Citations

Abstract ELEVATE-RR demonstrated noninferior progression-free survival and lower incidence of key adverse events (AEs) with acalabrutinib vs ibrutinib in previously treated chronic lymphocytic leukemia. We further characterize AEs of acalabrutinib and ibrutinib via post hoc analysis. Overall and exposure-adjusted incidence rate was assessed for common Bruton tyrosine kinase inhibitor–associated AEs and for selected events of clinical interest (ECIs). AE burden scores based on previously published methodology were calculated for AEs overall and selected ECIs. Safety analyses included 529 patients (acalabrutinib, n = 266; ibrutinib, n = 263). Among common AEs, incidences of any-grade diarrhea, arthralgia, urinary tract infection, back pain, muscle spasms, and dyspepsia were higher with ibrutinib, with 1.5- to 4.1-fold higher exposure-adjusted incidence rates. Incidences of headache and cough were higher with acalabrutinib, with 1.6- and 1.2-fold higher exposure-adjusted incidence rate, respectively. Among ECIs, incidences of any-grade atrial fibrillation/flutter, hypertension, and bleeding were higher with ibrutinib, as were exposure-adjusted incidence rates (2.0-, 2.8-, and 1.6-fold, respectively); incidences of cardiac events overall (the Medical Dictionary for Regulatory Activities system organ class) and infections were similar between arms. Rate of discontinuation because of AEs was lower for acalabrutinib (hazard ratio, 0.62; 95% confidence interval, 0.41-0.93). AE burden score was higher for ibrutinib vs acalabrutinib overall and for the ECIs atrial fibrillation/flutter, hypertension, and bleeding. A limitation of this analysis is its open-label study design, which may influence the reporting of more subjective AEs. Overall, event-based analyses and AE burden scores demonstrated higher AE burden overall and specifically for atrial fibrillation, hypertension, and hemorrhage with ibrutinib vs acalabrutinib. This trial was registered at www.clinicaltrials.gov as #NCT02477696.

Objective: To compare conventional low-temperature storage of transplant donor livers [static cold storage (SCS)] with storage of the organs at physiological body temperature [normothermic machine perfusion (NMP)]. Background: The high success rate of liver transplantation is constrained by the shortage of transplantable organs (eg, waiting list mortality >20% in many centers). NMP maintains the liver in a functioning state to improve preservation quality and enable testing of the organ before transplantation. This is of greatest potential value with organs from brain-dead donor organs (DBD) with risk factors (age and comorbidities), and those from donors declared dead by cardiovascular criteria (donation after circulatory death). Methods: Three hundred eighty-three donor organs were randomized by 15 US liver transplant centers to undergo NMP (n = 192) or SCS (n = 191). Two hundred sixty-six donor livers proceeded to transplantation (NMP: n = 136; SCS: n = 130). The primary endpoint of the study was “early allograft dysfunction” (EAD), a marker of early posttransplant liver injury and function. Results: The difference in the incidence of EAD did not achieve significance, with 20.6% (NMP) versus 23.7% (SCS). Using exploratory, “as-treated” rather than “intent-to-treat,” subgroup analyses, there was a greater effect size in donation after circulatory death donor livers (22.8% NMP vs 44.6% SCS) and in organs in the highest risk quartile by donor risk (19.2% NMP vs 33.3% SCS). The incidence of acute cardiovascular decompensation at organ reperfusion, “postreperfusion syndrome,” as a secondary outcome was reduced in the NMP arm (5.9% vs 14.6%). Conclusions: NMP did not lower EAD, perhaps related to the inclusion of lower-risk liver donors, as higher-risk donor livers seemed to benefit more. The technology is safe in standard organ recovery and seems to have the greatest benefit for marginal donors.

