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In recent years transcatheter approaches to treat heart valve disease have played an increasingly important role. This has been especially true for aortic stenosis, with two valves commercially available in Europe and several others under investigation in man. These least invasive therapies have expanded treatment options for the highest surgical risk patients, but there are fundamental differences from conventional surgical repair that warrant further investigation. This manuscript reviews the rapidly evolving field of transcatheter aortic valve intervention from the clinician's perspective. Anatomic, pathologic, and physiologic issues posed by the disease process are first reviewed. Device and design challenges to this new therapy are then addressed. Finally, newer devices and transcatheter approaches to other valve disease are briefly reviewed. The understanding that can come from an engineering approach to address these multiple issues should further improve outcomes and advance development of next-generation devices. [ABSTRACT FROM AUTHOR]

To investigate whether early postoperative changes in blood lactate concentration indicate the functional recovery of the newly grafted liver, changes in oxygen supply, oxygen consumption, acid-base equilibrium, and blood lactate concentrations were prospectively studied in a group of 53 postnecrotic cirrhotic patients during the various phases of orthotopic liver transplantation (preanhepatic, anhepatic, neohepatic) and for the first 48 h following reperfusion. The patients were divided into two groups according to the quality of the early graft function, as indicated by alanine aminotransferase, bile flow, and prothrombin activity: group A (49 patients), good immediate graft function and group B (4 patients), immediate graft non-function. Lactate levels rose in the same manner during the preanhepatic and anhepatic stages and peaked after revascularization of the graft. Following reperfusion, however, distinctly different blood lactate profiles were recorded in the two groups of patients. A fall in lactate concentration was recorded in group A patients, whereas a continuous rise occurred in group B patients: the difference becoming significant by the end of surgery (P<-0.05). During the first 48 h following revascularization of the graft, opposite trends in lactate concentration, bile flow, alanine aminotransferase, and prothrombin activity were evident in the two groups of patients: 24 h after reperfusion, lactate levels were below 2 mmol/1 in 47 of 49 patients from group A, while they plateaued above 4 mmol/1 in all patients from group B. Group A patients had lower alanine aminotransferase levels ( P<-0.001), higher prothrombin activity, ( P<-0.01), and greater bile flow (P<-0.02). If validated in larger series, the blood lactate profile, probably more than the absolute level, appears to be a useful indicator of the early recovery of liver metabolic capacities in the immediate postoperative period of orthotopic liver transplantation. [ABSTRACT FROM AUTHOR]

Significant advances in surgical techniques and relevant medium- and long-term outcomes over the past two decades have led to a substantial expansion in the indications for major liver resections. To support these outstanding results and to reduce perioperative complications, anesthesiologists must address and master key perioperative issues (preoperative assessment, proactive intraoperative anesthesia strategies, and implementation of the Enhanced Recovery After Surgery approach). Intensive care unit monitoring immediately following liver surgery remains a subject of active and often unresolved debate. Among postoperative complications, posthepatectomy liver failure (PHLF) occurs in different grades of severity (A-C) and frequency (9%-30%), and it is the main cause of 90-d postoperative mortality. PHLF, recently redefined with pragmatic clinical criteria and perioperative scores, can be predicted, prevented, or anticipated. This review highlights: (1) The systemic consequences of surgical manipulations anesthesiologists must respond to or prevent, to positively impact PHLF (a proactive approach); and (2) the maximal intensive treatment of PHLF, including artificial options, mainly based, so far, on Acute Liver Failure treatment(s), to buy time waiting for the recovery of the native liver or, when appropriate and in very selected cases, toward liver transplant. Such a clinical context requires a strong commitment to surgeons, anesthesiologists, and intensivists to work together, for a fruitful collaboration in a mandatory clinical continuum., Competing Interests: Conflict-of-interest statement: All the authors declare that they have no conflict of interest., (©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.)

