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Ann Thorac Surg 2008;86:1753-1761. doi:10.1016/j.athoracsur.2008.06.027
© 2008 The Society of Thoracic Surgeons
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Original Articles: General Thoracic

Cryopreserved Arterial Allograft Reconstruction After Excision of Thoracic Malignancies

Abel Gómez-Caro, MDa, Elisabeth Martinez, MDa, Alberto Rodríguez, MDa, David Sanchez, MDa, Jaume Martorell, MD, PhDb, Josep Maria Gimferrer, MDa, Axel Haverich, MD, PhDc, Wolfgang Harringer, MD, PhDd, Jose Louis Pomar, MD, PhDa, Paolo Macchiarini, MD, PhDa,*

a Department of General Thoracic Surgery, Hospital Clinic of Barcelona, University of Barcelona, Barcelona, Spain
b Department of Immunology, Hospital Clinic of Barcelona, University of Barcelona, Barcelona, Spain
c Department of Cardiothoracic and Vascular Surgery, Hannover Medical School, Hannover, Germany
d Department of Cardiothoracic and Vascular Surgery, Klinikum Braunschweig, Braunschweig, Germany

Accepted for publication June 9, 2008.

* Address correspondence to Dr Macchiarini, Department of General Thoracic Surgery, Hospital Clinic of Barcelona, University of Barcelona, 170 Villaroel, Barcelona, E-30889, Spain (Email: pmacchiarini{at}clinic.ub.es).

Presented at the Forty-fourth Annual Meeting of The Society of Thoracic Surgeons, Fort Lauderdale, FL, Jan 28–30, 2008.


   Abstract
Top
 Abstract
Introduction
 Patients and Methods
 Results
 Comment
 Discussion
 References
 
Background: The purpose of this study was to evaluate the long-term clinical and immunologic outcome of cryopreserved arterial allograft (CAA) revascularization of intrathoracic vessels invaded by malignancies.

Methods: Since January 2002, consecutive patients whose intrathoracic vessels were invaded by malignancies were operated on and revascularizion made using human lymphocyte antigen (HLA)– and ABO-mismatched CAAs. Immunologic studies were performed preoperatively, and 1, 3, 6, 12, and 24 months postoperatively. Postoperative oral anticoagulation therapy was not given.

Results: Twenty-six patients aged 53.1 ± 15 years with a nonsmall-cell lung cancer (n = 10), invasive mediastinal tumors (n = 7), pulmonary artery sarcoma (n = 3), laryngeal (n = 2), or other rare lung neoplasms (n = 4) underwent operation. Cardiopulmonary bypass was used in 10 cases (38%), and all resections were pathologically complete. Revascularization was either for venous (n = 12) or arterial (n = 14) vessels, and a total of 30 allografts revascularized the superior vena cava (n = 6), pulmonary artery (n = 7), innominate vein (n = 3) or artery (n = 2), ascendent (n = 4) or descending (n = 1) aorta, and subclavian vein (n = 3) or artery (n = 4). Hospital morbidity and mortality were 50% (n = 13) and 3.8% (n = 1), respectively, all CAA unrelated. With a median follow-up of 18 months (range, 3 to 60+), 5-year survival and allograft patency were 84% and 95%, respectively. Preoperative anti-HLA antibodies were detected in 2 patients (7.7%) and a postoperative anti-HLA antibody response, clinically irrelevant, in 1 of 24 patients (4%).

Conclusions: Revascularization of intrathoracic venous and arterial vessels in patients with malignancies using HLA- and ABO-mismatched CAA is technically feasible and clinically attractive because of no infection risk and postoperative anticoagulation, and excellent long-term survival, patency, and nonimmunogeneicity.


   Introduction
Top
 Abstract
 Introduction
Patients and Methods
 Results
 Comment
 Discussion
 References
 
Recent advances in the domains of oncology, anesthesia, and cardiovascular and thoracic surgery have unlocked the door to the surgical treatment of pulmonary, mediastinal, or other rare tumors involving intrathoracic vessels. The arguments that revascularization is usually made through different materials and techniques, each of which has its pros and cons, restricted to the superior vena cava or pulmonary artery, and associated with frequent perioperative graft infection and thrombosis or need for postoperative anticoagulation therapy are outweighed by the encouraging long-term benefits [1–5].

