patients who were HER2-low pre-NAC (n = 638), 32% of patients showed HER2 changes (low to zero), and 59% of patients had a constant HER2-low status post-NAC. Patients with constant HER2-low or transitions from HER2-low to zero had a higher proportion of hormone receptor positivity (84% and 79%) than those with changes from HER2-zero to low (77%) or with constant HER2-zero (56%), respectively. Multivariable logistic regression analysis revealed that patients with oestrogen receptor positivity had a higher probability of gaining HER2-low expression than those with oestrogen receptor negativity (odds ratio 2.48). No significant differences were observed in terms of overall survival or disease-free survival between patients with and without HER2-changes according to their hormone receptor status, except in the post-therapeutic HER2-low, hormone receptor-negativity subset. CONCLUSION: Temporal heterogeneity of HER2-low expression is observed in substantial numbers of post-NAC breast cancer patients. Clinical outcomes show no significant associations, except in the post-therapeutic HER2-low, hormone receptor negativity subset. The prognostic implications of HER2 transition in HER2-low breast cancer require further investigation.

Net clinical benefit of oral anticoagulants in Korean atrial fibrillation patients with low to intermediate stroke risk: A report from the Clinical Survey on Stroke Prevention in patients with Atrial Fibrillation (CS-SPAF).

Background: The balance of stroke risk reduction and potential bleeding risk associated with antithrombotic treatment (ATT) remains unclear in atrial fibrillation (AF) at non-gender CHA2DS2-VASc scores 0-1. A net clinical benefit (NCB) analysis of ATT may guide stroke prevention strategies in AF with non-gender CHA2DS2-VASc scores 0-1. Methods: This multi-center cohort study evaluated the clinical outcomes of treatment with a single antiplatelet (SAPT), vitamin K antagonist (VKA), and non-VKA oral anticoagulant (NOAC) in non-gender CHA2DS2-VASc score 0-1 and further stratified by biomarker-based ABCD score (Age [≥60 years], B-type natriuretic peptide [BNP] or N-terminal pro-BNP [≥300 pg/mL], creatinine clearance [<50 mL/min], and dimension of the left atrium [≥45 mm]). The primary outcome was the NCB of ATT, including composite thrombotic events (ischemic stroke, systemic embolism, and myocardial infarction) and major bleeding events. Results: We included 2465 patients (age 56.2 ± 9.5 years; female 27.0%) followed-up for 4.0 ± 2.8 years, of whom 661 (26.8%) were treated with SAPT; 423 (17.2%) with VKA; and 1040 (42.2%) with NOAC. With detailed risk stratification using the ABCD score, NOAC showed a significant positive NCB compared with the other ATTs (SAPT vs. NOAC, NCB 2.01, 95% confidence interval [CI] 0.37-4.66; VKA vs. NOAC, NCB 2.38, 95% CI 0.56-5.40) in ABCD score ≥1. ATT failed to show a positive NCB in patients with truly low stroke risk (ABCD score = 0). Conclusions: In the Korean AF cohort at non-gender CHA2DS2-VASc scores 0-1, NOAC showed significant NCB advantages over VKA or SAPT with ABCD score ≥1.

Randomized phase III trial of a neoadjuvant regimen of four cycles of adriamycin plus cyclophosphamide followed by four cycles of docetaxel (AC4-D4) versus a shorter treatment of three cycles of FEC followed by three cycles of docetaxel (FEC3-D3) in node-positive breast cancer (Neo-shorter; NCT02001506).

PURPOSE: To determine whether six cycles of FEC3-D3 has a comparable efficacy to eight of AC4-D4. METHODS: The enrolled patients (pts) were clinically diagnosed with stage II or III breast cancer. The primary endpoint was a pathologic complete response (pCR), and the secondary endpoints were 3 year disease-free survival (3Y DFS), toxicities, and health-related quality of life (HRQoL). We calculated that 252 pts were needed in each treatment group to enable the detection of non-inferiority (non-inferiority margin of 10%). RESULTS: In terms of ITT analysis, 248 pts were finally enrolled. The 218 pts who completed the surgery were included in the current analysis. The baseline characteristics of these subjects were well balanced between the two arms. By ITT analysis, pCR was achieved in 15/121 (12.4%) pts in the FEC3-D3 arm and 18/126 (14.3%) in the AC4-D4 arm. With a median follow up of 64.1 months, the 3Y DFS was comparable between the two arms (75.8% in FEC3-D3 vs. 75.6% in AC4-D4). The most common adverse event (AE) was Grade 3/4 neutropenia, which arose in 27/126 (21.4%) AC4-D4 arm pts vs 23/121 (19.0%) FEC3-D3 arm cases. The primary HRQoL domains were similar between the two groups (FACT-B scores at baseline, P = 0.35; at the midpoint of NACT, P = 0.20; at the completion of NACT, P = 0.44). CONCLUSION: Six cycles of FEC3-D3 could be an alternative to eight of AC4-D4. Trial registration ClinicalTrials.gov NCT02001506. Registered December 5,2013. https://clinicaltrials.gov/ct2/show/NCT02001506.