Immune checkpoint blockade has been largely unsuccessful for the treatment of bone metastatic castrate-resistant prostate cancer (mCRPC). Here, we report a combinatorial strategy to treat mCRPC using γδ-enriched chimeric antigen receptor (CAR) T cells and zoledronate (ZOL). In a preclinical murine model of bone mCRPC, γδ CAR-T cells targeting prostate stem cell antigen (PSCA) induced a rapid and significant regression of established tumors, combined with increased survival and reduced cancer-associated bone disease. Pretreatment with ZOL, a U.S. Food and Drug Administration-approved bisphosphonate prescribed to mitigate pathological fracture in mCRPC patients, resulted in CAR-independent activation of γδ CAR-T cells, increased cytokine secretion, and enhanced antitumor efficacy. These data show that the activity of the endogenous Vγ9Vδ2 T cell receptor is preserved in CAR-T cells, allowing for dual-receptor recognition of tumor cells. Collectively, our findings support the use of γδ CAR-T cell therapy for mCRPC treatment.

Background: Improved therapy in CF has led to an overall improvement in nutritional status. The objectives of our study are: to cross-sectionally assess nutritional status and serum levels of fat-soluble vitamins; to retrospectively evaluate the efficacy of modulators on nutritional status and fat-soluble vitamin levels., Methods: In patients younger than 2 years of age, we evaluated growth, in patients aged 2-18 years, we assessed BMI z-scores, and in adults, we assessed absolute BMI values. Levels of 25(OH)D, vitamins A, and E were measured., Results: A cross-sectional analysis was conducted on 318 patients, 109 (34.3%) with pancreatic sufficiency. Only three patients were under 2 years old. In 135 patients aged 2-18 years, the median BMI z-score was 0.11, and 5 (3.7%) patients had malnutrition (z-score ≤ 2SD). In 180 adults, the median BMI was 21.8 kg/m 2 . Overall, 15 (13.7%) males (M) and 18 (25.3%) females (F) were underweight (18 < BMI > 20); 3 (2.7%) M and 5 (7.0%) F had a BMI < 18. Suboptimal 25(OH)D levels were found in patients with pancreatic insufficiency. The prevalence of deficiency of vitamins A and E is low. After one year of treatment with modulators, the increase in BMI was more consistent (M: 1.58 ± 1.25 kg/m 2 F: 1.77 ± 1.21 kg/m 2 ) in elexacaftor/tezacaftor/ivacaftor (ETI)-treated patients compared with other modulators, with a significant increase in levels of all fat-soluble vitamins., Conclusions: Malnutrition is present in a limited number of subjects. The prevalence of subjects with suboptimal 25(OH)D levels is high. ETI showed a beneficial effect on nutritional status and circulating levels of fat-soluble vitamins.

Objective: To evaluate the effect of autologous whole blood (AWB) collection on intraoperative/postoperative allogeneic blood transfusion rate in complex aortic surgery with hypothermic circulatory arrest., Methods: This retrospective study included adults who underwent aortic surgery with hypothermic circulatory arrest at a single institution between 2014 and 2019. Out of 509 cases (414 patients), 110 (22%) received the AWB protocol. We performed propensity-score matching, including 35 preoperative and procedural variables, which resulted in 95 well-matched pairs, to compare outcomes in patients who received AWB protocol versus those who did not. Study outcomes were percentage of patients who received transfusion of allogeneic blood products intraoperatively and postoperatively., Results: Mean volume of collected autologous blood was 826 ± 263 mL. Intraoperatively, fewer AWB patients received red blood cell concentrate (33% vs 49%; P = .02), plasma (35% vs 62%; P = .0002), platelets (61% vs 81%; P = .003), and cryoprecipitate (43% vs 56%; P = .08) compared with non-AWB patients. During the entire hospital stay, the differences in transfusion rate between the 2 groups were: red blood cells (58% vs 62%; P = .6), plasma (49% vs 66%; P = .01), platelets (72% vs 82%; P = .09), and cryoprecipitate (56% vs 63%; P = .3)., Conclusions: Pre-pump autologous blood collection may reduce the need for intraoperative transfusion of allogenic non-red-cell blood products in patients undergoing complex aortic surgery with hypothermic circulatory arrest. A larger study is needed to clarify the influence of this association on patient outcomes and resource utilization., (Copyright © 2021 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)

