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Abstract Background Breast conserving therapy (BCT) is accepted as a preferred option for unifocal breast cancer. However, the oncologic safety of BCT for multiple ipsilateral breast cancer (MIBC), has not been demonstrated in a prospective study. The ACOSOG (Alliance) Z11102 phase II single arm prospective trial was designed to evaluate outcomes with BCT for MIBC. Methods Women age 40+ with 2 or 3 foci of biopsy proven breast cancer (BC) (each site < 5cm in size with at least 1 site invasive) separated by >2-3 cm of normal breast tissue and disease limited to two quadrants of the breast with cN0 or cN1 disease were eligible. All patients had pre-operative mammogram and breast MRI was initially required and subsequently made optional. Neoadjuvant therapy was not allowed. Patients were treated with lumpectomy resected to negative margins followed by whole breast radiation with boost to all lumpectomy beds. The primary endpoint of Z11102 is the cumulative incidence of local recurrence (LR, defined as histologic evidence of ductal carcinoma in situ or invasive BC in the ipsilateral breast or chest wall) at 5 years (treating death and distant and nodal/regional recurrence as competing risks) to assess whether the rate is greater than 8%. Data were frozen 5/25/2022. Results From 11/2012-8/2016, 270 women were enrolled. Of these, 33 were ineligible, 14 converted to mastectomy, 11 were unable to meet protocol-specific radiation endpoints, 1 had no definable tumor, 1 had 4 sites of cancer and 16 withdrew before completing surgery and radiation, leaving 194 patients [median age 61 (range 40-87)] eligible who completed breast conserving surgery and radiation therapy. With median follow-up of alive patients of 66.6 months (range: 4.1, 90.6), 6 patients have developed LR (5 ipsilateral breast and 1 chest wall), corresponding to an estimated cumulative incidence of local recurrence of 3.2% (95% CI: 1.3, 6.4) at 5 years. No patients have developed regional recurrence, 5 patients developed distant recurrence, 0 patients developed local and distant recurrence, 5 patients developed contralateral BC, 3 new non-BC primaries and 8 patients have died (1 related to BC). The rate of local recurrence in patients without a breast pre-op MRI (n=14) was 22.6% at 5 years compared to 1.7% among the 180 patients with a preop MRI (p=0.002). Patient age, number of sites of preoperative biopsy proven BC, HER2 status, pathologic T and N category were not statistically significantly associated with risk of LR. Conclusion The Z11102 clinical trial demonstrates that for women with MIBC breast conserving surgery with adjuvant radiation with lumpectomy site boosts has an acceptably low LR rate (3.2% at 5 years), making this a reasonable consideration for women with 2-3 ipsilateral foci. The LR rate was significantly higher in the small cohort of patients without preoperative breast MRI. Support: U10CA180821, U10CA180882; https://acknowledgments.alliancefound.org. ClinicalTrials.gov Identifier: NCT01556243 Table 1: Factors associated with LR after BCT for MIBC Citation Format: Judy C. Boughey, Kari M. Rosenkranz, Karla V. Ballman, Linda McCall, Bruce G. Haffty, Laurie W. Cuttino, Charlotte D. Kubicky, H. T. Carisa Le-Petross, Kimberly Van Zee, Armando E. Giuliano, Olwen M. Hahn, Kelly K. Hunt, Lisa Carey, Ann Partridge. Impact of Breast Conservation Therapy on Local Recurrence in Patients with Multiple Ipsilateral Breast Cancer – Results from ACOSOG Z11102 (Alliance) [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr GS4-01.

Background: Left bundle area branch pacing (LBBP) is a novel conduction system pacing method to achieve effective physiological pacing and an alternative to cardiac resynchronization therapy (CRT) with biventricular pacing (BVP) for patients with heart failure and reduced ejection fraction (HFrEF). Objective: To review current data comparing BVP and LBBP in patients with HFrEF and indication CRT. Methods: We searched PubMed/Medline, Web of Science, and Cochrane Library from the inception of the database to November 2022. All studies that compared LBBP with BVP in patients with HFrEF and indications of CRT were included. Two reviewers performed the study selection, data abstraction, and risk of bias assessment. We calculated risk ratios with the Mantel-Haenszel method and mean difference with inverse variance using random effect models. We assessed heterogeneity using the I 2 index, with I 2 > 50% indicating significant heterogeneity. Results: Ten studies (9 observational studies and 1 randomized controlled trial; 616 patients; 15 centers) published between 2020 and 2022 were included. We observed a shorter fluoroscopy time [mean difference (MD) 9.68, 95% CI 4.49-14.87, I 2 =95%, P<0.01, minutes] as well as a shorter procedure time (MD 33.68, 95% CI 17.80-49.55, I 2 =73%, P<0.01, minutes) during implantation of LBBP CRT compared to conventional BVP CRT. LBBP was shown to have a greater reduction in QRSd (MD 25.13, 95%CI 20.06-30.20, I 2 = 51%, P<0.01, milliseconds) a greater left ventricular ejection fraction (LVEF) improvement (MD 5.80, 95% CI 4.81-6.78, I 2 =0%, P<0.01, percentage) and a greater ventricular end-diastolic diameter (LVEDD) reduction (MD 2.11, 95% CI 0.12-4.10, I 2 =18%, P=0.04, millimeter). There was a greater improvement in New York Heart Association function (NYHA) class with LBBP (MD 0.37, 95% CI 0.05-0.68, I 2 =61%, P=0.02).LBBP was also associated with a lower risk of a composite of heart failure hospitalizations and all-cause mortality [Risk ratio (RR) 0.48, 95% CI 0.25-0.90, I 2 =0%, p=0.02] driven by reduced heart failure hospitalizations (RR 0.39, 95% CI 0.19-0.82, I 2 =0%, p=0.01). However, all-cause mortality rates were low in both groups (1.52% vs. 1.13%) and similar (RR 0.98, 95%CI 0.21-4.68, I 2 =0%, p=0.87). Conclusion: Compared to BVP, LBBP is associated with, a greater improvement in LV systolic function, and a lower rate of heart failure-related hospitalization. Dedicated randomized controlled trials and larger patient populations are needed to further elucidate the long-term safety and efficacy of LBBP CRT.

Microglia play a critical role in the clearance of myelin debris, thereby ensuring functional recovery from neural injury. Here, using mouse model of demyelination following two-point LPC injection, we show that the microglial autophagic–lysosomal pathway becomes overactivated in response to severe demyelination, leading to lipid droplet accumulation and a dysfunctional and pro-inflammatory microglial state, and finally failed myelin debris clearance and spatial learning deficits. Data from genetic approaches and pharmacological modulations, via microglial Atg5 deficient mice and intraventricular BAF A1 administration, respectively, demonstrate that staged suppression of excessive autophagic–lysosomal activation in microglia, but not sustained inhibition, results in better myelin debris degradation and exerts protective effects against demyelination. Combined multi-omics results in vitro further showed that enhanced lipid metabolism, especially the activation of the linoleic acid pathway, underlies this protective effect. Supplementation with conjugated linoleic acid (CLA), both in vivo and in vitro, could mimic these effects, including attenuating inflammation and restoring microglial pro-regenerative properties, finally resulting in better recovery from demyelination injuries and improved spatial learning function, by activating the peroxisome proliferator-activated receptor (PPAR-γ) pathway. Therefore, we propose that pharmacological inhibition targeting microglial autophagic–lysosomal overactivation or supplementation with CLA could represent a potential therapeutic strategy in demyelinated disorders.