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Ibrutinib-based therapies are costly and require continuous administration. We hypothesized combining BTK inhibition with anti-CD20 monoclonal antibodies would yield deep remissions allowing discontinuation. We enrolled 32 therapy-naïve CLL patients to receive ibrutinib plus obinutuzumab, followed by single-agent ibrutinib. Patients could discontinue ibrutinib after 36 months with sustained complete response (CR). We evaluated treatment safety, efficacy, and outcomes after ibrutinib discontinuation. The overall response rate was 100%, 28% achieved a CR, and 12.5% achieved bone marrow undetectable minimal residual disease. At a three-year median follow-up, 91% remain in remission with 100% overall survival. Five patients in sustained CR stopped ibrutinib and have not progressed. Eight non-CR patients discontinued for other reasons, with only two progressing. The treatment was safe, with a lower IRR rate. All patients responded to treatment with longer time-to-progression after discontinuation of ibrutinib. Our data support the evaluation of ibrutinib discontinuation strategies in more extensive clinical trials (https://Clinicaltrials.gov Identifier https://clinicaltrials.gov/ct2/show/NCT02315768).

Abstract Aims The current definition of post ST-segment elevation myocardial infarction (STEMI) left ventricular (LV) remodelling is purely structural (LV dilatation) and does not consider LV function (ejection fraction, EF), even though it is known to be a predictor of long-term post-STEMI outcome. This study aimed to reclassify LV remodelling after STEMI by integrating LV dilatation and function (LVEF) and to investigate the prognostic implications. Methods and results Data from an ongoing registry of STEMI patients who were treated with primary percutaneous coronary intervention (PCI) were retrospectively evaluated. Four distinct remodelling subgroups were identified: (i) no LV dilatation, no LVEF impairment,(ii) no LV dilatation but LVEF impairment, (iii) LV dilatation but no LVEF impairment, and (iv) LV dilatation and LVEF impairment. The impact of functional LV remodelling on outcomes was analysed. A total of 2346 patients were studied (mean age 60 ± 11 years, 76% men). During a median follow-up of 76 (interquartile range 52 to 107) months, 282 (12%) died, while the composite of death and heart failure hospitalization occurred in 305 (13%) patients. Those with LV remodelling and LVEF impairment had a significantly lower survival rate (P < 0.001) and event-free survival rate (P < 0.001) compared with other functional LV remodelling groups. Conclusions Employing a functional LV post-infarct remodelling classification has the potential to improve risk stratification beyond structural LV remodelling alone. Identification of patients with the worst prognosis by using a functional LV remodelling approach may allow institution of early preventative therapies.

PURPOSE Distant metastases are present in 6% or more of patients with newly diagnosed breast cancer. In this context, locoregional therapy for the intact primary tumor has been hypothesized to improve overall survival (OS), but clinical trials have reported conflicting results. METHODS Women presenting with metastatic breast cancer and an intact primary tumor received systemic therapy for 4-8 months; if no disease progression occurred, they were randomly assigned to locoregional therapy for the primary site (surgery and radiotherapy per standards for nonmetastatic disease) or continuing sysmetic therapy. The primary end point was OS; locoregional control and quality of life were secondary end points. The trial design provided 85% power to detect a 19.3% absolute difference in the 3-year OS rate in randomly assigned patients. The stratified log-rank test and Cox proportional hazards model were used to compare OS between arms. Cumulative incidence of locoregional progression was compared using Gray's test. Quality-of-life assessment used standard instruments. RESULTS Of 390 participants enrolled, 256 were randomly assigned: 131 to continued systemic therapy and 125 to early locoregional therapy. The 3-year OS was 67.9% without and 68.4% with early locoregional therapy (hazard ratio = 1.11; 90% CI, 0.82 to 1.52; P = .57). The median OS was 53.1 months (95% CI, 47.9 to not estimable) in the systemic therapy arm and 54.9 months (95% CI, 46.7 to not estimable) in the locoregional therapy arm. Locoregional progression was less frequent in those randomly assigned to locoregional therapy (3-year rate: 16.3% v 39.8%; P < .001). Quality-of-life measures were largely similar between arms. CONCLUSION Early locoregional therapy for the primary site did not improve survival in patients presenting with metastatic breast cancer. Although it was associated with improved locoregional control, this had no overall impact on quality of life.

