Metabolic Syndrome and Heart Transplantation: An Underestimated Risk Factor?

Metabolic Syndrome (MetS), a multifactorial condition that increases the risk of cardio-vascular events, is frequent in Heart-transplant (HTx) candidates and worsens with immunosuppressive therapy. The aim of the study was to analyze the impact of MetS on long-term outcome of HTx patients. Since 2007, 349 HTx patients were enrolled. MetS was diagnosed if patients met revised NCEP-ATP III criteria before HTx, at 1, 5 and 10 years of follow-up. MetS was present in 35% of patients pre-HTx and 47% at 1 year follow-up. Five-year survival in patients with both pre-HTx (65% vs. 78%, p < 0.01) and 1 year follow-up MetS (78% vs 89%, p < 0.01) was worst. At the univariate analysis, risk factors for mortality were pre-HTx MetS (HR 1.86, p < 0.01), hypertension (HR 2.46, p < 0.01), hypertriglyceridemia (HR 1.50, p=0.03), chronic renal failure (HR 2.95, p < 0.01), MetS and diabetes at 1 year follow-up (HR 2.00, p < 0.01; HR 2.02, p < 0.01, respectively). MetS at 1 year follow-up determined a higher risk to develop Coronary allograft vasculopathy at 5 and 10 year follow-up (25% vs 14% and 44% vs 25%, p < 0.01). MetS is an important risk factor for both mortality and morbidity post-HTx, suggesting the need for a strict monitoring of metabolic disorders with a careful nutritional follow-up in HTx patients.

Ice-cold storage or controlled hypothermia to preserve marginal grafts in high-risk heart transplantation.

BACKGROUND: To evaluate the effectiveness of the Paragonix SherpaPak cardiac transport system (PSP) compared to the standard ice-cold storage (ICS) in extended-criteria donor grafts implanted in high-risk recipients. METHODS: Data of all HTx at the University Centers of Udine and Bologna, between January 2020 and December 2023, employing extended-criteria donors in high-risk HTx conditions were retrospectively analyzed. Patient outcomes and complications after HTx were assessed. Endomyocardial biopsies were performed in donor hearts immediately after retrieval (T0), before implantation (T1) and at reperfusion (T2) to evaluate signs of myocardial damage. RESULTS: Overall, 90 patients who had heart transplantation (HTx) with a donor graft preserved with either ICS (n = 60) or PSP (n = 30) were included in the study. The 30-day mortality was 3% in both groups (p = 0.99), and 1-year survival 90% and 88% (p = 0.89) for recipients transplanted with PSP and ICS preserved grafts. Rates of moderate-to-severe graft dysfunction and bradi-arrhythmias for PSP and ICS groups were 7% versus 20% (p = 0.08), and 3% versus 15% (p = 0.09). Histologically, severe degrees of cellular and endothelial damage were absent in all PSP grafts while severe degree of contraction bands were higher in ICS hearts at T2. CONCLUSIONS: In high-risk donor-recipient matching, donor heart preservation with PSP seems to show a tendency toward better graft protection.

The impact of the distance between patient residency and heart transplant center on outcomes after heart transplantation.

INTRODUCTION: Heart transplant (HTx) recipients require continuous monitoring and care in order to prevent and treat possible complications related to the graft function or to the immunosuppressive treatment promptly. Since heart transplantation centers (HTC) are more experienced in managing HTx recipients than other healthcare facilities, the distance between patient residency and HTC could negatively affect the outcomes. METHODS: Data of patients discharged after receiving HTx between 2000 and 2021, collected into our institutional database, were retrospectively analyzed. The population was divided into three groups: A (n = 180), B (n = 157), and C (n = 134), according to the distance tertiles between patient residency and HTC. The primary end-point was survival, secondary end-points were incidences of complications. RESULTS: Recipient and donor characteristics did not differ between the three groups. Survival at 10 years was 66 ± 4%, 66 ± 4%, and 65 ± 5%, respectively, for groups A, B, and C (p = .34). Immunosuppressive regimen and rate of complications did not differ between groups. However, the rates of outpatient visits and of hospitalization performed at HTC were higher in group A than others. CONCLUSION: Distance from the HTC does not represent a barrier to a successful outcome for HTx recipients, as long as regular and continuous follow-up is provided.

