Therapeutic reconditioning of damaged lungs by transient heat stress during ex vivo lung perfusion.

Ex vivo lung perfusion (EVLP) may serve as a platform for the pharmacologic repair of lung grafts before transplantation (LTx). We hypothesized that EVLP could also permit nonpharmacologic repair through the induction of a heat shock response, which confers stress adaptation via the expression of heat shock proteins (HSPs). Therefore, we evaluated whether transient heat application during EVLP (thermal preconditioning [TP]) might recondition damaged lungs before LTx. TP was performed during EVLP (3 hours) of rat lungs damaged by warm ischemia by transiently heating (30 minutes, 41.5 °C) the EVLP perfusate, followed by LTx (2 hours) reperfusion. We also assessed the TP (30 minutes, 42 °C) during EVLP (4 hours) of swine lungs damaged by prolonged cold ischemia. In rat lungs, TP induced HSP expression, reduced nuclear factor κB and inflammasome activity, oxidative stress, epithelial injury, inflammatory cytokines, necroptotic death signaling, and the expression of genes involved in innate immune and cell death pathways. After LTx, heated lungs displayed reduced inflammation, edema, histologic damage, improved compliance, and unchanged oxygenation. In pig lungs, TP induced HSP expression, reduced oxidative stress, inflammation, epithelial damage, vascular resistance, and ameliorated compliance. Collectively, these data indicate that transient heat application during EVLP promotes significant reconditioning of damaged lungs and improves their outcomes after transplantation.

Physiological response to prone positioning in intubated adults with COVID-19 acute respiratory distress syndrome: a retrospective study.

BACKGROUND: COVID-19 related acute respiratory distress syndrome (ARDS) has specific characteristics compared to ARDS in other populations. Proning is recommended by analogy with other forms of ARDS, but few data are available regarding its physiological effects in this population. This study aimed to assess the effects of proning on oxygenation parameters (PaO2/FiO2 and alveolo-arterial gradient (Aa-gradient)), blood gas analysis, ventilatory ratio (VR), respiratory system compliance (CRS) and estimated dead space fraction (VD/VT HB). We also looked for variables associated with treatment failure. METHODS: Retrospective monocentric study of intubated COVID-19 ARDS patients managed with an early intubation, low to moderate positive end-expiratory pressure and early proning strategy hospitalized from March 6 to April 30 2020. Blood gas analysis, PaO2/FiO2, Aa-gradient, VR, CRS and VD/VT HB were compared before and at the end of each proning session with paired t-tests or Wilcoxon tests (p < 0.05 considered as significant). Proportions were assessed using Fischer exact test or Chi square test. RESULTS: Forty-two patients were included for a total of 191 proning sessions, median duration of 16 (5-36) hours. Considering all sessions, PaO2/FiO2 increased (180 [148-210] vs 107 [90-129] mmHg, p < 0.001) and Aa-gradient decreased (127 [92-176] vs 275 [211-334] mmHg, p < 0.001) with proning. CRS (36.2 [30.0-41.8] vs 32.2 [27.5-40.9] ml/cmH2O, p = 0.003), VR (2.4 [2.0-2.9] vs 2.3 [1.9-2.8], p = 0.028) and VD/VT HB (0.72 [0.67-0.76] vs 0.71 [0.65-0.76], p = 0.022) slightly increased. Considering the first proning session, PaO2/FiO2 increased (186 [165-215] vs 104 [94-126] mmHg, p < 0.001) and Aa-gradient decreased (121 [89-160] vs 276 [238-321] mmHg, p < 0.001), while CRS, VR and VD/VT HB were unchanged. Similar variations were observed during the subsequent proning sessions. Among the patients who experienced treatment failure (defined as ICU death or need for extracorporeal membrane oxygenation), fewer expressed a positive response in terms of oxygenation (defined as increase of more than 20% in PaO2/FiO2) to the first proning (67 vs 97%, p = 0.020). CONCLUSION: Proning in COVID-19 ARDS intubated patients led to an increase in PaO2/FiO2 and a decrease in Aa-gradient if we consider all the sessions together, the first one or the 4 subsequent sessions independently. When considering all sessions, CRS increased and VR and VD/VT HB only slightly increased.

