Citations

Objective: To define benchmark values for adult-to-adult living-donor liver transplantation (LDLT). Background: LDLT utilizes living-donor hemiliver grafts to expand the donor pool and reduce waitlist mortality. Although references have been established for donor hepatectomy, no such information exists for recipients to enable conclusive quality and comparative assessments. Methods: Patients undergoing LDLT were analyzed in 15 high-volume centers (≥10 cases/year) from 3 continents over 5 years (2016–2020), with a minimum follow-up of 1 year. Benchmark criteria included a Model for End-stage Liver Disease ≤20, no portal vein thrombosis, no previous major abdominal surgery, no renal replacement therapy, no acute liver failure, and no intensive care unit admission. Benchmark cutoffs were derived from the 75th percentile of all centers’ medians. Results: Of 3636 patients, 1864 (51%) qualified as benchmark cases. Benchmark cutoffs, including posttransplant dialysis (≤4%), primary nonfunction (≤0.9%), nonanastomotic strictures (≤0.2%), graft loss (≤7.7%), and redo-liver transplantation (LT) (≤3.6%), at 1-year were below the deceased donor LT benchmarks. Bile leak (≤12.4%), hepatic artery thrombosis (≤5.1%), and Comprehensive Complication Index (CCI ® ) (≤56) were above the deceased donor LT benchmarks, whereas mortality (≤9.1%) was comparable. The right hemiliver graft, compared with the left, was associated with a lower CCI ® score (34 vs 21, P < 0.001). Preservation of the middle hepatic vein with the right hemiliver graft had no impact neither on the recipient nor on the donor outcome. Asian centers outperformed other centers with CCI ® score (21 vs 47, P < 0.001), graft loss (3.0% vs 6.5%, P = 0.002), and redo-LT rates (1.0% vs 2.5%, P = 0.029). In contrast, non-benchmark low-volume centers displayed inferior outcomes, such as bile leak (15.2%), hepatic artery thrombosis (15.2%), or redo-LT (6.5%). Conclusions: Benchmark LDLT offers a valuable alternative to reduce waitlist mortality. Exchange of expertise, public awareness, and centralization policy are, however, mandatory to achieve benchmark outcomes worldwide.

Abstract Background Adjuvant abemaciclib (a CDK4 and 6 inhibitor) combined with ET resulted in significant and clinically meaningful improvement in invasive disease-free survival (IDFS) and distant relapse-free survival (DRFS) in patients (pts) with HR+, HER2-, node-positive, high risk EBC in the monarchE trial, and is an approved adjuvant therapy for these patients. Here we present efficacy results from a pre-specified overall survival interim analysis (OS IA2) which was planned to occur 2 years (yrs) after the primary outcome analysis. Methods Pts were randomized (1:1) to receive ET for up to 10 yrs +/- abemaciclib for 2 yrs (study treatment period). High-risk EBC was defined as either ≥4 positive axillary lymph nodes (ALN), or 1-3 ALN with either Grade 3 disease and/or tumor ≥5 cm (Cohort 1). While the proliferation biomarker Ki-67 was centrally assessed in all pts with available tissue sample, an additional smaller group of pts with 1-3+ ALN and central Ki-67 ≥20% as the only high-risk feature were included (Cohort 2). The intent-to-treat (ITT) population consisted of both Cohort 1 (5120 pts) and Cohort 2 (517 pts). Hazard ratios (HR) were estimated using Cox proportional hazard model. Results At a median follow-up of 42 months, all pts were off abemaciclib. IDFS and DRFS data illustrate a sustained benefit beyond the treatment period. In the ITT population, the HR for IDFS was 0.664 (95% CI: 0.578, 0.762) and