[Xenotransplantation of solid organs]. / Xenotransplantation von Organen.

Transplantation of genetically modified porcine hearts and kidneys could become a solution to the persistent shortage of human organ donors. Progress has been made in genetic engineering of donor pigs, preservation techniques after organ harvesting and immunosuppression using co-stimulation blockade with anti-CD40/CD40L monoclonal antibodies. Progress has also been made in in the development of methods that detect pathogenic porcine viruses and prevent their transmission to the recipient. As normal land breed pig organs continue to grow in the recipient to their original size, different pig breeds (such as Auckland Island pigs) are now used which reach a final size suitable for humans. Alternatively, a knock-out of the growth hormone receptor gene has been established, e.g., in the 10GM genetically modified pigs from Revivicor/United Therapeutics, USA. The first clinical pilot studies including patients suffering from terminal heart failure are expected to start in Germany in about 2 years.

Current Status of Cardiac Xenotransplantation: Report of a Workshop of the German Heart Transplant Centers, Martinsried, March 3, 2023.

This report comprises the contents of the presentations and following discussions of a workshop of the German Heart Transplant Centers in Martinsried, Germany on cardiac xenotransplantation. The production and current availability of genetically modified donor pigs, preservation techniques during organ harvesting, and immunosuppressive regimens in the recipient are described. Selection criteria for suitable patients and possible solutions to the problem of overgrowth of the xenotransplant are discussed. Obviously microbiological safety for the recipient and close contacts is essential, and ethical considerations to gain public acceptance for clinical applications are addressed. The first clinical trial will be regulated and supervised by the Paul-Ehrlich-Institute as the National Competent Authority for Germany, and the German Heart Transplant Centers agreed to cooperatively select the first patients for cardiac xenotransplantation.

Xenografts Show Signs of Concentric Hypertrophy and Dynamic Left Ventricular Outflow Tract Obstruction After Orthotopic Pig-to-baboon Heart Transplantation.

BACKGROUND: Orthotopic cardiac xenotransplantation has seen substantial advancement in the last years and the initiation of a clinical pilot study is close. However, donor organ overgrowth has been a major hurdle for preclinical experiments, resulting in loss of function and the decease of the recipient. A better understanding of the pathogenesis of organ overgrowth after xenotransplantation is necessary before clinical application. METHODS: Hearts from genetically modified ( GGTA1-KO , hCD46/hTBM transgenic) juvenile pigs were orthotopically transplanted into male baboons. Group I (control, n = 3) received immunosuppression based on costimulation blockade, group II (growth inhibition, n = 9) was additionally treated with mechanistic target of rapamycin inhibitor, antihypertensive medication, and fast corticoid tapering. Thyroid hormones and insulin-like growth factor 1 were measured before transplantation and before euthanasia, left ventricular (LV) growth was assessed by echocardiography, and hemodynamic data were recorded via a wireless implant. RESULTS: Insulin-like growth factor 1 was higher in baboons than in donor piglets but dropped to porcine levels at the end of the experiments in group I. LV mass increase was 10-fold faster in group I than in group II. This increase was caused by nonphysiological LV wall enlargement. Additionally, pressure gradients between LV and the ascending aorta developed, and signs of dynamic left ventricular outflow tract (LVOT) obstruction appeared. CONCLUSIONS: After orthotopic xenotransplantation in baboon recipients, untreated porcine hearts showed rapidly progressing concentric hypertrophy with dynamic LVOT obstruction, mimicking hypertrophic obstructive cardiomyopathy in humans. Antihypertensive and antiproliferative drugs reduced growth rate and inhibited LVOT obstruction, thereby preventing loss of function.

Overcoming perioperative inflammation as a hurdle for successful preclinical orthotopic cardiac xenogeneic transplantations - particular in regard of the mandatory use of heart-lung machines.