The multi-specific VH-based Humabody CB213 co-targets PD1 and LAG3 on T cells to promote anti-tumour activity.

BACKGROUND: Improving cancer immunotherapy long-term clinical benefit is a major priority. It has become apparent that multiple axes of immune suppression restrain the capacity of T cells to provide anti-tumour activity including signalling through PD1/PD-L1 and LAG3/MHC-II. METHODS: CB213 has been developed as a fully human PD1/LAG3 co-targeting multi-specific Humabody composed of linked VH domains that avidly bind and block PD1 and LAG3 on dual-positive T cells. We present the preclinical primary pharmacology of CB213: biochemistry, cell-based function vs. immune-suppressive targets, induction of T cell proliferation ex vivo using blood obtained from NSCLC patients, and syngeneic mouse model anti-tumour activity. CB213 pharmacokinetics was assessed in cynomolgus macaques. RESULTS: CB213 shows picomolar avidity when simultaneously engaging PD1 and LAG3. Assessing LAG3/MHC-II or PD1/PD-L1 suppression individually, CB213 preferentially counters the LAG3 axis. CB213 showed superior activity vs. αPD1 antibody to induce ex vivo NSCLC patient T cell proliferation and to suppress tumour growth in a syngeneic mouse tumour model, for which both experimental systems possess PD1 and LAG3 suppressive components. Non-human primate PK of CB213 suggests weekly clinical administration. CONCLUSIONS: CB213 is poised to enter clinical development and, through intercepting both PD1 and LAG3 resistance mechanisms, may benefit patients with tumours escaping front-line immunological control.

Cancer patient perspective in the arena of COVID-19 pandemic.

OBJECTIVE: The coronavirus disease 2019 (COVID-19) outbreak has been declared a global pandemic of unprecedented proportions. Italy is a country which has been heavily affected. Cancer patients are at a higher risk owing to their intrinsic fragility related to their underlying disease and oncologic treatment. Against this backdrop, we conducted a survey to investigate how patients perceived their condition, clinical management and availability of information during the pandemic. METHODS: Between 15 April and 1 May 2020 a survey was submitted to cancer patients at oncology departments in the Marche region. Questions regarding the perception of personal safety, continuity of cancer care, information quality and psychological distress. RESULTS: Seven hundred patients participated in the survey; 59% were female and 40% were aged between 46 and 65. The majority of the participants perceived compliance with appropriate safety standards by cancer care providers and 80% were reassured about their concerns during the medical interview. 40% were worried of being at a higher risk of infection and 71% felt they were at a greater risk because of chemotherapy. 55% felt that postponing cancer treatment could reduce its efficacy, however 76% declared they did not feel abandoned at the time of treatment postponement. Patients between 46 and 65 years declared a significant reduction in sleep (p < 0.01) and in concentration (p = 0.03). CONCLUSIONS: The emergency care offered to cancer patients has been deemed satisfactory in terms of both safety standards and care management. However, the majority of participants perceived the mutual negative influence between their oncologic disease and the risk of infection highlighting the need for special measures to ensure safe continuity of care.

Left subclavian artery as an alternative site for left ventricular assist device outflow graft in challenging situations.

Left ventricular assist device (LVAD) has emerged as an effective surgical therapy for end-stage heart failure. In an attempt to reduce invasiveness and avoid difficult sternal re-entries, alternative surgical approaches have been adopted. In particular, when the thoracic aorta is severely diseased or difficult to expose, subclavian arteries could serve as site for outflow graft anastomosis. However, major concerns regarding the utilization of subclavian arteries are the small caliber of these vessels that could lead to inadequate LVAD flow, arm complications related to excessive blood flow, and possible outflow graft compression. In the present case series, we describe an innovative technique for LVAD implantation, in which the left subclavian artery was employed as an outflow graft anastomosis site, and the left ventricular apex was approached through a mini-thoracotomy. Technical issues were considered to prevent possible complications: the adequacy of left subclavian artery diameter, the banding of the artery distal to the anastomosis site to limit left arm overflow, and the outflow graft covering with a reinforced vascular graft to avoid any external compression. During follow-up, the technique reported was found to be effective in ensuring good LVAD function and flow, and no complications related to the procedure were reported.