Safety and efficacy of intracardiac echocardiography-guided zero-fluoroscopic cryoballoon ablation for atrial fibrillation: a prospective randomized controlled trial.

AIMS: The development of intracardiac echocardiography (ICE) has enabled fluoroless atrial fibrillation (AF) ablation using three-dimensional electroanatomical mapping systems. However, fluoroless cryoballoon ablation (CBA) remains challenging, mainly because of the lack of a visual mapping system. Hence, this study aimed to investigate the safety and efficacy of fluoroless CBA for AF under ICE guidance. METHODS AND RESULTS: Patients (n = 100) who underwent CBA for paroxysmal AF were randomly assigned to zero-fluoroscopic (Zero-X) and conventional groups. Intracardiac echocardiography was used to guide the transseptal puncture and catheter and balloon manipulation in all enrolled patients. The patients were prospectively followed for 12 months after CBA. The mean age was 60.4 years, and the left atrial (LA) size was 39.4 mm. Pulmonary vein isolation (PVI) was achieved in all patients. In the Zero-X group, fluoroscopy was used in only one patient because of unstable phrenic nerve capture during right-sided PVI. The procedure time and LA indwelling time in the Zero-X group were not statistically different compared with that in the conventional group. Fluoroscopic time (9.0 vs. 0.008 min) and radiation exposure (29.4 vs. 0.02 mGy) were significantly shorter in the Zero-X group than in the conventional group (P < 0.001). The complication rate did not differ between the two groups. During a mean follow-up of 663.3 ± 172.3 days, the recurrence rate was similar (16.0 vs. 18.0%; P = 0.841) between the groups. Multivariate analysis revealed that LA size was the only independent predictor of clinical recurrence. CONCLUSION: Intracardiac echocardiography-guided fluoroless CBA for AF was a feasible strategy without compromising acute and long-term success or complication rates.

Cardiac Safety and Efficacy of SB3 Trastuzumab Biosimilar for ERBB2-Positive Early Breast Cancer: Secondary Analysis of a Randomized Clinical Trial.

Importance: Trastuzumab has been the standard of care for the treatment of patients with ERBB2-positive breast cancer; however, cardiac events have been reported. This long-term follow-up study provides clinical evidence supporting the similarity of a trastuzumab biosimilar (SB3) to reference trastuzumab (TRZ). Objective: To compare cardiac safety and efficacy between SB3 and TRZ for patients with ERBB2-positive early or locally advanced breast cancer after up to 6 years of follow-up. Design, Setting, and Participants: This prespecified secondary analysis of a randomized clinical trial, conducted from April 2016 to January 2021, included patients with ERBB2-positive early or locally advanced breast cancer from a multicenter double-blind, parallel-group, equivalence phase 3 randomized clinical trial of SB3 vs TRZ with concomitant neoadjuvant chemotherapy who completed neoadjuvant and adjuvant treatment. Interventions: In the original trial, patients were randomized to either SB3 or TRZ with concomitant neoadjuvant chemotherapy for 8 cycles (4 cycles of docetaxel followed by 4 cycles of fluorouracil, epirubicin, and cyclophosphamide). After surgery, patients continued SB3 or TRZ monotherapy for 10 cycles of adjuvant treatment per previous treatment allocation. Following neoadjuvant and adjuvant treatment, patients were monitored for up to 5 years. Main Outcomes and Measures: The primary outcomes were the incidence of symptomatic congestive heart failure and asymptomatic, significant decrease in left ventricular ejection fraction (LVEF). The secondary outcomes were event-free survival (EFS) and overall survival (OS). Results: A total of 538 female patients were included (median age, 51 years [range, 22-65 years]). Baseline characteristics were comparable between the SB3 and TRZ groups. Cardiac safety was monitored for 367 patients (SB3, n = 186; TRZ, n = 181). Median follow-up was 68 months (range, 8.5-78.1 months). Asymptomatic, clinically significant LVEF decreases were rarely reported (SB3, 1 patient [0.4%]; TRZ, 2 [0.7%]). No patient experienced symptomatic cardiac failure or death due to a cardiovascular event. Survival was evaluated for the 367 patients in the cardiac safety cohort and an additional 171 patients enrolled after a protocol amendment (538 patients [SB3, n = 267; TRZ, n = 271]). No difference was observed in EFS or OS between treatment groups (EFS: hazard ratio [HR], 0.84; 95% CI, 0.58-1.20; P = .34; OS: HR, 0.61; 95% CI, 0.36-1.05; P = .07). Five-year EFS rates were 79.8% (95% CI, 74.8%-84.9%) in the SB3 group and 75.0% (95% CI, 69.7%-80.3%) in the TRZ group, and OS rates were 92.5% (95% CI, 89.2%-95.7%) in the SB3 group and 85.4% (95% CI, 81.0%-89.7%) in the TRZ group. Conclusions and Relevance: In this secondary analysis of a randomized clinical trial, SB3 demonstrated cardiac safety and survival comparable to those of TRZ after up to 6 years of follow-up in patients with ERBB2-positive early or locally advanced breast cancer. Trial Registration: ClinicalTrials.gov Identifier: NCT02771795.