INTRODUCTION: After orthotopic cardiac xenotransplantation, the combination of both the inflammatory responses to the exposure of a recipient to the xenogeneic organ and the use of cardiopulmonary bypass has been assumed to cause detrimental side effects. These have been described not only to affect the transplanted organ (heart) itself, but also the recipient's lungs. In this article, we summarize how these possible detrimental processes can be minimized or even avoided. METHODS: Data from eight pig-to-baboon orthotopic cardiac xenotransplantation experiments were analyzed with a special focus on early (within the first week) postoperative organ dysfunction and systemic inflammatory responses. Non-ischemic heart preservation and the careful management of the heart-lung machine were deemed essential to guarantee not only the immediate function of the transplanted xenogeneic organ but also the prompt recovery of the recipient. RESULTS: After weaning from cardiopulmonary bypass, very low catecholamine amounts were needed to ensure an adequate pump function and cardiac output. Central venous oxygen saturation and serum lactate levels remained within normal ranges. All animals were successfully weaned from ventilation within the first postoperative hours. Serum parameters of the transplants and native kidneys and livers were initially slightly elevated or always normal, as were hemoglobin, LDH, and platelet measurements. Markers of systemic inflammation, C-reactive protein, and IL-6 were slightly elevated, but the reactions caused no lasting damage. CONCLUSION: Consistent short-term and long-term results were achieved after orthotopic cardiac pig-to-baboon transplantation without detrimental inflammatory responses or signs of multiorgan failure. In comparison to allogeneic procedures, non-ischemic heart preservation was important for successful immediate organ function, as was the management of the heart-lung machine. Thus, we believe that genetically modified porcine hearts are ready for use in the clinical setting.

Pediatric heart transplantation in infants and small children under 3 years of age: Single center experience - "Early and long-term results".

OBJECTIVES: We analyzed the early and long-term survival after ABO-compatible heart transplantation in children under 3 years of age from 1991 to 2021 at our center. This retrospective and descriptive study aimed to identify serious adverse events associated with mortality after pediatric heart transplantation. PATIENTS AND METHODS: 46 patients with congenital heart failure (37%) in end-stage heart failure have undergone a pediatric heart transplantation. Primary outcome of interest was survival at follow-up time. RESULTS: Median (IQR) follow-up time (y), age (y), body-weight (kg) and BMI (kg/cm2) were 13.2 (5.7-19.5), 0.9 (0.2-2.0), 6.8 (4.3-10.0) and 14.2 (12.3-15.7). Twenty-four (52%) patients were male. 15 patients (33%) had a single ventricle physiology. At 30- days survival rate was 94 ± 4%. Survival rate at 1, 5, 10 and 15 years post HTx was 87 ± 5%, 84 ± 6%, 79 ± 6% and 63 ± 8%. One child underwent re-transplantation after 4 years, and another one after 11 years - in both cases due to graft failure. Higher early mortality in patients under 3 months of age and in patients with single ventricle physiology. Transplant free survival at 15 years was in children with cardiomyopathy better (71 ± 10%) than in those with congenital heart disease (50 ± 13%). One or more previous heart surgeries prior to HTx (n = 21) were associated to more mortality. CONCLUSION: Pediatric heart transplantation has acceptable long-term results and is still the best therapeutic option in children with end-stage cardiac failure. Underlying anomalies and single ventricle physiology, age below 3 months had a significant impact on survival.

Long-Term Follow-Up of Mechanical Circulatory Support in Peripartum Cardiomyopathy (PPCM) Refractory to Medical Management: A Multicenter Study.

