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.

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.

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.

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.

Bentall procedure with the CarboSeal™ and CarboSeal Valsalva™ composite conduits: long-term outcomes.

OBJECTIVES: Data on the long-term results with the standard CarboSeal™ mechanical conduit used for the modified Bentall procedure are lacking as well as information on performance of the Valsalva CarboSeal™ conduit. METHODS: We have analysed 208 recipients of a standard (n = 110) or a Valsalva (n = 98) CarboSeal™ conduit. The median age was 60 years and 90% were males; 35 (17%) had type A aortic dissection and 65 (30%) a bicuspid aortic valve. Data were retrospectively analysed and results were compared between the 2 conduit models. RESULTS: Early mortality was 1.9%; the mean follow-up was 175 ± 95 for standard and 94 ± 51 months for Valsalva conduits (P < 0.01). Actuarial survival was 86 ± 4%, 75 ± 6%, 59 ± 7% and 51 ± 9% at 5, 10, 15 and 20 years, respectively. There were 13 thromboembolic episodes with 3 deaths with an actuarial freedom of 98 ± 1%, 94 ± 2%, 90 ± 3% and 89 ± 4% at 5, 10, 15 and 20 years, respectively. Reoperation on the aortic root was performed in 9 patients for endocarditis (n = 8) and pseudoaneurysm at the right coronary button (n = 1) with an actuarial freedom of 97 ± 1%, 95 ± 2%, 92 ± 3% and 87 ± 4% at 5, 10, 15 and 20 years, respectively. There were no differences between the 2 conduit models in survival and major postoperative complications. CONCLUSIONS: The CarboSeal™ conduit has shown gratifying overall performance up to 20 years and appears a valid option for a modified Bentall operation, when a mechanical prosthesis is indicated. Both CarboSeal™ conduit models provided not statistically different overall long-term results.

Impaired Baseline Renal Function May Not Influence Outcomes and Survival After Left Ventricular Assist Device Implantation.

BACKGROUND: We investigated changes in estimated glomerular filtration rate (eGFR) after left ventricular assist device (LVAD) implant and the impact on long-term outcomes. METHODS: A retrospective analysis was conducted for 255 patients with LVADs, divided into 2 groups based on preimplant eGFR (<60 or >60 mL/min/1.73 m2) and into 6 grades (grade 1, >90 mL/min/1.73 m2 normal; grade 2, 60-89 mild dysfunction; grade 3, 45-59 moderate; grade 4, 30-44 moderate to severe; grade 5, 15-29 severe; or grade 6, <15 kidney failure). Changes in eGFR and the impact on long-term outcome and survival were analyzed. RESULTS: One-month postimplant eGFR of the total cohort increased from a baseline of 75.19 ± 34.35 to 118.97 ± 67.62 mL/min/1.73 m2(P < .001). eGRF 4 years postimplant was higher than baseline but not significantly (P = .48). Patients with a preimplant eGFR > 60 followed the same pattern as the entire cohort. The preimplant eGFR < 60 group had a significant increase at 1 month (P < .001), eGFR remained significantly higher than baseline 4 years postimplant (P = .032), and there was a sustained transition to improved distribution of renal function grade after LVAD implant. Post-LVAD implant survival at 1, 3, and 5 years for baseline eGFR > 60 was 76%, 54%, and 48% and for eGFR < 60 was 71%, 60%, and 48%, respectively (P = .92). CONCLUSIONS: Patients with a low preimplant eGFR derive benefit from LVAD therapy, with eGFR remaining elevated above preimplant levels. Preimplant renal dysfunction did not impact negatively on long-term morbidity and mortality.

Heart transplant outcomes in patients with mechanical circulatory support: cold storage versus normothermic perfusion organ preservation.