Abstract Objective To study maternal anxiety in pregnant women without comorbidities in the context of the COVID-19 outbreak in Brazil and to study maternal knowledge and concerns about the pandemic. Methods This is a secondary analysis from a national multicenter cross-sectional study performed in 10 cities, from June to August, 2020, in Brazil. Interviewed postpartum women, without medical or obstetrical comorbidities, were included in the present subanalysis. A structured questionnaire and the Beck Anxiety Inventory (BAI) were applied. Results Out of the 1,662 women, 763 (45.9%) met the criteria for the current analysis and 16.1% presented with moderate and 11.5% with severe maternal anxiety. Moderate or severe maternal anxiety was associated with high school education (odds ratio [OR]:1.58; 95% confidence interval [CI]:1.04–2.40). The protective factor was cohabiting with a partner (OR: 0.46; 95%CI: 0.29–0.73). There was a positive correlation between the total BAI score and receiving information about care in the pandemic (rpartial 0.15; p < 0.001); concern about vertical transmission of COVID-19 (rpartial 0.10; p = 0.01); receiving information about breastfeeding (rpartial 0.08; p = 0.03); concerns about prenatal care (rpartial 0.10; p = 0.01), and concerns about the baby contracting COVID-19 (rpartial 0.11; p = 0.004). The correlation was negative in the following aspects: self-confidence in protecting from COVID-19 (rpartial 0.08; p = 0.04), having learned (rpartial 0.09; p = 0.01) and self-confidence in breastfeeding (rpartial 0.22; p < 0.001) in the context of the pandemic. Conclusion The anxiety of pregnant women without medical or obstetrical comorbidities was associated to high school educational level and not living with a partner during the COVID-19 pandemic. Self-confidence in protecting against COVID-19 and knowledge about breastfeeding care during the pandemic reduced maternal anxiety.

SummaryThe phase I/II AU‐003 study in patients with treatment‐naïve (TN) or relapsed/refractory (R/R) chronic lymphocytic leukaemia/small lymphocytic lymphoma demonstrated that zanubrutinib therapy results in clinically meaningful and durable responses with acceptable safety and tolerability. We report updated safety and efficacy data for 123 patients with a median follow‐up of 47·2 months. Patients received zanubrutinib 160 mg twice daily (81 patients), 320 mg once daily (40), or 160 mg once daily (two). Discontinuations due to adverse events or disease progression were uncommon. The overall response rate (ORR) was 95·9% (TN, 100%; R/R, 95%) with 18·7% achieving complete response (CR). Ongoing response at 3 years was reported in 85·7%. The ORR in patients with del(17p)/tumour protein p53 mutation was 87·5% (CR 16·7%). The 2‐ and 3‐year progression‐free survival estimates were 90% (TN, 90%; R/R, 91%) and 83% (TN, 81%; R/R, 83%) respectively. The most reported Grade ≥3 adverse events were neutropenia (15·4%), pneumonia (9·8%), hypertension (8·9%) and anaemia (6·5%). The annual incidence of atrial fibrillation, major haemorrhage, Grade ≥3 neutropenia and Grade ≥3 infection decreased over time. With a median follow‐up of ~4 years, responses remain clinically meaningful and durable and long‐term tolerability to zanubrutinib therapy continues.

The poly(ADP-ribose) binding protein CHFR regulates cellular responses to mitotic stress. The deubiquitinase UBC13, which regulates CHFR levels, has been associated with better overall survival in paclitaxel-treated ovarian cancer. Despite the extensive use of taxanes in the treatment of ovarian cancer, little is known about expression of CHFR itself in this disease. In the present study, tissue microarrays containing ovarian carcinoma samples from 417 women who underwent initial surgical debulking were stained with anti-CHFR antibody and scored in a blinded fashion. CHFR levels, expressed as a modified H-score, were examined for association with histology, grade, time to progression (TTP) and overall survival (OS). In addition, patient-derived xenografts from 69 ovarian carcinoma patients were examined for CHFR expression and sensitivity to paclitaxel monotherapy. In clinical ovarian cancer specimens, CHFR expression was positively associated with serous histology (p = 0.0048), higher grade (p = 0.000014) and higher stage (p = 0.016). After correction for stage and debulking, there was no significant association between CHFR staining and overall survival (p = 0.62) or time to progression (p = 0.91) in patients with high grade serous cancers treated with platinum/taxane chemotherapy (N = 249). Likewise, no association between CHFR expression and paclitaxel sensitivity was observed in ovarian cancer PDXs treated with paclitaxel monotherapy. Accordingly, differences in CHFR expression are unlikely to play a major role in paclitaxel sensitivity of high grade serous ovarian cancer.