BACKGROUND: Peripartum cardiomyopathy (PPCM) is a rare, life-threatening form of heart disease, frequently associated with gene alterations and, in some cases, presenting with advanced heart failure. Little is known about ventricular assist device (VAD) implantation in severe PPCM cases. We describe long-term follow-up of PPCM patients who were resistant to medical therapy and received mechanical circulatory support or heart transplant. METHODS AND RESULTS: A total of 13 patients were included with mean follow-up of eight years. Mean age of PPCM onset was 33.7 ± 7.7 years. All patients were initially treated with angiotensin-converting enzyme inhibitors and beta-blockers, and four received bromocriptine. Overall, five patients received VADs (three biventricular, two isolated left ventricular) at median 27 days (range: 3 to 150) following childbirth. Two patients developed drive line infection. Due to the short support time, none of those patients had a stroke or VAD thrombosis. In total, five patients underwent heart transplantation, of which four previously had implanted VADs. Median time to transplantation from PPCM onset was 140 days (range: 43 to 776), and time to transplantation from VAD implantation were 7, 40, 132, and 735 days, respectively. All patients survived until most recent follow up, with the exception of one patient who died following unrelated abdominal surgery two years after PPCM recovery. CONCLUSIONS: In patients with severe, life-threatening PPCM refractory to medical management, mechanical circulatory support with or without heart transplantation is a safe therapeutic option.

Cold non-ischemic heart preservation with continuous perfusion prevents early graft failure in orthotopic pig-to-baboon xenotransplantation.

BACKGROUND: Successful preclinical transplantations of porcine hearts into baboon recipients are required before commencing clinical trials. Despite years of research, over half of the orthotopic cardiac xenografts were lost during the first 48 hours after transplantation, primarily caused by perioperative cardiac xenograft dysfunction (PCXD). To decrease the rate of PCXD, we adopted a preservation technique of cold non-ischemic perfusion for our ongoing pig-to-baboon cardiac xenotransplantation project. METHODS: Fourteen orthotopic cardiac xenotransplantation experiments were carried out with genetically modified juvenile pigs (GGTA1- KO/hCD46/hTBM) as donors and captive-bred baboons as recipients. Organ preservation was compared according to the two techniques applied: cold static ischemic cardioplegia (IC; n = 5) and cold non-ischemic continuous perfusion (CP; n = 9) with an oxygenated albumin-containing hyperoncotic cardioplegic solution containing nutrients, erythrocytes and hormones. Prior to surgery, we measured serum levels of preformed anti-non-Gal-antibodies. During surgery, hemodynamic parameters were monitored with transpulmonary thermodilution. Central venous blood gas analyses were taken at regular intervals to estimate oxygen extraction, as well as lactate production. After surgery, we measured troponine T and serum parameters of the recipient's kidney, liver and coagulation functions. RESULTS: In porcine grafts preserved with IC, we found significantly depressed systolic cardiac function after transplantation which did not recover despite increasing inotropic support. Postoperative oxygen extraction and lactate production were significantly increased. Troponin T, creatinine, aspartate aminotransferase levels were pathologically high, whereas prothrombin ratios were abnormally low. In three of five IC experiments, PCXD developed within 24 hours. By contrast, all nine hearts preserved with CP retained fully preserved systolic function, none showed any signs of PCXD. Oxygen extraction was within normal ranges; serum lactate as well as parameters of organ functions were only mildly elevated. Preformed anti-non-Gal-antibodies were similar in recipients receiving grafts from either IC or CP preservation. CONCLUSIONS: While standard ischemic cardioplegia solutions have been used with great success in human allotransplantation over many years, our data indicate that they are insufficient for preservation of porcine hearts transplanted into baboons: Ischemic storage caused severe impairment of cardiac function and decreased tissue oxygen supply, leading to multi-organ failure in more than half of the xenotransplantation experiments. In contrast, cold non-ischemic heart preservation with continuous perfusion reliably prevented early graft failure. Consistent survival in the perioperative phase is a prerequisite for preclinical long-term results after cardiac xenotransplantation.

Impact of porcine cytomegalovirus on long-term orthotopic cardiac xenotransplant survival.