Cryopreserved human allograft tissues have been available for use as replacement for diseased valves or revascularization of major intrathoracic vessels for decades because of their excellent hemodynamics, resistance to infection, decreased thromboembolic events, ease of handling, and lack of need for anticoagulation therapy [6]. Unlike solid organ transplants, they are not typically human leukocyte antigen (HLA) typed or cross-matched with their donor before implantation, and the resulting immunologic uncertainties [7–9] may explain their anecdotal [10, 11] use in thoracic surgical oncology.

The present study prospectively evaluates the surgical feasibility of revascularizing intrathoracic arterial or venous vessels invaded by malignancies with CAAs, and whether the elicited immunologic response may interfere with the late functional or oncologic outcome.


   Patients and Methods
Top
 Abstract
 Introduction
 Patients and Methods
Results
 Comment
 Discussion
 References
 
Since January 2002, all consecutive patients whose intrathoracic vessels were invaded by operable malignancies were included in this prospective study, approved by the Institutional Review Board and Ethics Commision. Written informed consent was obtained for all patients. A single surgeon (P.M.) performed all procedures.

Eligibility and Preoperative Assessment
Patients 80 years of age or younger and with a histologic diagnosis of an intrathoracic malignancy, a performance status of 0 to 1, and normal lung, heart, liver, and renal function were considered. Preoperative anti-HLA antibodies were not a contraindication for operability. All patients underwent appropriate functional and oncologic investigation preoperatively, including computed tomography, 2-deoxy-2-[18F]fluoro-D-glucose positron emission tomography (FDG-PET), magnetic resonance imaging, esophageal endosonography, transthoracic and transesophageal echocardiography or cine-magnetic resonance imaging of the heart [12, 13], if required. Patients with mediastinal nodal involvement from a nonsmall-cell lung cancer (NSCLC) underwent preoperative cervical mediastinoscopy, and those with positive N2 nodes received neoadjuvant chemoradiationtherapy [13]. Complete nodal resection of the mediastinum or tumor-target area, for example, supraclavicular nodes, was routine. A coronary angiography was performed in all patients over 65 years of age or if cardiopulmonary bypass was planned. All mediastinal tumors were histologically diagnosed and assessed following our clinical pathways; for tumors located in the posteroinferior mediastinum or costovertebral growth of either side, the spinal cord blood supply was always investigated [14].

Cardiopulmonary Bypass
Any direct tumoral invasion of intrapericardial vessels, aorta ascendens, arch, isthmus, or descendens were made on cardiopulmonary bypass, used as well to provide hemodynamic stabilization during extensive heart manipulation. Care was paid to start cardiopulmonary bypass (CPB) only once tumor operability was assessed and after maximal tumor dissection. Total CPB with diastolic arrest was through a single aortic and bicaval cannulation technique whereas partial CPB was femorofemoral, and usually under normothermic or moderate hypothermia (28° to 32°C) [15] Stöckert roller pumps (Stöckert Instruments, Munich, Germany) and capillarity membrane oxygenators (Hilite 7000; Medos, Stolberg, Germany) primed with 1,500 mL Ringer's lactate and 40 mL Natrium bicarbonate 8.4% were used. The CBP circuits were heparin-coated CPB systems (Duraflo II, Baxter Bentley Healthcare Systems, Irvine, California) with leukocyte depletion arterial filters (AL8; Pall Biochemical Products, Glencoe, New York). Intravenous heparinization was given 400 IU/kg and adapted to the activated clotting time (<480 s). Anticoagulation was antagonized with protamine sulphate after weaning from CPB.

CAA Procurement, Selection, and Implantation
Cryopreserved arterial allografts (CAA) were from multiorgan donors of less than 50 years old, in whom the abdominal and thoracic aorta together with iliac and femoral vessels were harvested by the Transplant Service Foundation (Hospital Clinic, Barcelona). Within 24 hours of procurement, different segments of the vessels were divided and assessed both macroscopically and microbiologically, carefully sized, and placed in antibiotic solution for 24 hours at 4°C. The tissues were packed in double cryobag and treated as reported before [16, 17]. At removal from the liquid nitrogen, allografts were placed in dry ice (–80°C) and sent to the operating room to be thawed by placing the containers bags in a 37°C water bath for approximately 5 minutes. The bags were then opened and tissues were washed in saline for 5 minutes [16, 17]. Afterward, allografts were ready for implantation.

