Extending normothermic regional perfusion to the thorax in donors after circulatory death.

PURPOSE OF REVIEW: Despite a significant increase in the utilization of donors after circulatory death (DCD), the number of organs recovered and their function are largely inferior to those from donors after brain death. This review summarizes recent advances in in-situ normothermic regional perfusion of DCD organs prior to procurement. RECENT FINDINGS: The combination of warm and cold ischemia in DCD donation are detrimental to organ function. As a consequence, the acceptance criteria are far more restrictive and many organs are discarded.The application of extracorporeal circulation technology to DCD organ retrieval in the form of abdominal normothermic regional perfusion (NRP) made a significant impact on organ procurement. DCD heart transplantation has been made possible by technological developments of ex-situ preservation. Extending NRP to include cardio-thoracic organs is a recent development enabling conversion from a DCD to a donor after brain death-type procurement.NRP offers the opportunity for a dynamic assessment of function and may lead to expansion of acceptance criteria as well as allowing for early interventions to modulate organ function. SUMMARY: Thoraco-abdominal NRP may become the new gold standard for DCD organ retrieval. Further research and education are required to streamline logistics, define organ function markers and increase acceptance and utilization.

Outcome of pulmonary endarterectomy in symptomatic chronic thromboembolic disease.

Chronic thromboembolic disease is characterised by persistent pulmonary thromboembolic occlusions without pulmonary hypertension. Early surgical treatment with pulmonary endarterectomy may improve symptoms and prevent disease progression. We sought to assess the outcome of pulmonary endarterectomy in symptomatic patients with chronic thromboembolic disease. Patients with symptomatic chronic thromboembolic disease and a mean pulmonary artery pressure <25 mmHg at baseline with right heart catheterisation and treated with pulmonary endarterectomy between January 2000 and July 2013 were identified. Patients were reassessed at 6 months and at 1 year following surgery. A total of 42 patients underwent surgery and the median length of stay in hospital was 11 days. There was no in-hospital mortality but complications occurred in 40% of patients. At 1 year, following surgery, 95% of the patients remained alive. There was a significant symptomatic improvement with 95% of patients in the New York Heart Association functional classes I or II at 6 months. There was a significant improvement in quality of life assessed by the Cambridge pulmonary hypertension outcome review questionnaire. In this carefully selected cohort of chronic thromboembolic disease patients, pulmonary endarterectomy resulted in significant improvement in symptoms and quality of life. Appropriate patient selection is paramount given the known surgical morbidity and mortality, and surgery should only be performed in expert centres.

Tezosentan and right ventricular failure in patients with pulmonary hypertension undergoing cardiac surgery: the TACTICS trial.

OBJECTIVE: To evaluate the efficacy of tezosentan in reducing the incidence of right ventricular (RV) failure and associated mortality in patients with pre-existing pulmonary hypertension. The primary endpoint was the proportion of patients with RV failure during weaning from cardiopulmonary bypass (CPB), assessed 30 minutes after the end of CPB. DESIGN: Multicenter, double-blind, randomized, placebo-controlled trial. SETTING: Thirty-one cardiac surgical centers in 14 countries. PARTICIPANTS: Two hundred seventy-four patients with pulmonary hypertension aged ≥ 18 years scheduled to undergo cardiac surgery. INTERVENTION: Intravenous tezosentan (5 mg/h) during surgery and up to 24 hours afterwards (1 mg/h), or matched placebo. MEASUREMENTS AND MAIN RESULTS: One-hundred thirty-three patients received tezosentan and 141 placebo. RV failure occurred in 30 patients (10.9%), 37% of whom died. There was no difference in the incidence of RV failure between the two treatment groups (relative risk reduction: 0.07 [95% CI-0.83, 0.53; P = 0.8278]). CONCLUSION: A reduction in RV failure with tezosentan was not observed in this study.(Current Controlled Trials, identifier NCT00458276).

Pulmonary thromboendarterectomy-the Royal Papworth experience.