Xenotransplantation using pig organs has achieved survival times up to 195 days in pig orthotopic heart transplantation into baboons. Here we demonstrate that in addition to an improved immunosuppressive regimen, non-ischaemic preservation with continuous perfusion and control of post-transplantation growth of the transplant, prevention of transmission of the porcine cytomegalovirus (PCMV) plays an important role in achieving long survival times. For the first time we demonstrate that PCMV transmission in orthotopic pig heart xenotransplantation was associated with a reduced survival time of the transplant and increased levels of IL-6 and TNFα were found in the transplanted baboon. Furthermore, high levels of tPA-PAI-1 complexes were found, suggesting a complete loss of the pro-fibrinolytic properties of the endothelial cells. These data show that PCMV has an important impact on transplant survival and call for elimination of PCMV from donor pigs.

Pig-to-non-human primate heart transplantation: The final step toward clinical xenotransplantation?

BACKGROUND: The demand for donated human hearts far exceeds the number available. Xenotransplantation of genetically modified porcine organs provides an alternative. In 2000, an Advisory Board of the International Society for Heart and Lung Transplantation set the benchmark for commencing clinical cardiac xenotransplantation as consistent 60% survival of non-human primates after life-supporting porcine heart transplantations. Recently, we reported the stepwise optimization of pig-to-baboon orthotopic cardiac xenotransplantation finally resulting in consistent success, with 4 recipients surviving 90 (n = 2), 182, and 195 days. Here, we report on 4 additional recipients, supporting the efficacy of our procedure. RESULTS: The first 2 additional recipients succumbed to porcine cytomegalovirus (PCMV) infections on Days 15 and 27, respectively. In 2 further experiments, PCMV infections were successfully avoided, and 3-months survival was achieved. Throughout all the long-term experiments, heart, liver, and renal functions remained within normal ranges. Post-mortem cardiac diameters were slightly increased when compared with that at the time of transplantation but with no detrimental effect. There were no signs of thrombotic microangiopathy. The current regimen enabled the prolonged survival and function of orthotopic cardiac xenografts in altogether 6 of 8 baboons, of which 4 were now added. These results exceed the threshold set by the Advisory Board of the International Society for Heart and Lung Transplantation. CONCLUSIONS: The results of our current and previous experimental cardiac xenotransplantations together fulfill for the first time the pre-clinical efficacy suggestions. PCMV-positive donor animals must be avoided.

Update and breakthrough in cardiac xenotransplantation.

PURPOSE OF REVIEW: Considerable advancements have been made in the field of cardiac xenotransplantation in the recent years, achieving prolonged survival of the life-supporting cardiac xenograft and paving the way toward first clinical implications. RECENT FINDINGS: The combination of genetic modifications and novel immunosuppression with costimulation blockade, as well as supporting therapy with antiinflammatory treatment, growth prevention, and adaptation of the heart procurement system to reduce myocardial ischemia and reperfusion injury improves the overall cardiac xenograft function and overall survival in nonhuman primates. Through the newly identified xenoantigens and novel gene-editing techniques, further genetic modification of the porcine xenografts should be explored, to ensure clinical safety. SUMMARY: With continuous progress in all fields of cardiac xenotransplantation, first clinical use in humans seems accomplishable. To ensure the clinical safety and to conform to the ethical regulations, further investigation of the infectious and immunological implications on humans should be explored prior to first clinical use. The first clinical use of cardiac xenotransplantation will be limited to only highly selected patients.

Hemodynamic evaluation of anesthetized baboons and piglets by transpulmonary thermodilution: Normal values and interspecies differences with respect to xenotransplantation.