Objectives: The mortality rate in patients with anorexia nervosa (AN) is 5 to 10 times higher than in general population and, suicide is one of the main causes of death. We evaluated the prevalence of suicidality (ideation, self-injurious behaviour, suicidal attempts) in 100 adolescents with onset of AN and we explored the correlation between suicidality, severity of AN symptoms and psychiatric comorbidity., Methods: We subdivided AN patients into restrictive (R-AN; n = 66) and restrictive atypical (A-AN; n = 34), according to the European Guidelines criteria. Assessment was performed using the eating disorder inventory 3rd version, the schedule for affective disorders and schizophrenia for school-age children-present and lifetime version interview, and the Columbia-suicide severity rating scale. Fisher's exact test and Mann-Whitney test (with correction for multiple testing) were used to compare the distribution of categorical and continuous variables between R-AN and A-AN patients, and between patients with vs. without suicidal behaviours., Results: Twenty-seven patients (27%) presented suicidality as clinical feature, expressed as at least one of the following: suicidal ideation (24%), self-cutting (19%), and suicidal attempt (6%). Patients with suicidality showed greater severity of psychiatric symptoms related to AN psychopathology and presented psychiatric comorbidity, especially depression, more often than patients who did not reported suicidality (70,4% vs 29,6%). No significant differences in terms of suicidal behaviours and AN-specific psychopathology were found between R-AN and A-AN., Conclusions: Suicidality in adolescent patients with R-AN and A-AN seems to be related to ED symptoms. These data highlight the importance of screening for suicidality among adolescents at onset of AN, and confirms that A-AN should not be considered a milder disease., Level of Evidence: Level IV: Evidence obtained from multiple time series analysis such as case studies. (NB: Dramatic results in uncontrolled trials might also be regarded as this type of evidence)., (© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Objective: Surveillance metrics in pediatric and young adult Marfan syndrome (pMFS) are challenging. We evaluated the utility of aortic root cross-sectional area/height index (CSA/Ht) on echocardiogram among pMFS patients as a risk stratification and surgical triage metric., Methods: Genotype or phenotype positive pMFS patients aged 25 years or younger seen at our center from 2001 to 2020 were identified. Time-related transition to surgery was modeled using parametric methods. Predictive utility of CSA/Ht compared with aortic root diameter (ARd) and root Z score (ARz) were modeled using nonlinear multivariable parametric and nonparametric longitudinal regression models., Results: Seventy-nine patients (43% female) presented at median age of 5.8 years (15th-85th percentile, 0.75-17 years) with median follow-up of 4.4 years (range, 0-18.5 years). Baseline echocardiography data were: CSA/Ht, 3.9 ± 1.4 cm 2 /m; ARd, 2.4 ± 0.89 cm; and ARz, 2.4 ± 1.7. CSA/Ht tracked ARd better compared with ARz (r = 0.91 vs 0.24). Eighteen patients underwent surgery. Surgical procedures included at least 2 components in 17 (aortic, mitral, tricuspid, aortic root, and arch procedures) and isolated mitral valve procedures in 1 patient. Time-related transition to surgery showed a prominent early phase to 1 year post presentation, followed by a slowly increasing late phase. CSA/Ht had a more linear correlation versus ARz during periods of rapid somatic growth in surgical patients. Surgical repair occurred at CSA/Ht between 5 and 7 cm 2 /m., Conclusions: CSA/Ht tracked ARd well over time. CSA/Ht between 5 and 7 cm 2 /m might be a promising metric for surgical triage in pMFS patients. CSA/Ht surgical threshold values in pMFS patients occurred at lower than current accepted "surgical" threshold values for CSA/Ht in adult Marfan syndrome patients., (Copyright © 2022 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)