All CAAs were ABO- and HLA-unmatched and selected based on the situs, length, and maximum diameter of the native vessel to be replaced (Table 1). Briefly, the superior vena cava was revascularized with pediatric or adult thoracic or abdominal aorta, innominate artery and vein with common iliac artery, pulmonary artery trunk and intrapericardial pulmonary artery with an aortic arch, intrapulmonary artery with a common iliac and its bifurcation, thoracic aorta or aortic arc with either similar CAAs, and the subclavian vessels with common iliac or hypogastric CAAs. Intraoperative heparinization treatment in patients off CPB was intravenous sodium heparin (0.5 mg/kg) without any intraluminal flush. All vascular anastomoses were performed with polypropylene sutures of appropriate sizes. Patients received routine prophylactic antithrombosis therapy with low molecular weight heparin until mobilization, and were discharged without any anticoagulant or immunosuppression therapy.


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  		Table 1 Type of Cryopreserved Arterial Allografts
 
Alloimmune Response and Allografts Patency Surveillance
Preoperatively, recipient and donor were typed for ABO blood group and HLA antigens. Serologic and genomic techniques were utilized to identify class I (HLA-A, -B, -C) and II (HLA-DQ, -DR) HLA antigens, respectively. The T-lymphocyte subpopulations, namely, CD3 (total T lymphocytes), CD4 (helper T lymphocytes), and CD8 (cytotoxic/suppressor T lymphocytes) were determined in recipients by standard flow cytometric techniques. The recipient anti-HLA antibody production and antibody specificity was performed using the complement-dependent cytotoxicity test and by an enzyme-linked immunoabsorbent assay (ELISA) that simultaneously identifies serum immunoglobin (IgG) directed against either HLA class I or II antigens.

Preoperatively, and at 1, 3, 6, 12, and 24 months postoperatively, serologic search for anti-HLA antibodies was performed. Allograft patency was assessed clinically and with angio-computed tomography scan at 1, 3, 6, and 12 months to investigate the patency of the grafts.

Statistical Analyses
Mortality was defined as any death occurring during the hospital stay. Data are presented as mean ± SD, median (range), absolute numbers, or percentages. Survival was measured from the date of operation to death and included postoperative deaths. Disease-free survival was defined as the time from the operation to the histologic recurrence confirmation. Allografts, prostheses expenses, and anticoagulation therapy costs were expressed in Euros. Statistical analyses were carried out with the SPSS v.14 (SPSS, Chicago, Illinois).


   Results
Top
 Abstract
 Introduction
 Patients and Methods
 Results
Comment
 Discussion
 References
 
Twenty-six patients (21 male and 5 female) aged 53.1 ± 15 years were operated on and the type of tumor, native vessel involvement, and type of anastomoses are indicated on Table 2. As shown, the majority were operated on for pulmonary parenchymal (n = 14) or invasive mediastinal tumors (n = 7), followed by pulmonary artery sarcomas (n = 3) or other rare neoplasms (n = 2). Fourteen arterial and 12 venous vessels were resected, the most frequent being the pulmonary artery (n = 7), subclavian vessels (n = 7), superior vena cava (n = 6), innominate vessels (n = 5), and aorta (n = 5) (Fig 1); 30 CAAs were used to complete an anatomical vascular repair (Table 3).


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  		Table 2 Patient Characteristics, Surgery Description, and Outcome
 

Figure 1
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  		Fig 1. (A) Chest roentgenogram showing a tumor mass in the middle mediastinum that on (B) computed tomography was close to the descending supradiaphragmatic aorta and distal esophagus (case 14). (C) The operation was made through a right thoracophrenolaparotomy that allowed a safe clamping of the aorta both proximally and distally to the tumor-invaded segment. (D) Tumor resection included a right lower lobectomy, Ivor-Lewis esophagectomy and a revascularization of the affected aorta with two cryopreserved allografts.