The second modification of a dedicated staging system for lung metastases.

The topic of pulmonary metastases has long been of high interest and ongoing controversy. There is a group of patients with pulmonary metastases who may benefit from curative resection. It remains unclear which among them will benefit from surgery in terms of survival. This work updates a previously proposed classification system for pulmonary metastases, similar in its essence to the tumor, nodes, metastasis (TNM) classification used for primary tumors and named pmTNM classification, where 'pm' stands for 'pulmonary metastasis'. The objective is to allow future studies to explore predictive and survival prognostic factors for pulmonary metastases and separate patients who will benefit from lung metastasectomy from those who will not. The secondary aim is to provide a classification system that will allow physicians, oncologists and surgeons to speak the same language in comparing their data and assessing the results of treatment of lung metastases.

Treatment with 3-aminobenzamide during ex vivo lung perfusion of damaged rat lungs reduces graft injury and dysfunction after transplantation.

Ex vivo lung perfusion (EVLP) with pharmacological reconditioning may increase donor lung utilization for transplantation (LTx). 3-Aminobenzamide (3-AB), an inhibitor of poly(ADP-ribose) polymerase (PARP), reduces ex vivo lung injury in rat lungs damaged by warm ischemia (WI). Here we determined the effects of 3-AB reconditioning on graft outcome after LTx. Three groups of donor lungs were studied: Control (Ctrl): 1 hour WI + 3 hours cold ischemia (CI) + LTx; EVLP: 1 hour WI + 3 hours EVLP + LTx; EVLP + 3-AB: 1 hour WI + 3 hours EVLP + 3-AB (1 mg. mL-1 ) + LTx. Two hours after LTx, we determined lung graft compliance, edema, histology, neutrophil counts in bronchoalveolar lavage (BAL), mRNA levels of adhesion molecules within the graft, as well as concentrations of interleukin-6 and 10 (IL-6, IL-10) in BAL and plasma. 3-AB reconditioning during EVLP improved compliance and reduced lung edema, neutrophil infiltration, and the expression of adhesion molecules within the transplanted lungs. 3-AB also attenuated the IL-6/IL-10 ratio in BAL and plasma, supporting an improved balance between pro- and anti-inflammatory mediators. Thus, 3-AB reconditioning during EVLP of rat lung grafts damaged by WI markedly reduces inflammation, edema, and physiological deterioration after LTx, supporting the use of PARP inhibitors for the rehabilitation of damaged lungs during EVLP.

Precision surgery in lung metastasectomy.

The value of pulmonary metastasis (PM) resection in the context of controlled primary tumor sites was shown to improve survival of patients if complete resection could be achieved. The surgeon's approach can be modulated by various parameters pertaining to safety margins including local growth properties, size, spread and location of PMs. Lymph node dissection and assessment is recommended although its impact on survival remains unclear. Thoracoscopic surgery combined to thin slice chest CT scans has shown results comparable to thoracotomy in patients with few PMs. The management of PMs should therefore be discussed on an individual, interdisciplinary basis to offer the best possible oncological and surgical results as well as to maximize long term patient survival rates.

Impact of Compliance With Components of an ERAS Pathway on the Outcomes of Anatomic VATS Pulmonary Resections.