Aims: Patients with autoimmune connective tissue diseases (CTDs) have a high burden of valvular heart disease and are often thought of as high surgical risk patients., Methods and Results: Patients undergoing aortic valve replacement (AVR) were identified in the Nationwide Readmissions Database between January 2012 and December 2018. Patients with a history of systemic lupus erythematosus, rheumatoid arthritis, systemic sclerosis, mixed C, Sjögren syndrome, polymyositis, and dermatomyositis were included in the CTD cohort. Patients undergoing coronary artery bypass grafting concomitantly with AVR were excluded. A total of 569 600 hospitalizations were included, of which16 531 (2.9%) had CTD. CTD patients were more likely to be females, with higher rates of heart failure, pulmonary hypertension, and more likely to be insured by Medicare. CTD patients had lower mortality than non-CTD patients [odds ratio (OR) 0.66; 95% confidence interval (CI): 0.59-0.74] and stroke [OR 0.87; 95% (CI): 0.79-0.97]. CTD patients undergoing SAVR had lower mortality [OR 0.69; 95% (CI): 0.60-0.80] and stroke [OR 0.86; 95% (CI): 0.75-0.98). CTD patients undergoing TAVR had lower mortality outcomes [OR 0.67; 95% (CI): 0.56-0.80]; however, they had comparable stroke outcomes [OR 0.97; 95% (CI): 0.83-1.13, P  = 0.69]., Conclusions: Outcomes for patients with CTD requiring AVR are not inferior to their non-CTD counterparts. A comprehensive heart team selection of patients undergoing AVR approaches should place CTD history under consideration; however, pre-existing CTD should not be prohibitive of AVR interventions., (© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Cardiology.)