 

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  		Table 3 Cryopreserved Arterial Allografts (CAA) and Donor Characteristics
 
Operative time was 322 ± 97 minutes, and the surgical approach was through a median sternotomy in 10 cases (38.4%) (Fig 2), an ipsilateral muscle-sparing thoracotomy in 10 (38.4%), a Dartevelle's approach in 4 (13.7%), and others in 2 (7.6%). Cardiopulmonary bypass was used in 10 cases (4 femorofemoral and 6 aortobicaval) (Fig 3). Total CPB time was 86 ± 34 minutes. Complete resection (R0) was achieved in all the cases. Type of anastomosis, morbidity, mortality, and survival outcome are depicted in Table 4. As shown, morbidity was 50% (n = 13), including 4 major and 9 minor complications; all but 1 patient (3.8%), who died of severe unresponsive adult respiratory distress syndrome, were successfully managed.


Figure 2
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  		Fig 2. (A) Computed tomography showing an invasive thymoma (case 6) involving the innominate vein and ascending aorta, already having undergone an exploratory median sternotomy. (B) Through a redo median sternotomy, the entire tumor burden was dissected in free margins from the surrounding structures, preserving the left phrenic nerve (yellow rubber tap). (C) Resection of the vessles included the entire ascending aorta with a composite graft and aortic mechanical valve interposition. (D) Revascularization of both innominate vein (white arrow, iliac artery cryopreserved allograft) and ascending aorta (black arrow) was done under total cardiopulmonary bypass and cardiac arrest.

 

Figure 3
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  		Fig 3. (A) Computed tomography showing a subocclusion of the left pulmonary artery by a pulmonary artery sarcoma (case 12) with endoluminal growth (white arrows) (B) The trunk of the pulmonary artery was involved and needed to be replaced. (C) A cryopreserved aortic arch allograft was interposed, after closing all its supra-aortic branches, between the main, supravalvular pulmonary artery and intrapericardial, retrocaval right pulmonary artery just before the take off of its first branch. (D) Angio-computed tomography scan 12 months after surgery, showing the patency of the implanted allograft.

 

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  		Table 4 Operative Characteristics and Allograft and Patient Survival
 
The CAA patency was 95% at 6 months; a total thrombosis developed in 1 patient on the second postoperative day and was treated by completion pneumonectomy and allograft removal. There were no graft infections during a follow-up period of 18 months (range, 3 to 60+). Actuarial survival and disease-free survival were 84% and 80%, respectively; 3 patients died of unrelated (n = 1, massive stroke, without recurrent disease at autopsy) or distant metastasis (n = 2). Hospital stay was 22 ± 12.5 days. Donor-specific alloantibodies determination was negative in all the recipients but 1; only 1 patient had anti-HLA alloantibodies without clinical relevance postoperatively. The total cost of the 30 allografts was 30,731{euro}.


   Comment
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Comment
Discussion
 References
 
Intrathoracic pulmonary [18] or mediastinal [4, 19] malignancies invading the great vessels have long been considered unresectable and associated with a poor prognosis. However, certain aspects of indications, medical oncologic advances, anesthetic and surgical management, and revascularization materials have changed lately, and concurrent with these changes, disease-free survival rates have been increased significantly. Unfortunately, the 30-day mortality rates have not improved, probably linked to the rarity and technical complexity of these operations. Centralization of these operations has strongly been suggested in departments with continuous interest in such problems and a high degree of experience with both cardiac and general thoracic procedures [20]. Another key issue for mortality rate reduction has been the candidate selection restricting these operations only to very selected cases without nodal involvement, absence of distant metastasis [21], adequate cardiopulmonary reserve, and whenever a complete surgical resection of the entire tumor burden area is anticipated [22], conditionae sine qua non being the absence of prohibitive mortality.

The results of the present clinical experience derive from a series with a limited, albeit important, number of patients with locally advanced pulmonary and mediastinal malignancies invading the great vessels, and may provide further evidence that surgical resection can be curative in carefully selected patients without prohibitive morbidity and, more important, mortality. They also demonstrate that CPB is of paramount importance to resect tumors otherwise deemed unresectable without necessarily resulting in increased CPB-related morbidity or tumor dissemination, and that CAAs can be indifferentially implanted in the venous or arterial intrathoracic circulation with excellent long-term outcome, even if ABO and HLA unmatched.

