Venoarterial extracorporeal membrane oxygenation (ECMO) is a rescue therapy that can stabilize patients with hemodynamic compromise, with or without respiratory failure, for days or weeks. In ...cardiology, the main indications for ECMO include cardiac arrest, cardiogenic shock, post-cardiotomy shock, refractory ventricular tachycardia, and acute management of complications of invasive procedures. The fundamental premise underlying ECMO is that it is a bridge-to recovery, to a more durable bridge, to definitive treatment, or to decision. As a very resource- and effort-intensive intervention, ECMO should not be used on unsalvageable patients. As the use of this technology continues to evolve rapidly, it is important to understand the indications and contraindications; the logistics of ECMO initiation, management, and weaning; the general infrastructure of the program (including the challenges associated with transferring patients supported by ECMO); and ethical considerations, areas of uncertainty, and future directions.
Summary Background The Organ Care System is the only clinical platform for ex-vivo perfusion of human donor hearts. The system preserves the donor heart in a warm beating state during transport from ...the donor hospital to the recipient hospital. We aimed to assess the clinical outcomes of the Organ Care System compared with standard cold storage of human donor hearts for transplantation. Methods We did this prospective, open-label, multicentre, randomised non-inferiority trial at ten heart-transplant centres in the USA and Europe. Eligible heart-transplant candidates (aged >18 years) were randomly assigned (1:1) to receive donor hearts preserved with either the Organ Care System or standard cold storage. Participants, investigators, and medical staff were not masked to group assignment. The primary endpoint was 30 day patient and graft survival, with a 10% non-inferiority margin. We did analyses in the intention-to-treat, as-treated, and per-protocol populations. This trial is registered with ClinicalTrials.gov , number NCT00855712. Findings Between June 29, 2010, and Sept 16, 2013, we randomly assigned 130 patients to the Organ Care System group (n=67) or the standard cold storage group (n=63). 30 day patient and graft survival rates were 94% (n=63) in the Organ Care System group and 97% (n=61) in the standard cold storage group (difference 2·8%, one-sided 95% upper confidence bound 8·8; p=0·45). Eight (13%) patients in the Organ Care System group and nine (14%) patients in the standard cold storage group had cardiac-related serious adverse events. Interpretation Heart transplantation using donor hearts adequately preserved with the Organ Care System or with standard cold storage yield similar short-term clinical outcomes. The metabolic assessment capability of the Organ Care System needs further study. Funding TransMedics.
Timely referrals for transplantation and left ventricular assist device implantation play a key role in favorable outcomes in patients with advanced heart failure. Nonetheless, evaluation usually ...occurs at advanced heart failure centers and is obscured from referring physicians. The purposes of this review are to explain the decision-making process for candidacy for advanced therapies and to describe the potential impact of the new organ allocation algorithm on center decision making. The document first addresses the signs of advanced heart failure, specifically focusing on the importance of the syndrome of low cardiac output as a key feature of advanced heart failure, and then summarizes the evaluation as a 3-step process addressing the following questions: 1) Is transplantation or durable assist device placement indicated? 2) Are there contraindications to either intervention? 3) How can one choose between transplantation and left ventricular assist device implantation if advanced therapies are indicated and not contraindicated?
Human papillomavirus (HPV) is a necessary but insufficient cause of a subset of oral squamous cell carcinomas (OSCCs) that is increasing markedly in frequency. To identify contributory, secondary ...genetic alterations in these cancers, we used comprehensive genomics methods to compare 149 HPV-positive and 335 HPV-negative OSCC tumor/normal pairs. Different behavioral risk factors underlying the two OSCC types were reflected in distinctive genomic mutational signatures. In HPV-positive OSCCs, the signatures of APOBEC cytosine deaminase editing, associated with anti-viral immunity, were strongly linked to overall mutational burden. In contrast, in HPV-negative OSCCs, T>C substitutions in the sequence context 5'-ATN-3' correlated with tobacco exposure. Universal expression of HPV
and
oncogenes was a sine qua non of HPV-positive OSCCs. Significant enrichment of somatic mutations was confirmed or newly identified in
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Of these, many affect host pathways already targeted by HPV oncoproteins, including the p53 and pRB pathways, or disrupt host defenses against viral infections, including interferon (IFN) and nuclear factor kappa B signaling. Frequent copy number changes were associated with concordant changes in gene expression. Chr 11q (including
) and 14q (including
and
) were recurrently lost in HPV-positive OSCCs, in contrast to their gains in HPV-negative OSCCs. High-ranking variant allele fractions implicated
,
, and
mutations as candidate driver events in HPV-positive cancers. We conclude that virus-host interactions cooperatively shape the unique genetic features of these cancers, distinguishing them from their HPV-negative counterparts.