Esophageal squamous cell carcinoma (ESCC) is a heterogeneous cancer associated with a poor prognosis in advanced stages. In India, it is the sixth most common cause of cancer-related mortality. In this study, we employed high-resolution mass spectrometry-based quantitative proteomics to characterize the differential protein expression pattern associated with ESCC. We identified several differentially expressed proteins including PDPN, TOP2A, POSTN and MMP2 that were overexpressed in ESCC. In addition, we identified downregulation of esophagus tissue-enriched proteins such as SLURP1, PADI1, CSTA, small proline-rich proteins such as SPRR3, SPRR2A, SPRR1A, KRT4, and KRT13, involved in squamous cell differentiation. We identified several overexpressed proteins mapped to the 3q24-29 chromosomal region, aligning with CNV alterations in this region reported in several published studies. Among these, we identified overexpression of SOX2, TP63, IGF2BP2 and RNF13 that are encoded by genes in the 3q26 region. Functional enrichment analysis revealed proteins involved in cell cycle pathways, DNA replication, spliceosome, and DNA repair pathways. We identified the overexpression of multiple proteins that play a major role in alleviating ER stress, including SYVN1 and SEL1L. The SYVN1/SEL1L complex is an essential part of the ER quality control machinery clearing misfolded proteins from the ER. SYVN1 is an E3 ubiquitin ligase that ubiquitinates ER-resident proteins. Interestingly, there are also other non-canonical substrates of SYVN1 which are known to play a crucial role in tumor progression. Thus, SYVN1 could be a potential therapeutic target in ESCC.

Introduction: Cardiovascular complications are the main contributors towards morbidity and mortality in hemochromatosis. Iron overload can cause arrhythmias and heart failure (HF). There is a paucity of data on haemochromatosis and the burden of HF and its sequalae. Hypothesis: To determine characteristics of HF patients with and without haemochromatosis, and in-hospital outcomes (mortality, length of stay (LOS), mechanical circulatory support, and cardiac transplantation). Methods: Patients with HF, with and without hemochromatosis, were identified from the Nationwide Inpatient Sample Database. Results: Between 2016-2019, 2,940 (0.06%) of 4,823,994 HF patients had hemochromatosis. The hemochromatosis cohort was younger (mean age, 68 vs 71 years), predominantly men (63% vs 52%), White (77% vs 64%), and had less cardiovascular comorbidity burden (coronary artery disease (41% vs 51%), atrial fibrillation (45% vs 46%), hypertension (20% vs 24%), hyperlipidaemia (44% vs 53%), diabetes (42% vs 49%) and obesity (18% vs 25%), compared with HF patients without hemochromatosis (p<0.01 for all). However, hemochromatosis patients had a higher concomitant third degree atrio-ventricular block (1.2% vs 0.7%), ventricular tachycardia (7.8% vs 5.4%), ventricular fibrillation (0.5% vs 0.3%), chronic liver disease (24% vs 6%) and anemia (51% vs 37%) [p<0.01]. The hemochromatosis patients had a higher mean LOS (6.1 vs 5.4 days, p<0.01), need for mechanical circulatory support (0.9% vs 0.6%, p<0.01) and cardiac transplantation (0.2% vs 0.1%, p<0.01). Mortality (2.0% vs 2.7%, p=0.09) was comparable between the groups. Conclusion: Despite younger age and lower burden of cardiovascular comorbidities, patients with hemochromatosis had a higher burden of arrhythmias, need for mechanical circulatory support and cardiac transplantation and a higher LOS. This warrants the need to devise early management strategies for HF patients with hemochromatosis.

Background: RCTs studying the effect of sodium-glucose co-transporter 2 inhibitors (SGLT2i) on cardiovascular (CV) risk factors and outcomes have been underpowered to assess patients with overweight or obesity, thus presenting the need for a meta-analysis. Methods: Electronic databases were queried up till February 2022 for RCTs comparing SGLT2i with placebo in patients with overweight (BMI ≥25 kg/m2) or obesity (BMI ≥30 kg/m2) - irrespective of diabetes status - with a follow-up of ≥24 weeks. Meta-analyses were performed using the generic inverse variance technique and a random-effects model. Results are presented as weighted mean differences (WMD) for continuous outcomes, and hazard ratios (HR) for dichotomous outcomes. Outcomes studied were: (i) weight; (ii) systolic BP; (iii) diastolic BP; (iv) heart rate; (v) HDL-C; (vi) LDL-C; (vii) major adverse cardiac events (MACE), i.e., composite of CV death, non-fatal myocardial infarction (MI) and non-fatal stroke; (viii) composite of heart failure hospitalization and CV death (HFH/CV death); (ix) mortality; (x) MI; and (xi) stroke. Results: Seventeen RCTs (47,649 patients) were included. Compared with placebo, SGLT2i significantly reduced weight (WMD: -2.32 kg [-2.77, -1.88]), HbA1c (WMD: -0.79 % [-0.98, - 0.61]) and systolic BP (WMD: -2.15 mm Hg [-3.08, - 1.22]). SGLT2i did not have a significant effect on diastolic BP (WMD: -0.55 mmHg [-1.51, 0.41]), heart rate (WMD: 0.08 bpm. [-0.21, 0.37]), HDL-C (WMD: 1.62 mmol l -1 [-0.21, 3.45]) or LDL-C (WMD: 0.53 mmol l -1 [-0.88, 1.94]). Amongst CV outcomes, SGLT2i reduced the risk of MACE (HR: 0.90 [0.81, 0.99]), HFH/CV death (HR: 0.82 [0.75, 0.90]), and mortality (HR: 0.85 [0.77, 0.94]). No effect was noted on stroke (HR: 0.99 [0.85, 1.26]) or MI (HR: 0.89 [0.77, 1.02]). Conclusions: In patients with overweight or obesity, SGLT2i produce a modest but significant reduction in weight, systolic BP and HbA1c. SGLT2i may also reduce the risk of MACE, HFH/CV death, and mortality.