Retinal metastasis regression with eribulin in a heavily pretreated breast cancer patient.

The authors present the case of a heavily pretreated young woman with retinal and brain metastases from breast cancer who was successfully treated with eribulin. Eribulin was given at 1.1 mg/m(2) on day 1 and 8, every 3 weeks for a total of 12 courses. A significant reduction in the size of brain and retinal lesions was achieved after three cycles. The treatment was continued for 12 cycles, with a good profile of tolerability. In this clinical case, eribulin demonstrated to be active on brain and retinal metastases from breast cancer, although preclinical data showed limited ability to cross the blood-brain barrier.

A Case Report of Aortic Intramural Hematoma: From Diagnosis to Endovascular Treatment Guided by Transesophageal Echocardiography.

Aortic intramural hematoma (IMH) accounts for approximately 10%-25% of acute aortic syndromes (AAS), and multi-slice computed tomography and magnetic resonance imaging are the leading techniques for diagnosis and classification. In this context, endovascular strategies provide a valid alternative to traditional open surgery and transesophageal echocardiography (TEE) could play a role in therapeutic decision-making and in endovascular repair procedure guidance. A 57-year-old female patient with IMH extending from the left subclavian artery to the upper tract of the abdominal aorta, underwent endovascular aortic repair using an unibody single-branched stent grafting in the aortic arch and descending aorta with a side branch inserted in the left common carotid artery. To restore proper flow in the left axillary artery, a carotid-subclavian bypass graft was performed. The procedure was guided by angiography and TEE. Intraoperative TEE revealed aortic IMH with a significant fluid component in the middle tunic of the aorta with a wall thickness of over 13 mm. TEE was useful in monitoring of all steps of the procedure, showing the presence of the guidewires into the true lumen, the advancement of the prosthesis, and the phases of release and anchoring. This case highlights the importance of using multimodality imaging techniques to evaluate AAS and demonstrates the growing potential of TEE in guiding endovascular repairs.

Optical Coherence Tomography in Myocardial Infarction Management: Enhancing Precision in Percutaneous Coronary Intervention.

In acute myocardial infarction (AMI), the urgency of coronary revascularization through percutaneous coronary intervention (PCI) is paramount, offering notable advantages over pharmacologic treatment. However, the persistent risk of adverse events, including recurrent AMI and heart failure post-revascularization, underscores the necessity for enhanced strategies in managing coronary artery disease. Traditional angiography, while widely employed, presents significant limitations by providing only two-dimensional representations of complex three-dimensional vascular structures, hampering the accurate assessment of plaque characteristics and stenosis severity. Intravascular imaging, specifically optical coherence tomography (OCT), significantly addresses these limitations with superior spatial resolution compared to intravascular ultrasound (IVUS). Within the context of AMI, OCT serves dual purposes: as a diagnostic tool to accurately identify culprit lesions in ambiguous cases and as a guide for optimizing PCI procedures. Its capacity to differentiate between various mechanisms of acute coronary syndrome, such as plaque rupture and spontaneous coronary dissection, enhances its diagnostic potential. Furthermore, OCT facilitates precise lesion preparation, optimal stent sizing, and confirms stent deployment efficacy. Recent meta-analyses indicate that OCT-guided PCI markedly improves safety and efficacy in revascularization, subsequently decreasing the risks of mortality and complications. This review emphasizes the critical role of OCT in refining patient-specific therapeutic approaches, aligning with the principles of precision medicine to enhance clinical outcomes for individuals experiencing AMI.

Endomyocardial biopsy through the left internal jugular vein in heart transplant recipients: a single center experience.