BACKGROUND: Transpulmonary thermodilution is well established as a tool for in-depth hemodynamic monitoring of critically ill patients during surgical procedures and intensive care. It permits easy assessment of graft function following cardiac transplantation and guides post-operative volume and catecholamine therapy. Since no pulmonary catheter is needed, transpulmonary thermodilution could be useful in experimental cardiac pig-to-baboon xenotransplantation. However, normal values for healthy animals have not yet been reported. Here, we present data from piglets and baboons before xenotransplantation experiments and highlight differences between the two species and human reference values. METHODS: Transpulmonary thermodilution from baboons (body weight 10-34 kg) and piglets (body weight 10-38kg) were analyzed. Measurements were taken in steady state after induction of general anesthesia before surgical procedures commenced. Cardiac index (CI), mean arterial pressure (MAP), systemic vascular resistance index (SVRI), parameters quantifying cardiac filling (global end-diastolic volume index, GEDI), and pulmonary edema (extravascular lung water, ELWI) were assessed. RESULTS: Preload, afterload, and contractility parameters clearly correlated with total body weight or body surface area. Baboons had lower CI values than weight-matched piglets (4.2 ± 0.9l/min/m2 vs 5.3 ± 1.0/min/m2 , P < .01). MAP and SVRI were higher in baboons than piglets (MAP: 99 ± 22 mm Hg vs 62 ± 11 mm Hg, P < .01; SVRI: 1823 ± 581 dyn*s/cm5 *m2 vs 827 ± 204 dyn*s/cm5 *m2 , P < .01). GEDI and ELWI did differ significantly between both species, but measurements were within similar ranges (GEDI: 523 ± 103 mL/m2 vs 433 ± 78 mL/m2 , P < .01; ELWI: 10 ± 3 mL/kg vs 11 ± 2 mL/kg, P < .01). Regarding adult human reference values, CI was similar to both baboons and piglets, but all other parameters were different. CONCLUSIONS: Parameters of preload, afterload, and contractility differ between baboons and piglets. In particular, baboons have a much higher afterload than piglets, which might be instrumental in causing perioperative xenograft dysfunction and post-operative myocardial hypertrophy after orthotopic pig-to-baboon cardiac xenotransplantation. Most transpulmonary thermodilution-derived parameters obtained from healthy piglets and baboons lie outside the reference ranges for humans, so human normal values should not be used to guide treatment in those animals. Our data provide reference values as a basis for developing algorithms for perioperative hemodynamic management in pig-to-baboon cardiac xenotransplantation.

Author Correction: Consistent success in life-supporting porcine cardiac xenotransplantation.

In this Letter, Mayuko Kurome and Valeri Zakhartchenko have been added to the author list (affiliated with Institute of Molecular Animal Breeding and Biotechnology, Gene Center, LMU Munich, Munich, Germany). The author list and 'Author contributions' section have been corrected online; see accompanying Amendment.

Risk Factors and Outcome of Post Fallot Repair Junctional Ectopic Tachycardia (JET).

BACKGROUND: Junctional ectopic tachycardia (JET) is a common arrhythmia causing hemodynamic impairment following corrective cardiac surgery such as tetralogy of Fallot (TOF) repair. METHODS: We report our experience with postoperative JET following surgical repair of TOF. The retrospective study was done from 2003 to 2012 with a total of 105 patients who underwent TOF repair. These patients' clinical and electrocardiographic data (pre-, intra-, and postoperative) were monitored to identify risk factors for the occurrence of JET and to evaluate the outcome of the affected patients. RESULTS: Incidence-Fourteen patients developed JET, with only four patients going directly from sinus rhythm to JET. In all others, either a transient atrioventricular (AV) block or a junctional rhythm preceded JET, mostly intraoperatively, showing a significant relation ( P = .010). Age-Patients with JET were of younger age ( P = .025) and had longer cardiopulmonary bypass ( P = .044) and aortic cross-clamping times ( P = .038). Increased cost and care-The occurrence of JET was associated with a longer stay in the intensive care unit (ICU) and a prolonged need for inotropic support and mechanical ventilation. Time to rate control correlated with length of ICU and hospital stay. MORTALITY: All JET patients converted into sinus rhythm, one of them died shortly after cessation of JET and two patients subsequently developed a first-degree AV block. CONCLUSION: The occurrence of JET remains an important complication during the initial postoperative period by increasing mechanical ventilation time, the need for inotropic support, and prolonging the length of ICU and hospital stay. Risk factors are younger age, longer aortic cross-clamping/bypass times, and intraoperative arrhythmias.