DRFS was 0.659 (95% CI: 0.567, 0.767). At 4 yrs, this reflected an improvement in IDFS rates from 79.4% to 85.8% (absolute difference 6.4%), and in DRFS rates from 82.5% to 88.4% (absolute difference 5.9%). The continued separation of the curves was associated with an increase in absolute benefit in IDFS 4-year rates compared to 2-and 3-year IDFS rates (absolute difference 2.8% and 4.8% respectively). While OS remained immature, there was a lower number of deaths observed in the abemaciclib plus ET arm compared to the ET alone arm (157 [5.6%] vs 173 [6.1%], HR 0.929 [95% CI: 0.748, 1.153], p = 0.503), suggesting that the robust benefit in IDFS and DRFS began to translate into a numerically favorable OS HR. As previously described, within Cohort 1, a Ki-67 index of ≥20% was associated with a worse prognosis, but similar abemaciclib treatment effects were observed regardless of Ki-67 index. No new safety signals were observed. Conclusion The clinically meaningful benefit of adjuvant abemaciclib added to ET in HR+, HER2-, node-positive, high-risk EBC persists beyond completion of abemaciclib therapy, yielding an increase in absolute IDFS and DRFS benefit at 4 yrs. While OS remains immature at this time, the lower number of deaths in the abemaciclib arm compared to the ET arm suggest that a survival signal favoring abemaciclib is emerging. Citation Format: Stephen Johnston, Masakazu Toi, Joyce O’Shaughnessy, Priya Rastogi, Mario Campone, Patrick Neven, Chiun Sheng Huang, Jens Huober, Georgina Garnica Jaliffe, Irfan Cicin, Sara Tolaney, Matthew P. Goetz, Hope Rugo, Elżbieta Senkus, Laura Testa, Lucia Del Mastro, Chikako Shimizu, Ran Wei, Ashwin Shahir, Maria Munoz, Belen San Antonio, Valerie Andre, Nadia Harbeck, Miguel Martín. Abemaciclib plus endocrine therapy for HR+, HER2-, node-positive, high-risk early breast cancer: results from a pre-planned monarchE overall survival interim analysis, including 4-year efficacy outcomes [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 GS1-09.

Abstract Extracellular vesicles (EVs) are emerging as powerful players in cell‐to‐cell communication both in healthy and diseased brain. In Parkinson's disease (PD)—characterized by selective dopaminergic neuron death in ventral midbrain (VMB) and degeneration of their terminals in striatum (STR)—astrocytes exert dual harmful/protective functions, with mechanisms not fully elucidated. Here, this study shows that astrocytes from the VMB‐, STR‐, and VMB/STR‐depleted brains release a population of small EVs in a region‐specific manner. Interestingly, VMB‐astrocytes secreted the highest rate of EVs, which is further exclusively increased in response to CCL3, a chemokine that promotes robust dopaminergic neuroprotection in different PD models. The neuroprotective potential of nigrostriatal astrocyte‐EVs is investigated in differentiated versus undifferentiated SH‐SY5Y cells exposed to oxidative stress and mitochondrial toxicity. EVs from both VMB‐ and STR‐astrocytes counteract H 2 O 2 ‐induced caspase‐3 activation specifically in differentiated cells, with EVs from CCL3‐treated astrocytes showing a higher protective effect. High resolution respirometry further reveals that nigrostriatal astrocyte‐EVs rescue neuronal mitochondrial complex I function impaired by the neurotoxin MPP + . Notably, only EVs from VMB‐astrocyte fully restore ATP production, again specifically in differentiated SH‐SY5Y. These results highlight a regional diversity in the nigrostriatal system for the secretion and activities of astrocyte‐EVs, with neuroprotective implications for PD.