Background: Pulmonary thromboendarterectomy (PTE) was first introduced to the UK 25 years ago, and the UK national service is provided by a single hospital. The aim of this work is to summarize our experience and review activity and outcomes by era at a high-volume PTE center. During this period the understanding of chronic thromboembolic pulmonary hypertension (CTEPH) increased and drug treatments and balloon angioplasty were developed. We also review our contribution to the better understanding of this surgery and CTEPH. Methods: We retrospectively reviewed all patients undergoing PTE for CTEPH at our center between Jan 1997 and Sept 2019, dividing them into four equal cohorts. Pre-operative characteristics and post-operative outcomes are described by era. A MEDLINE search was performed and original scientific clinical publications from this unit were reviewed. Their contemporary relevance and influence to the evolution of the clinical service are discussed. Results: Over this 23-year period from the commencement of our program, 2,116 consecutive PTE were performed. The mean patient age was 57.8 years (range, 11-89 years). The first 25% of our PTE were performed over 12 years whilst the most recent 25% were performed in less than three years. Over time, the average pre-operative mean pulmonary artery pressure has not changed significantly. The 30-day mortality by era quartile has progressively fallen from 12.3% to 1.9% most recently (P<0.001). Overall, one year survival exceeded 90%. 17 publications influenced our practice development during this period. Conclusions: There was a consistent increase in activity and significant improvement in outcomes between the first and last quartiles of activity studied.

A state-of-the-art review of the current role of cardioprotective techniques in cardiac transplantation.

OBJECTIVES: The use of 'extended criteria' donor hearts and reconditioned hearts from donation after circulatory death has corresponded with an increase in primary graft dysfunction, with ischaemia-reperfusion injury being a major contributing factor in its pathogenesis. Limiting ischaemia-reperfusion injury through optimising donor heart preservation may significantly improve outcomes. We sought to review the literature to evaluate the evidence for this. METHODS: A review of the published literature was performed to assess the potential impact of organ preservation optimisation on cardiac transplantation outcomes. RESULTS: Ischaemia-reperfusion injury is a major factor in myocardial injury during transplantation with multiple potential therapeutic targets. Innate survival pathways have been identified, which can be mimicked with pharmacological conditioning. Although incompletely understood, discoveries in this domain have yielded extremely encouraging results with one of the most exciting prospects being the synergistic effect of selected agents. Ex situ heart perfusion is an additional promising adjunct. CONCLUSIONS: Cardiac transplantation presents a unique opportunity to perfuse the whole heart before, or immediately after, the onset of ischaemia, thus maximising the potential for global cardioprotection while limiting possible systemic side effects. While clinical translation in the setting of myocardial infarction has often been disappointing, cardiac transplantation may afford the opportunity for cardioprotection to finally deliver on its preclinical promise.

Mechanical circulatory support for AMI and cardiogenic shock.

Cardiogenic shock following acute myocardial infarction affects 5% to 10% of patients and carries a grave prognosis. The dismal prognosis associated with post-MI cardiogenic shock, allied with surgical and technological advancements, has shifted the treatment paradigm toward wider use of mechanical circulatory support devices (MCSD). Current experience demonstrates that better outcomes may be achieved with early MCSD deployment (prior to the onset of end-organ dysfunction). However, perceived limitations with existing devices mean that they remain infrequently applied. There is an urgent need for increased awareness of MCSD options among clinicians treating post-MI shock patients.

Improved outcomes in medically and surgically treated chronic thromboembolic pulmonary hypertension.

RATIONALE: The management of chronic thromboembolic pulmonary hypertension (CTEPH) has changed over recent years with the growth of pulmonary endarterectomy surgery and the availability of disease-modifying therapies. OBJECTIVES: To investigate the prognosis of CTEPH in a national setting during recent years. METHODS: All incident cases diagnosed in one of the five pulmonary hypertension centers in the United Kingdom between January 2001 and June 2006 were identified prospectively. Information regarding baseline characteristics, treatment, and follow-up was subsequently collected from hospital records. MEASUREMENTS AND MAIN RESULTS: A total of 469 patients received a diagnosis, of whom 148 (32%) had distal, nonsurgical disease. One- and three-year survival from diagnosis was 82 and 70% for patients with nonsurgical disease and 88 and 76% for those treated surgically (P = 0.023). Initial functional improvement in patients with nonsurgical disease was noted but did not persist at 2 years. Significant functional and hemodynamic improvements were seen in surgically treated patients with an increase in six-minute-walk distance of 105 m (P < 0.001) at 3 months. Five-year survival from surgery in the 35% of patients who survived to 3 months but had persistent pulmonary hypertension was 94%. CONCLUSIONS: The prognosis in nonsurgical disease has improved. We have confirmed the previously described good outcome in surgically treated disease. However, we have also demonstrated that the long-term prognosis for patients who have persistent pulmonary hypertension at 3 months after surgery is good. The observed improvements in outcome during the modern treatment era reinforce the importance of identifying patients with this increasingly treatable condition.