The effect of nicorandil on cardiac function and clinical outcomes in ST-segment elevation myocardial infarction patients undergoing primary percutaneous coronary intervention: a randomised trial.

BACKGROUND: We investigated the effect of nicorandil on infarct size, cardiac function assessed by cardiac magnetic resonance imaging (CMR) and outcomes in ST-segment elevation myocardial infarction (STEMI) patients undergoing primary percutaneous coronary intervention (PCI). METHODS: In a prospective, randomised, controlled trial, 83 patients with STEMI receiving primary PCI were randomised into the nicorandil (n =  40) or placebo (n  =  43) groups. Nicorandil was administered in the emergency room before primary PCI as an intravenous bolus of 4 mg followed by a continuous infusion of 6 mg/h for 24 h and as 2-mg intracoronary injections prior to balloon dilatation and coronary stenting. Nicorandil was continued orally at 10-20 mg/d for 6 months. Infarct size and cardiac function were measured by CMR at 5 d and 6 months after primary PCI. Furthermore, major adverse cardiac events (MACEs) including all-cause death, nonfatal myocardial infarction (MI), any revascularisation, stroke, and definite/probable stent thrombosis (ST) were compared. RESULTS: There were no significant differences in baseline clinical characteristics between the groups. Infarct size at baseline and 6 months as well as infarct size changes during 6 months as measured by CMR were similar between the groups. Similarly, other CMR parameters were comparable at baseline and 6 months between the groups. MACEs occurred in four patients (4.8%) during 6 months. No significant difference in the risk of MACEs was observed between the groups. CONCLUSIONS: Treatment with nicorandil for 6 months after primary PCI was not associated with any improvement in infarct size, CMR-determined cardiac function, and outcomes in STEMI patients.

E/e' Ratio Predicts the Atrial Pacing-Induced Left Atrial Pressure Response in Patients with Preserved Ejection Fraction.

Background and Objectives: Left atrial hypertension is one of the pathophysiologies of heart failure with preserved ejection fraction. We hypothesized that left atrial pressure response (LAPR) to incremental pacing is higher in patients with atrial fibrillation (AF) and can predict left ventricular diastolic dysfunction. Materials and Methods: Patients requiring left atrial access as a part of a therapeutic procedure for AF (n = 204, AF group) or supraventricular tachycardia (n = 34, control group) were analyzed (male n = 183, 54 ± 12 years old). LAPR was measured during incremental pacing. Results: Baseline left atrial pressure and LAPR at all pacing rates were not different between the AF and control groups. They were higher in patients with a high E/e' (≥ 8) than in those with a low E/e' (<8). LAPR at a pacing interval of 400 ms and E/e' were positively correlated (r = 0.373, p < 0.001). Body mass index and a high E/e' were independent predictors of pacing-induced left atrial hypertension. Conclusions: LAPR to incremental pacing was constant regardless of AF. The non-invasive echocardiographic marker E/e' reflected pacing-induced left atrial hypertension.