OBJECTIVES: Implementation of an Enhanced Recovery After Surgery (ERAS) program is associated with better postoperative outcomes. The aim of this study was to evaluate the impact of ERAS compliance (overall and to specific elements of the program) on them. DESIGN: Retrospective analysis of prospectively collected data. SETTING: University hospital, monocentric. PARTICIPANTS: All adult (≥18 years old) patients undergoing video-assisted thoracic surgery (VATS) anatomic pulmonary resection. INTERVENTIONS: ERAS-governed VATS anatomic pulmonary resection. MEASUREMENTS AND MAIN RESULTS: Demographics, surgical characteristics and pre-, peri-, and postoperative compliance with 16 elements of the ERAS program were assessed. Postoperative outcomes and length of stay were compared between low- (<75% of adherence) and high-compliance (≥75%) groups. From April 2017 to November 2018, 192 ERAS patients (female/male: 98/94) of median age of 66 years (interquartile range 58-71) underwent VATS resection (109 lobectomies, 83 segmentectomies). There was no 30-day mortality and resurgery rate was 5.7%. Overall ERAS compliance was 76%. High compliance was associated with fewer complications (18% v 48%, p < 0.0001) and lower rate of delayed discharge (37% v 60%, p = 0.0013). Early removal of chest tubes (odds ratio [OR]: 0.26, p < 0.002), use of electronic drainage (OR: 0.39, p = 0.036), opioid cessation on day 3 (OR: 0.28, p = 0.016), and early feeding (OR: 0.12, p = 0.014) were associated with reduced rates of postoperative complications. Shorter hospital stay was correlated with early removal of chest tubes (OR: 0.12, p < 0.0001) and opioid cessation on day 3 (OR: 0.23, p = 0.001). CONCLUSIONS: High ERAS compliance is associated with better postoperative outcomes in patients undergoing anatomic pulmonary VATS resections.

Vascular-targeted low dose photodynamic therapy stabilizes tumor vessels by modulating pericyte contractility.

Vascular-targeted low-dose photodynamic therapy (L-PDT) was shown to improve chemotherapy distribution in malignant pleural tumors such as malignant pleural mesothelioma (MPM). However, the mechanisms triggered by L-PDT on the tumor vasculature are still debated. In pericyte and endothelial cell co-cultures, we show that pericytes exhibit enhanced sensitivity towards L-PDT compared to endothelial cells, displaying actin stress fibers and cellular contraction via Rho/ROCK kinase signaling myosin light chain and focal adhesion kinase phosphorylation (MLC-P, FAK-P). We then confirm, in two separate MPM models, in mice the phosphorylation of the MLC in pericytes specifically following L-PDT. Furthermore, while L-PDT does not affect tumor vascular density or diameter, we show that it enhances tumor vascular pericyte coverage, leads to a drop in tumor interstitial fluid pressure and enhances the transport of FITC-dextran throughout tumors. In conclusion, L-PDT has the potential to stabilize the tumor vascular bed which improves vascular transport. The mechanism described in the present study may help translate and optimize this approach in patients. Lasers Surg. Med. 51:550-561, 2019. © 2019 Wiley Periodicals, Inc.

[Pulmonary metastasectomy]. / Métastases pulmonaires†: une maladie chirurgicale†?

The lung is the second site of metastasis after the liver, affecting 30 to 40 % of all patients with a malignant tumor. Chemotherapy seems to be ineffective for some types of tumor. Although there are no prospective randomized studies that confirm the benefit of surgical pulmonary metastasectomy, many studies have shown the existence of a group of patients with pulmonary metastases who benefit from a complete resection for curative purposes in case of complete resection of lung metastases. Different approaches are known to achieve a complete resection with maximum lung parenchyma sparing. Minimal invasive approaches appear to offer a better quality of life and have equivalent oncologic outcomes compared to the open approach.

Au cours d'un cancer, 40 % des patients vont développer des métastases pulmonaires et dans cette situation un traitement seul de chimiothérapie est généralement peu efficace. Même s'il n'existe pas d'études randomisées prospectives qui confirment le bénéfice de la métastasectomie pulmonaire chirurgicale, diverses études ont montré l'existence d'un groupe de patients atteints de métastases pulmonaires qui bénéficient d'une résection à visée curative en cas de résection complète des métastases pulmonaires. Différentes approches chirurgicales peuvent être utilisées ayant pour but principal une résection complète et une épargne maximale du parenchyme pulmonaire. Les approches minimales invasives semblent offrir une meilleure qualité de vie et un résultat oncologique équivalent à l'approche par voie ouverte.

A plea for thoracoscopic resection of solitary pulmonary nodule in cancer patients.