Pulmonary endarterectomy is possible and effective without the use of complete circulatory arrest--the UK experience in over 150 patients.

OBJECTIVE: Pulmonary endarterectomy is the best treatment for patients with chronic thromboembolic pulmonary hypertension. Traditionally pulmonary endarterectomy has been performed utilising deep hypothermic circulatory arrest to provide a bloodless field, but some recent reports have challenged this concept. We reviewed our experience with selective antegrade cerebral perfusion as the initial strategy of controlling bronchial collateral flow to avoid complete circulatory arrest in patients undergoing pulmonary endarterectomy. METHODS: A retrospective review of all patients meeting the above criteria between July 2003 and June 2006. Selective antegrade cerebral perfusion at 20 degrees C was used as the initial means of reducing blood flow to the operative field. RESULTS: One hundred and fifty-one patients (83 male, 68 female, mean age 56+/-16 years) were operated on using this strategy. The preoperative New York Heart Association class distribution showed the majority to be in class III or IV (142 of 151). At initial assessment, mean pulmonary artery pressure was 49+/-12 mmHg and mean pulmonary vascular resistance was 851+/-391 dynes s cm(-5). Selective antegrade cerebral perfusion was required in 145 for a total period of 63+/-24 min. Thirteen (9%) patients required conversion to deep hypothermic arrest for completion of the operation. In-hospital mortality was 22 (15%). There were no instances of focal neurological deficit. Prearranged clinical follow-up for 3 and 12 months was 97% complete with one late death by 3 months and one more by 12 months. The majority were in New York Heart Association class I or II at 3 months (102 of 115) and 12 months (65 of 74). At 3-month follow-up the mean pulmonary artery pressure was 27+/-10 mmHg and pulmonary vascular resistance was 304+/-220 dynes s cm(-5). CONCLUSIONS: Overall results improved with era and institutional experience. The use of selective antegrade cerebral perfusion for pulmonary endarterectomy appears to be technically feasible in the majority of patients and is an alternative to complete circulatory arrest. To clarify its role further, comparison with deep hypothermic circulatory arrest in a randomised controlled trial is necessary.

Improving anticoagulation of patients with an implantable left ventricular assist device.

Patients supported with implantable left ventricular assist devices (LVAD) have a significant risk of bleeding and thromboembolic complications. All patients require anticoagulation with warfarin, aiming for a target international normalised ratio (INR) of 2.5 and most patients also receive antiplatelet therapy. We found marked variation in the frequency of INR measurements and proportion of time outside the therapeutic INR range in our LVAD-supported patients. As part of a quality improvement initiative, home INR monitoring and a networked electronic database for recording INR results and treatment decisions were introduced. These changes were associated with increased frequency of INR measurement. We anticipate that changes introduced in this quality improvement project will reduce the likelihood of adverse events during long-term LVAD support.

Biventricular assist device use in non-dilated hypertrophic cardiomyopathy.

Advanced heart failure is a rare but important complication of hypertrophic cardiomyopathy (HCM). The only definitive treatment is heart transplantation and the role of ventricular assist devices remains uncertain. We describe the use of implantable biventricular assist devices in the treatment of a patient with 'end-stage' non-dilated HCM.

Swan-Ganz catheter assessment of donor hearts: outcome of organs with borderline hemodynamics.