Heritable defects in telomere and mitotic function selectively predispose to sarcomas.

Cancer genetics has to date focused on epithelial malignancies, identifying multiple histotype-specific pathways underlying cancer susceptibility. Sarcomas are rare malignancies predominantly derived from embryonic mesoderm. To identify pathways specific to mesenchymal cancers, we performed whole-genome germline sequencing on 1644 sporadic cases and 3205 matched healthy elderly controls. Using an extreme phenotype design, a combined rare-variant burden and ontologic analysis identified two sarcoma-specific pathways involved in mitotic and telomere functions. Variants in centrosome genes are linked to malignant peripheral nerve sheath and gastrointestinal stromal tumors, whereas heritable defects in the shelterin complex link susceptibility to sarcoma, melanoma, and thyroid cancers. These studies indicate a specific role for heritable defects in mitotic and telomere biology in risk of sarcomas.

A Phase II Trial of S-1 and Oxaliplatin in Patients with Metastatic Breast Cancer Previously Treated with Anthracycline and Taxane (KCSG-BR07-03).

PURPOSE: This single-arm phase II trial investigate the efficacy and safety of S-1 plus oxaliplatin (SOX) in patients with metastatic breast cancer. Materials and Methods: Patients with metastatic breast cancer previously treated with anthracyclines and taxanes were enrolled. Patients received S-1 (40-60 mg depending on patient's body surface area, twice a day, day 1-14) and oxaliplatin (130 mg/m2, day 1) in 3 weeks cycle until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR) according to Response Evaluation Criteria in Solid Tumor 1.1. Secondary endpoints included time-to-progression (TTP), duration-of-response (DoR), overall survival (OS), and adverse events. RESULTS: A total of 87 patients were enrolled from 11 institutions in Korea. Hormone receptor was positive in 54 (62.1%) patients and six (6.9%) had human epidermal growth factor receptor 2-positive disease. Forty-eight patients (85.1%) had visceral metastasis and 74 (55.2%) had more than three sites of metastases. The ORR of SOX regimen was 38.5% (95% confidence interval [CI], 26.9 to 50.0) with a median TTP of 6.0 months (95% CI, 5.1 to 6.9). Median DoR and OS were 10.3 months (95% CI, 5.5 to 15.1) and 19.4 (95% CI, not estimated) months, respectively. Grade 3 or 4 neutropenia was reported in 28 patients (32.1%) and thrombocytopenia was observed in 23 patients (26.6%). CONCLUSION: This phase II study showed that SOX regimen is a reasonable option in metastatic breast cancer previously treated with anthracyclines and taxanes.

Safety of a single bolus administration of heparin without the measurement of activated clotting time during cryoballoon ablation: a prospective randomized controlled trial.

BACKGROUND: Single-shot ablation has emerged as an effective technique for index atrial fibrillation (AF) ablation, with an advantage of short procedure time. Although recent guidelines recommend peri-procedural uninterrupted oral anticoagulants (OACs), the intra-procedural anticoagulation strategy remains uncertain under non-vitamin K OACs (NOACs). We investigated procedural safety of a single bolus administration of heparin without activated clotting time (ACT) measurement during cryoballoon ablation (CBA). METHODS: Two hundred patients (64.2 ± 10.0 years, 70% with non-paroxysmal AF) who underwent CBA with uninterrupted NOACs were randomly assigned to No-ACT group and ACT group. A bolus of heparin (100 U/kg) was routinely administered immediately after transseptal puncture. In the ACT group, an additional injection of heparin (30 U/kg) was administered if ACT at 30 min after the initial bolus was < 300 s. RESULTS: There were no differences in baseline characteristics including CHA2DS2-VASc score between the two groups. The left atrium indwelling and procedure times were 60.4 ± 13.1 min and 78.9 ± 13.9 min, respectively, and not significantly different between the two groups. The mean ACT was 335.2 ± 59.9 s in the ACT group. Any bleeding rate was 3.2% in all patients and there was no statistically significant difference in bleeding complications between the two groups. In the ACT group, groin hematoma, laryngopharyngeal bleeding, and hemoptysis occurred in 3, 1, and 1 patient, respectively. Cardiac tamponade occurred in 1 patient in the No-ACT group. No thromboembolic events occurred during the 30-day follow-up after CBA. CONCLUSIONS: Single bolus administration of heparin without ACT measurement is a feasible anticoagulation strategy for CBA in patients with uninterrupted NOAC intake.