BACKGROUND: Solitary pulmonary nodules (SPN) are frequently detected in cancer patients. These lesions are often considered as pulmonary metastases and increasingly treated by non-surgical techniques without histological confirmation. The aim of this study is to determine the histological nature of SPN resected by thoracoscopy and to identify risk factors of malignancy. METHODS: Single-institution retrospective analysis of all consecutive patients with previously known malignancies who underwent thoracoscopic resection of SPN with unknown diagnosis between 2001 and 2014. RESULTS: One hundred and forty cancer patients underwent thoracoscopic resection of a SPN. The resected SPN was benign in 34 patients (24.3%) and malignant in 106 patients. The latter were metastasis in 70 patients (50%) and a primary lung cancer in 36 patients (25.7%). Upon univariate analysis, malignancy was significantly associated with age >60 years, disease-free interval ≥24 months, SPN size >8 mm, upper lobe localization and SUVmax > 2.5 on PET-CT. Upon multivariate analysis, upper lobe localization and SUVmax > 2.5 were associated with malignancy. Smoking was significantly associated with SPN containing primary lung cancer. CONCLUSION: In this series, only 50% of SPN in patients with known malignant disease were pulmonary metastases and 25% had a newly diagnosed NSCLC. Smoking was associated with primary lung cancer but no other predictor was found to allow the distinction between pulmonary metastasis and lung cancer. These results endorse the need of histological confirmation of SPN in patients with previous malignancies to avoid diagnostic uncertainty and suboptimal treatments.

Interstitial fluid pressure: A novel biomarker to monitor photo-induced drug uptake in tumor and normal tissues.

BACKGROUND: Low-dose photodynamic therapy PDT (photoinduction) can modulate tumor vessels and enhance the uptake of liposomal cisplatin (Lipoplatin®) in pleural malignancies. However, the photo-induction conditions must be tightly controlled as overtreatment shuts down tumor vessels and enhances normal tissue drug uptake. MATERIAL AND METHODS: In a pleural sarcoma and adenocarcinoma rat model (n = 12/group), we applied photoinduction (0.0625 mg/kg Visudyne®, 10 J/cm2 ) followed by intravenous Lipoplatin® (5 mg/kg) administration. Tumor and normal tissue IFP were assessed before and up to 1 hour following photoinduction. Lipoplatin® uptake was determined 60 minutes following photoinduction. We then treated the pleura of tumor-free minipigs with high dose photodynamic therapy (PDT) (0.0625 mg/kg Visudyne®, 30 J/cm2 , n = 5) followed by Lipoplatin (5 mg/kg) administration. RESULTS: In rodents, photoinduction resulted in a significant decrease of IFP (P < 0.05) in both tumor types but not in the surrounding normal lung, equally exposed to light. Also, photoinduction resulted in a significant increase of Lipoplatin® uptake in both tumor types (P < 0.05) but not in normal lung. Tumor IFP variation and Lipoplatin® uptake fitted an inverted parabola. In minipigs, high dose photodynamic treatment resulted in pleural IFP increase of some animals which predicted higher Lipoplatin® uptake levels. CONCLUSION: Normal and tumor vasculatures react differently to PDT. Continuous IFP monitoring in normal and tumor tissues is a promising biomarker of vessel photoinduction. Moderate drop in tumor with no change in normal tissue IFP are predictive of specific Lipoplatin® uptake by cancer following PDT. Lasers Surg. Med. 49:773-780, 2017. © 2017 Wiley Periodicals, Inc.

Probabilistic cognition in two indigenous Mayan groups.

Is there a sense of chance shared by all individuals, regardless of their schooling or culture? To test whether the ability to make correct probabilistic evaluations depends on educational and cultural guidance, we investigated probabilistic cognition in preliterate and prenumerate Kaqchikel and K'iche', two indigenous Mayan groups, living in remote areas of Guatemala. Although the tested individuals had no formal education, they performed correctly in tasks in which they had to consider prior and posterior information, proportions and combinations of possibilities. Their performance was indistinguishable from that of Mayan school children and Western controls. Our results provide evidence for the universal nature of probabilistic cognition.

Survival and Local Recurrence After Video-Assisted Thoracoscopic Lung Metastasectomy.