The low mortality observed in this study, namely, 3.8%, may reflect different issues apart than patient selection, like intraoperative strategy and systemic usage of biocompatible CPB circuits, use of CAA grafts, and last but not least, surgical-driven intensive care unit management. Regarding intraoperative strategy, we systematically used total intravenous anaesthesia and protective ventilation modes, a combination able to prevent lung injury to the residual lung parenchyma during aggressive tracheobronchial resection and reconstruction [13]. Moreover, in those patients whose tumors invaded or were prohibitively close to the heart or the great vessels, systemic heparinization administration was not started before fully completing tumor dissection and was systematically reversed after being off pump to reduce bleeding, particularly after pneumonectomy. However, we support Byrne and colleagues [23] who state that limited pulmonary resection before heparinization and the institution of CPB is not always possible [24], and that postoperative bleeding often requires urgent surgical reexploration.

With regard to the use of CPB, its value during surgery for intrathoracic malignancies has always been highly controversial because of its potential adverse effects on hemostasis, lung function, and tumor direct or indirect dissemination. However, increasing series worldwide have demonstrated that CPB can be safely used during resection of intrathoracic malignancies, resulting in an excellent long-term outcome and even cure in some rather selected patients [23, 25]. Adverse effects related to CPB other than a case of rebleeding were not observed in the present study, and that may be related to the systemic use of biological circuits to prevent leukocyte-mediated endothelial cell injury such as platelet, complement, and neutrophil activation, factors known to trigger lung dysfunction postoperatively. Moreover, the systematic use of a leukocyte-depleting arterial filter may have played as well a pivotal role, not only to improve postoperative oxygenation, reduce extravascular lung water accumulation, and weaning time of the mechanical ventilator after CPB [26] but also to prevent or mitigate tumor dissemination during CPB [27].

Other operative strategies worthy of mention and used in our experience were the avoidance of deep hyporthermia and prolonged periods of cardiocirculatory arrests during reconstruction of the pulmonary artery circuit [15], routine monitoring with transesophageal echocardiography-guided deairing, confirming that higher clinical expertise in both domains of cardiac and thoracic surgery are possible and may reduce the morbidity not only of the CPB but also that arising from the aggressive resection of intrathoracic structures [20]. That our patients all had a postoperative course in a postoperative intensive care unit conducted by thoracic surgeons experienced in cardiothoracic issues may have a sensitive impact over the reduction in the complication rates observed.

One major concern during this surgery is how to safely revascularize the invaded intrathoracic vessels, and the availability of the CAA grafts was a great helping platform. Presented results demonstrate that CAAs can be uniformly implanted in the venous and arterial intrathoracic circulation with excellent long-term outcome, even if ABO and HLA unmatched. In fact, cryopreserved allografts have long been used mainly in pediatric and adult cardiac surgery to either reconstruct the right ventricular outflow tract [28] or as an effective strategy for treating infected aortic prosthetic grafts and mycotic aneurysms [29], but experiences in general thoracic surgery have been very scattered. The cryopreservation process of arterial conduits almost eliminates the antigenity related to the complications of fresh arterial allografts such as rupture of the wall, aneurysmal dilatation, and thrombosis by reducing the amount of antigen-triggering cells on their endoluminal suface. However, this immunologic cryopreservation effect has been questioned recently, in several animal models [30]. Solanes and associates [16, 17] proved that CAAs, in contrast to fresh allograft, may have a certain immunogenity that may trigger different degrees of rejection reaction, recommending ABO and HLA donor-recipient matched allografts, whenever possible.

Although this rejection reaction, whether acute or chronic, was our most important fear when we started the usage of CAAs in neoplasic patients, the presented results demonstrate that CAA implantation is technically feasible and reliable, even without anticoagulant or immunosuppressive therapy. In effect, the immunologic surveillance showed a low rate of donor-specific alloantibodies detected during this period even though we did not match (ABO, HLA) donor and recipient. Potential antigenity of CAAs may provoke alloantibodies formation, but this fact seems to be clinically irrelevant at least in large-caliber vessels. In our experience, donor-specific alloantibodies developed in only 1 of 25 recipients, but this allograft remains patent 17 months after his HLA conversion.