Pathological complete response, long-term outcomes, and recurrence patterns in HER2-low versus HER2-zero breast cancer after neoadjuvant chemotherapy.

BACKGROUND: The interest in HER2-low breast cancer (BC) has increased in recent years with the development of novel anti-HER2 antibody-drug conjugates. Here, we investigated the clinical outcomes and relapse patterns of patients with HER2-low or -zero BCs in an Asian population. METHODS: We retrospectively identified HER2-low or -zero BC patients with stage I-III tumours who were treated with neoadjuvant chemotherapy and underwent curative surgery, between 2014 and 2018 at Asan Medical Center, Seoul, Korea. RESULTS: A total of 818 and 754 HER2-zero and HER2-low BC patients, respectively, were consecutively included in this analysis. The HER2-low group had more hormone receptor [HR]-positive patients (81% versus 56%, P < 0.001). The HER2-zero group had a higher proportion of patients who achieved pathological complete response (pCR) (14.7% versus 9.8%, P = 0.003); however, no significant differences of pCR rate by HER2 status were identified in the HR-positive (P = 0.4) and HR-negative groups (P = 0.3) when analysed separately. The HER2-low BC cases had higher 5-year overall survival (OS) and disease-free survival (DFS) rates (P < 0.001 for OS; P = 0.002 for DFS); however, no differences were observed in terms of OS and DFS by HER2 status in the HR-positive group (P = 0.21 for OS and P = 0.66 for DFS). CONCLUSIONS: Our current findings do not support that HER2-low BC had different biology and clinical features compared to HER2-zero BC in patients who treated with neoadjuvant chemotherapy. However, the prognostic impact of HER2-low status in BC remains controversial; thus warranting further research.

Validation of Biomarker-Based ABCD Score in Atrial Fibrillation Patients with a Non-Gender CHA2DS2-VASc Score 0-1: A Korean Multi-Center Cohort.

PURPOSE: Atrial fibrillation (AF) patients with low to intermediate risk, defined as non-gender CHA2DS2-VASc score of 0-1, are still at risk of stroke. This study verified the usefulness of ABCD score [age (≥60 years), B-type natriuretic peptide (BNP) or N-terminal pro-BNP (≥300 pg/mL), creatinine clearance (<50 mL/min/1.73 m²), and dimension of the left atrium (≥45 mm)] for stroke risk stratification in non-gender CHA2DS2-VASc score 0-1. MATERIALS AND METHODS: This multi-center cohort study retrospectively analyzed AF patients with non-gender CHA2DS2-VASc score 0-1. The primary endpoint was the incidence of stroke with or without antithrombotic therapy (ATT). An ABCD score was validated. RESULTS: Overall, 2694 patients [56.3±9.5 years; female, 726 (26.9%)] were followed-up for 4.0±2.8 years. The overall stroke rate was 0.84/100 person-years (P-Y), stratified as follows: 0.46/100 P-Y for an ABCD score of 0; 1.02/100 P-Y for an ABCD score ≥1. The ABCD score was superior to non-gender CHA2DS2-VASc score in the stroke risk stratification (C-index=0.618, p=0.015; net reclassification improvement=0.576, p=0.040; integrated differential improvement=0.033, p=0.066). ATT was prescribed in 2353 patients (86.5%), and the stroke rate was significantly lower in patients receiving non-vitamin K antagonist oral anticoagulant (NOAC) therapy and an ABCD score ≥1 than in those without ATT (0.44/100 P-Y vs. 1.55/100 P-Y; hazard ratio=0.26, 95% confidence interval 0.11-0.63, p=0.003). CONCLUSION: The biomarker-based ABCD score demonstrated improved stroke risk stratification in AF patients with non-gender CHA2DS2-VASc score 0-1. Furthermore, NOAC with an ABCD score ≥1 was associated with significantly lower stroke rate in AF patients with non-gender CHA2DS2-VASc score 0-1.

Response Rate and Safety of a Neoadjuvant Pertuzumab, Atezolizumab, Docetaxel, and Trastuzumab Regimen for Patients With ERBB2-Positive Stage II/III Breast Cancer: The Neo-PATH Phase 2 Nonrandomized Clinical Trial.