Abstract Background monarchE is a phase 3, open-label study evaluating abemaciclib combined with endocrine therapy (ET) compared to ET alone in patients with node positive, HR+, HER2-, high risk early breast cancer (EBC) that resulted in a statistically significant improvement in invasive disease-free survival (IDFS) at a pre-planned interim analysis. Following the positive interim analysis, patients continued to be followed for IDFS, distant recurrence, and overall survival. Methods After surgery and, as indicated, radiotherapy and/or chemotherapy, 5,637 patients with HR+, HER2-, high risk EBC were randomized (1:1) to standard of care adjuvant ET with or without abemaciclib (150 mg BD for 2 years). Patients with ≥4 positive nodes, or 1-3 nodes and either grade 3 disease, tumor size ≥5 cm, or central Ki-67 ≥20% were eligible. Here we present results of the primary outcome IDFS analysis which was planned after approximately 390 IDFS events. Results At the primary outcome analysis, median follow-up was approximately 19 months in both arms (an increase of 3.5 months from the interim analysis). A total of 1437 (25.5%) patients had completed the 2-year treatment period; 3281 (58.2%) were still in the 2-year treatment period. With 395 IDFS events observed in the intent-to-treat population, abemaciclib plus ET continued to demonstrate superior IDFS versus ET alone, with a 28.7% reduction in the risk of developing invasive disease (p=.0009; HR = 0.713; 95% CI = 0.583, 0.871). Two-year IDFS rates were 92.3% in the abemaciclib plus ET arm and 89.3% in the ET alone arm. There was a consistent benefit of abemaciclib in all prespecified subgroups. The addition of abemaciclib to ET also resulted in an improvement in distant relapse-free survival (DRFS). Overall survival was immature at the time of analysis. A key secondary endpoint was efficacy in patients with centrally assessed high Ki-67 (≥20%) (Ki-67H) (n=2498). Disease characteristics were well balanced between the arms of this population. Abemaciclib plus ET demonstrated superior IDFS vs ET alone, with a 30.9% reduction in risk of developing invasive disease (p=.0111; HR = 0.691; 95% CI = 0.519, 0.920) and 2-year IDFS rates of 91.6% and 87.1%, respectively. An improvement in DRFS treatment effect was also observed in the Ki-67H population. At the time of data cutoff, the median treatment duration of abemaciclib was 17.3 months and the median duration of ET was balanced between the arms (18.3 months in the abemaciclib arm and 18.7 months in the ET alone arm). Safety was consistent with the results at the interim IDFS analysis and with the known safety profile of abemaciclib. Conclusions At the primary outcome analysis, with a median follow-up of approximately 19 months, abemaciclib combined with ET continued to demonstrate a clinically meaningful improvement in IDFS in patients with HR+, HER2-, node-positive, high risk, EBC with a statistically significant improvement in IDFS in patients with central Ki-67 ≥20%. ClinicalTrials.gov: NCT03155997 Table 1: PrimaryOutcome EfficacyIntent-to-Treat PopulationIntent-to-Treat PopulationKi-67 ≥20% (Ki-67H) PopulationKi-67 ≥20% (Ki-67H) PopulationEndpointAbemaciclib + ET N=2808ET alone N=2829Abemaciclib + ET N=1262ET alone N=1236IDFS# events, n (%)163 (5.8)232 (8.2)82 (6.5)115 (9.3)log rank P value, HR (95% CI)p=.0009 0.713 (0.583, 0.871)p=.0111 0.691 (0.519, 0.920)Rate (%) at 2 years (95% CI)92.3 (90.9, 93.5)89.3 (87.7, 90.7)91.6 (89.4, 93.4)87.1 (84.3, 89.5)Difference (%) in 2-year rates (95% CI)3 (1.1, 5.0)4.5 (1.2, 7.7)DRFS# events, n (%)131 (4.7)193 (6.8)65 (5.2)102 (8.3)log rank P value, HR (95% CI)p=.0009 0.687 (0.551, 0.858)0.609 (0.445, 0.833)Rate (%) at 2 years (95% CI)93.8 (92.6, 94.9)90.8 (89.3, 92.1)93.6 (91.6, 95.1)88.5 (85.7, 90.7)Difference (%) in 2-year rates (95%CI)3 (1.2, 4.8)5.1 (2.1, 8.1) Citation Format: Joyce A. O'Shaughnessy, Stephen Johnston, Nadia Harbeck, Masakazu Toi, Young-Hyuck Im, Mattea Reinisch, Zhimin Shao, Pirkko Liisa Kellokumpu Lehtinen, Chiun-Sheng Huang, Alexey Tryakin, Matthew Goetz, Hope S Rugo, Elzbieta Senkus, Laura Testa, Michael Andersson, Kenji Tamura, Guenther G. Steger, Lucia Del Mastro, Joanne Cox, Tammy Forrester, Sarah Sherwood, Xuelin Li, Ran Wei, Miguel Martin, Priya Rastogi. Primary outcome analysis of invasive disease-free survival for monarchE: abemaciclib combined with adjuvant endocrine therapy for high risk early breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr GS1-01.

