Citations

Hepatorenal syndrome-acute kidney injury (HRS-AKI) is associated with significant morbidity and mortality. While liver transplantation is the definitive treatment, continuous terlipressin infusion for HRS-AKI may provide benefit and, as such, was assessed in a population composed of candidates for liver transplant (LT). Fifty hospitalized LT-eligible patients with HRS-AKI received a single bolus followed by continuous terlipressin infusion. Acute-on-chronic liver failure grade 3, serum creatinine (SCr)>5.0 mg/dL, or Model for End-Stage Liver Disease (MELD) ≥35 were exclusions. Fifty hospitalized patients who received midodrine and octreotide or norepinephrine for HRS-AKI served as a historical comparator cohort. Complete response (CR) was defined as a ≥30% decrease in SCr with end-of-treatment (EOT) SCr≤1.5, partial response as a ≥30% decrease in SCr with EOT SCr>1.5, and nonresponse as a <30% decrease in SCr. CR rate was significantly higher in the terlipressin cohort compared to the historical cohort (64% vs. 16%, p<0.001). Survival, while numerically higher in those who received terlipressin, was statistically similar (D30: 94% vs. 82%, p=0.12; D90: 78% vs. 68%, p=0.37). Renal replacement therapy (RRT) was more common among terlipressin NR than CR and PR (70% vs. 3% vs. 13%, p < 0.001). EOT MELD and SCr were significantly lower within terlipressin cohort (MELD: 19 vs. 25, SCr: 1.4 vs. 2.1 mg/dL, p<0.001). Sixteen of 40 terlipressin-treated patients received LT-alone (terlipressin CR in 10/16). One patient on terlipressin had a hypoxic respiratory failure that responded to diuretics; one possibly had drug-related rash. With continuous terlipressin infusion, a CR rate of 64% was observed with a favorable safety profile. Terlipressin use was associated with lower EOT MELD and SCr than the historical midodrine and octreotide/norepinephrine cohort; LT-alone was accomplished in a high proportion of complete terlipressin responders.

Alloreactive memory, unlike naive, CD8 + T cells resist transplantation tolerance protocols and are a critical barrier to long-term graft acceptance in the clinic. We here show that semiallogeneic pregnancy successfully reprogrammed memory fetus/graft-specific CD8 + T cells (T FGS ) toward hypofunction. Female C57BL/6 mice harboring memory CD8 + T cells generated by the rejection of BALB/c skin grafts and then mated with BALB/c males achieved rates of pregnancy comparable with naive controls. Postpartum CD8 + T FGS from skin-sensitized dams upregulated expression of T cell exhaustion (T EX ) markers (Tox, Eomes, PD-1, TIGIT, and Lag3). Transcriptional analysis corroborated an enrichment of canonical T EX genes in postpartum memory T FGS and revealed a downregulation of a subset of memory-associated transcripts. Strikingly, pregnancy induced extensive epigenetic modifications of exhaustion- and memory-associated genes in memory T FGS , whereas minimal epigenetic modifications were observed in naive T FGS . Finally, postpartum memory T FGS durably expressed the exhaustion-enriched phenotype, and their susceptibility to transplantation tolerance was significantly restored compared with memory T FGS . These findings advance the concept of pregnancy as an epigenetic modulator inducing hypofunction in memory CD8 + T cells that has relevance not only for pregnancy and transplantation tolerance, but also for tumor immunity and chronic infections.

Abstract Background and Aims Incidence and types of secondary tricuspid regurgitation (TR) are not well defined in atrial fibrillation (AFib) and sinus rhythm (SR). Atrial secondary TR (A-STR) is associated with pre-existing AFib; however, close to 50% of patients with A-STR do not have AFib. The aim of this study was to assess incidence, types, and outcomes of ≥ moderate TR in AFib vs. SR. Methods Adults with and without new-onset AFib without structural heart disease or ≥ moderate TR at baseline were followed for the development of ≥ moderate TR. Tricuspid regurgitation types were pacemaker, left-sided valve disease, left ventricular (LV) dysfunction, pulmonary hypertension (PH), isolated ventricular, and A-STR. Results Among 1359 patients with AFib and 20 438 in SR, 109 and 378 patients developed ≥ moderate TR, respectively. The individual types of TR occurred more frequently in AFib related to the higher pacemaker implantation rates (1.12 vs. 0.19 per 100 person-years, P &lt; .001), larger right atrial size (median 78 vs. 53 mL, P &lt; .001), and higher pulmonary pressures (median 30 vs. 28 mmHg, P &lt; .001). The most common TR types irrespective of rhythm were LV dysfunction-TR and A-STR. Among patients in SR, those with A-STR were older, predominantly women with more diastolic abnormalities and higher pulmonary pressures. All types of secondary TR were associated with all-cause mortality, highest in PH-TR and LV dysfunction-TR. Conclusions New-onset AFib vs. SR conferred a higher risk of the individual TR types related to sequelae of AFib and higher pacemaker implantation rates, although the distribution of TR types was similar. Secondary TR was universally associated with increased mortality.