BACKGROUND: Pulmonary metastasectomy is increasingly performed in selected patients by video-assisted thoracic surgery (VATS) on the base of thin-slice high-resolution CT-Scan (HRCT). This study determines the overall survival and ipsilateral recurrence rate and of patients undergoing after VATS lung metastasectomy. PATIENTS AND METHOD: Retrospective single institution study of all patients who underwent VATS pulmonary metastasectomy on the base of HRCT with curative intent between 2005 and 2014. RESULTS: Seventy-seven patients (41 males, 36 females) underwent VATS pulmonary metastasectomy for solitary (n = 63) or multiple (n = 14) lung metastases in the context of colorectal carcinoma (n = 26), sarcoma (n = 17), melanoma (n = 16), or other primaries (n = 18). Nine patients had bilateral lung metastases and underwent synchronous (n = 4) or sequential (n = 5) VATS resections. Preoperative CT-guided hook wire localization of the lesions was performed in 65 patients (84 %). The postoperative mortality and morbidity rates were 0 and 5.2 %, respectively. During a mean follow-up time of 24 months (range 1­120 months), tumor progression occurred in 46 patients. Twenty-three patients (30 %) had pulmonary recurrence only, of them, eight patients (10 %) in the operated lungs. Seven of eight patients with recurrence in the operated lungs underwent a second metastasectomy by VATS (n = 5) or thoracotomy (n = 2). The overall 5-year survival rate was 54 % and without difference between patients without tumor recurrence and those with pulmonary recurrence treated by re-metastasectomy. CONCLUSION: Ipsilateral recurrence remains low after VATS pulmonary metastasectomy guided by preoperative HRCT and can be efficiently treated by re-metastasectomy.

Extracorporeal support for pulmonary resection: current indications and results.

Extracorporeal assistances are exponentially used for patients, with acute severe but reversible heart or lung failure, to provide more prolonged support to bridge patients to heart and/or lung transplantation. However, experience of use of extracorporeal assistance for pulmonary resection is limited outside lung transplantation. Airways management with standard mechanical ventilation system may be challenging particularly in case of anatomical reasons (single lung), presence of respiratory failure (ARDS), or complex tracheo-bronchial resection and reconstruction. Based on the growing experience during lung transplantation, more and more surgeons are now using such devices to achieve good oxygenation and hemodynamic support during such challenging cases. We review the different extracorporeal device and attempt to clarify the current practice and indications of extracorporeal support during pulmonary resection.

[Subsolid pulmonary nodules]. / Nodules pulmonaires subsolides.

Subsolid nodules represent almost 20% of all pulmonary nodules found incidentally at chest computed tomography (CT). Their detection is steadily rising, in parallel with the increasing number of CT scans performed. Subsolid nodules differ from solid lung nodules in several ways: morphology, course of progression, risk of malignancy and prognosis. Although they remain a diagnostic challenge, a good correlation has been established between radiological appearance and histopathology. Whilst 75% of persistent subsolid nodules represent a form of adenocarcinoma, their prognosis is generally excellent when resected. Non-resected subsolid nodules require a long follow-up of 3 to 5 years due to their slow-growing nature and high prevalence of malignancy. Specific guidelines have been published in 2013 and in 2015.

Les nodules subsolides représentent près de 20% des nodules pulmonaires découverts fortuitement lors d'un scanner thoracique. Leur détection ne fait qu'augmenter, parallèlement au nombre croissant de scanners réalisés. Ils se distinguent des nodules solides par leur morphologie, leur comportement évolutif, leur risque de malignité et leur pronostic. Ils restent un challenge diagnostique, mais une bonne corrélation entre les présentations radiologiques et histologiques a été démontrée. Bien que 75% des nodules subsolides persistants soient une forme d'adénocarcinome, leur pronostic est en général excellent après résection. Un suivi prolongé de 3 à 5 ans est requis pour les nodules subsolides non opérés, étant donné leur croissance lente et la haute prévalence de malignité. Des recommandations spécifiques ont été publiées en 2013 et 2015.

[Sarcoma centres : a necessary tool in the management of patients and for research.] / Centre des sarcomes : un nouvel outil pour améliorer la prise en charge du patient et soutenir la recherche.

Sarcomas are rare diseases, the treatment of which requires an appropriate technical plateform and a broad spectrum of multidisciplinary specialists. Many are initially treated by unplanned excision, and then referred to specialized centres. Secondary treatments may lead to higher complication rates and local recurrence, with lower functional outcome, life quality and possibly overall survival. In order to improve the accessibility for referral to a specialist centre, the coordination of clinical and research activities, and the quality of the management of sarcomas in general, Lausanne University Hospital (CHUV) has opened a Sarcoma centre on October 1st 2016. The objective of the present paper is to illustrate the concept and provide useful clinical recommendations.