Objectives: Platelet count reduction is a common but not fully understood phenomenon after aortic valve replacement (AVR) with bioprosthesis implantation. The aim of the present study was to investigate the occurrence and the clinical impact of platelet count reduction in patients receiving the Perceval bioprosthesis compared to those receiving standard sutured stented bioprosthetic aortic valve in a randomized, controlled AVR study., Methods: PERceval Sutureless Implant versus STandard Aortic Valve Replacement is a prospective, randomized, adaptive, open-label trial. Patients were randomized (March 2016-September 2018) to AVR with a sutureless or stented valve. Ad hoc analyses have been performed to evaluate the occurrence of platelet count reduction and the clinical impact of the platelet variations in the 2 groups., Results: The Perceval group showed a higher platelet reduction than the control group (46% vs 32%). The phenomenon was transient in both groups, with a slow recovery of the platelet count by hospital discharge. No differences were observed between groups regarding need of transfusions, blood loss, major bleeding and stroke events., Conclusions: The Perceval sutureless aortic bioprosthesis implantation is associated with higher rate of transient platelet reduction as compared to stented bioprostheses for AVR. However, the platelet count reduction is transient and the decline does not affect the patient's clinical outcomes. Current explanations for this phenomenon are speculative, and further investigations are required to elucidate it., Clinical Trial Registration Number: NCT02673697-ClinicalTrials.gov-4 February 2016., (© The Author(s) 2021. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Background: Co-stimulatory signals regulate the expansion, persistence, and function of chimeric antigen receptor (CAR) T cells. Most studies have focused on the co-stimulatory domains CD28 or 4-1BB. CAR T cell persistence is enhanced by 4-1BB co-stimulation leading to nuclear factor kappa B (NF-κB) signaling, while resistance to exhaustion is enhanced by mutations of the CD28 co-stimulatory domain., Methods: We hypothesized that a third-generation CAR containing 4-1BB and CD28 with only PYAP signaling motif (mut06) would provide beneficial aspects of both. We designed CD19-specific CAR T cells with either 4-1BB or mut06 together with the combination of both and evaluated their immune-phenotype, cytokine secretion, real-time cytotoxic ability and polyfunctionality against CD19-expressing cells. We analyzed lymphocyte-specific protein tyrosine kinase (LCK) recruitment by the different constructs by immunoblotting. We further determined their ability to control growth of Raji cells in NOD scid gamma (NSG) mice. We also engineered bi-specific CARs against CD20/CD19 combining 4-1BB and mut06 and performed repeated in vitro antigenic stimulation experiments to evaluate their expansion, memory phenotype and phenotypic (PD1 + CD39 + ) and functional exhaustion. Bi-specific CAR T cells were transferred into Raji or Nalm6-bearing mice to study their ability to eradicate CD20/CD19-expressing tumors., Results: Co-stimulatory domains combining 4-1BB and mut06 confers CAR T cells with an increased central memory phenotype, expansion, and LCK recruitment to the CAR. This enhanced function was dependent on the positioning of the two co-stimulatory domains. A bi-specific CAR targeting CD20/CD19, incorporating 4-1BB and mut06 co-stimulation, showed enhanced antigen-dependent in vitro expansion with lower exhaustion-associated markers. Bi-specific CAR T cells exhibited improved in vivo antitumor activity with increased persistence and decreased exhaustion., Conclusion: These results demonstrate that co-stimulation combining 4-1BB with an optimized form of CD28 is a valid approach to optimize CAR T cell function. Cells with both mono-specific and bi-specific versions of this design showed enhanced in vitro and in vivo features such as expansion, persistence and resistance to exhaustion. Our observations validate the approach and justify clinical studies to test the efficacy and safety of this CAR in patients., Competing Interests: Competing interests: The mut06 CAR has been patented by Moffitt Cancer Center and licensed to Atara Biotherapeutics. MLD has received licensing fees and research support from Atara Biotherapeutics., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Characterization of breast cancer (BC) through the determination of conventional markers such as ER, PR, HER2, and Ki67 has been useful as a predictive and therapeutic tool. Also, assessment of tumor-infiltrating lymphocytes has been proposed as an important prognostic aspect to be considered in certain BC subtypes. However, there is still a need to identify additional biomarkers that could add precision in distinguishing therapeutic response of individual patients. To this end, we focused in the expression of interferon regulatory factor 8 (IRF8) in BC cells. IRF8 is a transcription factor which plays a well-determined role in myeloid cells and that seems to have multiple antitumoral roles: it has tumor suppressor functions; it acts downstream IFN/STAT1, required for the success of some therapeutic regimes, and its expression in neoplastic cells seems to depend on a cross talk between the immune contexture and the tumor cells. The goal of the present study was to examine the relationship between IRF8 with the therapeutic response and the immune contexture in BC, since its clinical significance in this type of cancer has not been thoroughly addressed., Methods: We identified the relationship between IRF8 expression and the clinical outcome of BC patients and validated IRF8 as predictive biomarker by using public databases and then performed in silico analysis. To correlate the expression of IRF8 with the immune infiltrate in BC samples, we performed quantitative multiplex immunohistochemistry., Results: IRF8 expression can precisely predict the complete pathological response to monoclonal antibody therapy or to select combinations of chemotherapy such as FAC (fluorouracil, adriamycin, and cytoxan) in ER-negative BC subtypes. Analysis of immune cell infiltration indicates there is a strong correlation between activated and effector CD8 + T cell infiltration and tumoral IRF8 expression., Conclusions: We propose IRF8 expression as a potent biomarker not only for prognosis, but also for predicting therapy response in ER-negative BC phenotypes. Its expression in neoplastic cells also correlates with CD8 + T cell activation and infiltration. Therefore, our results justify new efforts towards understanding mechanisms regulating IRF8 expression and how they can be therapeutically manipulated.

Chimeric antigen receptor (CAR) T cell therapy has shown considerable promise for hematologic malignancies, leading to the US Food and Drug Administration approval of two CAR T cell-based therapies for the treatment of B cell acute lymphoblastic leukemia and large B cell lymphoma. Despite success in hematologic malignancies, the treatment landscape of CAR T cell therapy for solid tumors has been limited. There are unique challenges in the development of novel CAR T cell therapies to improve both safety and efficacy. Improved understanding of the immunosuppressive tumor microenvironment and resistance mechanisms has led to encouraging approaches to mitigating these obstacles. This Review will characterize challenges with current CAR T designs for hematologic malignancies and solid tumors and emphasize preclinical and clinical strategies to overcome them with novel CAR T cell therapies.