Importance: Addition of immune checkpoint inhibitors to anti-ERBB2 treatment has shown synergistic efficacy in preclinical studies and is thus worth investigating as a neoadjuvant treatment to maximize efficacy and to minimize toxic effects. Objective: To determine if neoadjuvant atezolizumab, docetaxel, trastuzumab, and pertuzumab therapy for ERBB2-positive early breast cancer warrants continuation to the next phase. Design, Setting, and Participants: This nonrandomized, open label, multicenter, phase 2 trial was conducted by the Korean Cancer Study Group and enrolled patients across 6 institutions in Korea from May 2019 to May 2020. Eligible patients were diagnosed with ERBB2-positive breast cancer (primary tumor size >2 cm or pathologically confirmed lymph node-positive cancer, without distant metastases) with a clinical stage of II or III. Interventions: Patients received 6 cycles of neoadjuvant pertuzumab (840 mg at first cycle, 420 mg during subsequent cycles), atezolizumab (1200 mg), docetaxel (75 mg/m2), and trastuzumab (600 mg via subcutaneous injection) every 3 weeks, followed by surgery. Patients with pathologic complete response (pCR) received 12 cycles of adjuvant atezolizumab, trastuzumab, and pertuzumab every 3 weeks after surgery. Patients without pCR were treated with 14 cycles of atezolizumab, 1200 mg, plus trastuzumab emtansine, 3.6 mg/kg, every 3 weeks. Main Outcomes and Measures: The primary end point was pCR rate, which was defined as the absence of invasive cancer cells in the primary tumor and regional lymph nodes (ypT0/isN0). Secondary end points included clinical objective response rate, 3-year event-free survival rate according to pCR achievement, disease-free survival, overall survival, toxic effects, and quality-of-life outcomes. Results: A total of 67 women (median [range] age, 52 [33-74] years) were enrolled. Hormone receptor expression was positive in 32 (48%) patients. Curative surgery was performed in 65 patients because 2 patients showed disease progression during neoadjuvant treatment and their tumors became unresectable. The overall pCR rate was 61% (41 of 67 patients). The pCR rate was higher in hormone receptor-negative disease vs hormone receptor-positive disease (27 of 35 [77%] patients vs 14 of 32 [44%] patients) and in programmed cell death 1-positive expression vs programmed cell death 1-negative expression (13 of 13 [100%] patients vs 28 of 53 [53%] patients). Grade 3 and 4 neutropenia and febrile neutropenia occurred in 8 (12%) patients and 5 (8%) patients, respectively. Grade 3 and 4 immune-related adverse events occurred in only 4 patients (grade 3 skin rash, encephalitis, hepatitis, and fever). No treatment-related death occurred during the neoadjuvant phase. Conclusions and Relevance: In this nonrandomized clinical trial, treatment with the neoadjuvant atezolizumab, docetaxel, trastuzumab, and pertuzumab regimen in patients with stage II or III ERBB2-positive breast cancer appears to have had an acceptable pCR rate and modest toxic effects. Further investigation of this immunotherapy combination in ERBB2-positive early breast cancer is warranted. Trial Registration: ClinicalTrials.gov Identifier: NCT03881878.

Association between tumor 18F-fluorodeoxyglucose metabolism and survival in women with estrogen receptor-positive, HER2-negative breast cancer.

We examined whether 18F-fluorodeoxyglucose metabolism is associated with distant relapse-free survival (DRFS) and overall survival (OS) in women with estrogen receptor (ER)-positive, HER2-negative breast cancer. This was a cohort study examining the risk factors for survival that had occurred at the start of the study. A cohort from Asan Medical Center, Korea, recruited between November 2007 and December 2014, was included. Patients received anthracycline-based neoadjuvant chemotherapy. The maximum standardized uptake value (SUV) of 18F-fluorodeoxyglucose positron emission tomography/computed tomography (PET/CT) was measured. The analysis included 466 women. The median (interquartile range) follow-up period without distant metastasis or death was 6.2 (5.3-7.6) years. Multivariable analysis of hazard ratio (95% confidence interval [CI]) showed that the middle and high tertiles of SUV were prognostic for DRFS (2.93, 95% CI 1.62-5.30; P < 0.001) and OS (4.87, 95% CI 1.94-12.26; P < 0.001). The 8-year DRFS rates were 90.7% (95% CI 85.5-96.1%) for those in the low tertile of maximum SUV vs. 73.7% (95% CI 68.0-79.8%) for those in the middle and high tertiles of maximum SUV. 18F-fluorodeoxyglucose PET/CT may assess the risk of distant metastasis and death in ER-positive, HER2-negative patients.