Pump thrombosis is a dreaded complication of long-term implantable ventricular assist devices. No guidance exists regarding the diagnosis and management of this entity despite its significant ...morbidity. After considerable thought and deliberation, a group of leading investigators in the field of mechanical support propose an algorithm for the diagnosis and management of this vexing entity based on clinical symptoms and serologic and imaging studies.
Used frequently for right ventricular dysfunction (RVD), the clinical benefit of inhaled nitric oxide (iNO) is still unclear. We conducted a randomized, double-blind, controlled trial to determine ...the effect of iNO on post-operative outcomes in the setting of left ventricular assist device (LVAD) placement.
Included were 150 patients undergoing LVAD placement with pulmonary vascular resistance ≥ 200 dyne/sec/cm(-5). Patients received iNO (40 ppm) or placebo (an equivalent concentration of nitrogen) until 48 hours after separation from cardiopulmonary bypass, extubation, or upon meeting study-defined RVD. For ethical reasons, crossover to open-label iNO was allowed during the 48-hour treatment period if RVD criteria were met.
RVD criteria were met by 7 of 73 patients (9.6%; 95% confidence interval, 2.8-16.3) in the iNO group compared with 12 of 77 (15.6%; 95% confidence interval, 7.5-23.7) who received placebo (p = 0.330). Time on mechanical ventilation decreased in the iNO group (median days, 2.0 vs 3.0; p = 0.077), and fewer patients in the iNO group required an RVAD (5.6% vs 10%; p = 0.468); however, these trends did not meet statistical boundaries of significance. Hospital stay, intensive care unit stay, and 28-day mortality rates were similar between groups, as were adverse events. Thirty-five patients crossed over to open-label iNO (iNO, n = 15; placebo, n = 20). Eighteen patients (iNO, n = 9; placebo, n = 9) crossed over before RVD criteria were met.
Use of iNO at 40 ppm in the perioperative phase of LVAD implantation did not achieve significance for the primary end point of reduction in RVD. Similarly, secondary end points of time on mechanical ventilation, hospital or intensive care unit stay, and the need for RVAD support after LVAD placement were not significantly improved.
Fumarate hydratase-deficient renal cell carcinoma (FH-RCC) is a rare, aggressive form of RCC associated with hereditary leiomyomatosis and RCC syndrome. Evidence for systemic therapy efficacy is ...lacking.
We studied clinical and genomic characteristics of FH-RCC, including response objective response rate (ORR) to systemic therapies and next-generation sequencing (NGS). Patients with metastatic FH-RCC, defined by presence of pathogenic germline or somatic
mutation plus IHC evidence of FH loss, were included.
A total of 28 of 32 included patients (median age 46; range, 20-74; M:F, 20:12) underwent germline testing; 23 (82%) harbored a pathogenic
germline variant. Five (16%) were negative for germline
mutations; all had biallelic somatic
loss. Somatic NGS (31/32 patients) revealed co-occurring
mutation most frequently (
= 5). Compared with clear-cell RCC, FH-RCC had a lower mutation count (median 2 vs. 4;
< 0.001) but higher fraction of genome altered (18.7% vs. 10.3%;
= 0.001). A total of 26 patients were evaluable for response to systemic therapy: mTOR/VEGF combination (
= 18, ORR 44%), VEGF monotherapy (
= 15, ORR 20%), checkpoint inhibitor therapy (
= 8, ORR 0%), and mTOR monotherapy (
= 4, ORR 0%). No complete responses were seen. Median overall and progression-free survival were 21.9 months 95% confidence interval (CI): 14.3-33.8 and 8.7 months (95% CI: 4.8-12.3), respectively.
Although most FH-RCC tumors are due to germline
alterations, a significant portion result from biallelic somatic
loss. Both somatic and germline FH-RCC have similar molecular characteristics, with NF2 mutations, low tumor mutational burden, and high fraction of genome altered. Although immunotherapy alone produced no objective responses, combination mTOR/VEGF therapy showed encouraging results.