Endomyocardial biopsies for rejection monitoring after heart transplantation are generally performed through the right internal jugular vein. We aimed to assess the feasibility and safety of using the left internal jugular vein approach as a valid alternative to a femoral vein for endomyocardial biopsies whenever thrombosis of the right internal jugular vein precludes insertion of a bioptome. We have reviewed our experience with heart transplantation in the last 2 decades to identify patients in whom surveillance endomyocardial biopsy was performed through the left internal jugular vein. We herein describe the step-by-step procedure and report the preliminary results. From May 1, 2000 to January 31, 2024, 561 orthotopic heart transplants have been performed in our unit. In 49 patients (8.7%), the right internal jugular vein access was found to be unsuitable or occluded at eco-Doppler evaluation; in 15 of them (30%) a total of 206 endomyocardial biopsies have been performed, using the left internal jugular vein, without complications. Our experience demonstrates that the left internal jugular vein is a valid alternative approach for endomyocardial biopsies when the right internal jugular vein is not available. This technique is feasible, safe and reproducible and allows adequate rejection monitoring after heart transplantation.

Impact of Leaflet-to-Annulus Index on Residual Regurgitation Following Transcatheter Edge-to-Edge Repair of the Tricuspid Valve.

Background: The mismatch between tricuspid valve (TV) leaflet length and annulus dilation, assessed with the septal-lateral leaflet-to-annulus index (SL-LAI), predicts residual tricuspid regurgitation (TR) following tricuspid transcatheter edge-to-edge-repair (T-TEER). When posterior leaflet grasping is required, the anterior-posterior leaflet-to-annulus index (AP-LAI) may offer additional information. Methods: This single-center retrospective cohort study included all patients referred for T-TEER with severe and symptomatic TR with high surgical risk from April 2021 to March 2024. Patients were categorized into 'optimal result' (

Clinical Features and Patient Outcomes in Infective Endocarditis with Surgical Indication: A Single-Centre Experience.

BACKGROUND: Infective endocarditis (IE) is marked by a heightened risk of embolic events (EEs), uncontrolled infection, or heart failure (HF). METHODS: Patients with IE and surgical indication were enrolled from October 2015 to December 2018. The primary endpoint consisted of a composite of major adverse events (MAEs) including all-cause death, hospitalizations, and IE relapses. The secondary endpoint was all-cause death. RESULTS: A total of 102 patients (66 ± 14 years) were enrolled: 50% with IE on prosthesis, 33% with IE-associated heart failure (IE-aHF), and 38.2% with EEs. IE-aHF and EEs were independently associated with MAEs (HR 1.9, 95% CI 1.1-3.4, p = 0.03 and HR 2.1, 95% CI 1.2-3.6, p = 0.01, respectively) and Kaplan-Meier survival curves confirmed a strong difference in MAE-free survival of patients with EEs and IE-aHF (p < 0.01 for both). IE-aHF (HR 4.3, 95% CI 1.4-13, p < 0.01), CRP at admission (HR 5.6, 95% CI 1.4-22.2, p = 0.01), LVEF (HR 0.9, 95% CI 0.9-1, p < 0.05), abscess (HR 3.5, 95% CI 1.2-10.6, p < 0.05), and prosthetic detachment (HR 4.6, 95% CI 1.5-14.1, p < 0.01) were independently associated with the all-cause death endpoint. CONCLUSIONS: IE-aHF and EEs were independently associated with MAEs. IE-aHF was also independently associated with the secondary endpoint.

Enfortumab Vedotin Following Platinum Chemotherapy and Avelumab Maintenance in Patients with Metastatic Urothelial Carcinoma: A Retrospective Data from the ARON-2EV Study.