BACKGROUND: High-dosage inotrope use or periods of hypotension may cause rejection of donor hearts for transplantation. At our institution, we do not refuse potential donor organs based on these criteria alone before Swan-Ganz catheter (SGC) assessment. In this study, we evaluate the role of the SGC in donor heart resuscitation and selection and assess the outcome of using borderline organs. METHODS: We retrospectively analyzed 129 donors assessed between 1996 and 1999, all with complete hemodynamic data. Two sets of SGC measurements were analyzed: one set from the initial assessments, and one set from assessments made just before organ harvesting. The physiologic targets were mean blood pressure >60 mm Hg, central venous pressure <12 mm Hg, pulmonary capillary wedge pressure <12 mm Hg, left ventricular stroke work index >15 x g.m/m(2), and use of only one inotrope. A poorly functioning heart was defined as an organ failing on 2 or more of these criteria. Hemodynamic categories were defined as A, good function throughout assessment; B, sub-optimal function and then improvement; and C, decreasing or poor function throughout. We have a policy to avoid allocating sub-optimal organs to high-risk recipients. RESULTS: One hundred fourteen donor hearts went on to be transplanted: 75 as orthotopic hearts and 39 as heart-lungs (5 of these were heart, lung, and liver transplantations, not reported further here). Of the 75 donor hearts used for heart transplantations, 53 were from Category A, 9 were from Category B, and 13 were from Category C. Of the donor hearts used for the 34 heart-lung transplantations 16 were from Category A, 10 were from Category B, and 8 were from Category C. Three patients died of donor organ failure: 1 of the corresponding hearts was from Category B, and 2 were from Category C. When comparing separately the outcome of the 2 procedures, we found no significant difference in duration of stay in the intensive care unit, requirement for mechanical support, 30-day mortality, or 1-year survival among patients with hearts from Categories A, B, and C. Ischemic time was the only significant risk factor for death (p = 0.006). CONCLUSIONS: Use of organs from Categories B and C permitted expansion of the donor pool without compromising short-term outcome. However, these organs should be used with caution in combination with other risk factors, in particular long ischemic time.

Are non-brain stem-dead cardiac donors acceptable donors?

BACKGROUND: The deleterious effects of brainstem death (BSD) on donor cardiac function and endothelial integrity have been documented previously. Domino cardiac donation (heart of a heart-lung recipient transplanted into another recipient) is a way to avoid the effects of brainstem death and may confer both short- and long-term benefits to allograft recipients. METHODS: This study evaluates short- and long-term outcome in heart recipients of BSD donors (cadaveric) as compared with domino hearts explanted from patients who underwent heart-lung transplantation. RESULTS: Patients having undergone cardiac transplantation between April 1989 and August 2001 at Papworth Hospital were included (n = 571). Domino donor hearts were used in 81 (14%) of these cases. The pre-operative transpulmonary gradient was not significantly different between the two groups (p = 0.7). There was no significant difference in 30-day mortality (4.9% for domino vs 8.6% for BSD, p = 0.38) or in actuarial survival (p = 0.72). Ischemic time was significantly longer in the BSD group (p < 0.001). Acute rejection and infection episodes were not significantly different (p = 0.24 vs: 0.08). Relative to the BSD group, the risk (95% confidence interval) of acute rejection in the domino group was 0.89 (0.73 to 1.08). Similarly, the relative risk of infection was 0.78 (0.59 to 1.03). The 5-year actuarial survival rates (95% confidence interval) were 78% (69% to 87%) and 69% (65% to 73%) in the domino and BSD groups respectively. Angiography data at 2 years were available in 50 (62%) and 254 (52%) patients in the domino and BSD groups, respectively. The rates for 2-year freedom from cardiac allograft vasculopathy (CAV) were 96% (91% to 100%) and 93% (90% to 96%), respectively. CONCLUSION: Despite the lack of endothelial cell activation after brainstem death and a shorter ischemic time, the performance of domino donor hearts was similar to that of BSD donor hearts. This may indicate a similar pathology (i.e., endothelial cell activation) in the domino donors.

Use of centrifugal left ventricular assist device as a bridge to candidacy in severe heart failure with secondary pulmonary hypertension.