Consistent success in life-supporting porcine cardiac xenotransplantation.

Heart transplantation is the only cure for patients with terminal cardiac failure, but the supply of allogeneic donor organs falls far short of the clinical need1-3. Xenotransplantation of genetically modified pig hearts has been discussed as a potential alternative4. Genetically multi-modified pig hearts that lack galactose-α1,3-galactose epitopes (α1,3-galactosyltransferase knockout) and express a human membrane cofactor protein (CD46) and human thrombomodulin have survived for up to 945 days after heterotopic abdominal transplantation in baboons5. This model demonstrated long-term acceptance of discordant xenografts with safe immunosuppression but did not predict their life-supporting function. Despite 25 years of extensive research, the maximum survival of a baboon after heart replacement with a porcine xenograft was only 57 days and this was achieved, to our knowledge, only once6. Here we show that α1,3-galactosyltransferase-knockout pig hearts that express human CD46 and thrombomodulin require non-ischaemic preservation with continuous perfusion and control of post-transplantation growth to ensure long-term orthotopic function of the xenograft in baboons, the most stringent preclinical xenotransplantation model. Consistent life-supporting function of xenografted hearts for up to 195 days is a milestone on the way to clinical cardiac xenotransplantation7.

Perioperative Telemetric Monitoring in Pig-to-Baboon Heterotopic Thoracic Cardiac Xenotransplantation.

BACKGROUND Perioperative monitoring and hemodynamic management after heterotopic thoracic cardiac xenotransplantation is challenging due to 2 independently beating hearts. Telemetry allows continuous monitoring of hemodynamic parameters of both the donor and recipient hearts. We describe our experience and report on the validity of a telemetric system during and after surgery. MATERIAL AND METHODS Wireless telemetry transmitters were implanted in 3 baboons receiving porcine donor hearts. Left ventricular pressure and ECG were assessed from the donor heart, whereas aortic pressure and temperature were assessed from the recipient. Telemetric data were validated with invasive blood pressure measurements. RESULTS Telemetric blood pressure was lower than invasive blood pressure. Intraoperatively, the probe in the graft's left ventricle measured negative end-diastolic pressures. Telemetry allowed simple discrimination between donor's and recipient's heart rates. Body temperature was underestimated by telemetry. Telemetric monitoring facilitates recognition of graft arrhythmias and volume demand. CONCLUSIONS In heterotopic thoracic cardiac xenotransplantation, telemetric implants are useful tools to continuously monitor the animals' hemodynamic parameters and to discriminate donor and recipient organs. Accuracy is sufficient for systemic pressure measurement, but perioperative use of left ventricular end-diastolic pressure as a surrogate parameter for graft function is not advisable. Temperature measurements by telemetry do not reflect body core temperature.

Hemodynamic and perioperative management in two different preclinical pig-to-baboon cardiac xenotransplantation models.