Background: Aesthetic soft-tissue filler injections for lip enhancement are popular and performed throughout the world. When injecting lips with a cannula, as the cannula is advanced, resistance is perceived in consistent locations, potentially indicating boundaries between intralabial compartments. Objective: We aimed to investigate whether intralabial compartments exist and, if so, to describe their volumes, location, boundaries, and dimensions. Methods: This cadaveric study investigated a total of 20 human body donors (13 male, seven female) with a mean (SD) age at death of 61.9 years (23.9) and body mass index of 24.3 kg/m2 (3.7). The investigated cohort included 11 White donors, eight Asian donors, and one Black donor. Dye injections simulating minimally invasive lip treatments were conducted. Results: Independent of sex or race, six anterior and six posterior compartments in the upper and lower lip were identified, for a total of 24 lip compartments. Compartment boundaries were formed by vertically oriented septations that were found in consistent locations. The anterior compartments had volumes ranging from 0.30 to 0.39 cc; the posterior compartment volume ranged from 0.44 to 0.52 cc. The compartment volumes were larger centrally and decreased gradually toward the oral commissure. Conclusions: The volume and size of each of 24 compartments contribute to the overall appearance and shape of the lips. To achieve a natural lip shape preserving aesthetic outcome it may be preferable to administer the volumizing product using a compartment-respecting injection approach.

Abstract Immune related adverse events (irAEs) from immune checkpoint inhibitors (ICIs) are well documented for nearly every organ system, except for the reproductive system. Mouse models have demonstrated that ICIs can decrease ovarian follicular reserve and impair oocyte maturation, which may have implications for fertility (PMID: 36008687). There are no studies investigating the effect of ICIs on fertility in humans. We sought to evaluate ovarian function in women treated with ICIs compared to untreated women by evaluating non-invasive surrogate markers of ovarian reserve, anti-müllerian hormone (AMH) and antral follicle counts (AFC). We enrolled women 18 - 40 years old diagnosed with stage III or IV melanoma. Participants underwent phlebotomy for AMH levels and a pelvic ultrasound to assess AFC. The medical record was retrospectively reviewed to obtain data on patient characteristics, treatments, and outcomes. A total of 14 patients with stage IIIA - IV melanoma participated. Six patients received ICI treatment before AMH and AFC testing while 8 had no prior ICI exposure. The ICI group ages ranged from 22-40 years with a median age of 31 years. The untreated group ages ranged from 25-39 years with a median age of 32 years. The time between starting an ICI and enrolling in the study ranged from 28 - 351 days. ICI regimens included ipilimumab/nivolumab, nivolumab, pembrolizumab, and atezolizumab (on a clinical trial). Four of these six patients experienced an irAE during their course, including: dermatitis, hepatitis, colitis, thyroid dysfunction, and adrenal insufficiency. Median AMH levels were lower for patients treated with ICIs (2.9 vs 4.0 ng/mL), as was median AFC (22.5 vs 23.5 ng/mL). Only three patients’ clinicians discussed fertility preservation. None of the patients underwent fertility preservation. Our study found lower AMH and AFC in women with melanoma who were treated with an ICI compared to untreated women. Although AMH and AFC are surrogate markers for ovarian reserve and fertility, and our study is a small cohort, these early results suggest that ICIs may impact ovarian function. Age is less likely to be a confounding factor as the median age of the treated group was younger than the untreated group. While these results are preliminary, when considered in conjunction with recent pre-clinical data showing changes within the ovaries after ICI treatment, fertility consultation should be considered for young women prior to ICI initiation. We are investigating associations between AMH, AFC, age, ICI exposure, and future pregnancies in an ongoing prospective study. Citation Format: Ashley Hickman, Katherine Smith, Zaraq Khan, Elizabeth Ann Enninga, Yulian Zhao, Elizabeth Cathcart-Rake, Haidong Dong, Lisa Kottschade, Svetomir Markovic, Heather Montane, Anastasios Dimou, Yiyi Yan. Investigating the effect of immune checkpoint inhibitors (ICI) on ovarian function in young patients with melanoma. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6644.