Abstract Rationale Inhibition of aromatase with anastrozole reduces pulmonary hypertension in experimental models. Objectives We aimed to determine whether anastrozole improved the 6-minute-walk distance (6MWD) at 6 months in pulmonary arterial hypertension (PAH). Methods We performed a randomized, double-blind, placebo-controlled phase II clinical trial of anastrozole in subjects with PAH at seven centers. Eighty-four postmenopausal women with PAH and men with PAH were randomized in a 1:1 ratio to receive anastrozole 1 mg or placebo by mouth daily, stratified by sex using permuted blocks of variable sizes. All subjects and study staff were masked. The primary outcome was the change from baseline in 6MWD at 6 months. By intention-to-treat analysis, we estimated the treatment effect of anastrozole using linear regression models adjusted for sex and baseline 6MWD. Assuming 10% loss to follow-up, we anticipated having 80% power to detect a difference in the change in 6MWD of 22 meters. Measurements and Main Results Forty-one subjects were randomized to placebo and 43 to anastrozole, and all received the allocated treatment. Three subjects in the placebo group and two in the anastrozole group discontinued the study drug. There was no significant difference in the change in 6MWD at 6 months (placebo-corrected treatment effect, −7.9 m; 95% confidence interval, −32.7 to 16.9; P = 0.53). There was no difference in adverse events between the groups. Conclusions Anastrozole did not show a significant effect on 6MWD compared with placebo in postmenopausal women with PAH and in men with PAH. Anastrozole was safe and did not have adverse effects. Clinical trial registered with www.clincialtrials.gov (NCT03229499).

Abstract The fourth Society for Academic Emergency Medicine (SAEM) Guidelines for Reasonable and Appropriate Care in the Emergency Department (GRACE‐4) is on the topic of the emergency department (ED) management of nonopioid use disorders and focuses on alcohol withdrawal syndrome (AWS), alcohol use disorder (AUD), and cannabinoid hyperemesis syndrome (CHS). The SAEM GRACE‐4 Writing Team, composed of emergency physicians and experts in addiction medicine and patients with lived experience, applied the Grading of Recommendations Assessment Development and Evaluation (GRADE) approach to assess the certainty of evidence and strength of recommendations regarding six priority questions for adult ED patients with AWS, AUD, and CHS. The SAEM GRACE‐4 Writing Team reached the following recommendations: (1) in adult ED patients (over the age of 18) with moderate to severe AWS who are being admitted to hospital, we suggest using phenobarbital in addition to benzodiazepines compared to using benzodiazepines alone [ low to very low certainty of evidence ]; (2) in adult ED patients (over the age of 18) with AUD who desire alcohol cessation, we suggest a prescription for one anticraving medication [ very low certainty of evidence ]; (2a) in adult ED patients (over the age of 18) with AUD, we suggest naltrexone (compared to no prescription) to prevent return to heavy drinking [ low certainty of evidence ]; (2b) in adult ED patients (over the age of 18) with AUD and contraindications to naltrexone, we suggest acamprosate (compared to no prescription) to prevent return to heavy drinking and/or to reduce heavy drinking [ low certainty of evidence ]; (2c) in adult ED patients (over the age of 18) with AUD, we suggest gabapentin (compared to no prescription) for the management of AUD to reduce heavy drinking days and improve alcohol withdrawal symptoms [ very low certainty of evidence ]; (3a) in adult ED patients (over the age of 18) presenting to the ED with CHS we suggest the use of haloperidol or droperidol (in addition to usual care/serotonin antagonists, e.g., ondansetron) to help with symptom management [ very low certainty of evidence ]; and (3b) in adult ED patients (over the age of 18) presenting to the ED with CHS, we also suggest offering the use of topical capsaicin (in addition to usual care/serotonin antagonists, e.g., ondansetron) to help with symptom management [ very low certainty of evidence ].