BACKGROUND: The perioperative phase of preclinical cardiac xenotransplantations significantly affects the experimental outcome. Moderate or even severe hemodynamic and respiratory impairment occurs frequently in baboons after receiving a cardiac transplant. The perioperative management of such postoperative instability is very demanding, especially in the experimental setting. We compared perioperative changes of hemodynamic and laboratory findings during orthotopic and heterotopic thoracic cardiac xenotransplantations and describe our monitoring, treatment and intensive care. METHODS: Twenty-eight pig-to-baboon cardiac xenotransplantations were performed using either the orthotopic (oHTx, n=5) or heterotopic thoracic (htHTx; n=23) technique. In both techniques, cardioplegia and an intraoperative cardiopulmonary bypass (CPB) were required. Preoperatively, intensive care (eg, transfusions, catecholamine therapy) was provided and fast extubation was targeted. A central venous catheter, a femoral arterial thermodilution catheter, a telemetric pressure transmitter and transthoracic echocardiography were used to monitor the animal. Baboon jackets with a tethering system were used to continuously apply medication postoperatively and permit blood sampling, also after extubation of the animal and transfer into the cage. Perioperative survival, hemodynamics, catecholamine doses, respiratory function and weaning from respirator were compared. Perioperative organ damage was evaluated based on laboratory findings 12 hours after transplantation. RESULTS: Recipients could be weaned from CPB in the 20 htHTx and all five oHTx experiments, and three htHTx procedures were terminated during the operation. The time of cardiopulmonary bypass was significantly lower in the heterotopic group (oHTx median 171 [157-193] minutes; htHTx median 144 [100-190] minutes; P=.02). In 17 htHTx procedures, no inotropics were used, whereas epinephrine had to be administered in four of the five oHTx experiments; the mean time of catecholamine support was longer in the oHTx group (oHTx 972±348 minutes vs htHTx 111±92 minutes; P<.01). After htHTx, weaning off the respirator was possible in 19 of 20 cases (one died due to pneumothorax). After oHTx, three of the five baboons could be weaned off the respirator; in these cases, the arterial saturation was higher compared with the extubated baboons after htHTx (oHTx 99±1% vs htHTx 91±4%, P=.01). Intraoperative blood loss was similar between the two groups, and hemostasis was impaired after all procedures, but relevant postoperative bleeding never occurred. CONCLUSION: Intensive intra- and postoperative monitoring and care is required in both transplantation techniques as a requirement for successful weaning from CPB and respirator. After htHTx, the animals needed less catecholamines and were hemodynamically more stable. Even though pulmonary function was often impaired after htHTx, weaning from the respirator and extubation was more successful in this group.

Long-term outcomes after resection of Stage IV cavoatrial tumour extension using deep hypothermic circulatory arrest.

OBJECTIVES: Renal neoplasms frequently expand into renal veins and inferior vena cava from the early stages of the disease. In this study, we set out to define the long-term outcomes of patients with Stage IV tumorous cavoatrial extension, undergoing radical nephrectomy with excision of cavoatrial extension in deep hypothermic circulatory arrest (DHCA). METHODS: Thirty-five patients with Stage IV cavoatrial extension of renal cell carcinoma underwent radical nephrectomy combined with en bloc excision of cavoatrial tumour-thrombus extension, performed in DHCA. The preoperative staging of the tumour and assessment of the intravascular position of the tumour were performed using standard imaging techniques, including computed tomography angiography, magnetic resonance imaging and echocardiography. Patient data were collected in the patient data bank and analysed retrospectively. RESULTS: In this study cohort, we demonstrate acceptable long-term results (the mean overall survival of 4.9 ± 1.0 years and the 5-year survival rate of 40%) and outline several clear predictors for postoperative long-term survival of the patients. Preoperative evidence of remote tumour metastases and tumourous lymph node involvement conversely predicts inferior postoperative survival. However, a high local postoperative tumour recurrence rate does not limit patient survival in this group. CONCLUSIONS: The data provide evidence for perioperative safety and acceptable long-term results of radical nephrectomy with excision of cavoatrial extension in DHCA in patients with Stage IV cavoatrial extension of renal neoplasm. Thus, this radical surgical procedure can provide effective long-term palliation in the absence of evident metastatic disease.

First Biventricular Jarvik 2000 Implants (Retroauricular Version) Via a Median Sternotomy.