BACKGROUND: Enfortumab vedotin (EV) has been approved for the treatment of patients with locally advanced/metastatic urothelial carcinoma (la/mUC) who previously received platinum-based chemotherapy followed by immune checkpoint inhibitors. However, the pivotal clinical trials did not include patients previously treated with avelumab maintenance therapy. OBJECTIVE: The aim of the present retrospective analysis was to assess the effectiveness of EV following avelumab in patients with mUC enrolled in the ARON-2EV study. PATIENTS AND METHODS: The study included 182 patients with mUC treated with EV following avelumab maintenance. The primary objective was to assess clinical outcomes, including progression-free survival (PFS), overall survival (OS), overall response rate (ORR), and duration of response (DoR). Statistical analysis involved Fisher exact test, Kaplan-Meier method, log-rank test, and univariate/multivariate Cox proportional hazard regression models. RESULTS: Median OS and PFS were 12.7 (95% CI 10.2-14.1) and 7.9 (95% CI 6.4-9.9) months, respectively. Complete response (CR) was achieved in 5% and partial response (PR) in 34% of patients, with an ORR of 39%. The DoR in patients who achieved CR/PR was 10.9 months (95% CI 8.1-11.4). The incidence of grade ≥ 3 peripheral neuropathy and skin rash was 9%, followed by 8% of grade ≥ 3 diarrhea and 4% of grade ≥ 3 hyperglycemia. CONCLUSIONS: The results of our large international retrospective study confirm the effectiveness of EV and endorse its use in the population of patients with mUC treated with EV following the frontline platinum-based chemotherapy and subsequent maintenance treatment with avelumab.

A Case of Type B Aortic Dissection: The Role of Transesophageal Ultrasound Guidance in Thoracic Endovascular Aortic Repair.

Thoracic endovascular aortic repair (TEVAR) plays a central role in managing acute and chronic aortic pathologies. With the advancement of transcatheter structural heart procedures, echocardiography has become a key in procedural guidance. Despite consensus on its use for cardiac interventions, ultrasound assistance in aortic procedures is not widely standardized. A 71-year-old obese man with chronic type B aortic dissection underwent a TEVAR procedure, using a single-branched aortic stent graft (Endovastec™ Castor™) and with transesophageal ultrasound guidance. The preprocedural assessment confirmed the presence of aortic dissection of the descending thoracic aorta with a posterior true lumen (TL) and an anterior false lumen (FL), normal aortic valve anatomy and function, normal left ventricular function, absence of intracavity thrombus, and absence of aortic plaques that could prevent the optimal implantation of the stent graft. During the procedure, a transesophageal echocardiogram (TEE) monitored the positioning of the guide wires, the arrival of the catheter of the thoracic endoprosthesis, and then the implantation of this at the level of the aortic arch and the descending thoracic aorta. Postprocedure TEE evaluation underlined full stent-graft deployment without leaks and successful exclusion of FL with the beginning of thrombosis. Angiography confirms the exclusion of the aneurysm and the absence of endoleaks. This clinical case demonstrates how transesophageal echocardiographic guidance can improve the TEVAR procedure by minimizing fluoroscopy time, contrast medium use, and enabling a better assessment of the dissection anatomy with real-time monitoring of both the TL and the FL. In conclusion, TEE can serve as an auxiliary intraoperative imaging tool to provide good information before, during, and after the procedure, increasing the success and safety of the TEVAR.

Graft preservation in heart transplantation: current approaches.

Heart transplantation (HTx) represents the current best surgical treatment for patients affected by end-stage heart failure. However, with the improvement of medical and interventional therapies, the population of HTx candidates is increasingly old and at high-risk for mortality and complications. Moreover, the use of "extended donor criteria" to deal with the shortage of donors could increase the risk of worse outcomes after HTx. In this setting, the strategy of donor organ preservation could significantly affect HTx results. The most widely used technique for donor organ preservation is static cold storage in ice. New techniques that are clinically being used for donor heart preservation include static controlled hypothermia and machine perfusion (MP) systems. Controlled hypothermia allows for a monitored cold storage between 4°C and 8°C. This simple technique seems to better preserve the donor heart when compared to ice, probably avoiding tissue injury due to sub-zero °C temperatures. MP platforms are divided in normothermic and hypothermic, and continuously perfuse the donor heart, reducing ischemic time, a well-known independent risk factor for mortality after HTx. Also, normothermic MP permits to evaluate marginal donor grafts, and could represent a safe and effective technique to expand the available donor pool. However, despite the increasing number of donor hearts preserved with these new approaches, whether these techniques could be considered superior to traditional CS still represents a matter of debate. The aim of this review is to summarize and critically assess the available clinical data on donor heart preservation strategies employed for HTx.