Abstract Background: Germline Pathogenic Variants (PVs) in ATM, BRCA1, BRCA2, CHEK2, and PALB2 are known to increase breast cancer (BCa) risk, but the effect of these PVs on tumor biology is not well-understood. Ki-67 is an established prognostic marker in hormone receptor (HR) positive breast cancer but the distribution of Ki-67 in breast cancer associated with germline PVs is not known. Methods: The study included patients with loco-regional (Stage I-III) HR-positive (ER+ or PR+), HER2-negative invasive ductal or lobular breast cancer evaluated at Mayo Clinic for curative intent treatment between 2012 and 2021. PV carrier status was ascertained in more than two-thirds of cases from germline whole exome sequencing (Regeneron) of patients who participated in a prospective registry at Mayo Clinic. Additional PV carriers were identified through a review of the results of clinical germline genetic testing in electronic medical records aided by natural language processing. Clinically performed Ki-67 values were abstracted from electronic medical records and analyzed as continuous and categorical variables (low: &lt; 20% vs. high: ≥20%). Throughout the timeline of the study, a consistent method for assessment of Ki-67 was utilized at Mayo Clinic, Rochester: Immunohistochemical staining of the Ki-67 antigen in formalin-fixed paraffin-embedded tissue was performed using MIB-1 clone, the scanned slides were reviewed by a technologist and traced areas further analyzed for Ki-67 using Aperio Software. Patients who received neoadjuvant therapy prior to the assessment of Ki-67, with metastatic disease at diagnosis, with PVs in two or more genes of interest, or unknown germline PV or Ki-67 status were excluded from the analysis. Multiple primary tumors in the same patient diagnosed within one year of each other were analyzed independently. The control (non-carrier) group included randomly selected patients from the prospective registry who tested negative for PVs in the five genes over the same time period. Ki-67 values were compared between germline PV carriers and non-carriers in a multivariable logistic regression analysis adjusting for sex, race, age at diagnosis, stage at presentation, and histology of the tumor. Results: A total of 113 HR+/HER2- tumors from 111 PV carriers (ATM: 27, BRCA1: 24, BRCA2: 28, CHEK2: 22, and PALB2:12) along with 431 HR+/HER2- tumors from 422 randomly selected non-carriers were evaluated. The majority (&gt;95%) of patients were non-Hispanic White. Germline PV carriers in each gene were diagnosed at a significantly younger age (P&lt; 0.05) compared to non-carriers. The median Ki-67 value was 12 (Range: 1 to 93) for non-carriers, 16 (Range: 0 to 79) for ATM, 31 (Range: 4 to 86) for BRCA1, 30 (Range: 6 to 80) for BRCA2, 13 (Range: 1 to 38) for CHEK2, and 20 (Range: 3 to 46) for PALB2 PV carriers. In multivariable analysis, compared to non-carriers, we observed significantly higher odds of a high Ki67 value (≥20%) for tumors arising from germline PV carriers in BRCA1 (Odds Ratio (OR): 7.3, 95%CI: 2.3 – 23.3, p&lt; 0.001), BRCA2 (OR: 3.0, 95%CI: 1.2 – 7.4, p=0.02) and PALB2 (OR: 3.9, 95%CI: 1.1 – 14.5, p=0.04). No such relationship was observed with either ATM (OR: 1.1, 95%CI: 0.4 – 2.9, p=0.81) or CHEK2 (OR: 0.8, 95%CI: 0.3 – 2.2, p=0.63). Conclusion: This study reveals that HR+/HER2- tumors in BRCA1, BRCA2, and PALB2 PV carriers have a significantly higher Ki-67 expression compared to non-carriers. These findings have implications for understanding prognosis and endocrine response PV with HR+ breast cancer. Further exploration of the relationships between Ki67 and germline PV status is necessary to personalize systemic therapy options in germline PV carriers. Acknowledgments: Thank you to Regeneron Genetics Center. The study was funded in part by the NIH Specialized Program of Research Excellence in Breast Cancer [P50CA116201] to Mayo Clinic, Mayo Clinic Department of Oncology Small Grants Program, and the Paul Calabresi Program at Mayo Clinic Citation Format: Robert Scheel, Grace Choong, Tara Rao, Nicholas Boddicker, Chunling Hu, Jie Na, Vinod Kaggal, Sean Murphy, Karthik Giridhar, Saba Yasir, Matthew Goetz, Fergus Couch, Siddhartha Yadav. Ki-67 Expression in Breast Cancer associated with ATM, BRCA1, BRCA2, CHEK2 and PALB2 Pathogenic Variants [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-08-07.

Abstract Background: Based on preclinical data showing addition of CDK4/6 inhibitors to gemcitabine is synergistic, ribociclib was evaluated in combination with gemcitabine to determine the maximum tolerated dose (MTD) and dose limiting toxicities (DLT). Methods: In this single arm multicohort phase I trial, we evaluated the safety and efficacy of Ribociclib plus Gemcitabine in patients with advanced solid tumors. Patients received Gemcitabine intravenously on days 1 and 8 followed by Ribociclib days 8–14, with treatment repeated every 3 weeks. Results: The study enrolled 43 patients between October 2017 and September 2019. The escalation phase (19 patients) determined the MTD and recommended phase II dose (RP2D) to be ribociclib 800mg daily and gemcitabine 1000mg/m2 for the expansion phase (24 patients). One patient experienced Grade 4 thrombocytopenia. Eleven patients experienced Grade 3 adverse events (AE), the most common being neutropenia, thrombocytopenia, and anemia. No partial or complete responses were observed. 15/22 (68%) of efficacy evaluable patients who received the MTD achieved best response of stable disease. Conclusions: The addition of Ribociclib to Gemcitabine was tolerated well and yielded stability of tumors in both cohorts. Ribociclib and gemcitabine could have synergistic activity in certain tumor types, and our data provides support for the combination. Clinical Trial Registration: NCT03237390