OBJECTIVES: Raised pulmonary artery pressure (PAP), trans-pulmonary gradient (TPG) and pulmonary vascular resistance (PVR) are risk factors for poor outcomes after heart transplant in patients with secondary pulmonary hypertension (PH) and may contraindicate transplant. Unloading of the left ventricle with an implantable left ventricular assist device (LVAD) may reverse these pulmonary vascular changes. We studied the effect of implanting centrifugal LVADs in a cohort of patients with secondary PH as a bridge to candidacy. METHODS: Pulmonary haemodynamics on patients implanted with centrifugal LVADs at a single unit between May 2005 and December 2010 were retrospectively reviewed. RESULTS: Twenty-nine patients were implanted with centrifugal LVADs (eight HeartWare ventricular assist device (HVAD), HeartWare International, USA and 21 VentrAssist, Ventracor Ltd., Australia). Seventeen were ineligible for transplant by virtue of high TPG/PVR. All the patients were optimized with inotrope/balloon pump followed by LVAD insertion. Four required temporary right VAD support. Thirty-day mortality post-LVAD was 3.4% (1 of 29) with a 1-year survival of 85.7% (24 of 28). Thirteen patients have been transplanted to date: 30-day mortality was 7.7% (1 of 13) and 1-year survival was 91% (10 of 11). Baseline and post-VAD pulmonary haemodynamics were significantly improved: systolic PAP (mmHg), mean PAP, TPG (mmHg) of 57 ± 9.5, 42 ± 4.4 and 14 ± 3.9 reduced to 32 ± 7.5, 18 ± 5.5 and 9 ± 3.3, respectively. PVR reduced from 5 ± 1.5 to 2.1 ± 0.5 Wood units (P < 0.05). CONCLUSIONS: In selected heart failure patients with secondary PH, use of centrifugal LVAD results in significant reductions in PAP, TPG and PVR, which are observed within 1 month, reaching a nadir by 3 months. Such patients bridged to candidacy have post-transplant survival comparable with those having a heart transplant as primary treatment.

Survival after pulmonary thromboendarterectomy: effect of residual pulmonary hypertension.

OBJECTIVE: Pulmonary endarterectomy is the treatment of choice for chronic thromboembolic pulmonary hypertension. In many patients hemodynamics are normalized early after surgical intervention. However, the effect of residual pulmonary hypertension on postoperative clinical status and survival is unknown. METHODS: Data were collected prospectively on all patients who underwent pulmonary endarterectomy in a continuous national series between 1997 and December 2007. Postoperatively, patients underwent scheduled reinvestigation, including functional testing and right heart catheterization, at 3 months after the operation. They were divided into 2 groups based on mean pulmonary artery pressure: group 1, less than 30 mm Hg; group 2, 30 mm Hg or greater. RESULTS: Three hundred fourteen patients underwent pulmonary endarterectomy, survived to hospital discharge, and completed the 3-month follow-up period. At 3 months after pulmonary endarterectomy, there was a significant reduction in mean pulmonary artery pressure for the whole cohort (48±12 to 26±10 mm Hg, P<.001). However, 31% of the patients had residual pulmonary hypertension. Group 1 patients enjoyed significantly better exercise capacity and improved symptoms compared with group 2 patients. In addition, there were significantly fewer patients receiving targeted medical therapy in group 1 versus group 2 (0% vs 25%, P<.001). Conditional survival after discharge from the hospital for the whole cohort was 90.0% at 5 years and was not different between groups (90.3% for group 1 vs 89.9% for group 2, P=.36). CONCLUSIONS: For patients undergoing pulmonary endarterectomy, survival after hospital discharge is excellent. Residual pulmonary hypertension significantly compromised symptom status and functional capacity but did not appear to adversely affect medium-term survival. The effect of targeted medical therapy in patients with residual pulmonary hypertension after pulmonary endarterectomy needs to be evaluated further.

Thoratec implantable ventricular assist device: the Papworth experience.

OBJECTIVE: The Thoratec (Thoratec Corp, Pleasanton, Calif) implantable ventricular assist device (IVAD) can be used for univentricular or biventricular support. The objective of this study is to review the 5-year experience of bridging patients to heart transplantation with this device in a single center. Surgical aspects, including hybrid pump pocket, double tunneling of driveline, and optimal cannulae placement, are discussed. METHODS: This is a retrospective review of 24 patients treated between January 2002 and December 2007. Nineteen patients (79.1%) received a single implantable ventricular assist device as left ventricular assist devices, and 5 patients (21.9%) received 2 implantable ventricular assist devices as biventricular assist devices. The devices were implanted in pre-peritoneal/posterior rectus hybrid pump pockets. The driveline was passed through a 2-stage double-tunnel to exit onto the lateral chest wall. Patients were anticoagulated with Warfarin aiming for an international normalized ratio of 2.0 to 3.0. RESULTS: Twenty male and 4 female patients with a mean age of 39.8 years (17-57 years) and a body surface area of 1.87 m(2) (1.63-2.2 m(2)) were supported for a total of 2308 patient-days. Mean duration of support was 96 days (10-301 days). The cause of heart failure was dilated cardiomyopathy in 18 patients and ischemic cardiomyopathy in 6 patients. Preoperatively, 23 patients were receiving inotropes, 12 patients required intra-aortic balloon pump support, 5 patients were intubated and mechanically ventilated, and 3 patients required continuous venovenous hemofiltration for renal support. Eleven patients (45.8%) were discharged with ventricular assist device support (1015 home patient-days). Complications observed were a) neurologic: stroke in 3 patients, transient ischemic attacks in 4 patients; and b) infection: driveline infection in 3 patients and pump pocket infection in 1 patient. There was no mechanical device failure. Support to transplantation was achieved in 17 patients (70.8%): 3 of 5 biventricular assist devices (60%) and 14 of 19 left ventricular assist devices (73.7%). CONCLUSION: The Thoratec IVAD is a versatile and reliable ventricular assist device. It can provide univentricular or biventricular support for bridging patients to heart transplantation with acceptable complication rates. The portable Thoratec TLC-II console facilitated discharge while patients waited for a suitable donor heart.