Background: Mitral valve-in-valve (ViV) and valve-in-ring (ViR) are alternatives to surgical reoperation in patients with recurrent mitral valve failure after previous surgical valve repair or replacement. Our aim was to perform a large-scale analysis examining midterm outcomes after mitral ViV and ViR. Methods: Patients undergoing mitral ViV and ViR were enrolled in the Valve-in-Valve International Data Registry. Cases were performed between March 2006 and March 2020. Clinical endpoints are reported according to the Mitral Valve Academic Research Consortium (MVARC) definitions. Significant residual mitral stenosis (MS) was defined as mean gradient ≥10 mm Hg and significant residual mitral regurgitation (MR) as ≥ moderate. Results: A total of 1079 patients (857 ViV, 222 ViR; mean age 73.5±12.5 years; 40.8% male) from 90 centers were included. Median STS-PROM score 8.6%; median clinical follow-up 492 days (interquartile range, 76–996); median echocardiographic follow-up for patients that survived 1 year was 772.5 days (interquartile range, 510–1211.75). Four-year Kaplan-Meier survival rate was 62.5% in ViV versus 49.5% for ViR ( P <0.001). Mean gradient across the mitral valve postprocedure was 5.7±2.8 mm Hg (≥5 mm Hg; 61.4% of patients). Significant residual MS occurred in 8.2% of the ViV and 12.0% of the ViR patients ( P =0.09). Significant residual MR was more common in ViR patients (16.6% versus 3.1%; P <0.001) and was associated with lower survival at 4 years (35.1% versus 61.6%; P =0.02). The rates of Mitral Valve Academic Research Consortium–defined device success were low for both procedures (39.4% total; 32.0% ViR versus 41.3% ViV; P =0.01), mostly related to having postprocedural mean gradient ≥5 mm Hg. Correlates for residual MS were smaller true internal diameter, younger age, and larger body mass index. The only correlate for residual MR was ViR. Significant residual MS (subhazard ratio, 4.67; 95% CI, 1.74–12.56; P =0.002) and significant residual MR (subhazard ratio, 7.88; 95% CI, 2.88–21.53; P <0.001) were both independently associated with repeat mitral valve replacement. Conclusions: Significant residual MS and/or MR were not infrequent after mitral ViV and ViR procedures and were both associated with a need for repeat valve replacement. Strategies to improve postprocedural hemodynamics in mitral ViV and ViR should be further explored.

Background and Aims Among patients with cirrhosis awaiting liver transplantation, prediction of wait‐list (WL) mortality is adjudicated by the Model for End Stage Liver Disease–Sodium (MELD‐Na) score. Replacing serum creatinine (SCr) with estimated glomerular filtration rate (eGFR) in the MELD‐Na score may improve prediction of WL mortality, especially for women and highest disease severity. Approach and Results We developed (2014) and validated (2015) a model incorporating eGFR using national data (n = 17,095) to predict WL mortality. Glomerular filtration rate (GFR) was estimated using the GFR assessment in liver disease (GRAIL) developed among patients with cirrhosis. Multivariate Cox proportional hazard analysis models were used to compare the predicted 90‐day WL mortality between MELD‐GRAIL‐Na (re‐estimated bilirubin, international normalized ratio [INR], sodium, and GRAIL) versus MELD‐Na. Within 3 months, 27.8% were transplanted, 4.3% died on the WL, and 4.7% were delisted for other reasons. GFR as estimated by GRAIL (hazard ratio [HR] 0.382, 95% confidence interval [CI] 0.344‐0.424) and the re‐estimated model MELD‐GRAIL‐Na (HR 1.212, 95% CI 1.199‐1.224) were significant predictors of mortality or being delisted on the WL within 3 months. MELD‐GRAIL‐Na was a better predictor of observed mortality at highest deciles of disease severity (≥ 27‐40). For a score of 32 or higher (observed mortality 0.68), predicted mortality was 0.67 (MELD‐GRAIL‐Na) and 0.51 (MELD‐Na). For women, a score of 32 or higher (observed mortality 0.67), the predicted mortality was 0.69 (MELD‐GRAIL‐Na) and 0.55 (MELD‐Na). In 2015, use of MELD‐GRAIL‐Na as compared with MELD‐Na resulted in reclassification of 16.7% (n = 672) of patients on the WL. Conclusion Incorporation of eGFR likely captures true GFR better than SCr, especially among women. Incorporation of MELD‐GRAIL‐Na instead of MELD‐Na may affect outcomes for 12%‐17% awaiting transplant and affect organ allocation.