Abstract Introduction: Cytokines are protein factors that regulate diverse cellular processes. The malignant progression of immunoglobulin M monoclonal gammopathy of undetermined significance (IgM-MGUS) to Waldenstrom macroglobulinemia (WM) is in part cytokine mediated, and we have previously shown IL-6 mediates IgM secretion in WM via the JAK/STAT pathway. Cytokine signaling can be epigenetically modulated by micro-RNAs (miRs). We aimed to identify the role of miRs in the regulation of inflammatory cytokine pathways between these diseases. Methods: Bone marrow samples of patients with IgM-MGUS (n=7) and WM (n=25) were prospectively collected and sorted for CD19+ and/or CD138+ malignant cells. Total RNA extraction and sequencing were performed, miR and mRNA profiling was conducted, and differential expression was calculated between WM and IgM-MGUS using a log2 fold change (FC)&gt;0.5 and ←0.5, false discovery rate&lt;0.05. Experimental differentially expressed miR-mRNA pairing was performed, and pairs were filtered for correlated expression (i.e., upregulated miR/downregulated mRNA, and vice-versa). Filtered pairs were analyzed using the Ingenuity Pathway Analysis to identify pathways between WM and IgM-MGUS with absolute activation Z-score ≥1. Results: We identified 34 differentially expressed miRs experimentally targeting 1132 mRNAs. Pathway analysis showed overall miR-based inactivation of inflammatory cytokine signaling pathways in WM compared to IgM-MGUS, especially of the interleukin (IL) family: IL-2, IL-6, IL-8, IL-9, IL-15, and IL-17. Underlying multiple pathways was upregulation of miRs-146a, 150, 194, all targets of Signal Transducer and Activator of Transcription 1 (STAT1), observed to be downregulated. Of relevance, miR-146a has been previously shown to be an inhibitor of inflammatory cytokines, including IL-6. Next, we observed upregulation of miR-142 which targets phosphoinositide-3-kinase regulatory subunit 6 (PIK3R6), observed to be downregulated. Both the STAT and PIK3 families are important cytokine signal transducers, and we have previously shown the PI3k-AKT-IkB-p65 pathway induces expression of IL-6 via a GLI2-mediated mechanism. We additionally observed granulocyte-macrophage colony-stimulating factor (GM-CSF) signaling to be inactivated in WM. Here, miR-19b and miR-30e were upregulated, both target CSF 2 receptor subunit beta (CSF2RB), found to be downregulated. CSF2RB is the common receptor subunit of GM-CSF, IL-3, and IL-5. Conclusion: Our study identifies multiple cytokines pathways involved in inflammation and the tumor microenvironment to be potentially inactivated by differentially expressed miRs in WM compared to IgM-MGUS. Downregulation of these pathways and targeting of the STAT and PIK3 family indicates a possible miR-based negative feedback loop to down-modulate inflammatory cytokine signaling in WM. Citation Format: Karan Chohan, Jonas Paludo, Surendra Dasari, Jithma P. Abeykoon, Prashant Kapoor, Esteban Braggio, Michelle K. Manske, Aneel Paulus, Craig B. Reeder, Sikander Ailawadhi, Asher A. Chanan-Khan, Robert A. Kyle, Morie A. Gertz, Anne J. Novak, Stephen M. Ansell. Micro-RNA induced inactivation of inflammatory cytokine signaling pathways in Waldenstrom macroglobulinemia compared to IgM-MGUS. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3811.