OBJECTIVES: Patients with mechanical circulatory support bridged to a heart transplant (HTx) are at higher risk of postoperative graft dysfunction. In this subset, a mode of graft preservation that shortens graft ischaemia should be beneficial. METHODS: The outcomes of 38 patients on mechanical circulatory support (extracorporeal life support, left ventricular assist device and biventricular assist device) who received a HTx between 2015 and 2020 were analysed according to the method of graft preservation: cold storage (CS) group, 24 (63%) or ex vivo perfusion (EVP) group, 14 (37%). RESULTS: The median age was 57 (range 30-73) vs 64 (35-75) years (P = 0.10); 88% were men (P = 0.28); extracorporeal life support was more frequent in the CS group (54% vs 36%; P = 0.27) versus left ventricular and biventricular assist devices in the EVP group (46% vs 64%; P = 0.27). Clamping time was shorter in the EVP group (P < 0.001) and ischaemic time >4 h was higher in the CS group (P = 0.01). Thirty-day mortality was 13% (0-27%) in the CS group and 0% (P = 0.28) in the EVP group. A significantly lower primary graft failure [7% (0-23%) vs 42% (20-63%); P = 0.03] was observed in the EVP group. Survival at 1 year was 79 ± 8% (63-95%) in the CS group and 84 ± 10% (64-104%) in the EVP group (P = 0.95). CONCLUSIONS: Our results support the use of ex vivo graft perfusion in patients on mechanical circulatory support as a bridge to a HTx. This technique, by shortening graft ischaemic time, seems to improve post-HTx outcomes.

Infective endocarditis following a valve-in-valve procedure.

An 83-year-old man had aortic valve replacement for aortic stenosis with a pericardial bioprosthesis and subsequent implantation of a CoreValve™ prosthesis as a valve-in-valve procedure. Approximately 4 years later, he developed endocarditis on the CoreValve™ with severe prosthetic stenosis, a periannular abscess and systemic embolization. At reoperation both prostheses were removed and another bioprosthesis inserted after reconstruction of the aortic root. Endocarditis after transaortic valve implantation is an uncommon event with dismal prognosis. Infection of a self-expandable device as a valve-in-valve has not been previously reported. This complication represents a surgical challenge which, however, can be successfully managed.

Short-term mechanical circulatory support as bridge to heart transplantation: paracorporeal ventricular assist device as alternative to extracorporeal life support.

Extracorporeal life support (ECLS) is generally considered to be the treatment of choice for bridging to heart transplantation (HTx) patients with cardiogenic shock; however, alternative mechanical circulatory support (MCS) devices have been proposed with satisfactory results and, among those, paracorporeal systems have demonstrated to be safe and effective. This technology has been used for decades as bridge to transplant, especially in patients with advanced right ventricular dysfunction or evidence of multiorgan failure (MOF), which could be difficult to manage with an isolated left ventricular support. Paracorporeal systems are defined by having the pump located outside of the body, with inflow and outflow cannulas that traverse the skin connecting the pump with the heart and great vessels. They can be utilised in a uni- or bi-ventricular configuration and can provide pulsatile or continuous flow, depending on the device technology (pneumatic vs. centrifugal). In particular, pneumatic devices allow for patient mobilization and hospital discharge, improving rehabilitation and organ recovery while bridging to transplant. In our institution at the University Hospital of Udine, 34 pneumatic paracorporeal ventricular assist devices (VADs) have been implanted since 1998: in most cases (32 pts), as biventricular support for patients in INTERMACS class I-II. After a median support time of 34 (range, 0-385) days, with 19 patients (56%) supported for more than 1 month, 23 patients (68%) underwent HTx and 3 (9%) were successfully weaned to hospital discharge, resulting in an overall combined 76% survival to HTx or weaning. After transplant, the survival rate was similar to the one of the patients not bridged with MCS. In conclusion, pneumatic VADs can effectively assist patients with severe biventricular failure, especially those with contraindications to ECLS or expected long waiting times for HTx. Moreover, they can potentially result in hospital discharge, optimal organ and patient recovery and donor-recipient matching, resulting in a satisfactory transplant outcome.