OBJECTIVES: Organ shortages and increased numbers of nontransplant older patients have necessitated a search for alternatives to heart transplants. The Jarvik 2000 assist device (Jarvik Heart, Inc., Manhattan, NY, USA), as a small long-term axial flow pump, offers many advantages, such as retroauricular power supply, which minimizes driveline infection risks. When implanted biventricularly, the device may offer support for patients with biventricular heart failure, especially for nontransplant patients as a destination therapy. MATERIALS AND METHODS: We implanted biventricular Jarvik 2000 systems into 3 men (aged, 65.3 ± 5.0 y; ejection fraction, 24.7% ± 1.5% for left ventricle and 17.7% ± 5.0% for right ventricle). These were the first patients worldwide to receive a biventricular Jarvik 2000 device with retroauricular power supply via a median sternotomy and with additional cardiac surgical procedures. RESULTS: No technical problems were noted during biventricular assist device implant. Mean support time on the device was 224 ± 198 days. All 3 patients showed sufficient cardiac support; 2 patients died from noncardiac complications. Patient 1 died on day 3 as a result of postoperative hepatic failure after preoperative reanimation, and patient 3 died as a result of an ileus and colon perforation after 50 days. Patient 2 died of ventricular fibrillation (after 1.5 y), which occurred 1 year after right ventricular pump shutdown, although significant improvement of right ventricle function was shown (ejection fraction increased by 48%). CONCLUSIONS: Our 3 patients were old, had multiple comorbidities, and needed further cardiac surgery. None of the patients died as a result of technical failure of the device but because of complications accompanying their morbidities. If complication rates can be reduced, a biventricular assist device implant could and should be considered as a potential alternative for nontransplant patients.

Pre-clinical heterotopic intrathoracic heart xenotransplantation: a possibly useful clinical technique.

BACKGROUND: As a step towards clinical cardiac xenotransplantation, our experimental heterotopic intrathoracic xenotransplantation model offers a beating and ejecting donor heart while retaining the recipient's native organ as a backup in case of graft failure. Clinically applicable immunosuppressive regimens (IS) were investigated first, then treatments known to be effective in hypersensitized patients or those with recalcitrant rejection reactions. METHODS: Consecutive experiments were carried out between 2009 and 2013. Twenty-one genetically modified pigs (GGTA1-knockout/hCD46/± thrombomodulin, in one case HLA-E instead) were used as donors. In all experiments, two cycles of immunoabsorption reduced preformed antibodies. Recipient baboons were divided into two groups according to IS regimen: In group one (n = 10), pre-treatment started either one (anti-CD20) or four weeks (anti-CD20 plus the proteasome inhibitor bortezomib) prior to transplantation. The extended conventional (as for allotransplantation) immunosuppressive maintenance regimen included anti-thymocyte globuline, tacrolimus, mycophenolate mofetil, methylprednisolone and weekly anti-CD20. In group two (n = 11), myeloablative pre-treatment as in multiple myeloma patients (long and short regimens) was added to extended conventional IS; postoperative total thoracic and abdominal lymphoid irradiation (TLI; single dose of 600 cGY) was used to further reduce antibody-producing cells. RESULTS: In the perioperative course, the surgical technique was safely applied: 19 baboons were weaned off extracorporeal circulation and 17 extubated. Nine animals were lost in the early postoperative course due to causes unrelated to surgical technique or IS regimen. Excluding these early failures, median graft survival times of group 1 and 2 were 18.5 (12-50) days and 16 (7-35) days. Necropsy examination of group 1 donor organs revealed hypertrophy of the left ventricular wall in the six longer-lasting grafts; myocardial histology confirmed pre-clinical suspicion of humoral rejection, which was not inhibited by the extended conventional IS including intensified treatments, and signs of thrombotic microangiopathy. Grafts of group 2 presented with only mild-to-moderate features of humoral rejection and thrombotic microangiopathy, except in one case of delayed rejection on day 17. The other experiments in this group were terminated because of untreatable pulmonary oedema, recurring ventricular fibrillation, Aspergillus sepsis, as well as a combination of a large donor organ and late toxic side effects due to TLI. CONCLUSIONS: Longer-term results were difficult to achieve in this model due to the IS regimens used. However, we conclude that heterotopic intrathoracic heart transplantation may be an option for clinical xenotransplantation.