In vitro and in vivo characterization of a novel Hedgehog signaling antagonist in human glioblastoma cell lines.

Glioblastoma multiforme (GBM) is composed of heterogeneous and genetically different cells, which are highly invasive and motile. The standard chemotherapeutic agent, temozolomide, affects GBM cell proliferation but is generally unable to prevent tumor recurrence. Hedgehog pathway activation has been reported to be relevant in GBM and different pharmacological pathway modulators have been identified. We report that by growing a commercially available recurrent GBM cell line (DBTRG-05MG) without serum and in the presence of defined growth factors; we obtained a less differentiated cell population, growing in suspension as neurospheres, in which the Hedgehog pathway is activated. Furthermore, the expression profile of Hedgehog pathway components found in DBTRG-05MG neurospheres is similar to primary stem-like cells derived from recurrent GBM patients. We report the effect of our novel specific Smoothened receptor antagonist (SEN450) on neurosphere growing cells and compared its effect to that of well known benchmark compounds. Finally, we showed that SEN450 is both antiproliferative on its own and further reduces tumor volume after temozolomide pretreatment in a mouse xenograft model using DBTRG-05MG neurosphere cells. Altogether our data indicate that the Hedgehog pathway is not irreversibly switched off in adherent cells but can be reactivated when exposed to well-defined culture conditions, thus restoring the condition observed in primary tumor-derived material, and that pharmacological modulation of this pathway can have profound influences on tumor proliferation. Therefore, pharmacological inhibition of the Hedgehog pathway is a potentially useful therapeutic approach in GBM.

Discovery, Characterization, and Structure-Based Optimization of Small-Molecule In Vitro and In Vivo Probes for Human DNA Polymerase Theta.

Human DNA polymerase theta (Polθ), which is essential for microhomology-mediated DNA double strand break repair, has been proposed as an attractive target for the treatment of BRCA deficient and other DNA repair pathway defective cancers. As previously reported, we recently identified the first selective small molecule Polθ in vitro probe, 22 (ART558), which recapitulates the phenotype of Polθ loss, and in vivo probe, 43 (ART812), which is efficacious in a model of PARP inhibitor resistant TNBC in vivo. Here we describe the discovery, biochemical and biophysical characterization of these probes including small molecule ligand co-crystal structures with Polθ. The crystallographic data provides a basis for understanding the unique mechanism of inhibition of these compounds which is dependent on stabilization of a "closed" enzyme conformation. Additionally, the structural biology platform provided a basis for rational optimization based primarily on reduced ligand conformational flexibility.

Coronary artery anomalies and their clinical relevance.

Coronary artery anomalies (CAAs) represent one of the most confusing topic in cardiology and affect approximately 1% of the general population. Although some anomalies seem to be only anatomical curiosities, others may sometimes have fatal consequences. This review describes the anatomical characteristics of main CAAs and focuses on the pathophysiological mechanisms by which CAAs may cause a pathological state. The last section describes these therapeutical options of this congenital disorders.

Use of Sutureless and Rapid Deployment Prostheses in Challenging Reoperations.

Sutureless and rapid-deployment bioprostheses have been introduced as alternatives to traditional prosthetic valves to reduce cardiopulmonary and aortic cross-clamp times during aortic valve replacement. These devices have also been employed in extremely demanding surgical settings, as underlined in the present review. Searches on the PubMed and Medline databases aimed to identify, from the English-language literature, the reported cases where both sutureless and rapid-deployment prostheses were employed in challenging surgical situations, usually complex reoperations sometimes even performed as bailout procedures. We have identified 25 patients for whom a sutureless or rapid-deployment prosthesis was used in complex redo procedures: 17 patients with a failing stentless bioprosthesis, 6 patients with a failing homograft, and 2 patients with the failure of a valve-sparing procedure. All patients survived reoperation and were reported to be alive 3 months to 4 years postoperatively. Sutureless and rapid-deployment bioprostheses have proved effective in replacing degenerated stentless bioprostheses and homografts in challenging redo procedures. In these settings, they should be considered as a valid alternative not only to traditional prostheses but also in selected cases to transcatheter valve-in-valve solutions.