Life-years gained by reducing donor heart ischemic times.

BACKGROUND: Transplantation is limited by the number of available donor organs. Donor organ maintenance systems are a recent technological advance. These systems may increase the number of donor organs that can be used and improve outcomes by decreasing donor organ ischemic time (IT). The purpose of this study was to determine the potential life-years gained if IT in the United Kingdom were decreased for cardiac transplantation. METHODS: Proportional hazards regression and extrapolation of survival rates beyond 20 years posttransplantation were used to estimate the effect of decreasing total IT on survival and the life-years gained over the lifetime of UK heart transplantation patients. RESULTS: Median survival posttransplantation was 10.4 years (95% CI 9.9 to 10.9). For each additional hour of donor organ IT, patients had a 25% increased risk of death after heart transplantation in the first year after transplant, with a 5% increase thereafter (P<0.001). On average, a recipient surviving 10 years posttransplantation could potentially gain 0.4 (95% CI 0.1 to 0.7) life-years if IT was reduced to 1 hr. The longer the IT, the greater the potential life-years to gain; for example, a recipient of an organ that would have had an IT of 6 hr without the use of an organ maintenance system might expect to gain 2.9 life-years (95% CI -0.6 to 6.4) if IT was reduced to 1 hr. CONCLUSIONS: Use of cardiac donor organ maintenance systems has the potential to increase posttransplantation survival.

Functional and haemodynamic outcome 1 year after pulmonary thromboendarterectomy.

OBJECTIVE: Chronic thromboembolic pulmonary hypertension (CTEPH) results in severe symptoms and impaired survival. Pulmonary thromboendarterectomy (PTE) is considered the gold standard treatment. Many units have reported excellent early results post PTE, but there is less information on whether benefit is sustained. We sought to determine the medium-term functional and haemodynamic outcome for patients following PTE and the longer-term survival after discharge from hospital. METHODS: Data were collected prospectively on all patients who underwent PTE in the UK between 1997 and June 2006. Patients were reassessed at 3 and 12 months after operation. Follow-up over time was assessed using repeated measures ANOVA, the Friedman test or Wilcoxon signed ranks test as appropriate. RESULTS: Two hundred and twenty-nine patients underwent PTE, survived to hospital discharge, and completed follow-up. At 3 months following operation, there was a significant reduction in mean pulmonary artery pressure (47+/-14 to 25+/-14mmHg, p<0.001), a significant increase in cardiac index (1.9+/-0.7 to 2.5+/-0.6l/minm(2), p<0.001) and a significant increase in 6-min walk distance (269+/-123 to 375+/-104m, p<0.001). At 12-month follow-up, the haemodynamic improvements were sustained and there was a further increase in 6-min walk distance (375+/-104 to 392+/-108m, p=0.004). NYHA class was significantly reduced at 3 months, with the improvement sustained at 12 months. Conditional survival following discharge from hospital was 92.5% at 5 years and 88.3% at 10 years. CONCLUSIONS: PTE is a very effective therapy for CTEPH. This is the first report from a continuous national series to fully characterise haemodynamic and functional outcome 1 year after PTE. Patients enjoy continued improvement in haemodynamic status that translates into better exercise capacity, reduced symptoms and excellent survival.