Survival despite prolonged non‐adherence with immunosuppression is rare but has been reported in kidney, lung, and liver transplantation. Its occurrence in heart transplantation is quite rare. Our ...study was prompted by an index patient who survived despite prolonged medication non‐adherence. Prospective consent and blood collection were conducted for seven additional patients who presented in a similar fashion. The blood of patients who were diagnosed with rejection, stable early post‐transplant, and stable more than 5 years post‐transplant were all compared with a custom gene array focusing on T‐regulatory cell processes. The two genes that were differentially expressed in every comparison were TGF beta and RNASEN with very low expression in the rejector group. The prolonged non‐adherent group had the maximum expression for TGF beta but average RNASEN expression as compared to the low expression for rejectors and high for post‐5 years patients. The patients presented survived for varying lengths of time without immunosuppression. The gene array analysis showed intriguing differences between these rare patients and important patient cohorts. Further efforts should be directed to finding and studying more patients who survive despite lack of prescribed immunosuppression. The mechanisms underlying this phenomenon may inform future advances in transplant immunosuppression.
Lung transplantation is a widely accepted treatment for patients with end-stage lung disease related to idiopathic pulmonary fibrosis (IPF). However, there are conflicting data on whether double lung ...transplant (DLT) or single lung transplant (SLT) is the superior therapy in these patients. The purpose of this study was to determine whether actuarial post-transplant graft survival among IPF patients concurrently listed for DLT and SLT is greater for recipients undergoing the former or the latter.
The United Network for Organ Sharing provided de-identified patient-level data. Analysis included lung transplant candidates with IPF listed between January 1, 2001 and December 31, 2009 (n = 3,411). The study population included 1,001 (29.3%) lung transplant recipients concurrently listed for DLT and SLT, all ≥18 years of age. The primary outcome measure was actuarial post-transplant graft survival, expressed in years.
Among the study population, 433 (43.26%) recipients underwent SLT and 568 (56.74%) recipients underwent DLT. The analysis included 2,722.5 years at risk, with median graft survival of 5.31 years. On univariate (p = 0.317) and multivariate (p = 0.415) regression analyses, there was no difference in graft survival between DLT and SLT.
Among IPF recipients concurrently listed for DLT and SLT, there is no statistical difference in actuarial graft survival between recipients undergoing DLT vs SLT. This analysis suggests that increased use of SLT for IPF patients may increase the availability of organs to other candidates, and thus increase the net benefit of these organs, without measurably compromising outcomes.
Milrinone infusion is one of a few select “non-device” therapies for patients with New York Heart Association (NYHA) class IV, stage D heart failure, which has been associated with an increase in ...ventricular tachyarrhythmia and atrial fibrillation. Milrinone improves hemodynamics and provides symptomatic relief. Many patients with end-stage heart failure die from cardiac pump failure, and the impact of ventricular tachyarrhythmia and atrial fibrillation on their mortality is unclear.
This is a retrospective study of 98 consecutive patients receiving outpatient milrinone in a single center from 2008 to 2016. The primary endpoint of the study was overall survival on milrinone. Secondary endpoints were incidence of post-milrinone implantable cardioverter defibrillator (ICD) shocks and development of ventricular tachyarrhythmia or atrial fibrillation.
Median survival was 581 ± 96 days with no difference between those with prior ventricular tachyarrhythmia and those without at 1 month (92% vs 97%, P = 0.34), 6 months (67% vs 73%, P = 0.75), and 12 months (67% vs 61%, P = 0.88). Seven out of 12 (58%) patients with prior ventricular tachyarrhythmia had ICD shocks, as compared to 5 out of 78 (6.4%) (P <0.001). Thirty-five patients had atrial fibrillation prior to starting milrinone, which decreased to 72% (P <0.05) by the third follow-up time period (7-9 months). Amiodarone use was protective against new onset atrial fibrillation.
Patients with stage D heart failure with a history of ventricular tachyarrhythmia have similar survival on outpatient milrinone compared to those without. However, those with prior ventricular tachyarrhythmia received more ICD shocks for more ventricular tachyarrhythmias. Milrinone remains a viable therapy for patients with stage D heart failure with limited therapeutic options.
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