Another advantage of CAA grafts was the avoidance of postoperative antithrombotic therapy; the resulting long-term patency of these CAAs was 95% after a follow-up of 18 months with only one postoperative thrombosis detected in a pulmonary artery substitution during a pulmonary-sparing technique, possibly because of the low pressure circulation through the remaining lung. This prompted us to consider the replacement of the extrapericardical pulmonary artery by inferior cava vein cryopreserved allografts, harvested essentially only for this use. Another issue was to have available a revascularization material unlikely to become infected during airway or esophageal anastomoses; experimental and clinical studies have clearly shown that aortic homografts are less susceptible to infection that nonbiological prosthetic grafts [6]. We did not encounter any instances of allograft infection, degeneration, or disruption over a mean follow-up of 1.5 years. However, we observed one graft thrombosis that required an allograft revision and excision. Even though allograft-related complications were uncommon in our midterm evaluation, long-term follow-up of those patients surviving more than 5 years showed no potential complications of graft infection, thrombosis, or aneurysmal change. Our CAAs were procured mostly from donors younger than 50 years, to avoid the stiffness or atheroma plaque formation in the allograft. The malleability of the homograft tissue is considered a technical advantage because it enables the graft to conform to all intrathoracic vessels, including arterial and venous vessels (Fig 4). Although one limitation may be the relatively low tensile strength of the preserved homograft tissue, that can be prevented by avoiding tension, using an appropriate graft length, and most eventually, multiple allografts. In addition, CAA cost is sensibly cheaper than nonbiological prostheses, which are a burden with the chronic anticoagulation therapy expense as well.


Figure 4
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  		Fig 4. (A) A pediatric cryopreserved distal aorta with its bifurcation is surgically manipulated to increase its total length. (B) The graft is first opened in its medial aspects taking off the origin of both internal femoral arteries. (C) Then, the medial aspects are sutured together with a running polypropylene 5-0 sutures. Next, the same with the residual aspects. This technique has the great advantage of being able to adapt whatever cryopreserved allograft to any intrathoracic native vessel, avoiding overstretching and kinking. (D) Intraoperative view of the completed revascularization of the left innominate vein (white arrow).

 
The excellent long-term outcome observed in this series probably reflects the systematic use of positron emission tomography scans and mediastinoscopy, the fact that operation was offered only to patients without nodal involvement or after maximal neoadjuvant chemoradiation therapy for those with chemoradiation-sensitive tumors, the performance of radical lymphadenectomy, and completion of the multimodality treatment with adjuvant therapy. Intermediate and long-term outcome depends on the underlying cause. The better results in terms of survival have been obtained in mediastinal tumors.

In conclusion, revascularization of intrathoracic venous and arterial vessels in patients with malignancies using HLA- and ABO-mismatched CAA is technically feasible and clinically attractive because of low infection risk, no need for oral postoperative anticoagulation therapy, and excellent long-term patient survival, graft patency, and nonimmune response.


   Discussion
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Comment
 Discussion
References
 
DR CARLOS A. MESTRES (Barcelona, Spain): I congratulate you on your presentation, which is a fine one, but it doesn't surprise me at all. What surprises me is why you used "long term" in this paper because your average follow-up is just 18 months. In cancer surgery, anything below 5 years is short or almost immediate. I think it's going to be basically semantics, but I do recommend that you change the title of your paper when I see that published in the Annals, hopefully.

Second, it doesn't surprise me that you have no clinical or immunologic response, because allografts usually won't have endothelium. I think this is quite a good series, but in any case, it doesn't surprise me; we have used homografts for 18 years in a series of close to 100 cases with a median follow-up of 9 years. I think this approach is obviously new in thoracic oncology, but I think you should pursue and make some minor changes in your terminology and state very clearly in your conclusions that this is absolutely nothing new, because both in the arterial and venous systems they work, and we have known that for about 20 years.

DR MACCHIARINI: It's always difficult to reply to a colleague who works in the same institution, but coming from a cardiac surgeon, I'm not surprised. That fact is that it might not be new for cardiac surgery, but we do have the need in the thoracic arena to have something that can be uniformly used every time that we do need to revascularize a vessel, whatever, on the venous or arterial side. And I think that the idea of using these grafts is very interesting because we can revascularize whatever we want.

Coming to the semantic question about the term "long-term follow-up," we updated the results. I don't think that in the original abstract there are 26 patients who had less, almost 6, and this 18 median follow-up is quite interesting for us. And last, but not least, I think that given 84% actuarial survival rates where most of these patients have not been operated on, and I remember one of them excluded from yourself, I think it's good results.


   References
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Comment
 Discussion
 References
 

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