Les sarcomes sont des maladies rares, dont la prise en charge multidisciplinaire nécessite un plateau technique important. Ils font souvent l'objet d'une excision initiale accidentelle, nécessitant une reprise en milieu spécialisé, avec un risque majoré de complications et de récidive locale, un impact sur la fonction, voire la survie. La prise en charge des sarcomes est réservée aux centres de référence, où il est souvent difficile pour le praticien de trouver un interlocuteur à qui adresser un patient ou demander un avis. Pour les cliniciens et les chercheurs, il est souvent compliqué de coordonner les activités. Pour en améliorer la prise en charge globale, le CHUV a donc créé un centre des sarcomes, inauguré le 1er octobre 2016. Le présent article a pour but d'illustrer cette problématique et de rappeler quelques données cliniques utiles.

Pulmonary metastasectomy in colorectal cancer patients with previously resected liver metastasis: pooled analysis.

BACKGROUND: Data addressing the outcomes and patterns of recurrence after pulmonary metastasectomy (PM) in patients with colorectal cancer (CRC) and previously resected liver metastasis are limited. METHODS: We searched the PubMed database for studies assessing PM in CRC and gathered individual data for patients who had PM and a previous curative liver resection. The influence of potential factors on overall survival (OS) was analyzed through univariate and multivariate analysis. RESULTS: Between 1983 and 2009, 146 patients from five studies underwent PM and had previous liver resection. The median interval from resection of liver metastasis until detection of lung metastasis and the median follow-up from PM were 23 and 48 months, respectively. Five-year OS and recurrence-free survival rates calculated from the date of PM were 54.4 and 29.3 %, respectively. Factors predicting inferior OS in univariate analysis included thoracic lymph node (LN) involvement and size of largest lung nodule ≥2 cm. Adjuvant chemotherapy and whether lung metastasis was detected synchronous or metachronous to liver metastasis had no influence on survival. In multivariate analysis, thoracic LN involvement emerged as the only independent factor (hazard ratio 4.86, 95 % confidence interval 1.56-15.14, p = 0.006). CONCLUSIONS: PM offers a chance for long-term survival in selected patients with CRC and previously resected liver metastasis. Thoracic LN involvement predicted poor prognosis; therefore, significant efforts should be undertaken for adequate staging of the mediastinum before PM. In addition, adequate intraoperative LN sampling allows proper prognostic stratification and enrollment in novel adjuvant therapy trials.

Risk factors for survival after lung metastasectomy in colorectal cancer patients: systematic review and meta-analysis.

Despite the lack of randomized trials, lung metastasectomy is currently proposed for colorectal cancer patients under certain conditions. Many retrospective studies have reported different prognostic factors of poorer survival, but eligibility for pulmonary metastasectomy remains determined by the complete resection of all pulmonary metastases. The aim of this review is to clarify which pre-operative risk factors reported in systematic reviews or meta-analysis are determinant for survival in colorectal metastatic patients. Different criteria have been now identified to select which patient will really benefit from lung metastasectomy.

Incidence and Risk Factors of Abdominal Complications After Lung Transplantation.

BACKGROUND: Due to the underlying diseases and the need for immunosuppression, patients after lung transplantation are particularly at risk for gastrointestinal (GI) complications that may negatively influence long-term outcome. The present study assessed the incidences and impact of GI complications after lung transplantation and aimed to identify risk factors. METHODS: Retrospective analysis of all 227 consecutively performed single- and double-lung transplantations at the University hospitals of Lausanne and Geneva was performed between January 1993 and December 2010. Logistic regressions were used to test the effect of potentially influencing variables on the binary outcomes overall, severe, and surgery-requiring complications, followed by a multiple logistic regression model. RESULTS: Final analysis included 205 patients for the purpose of the present study, and 22 patients were excluded due to re-transplantation, multiorgan transplantation, or incomplete datasets. GI complications were observed in 127 patients (62%). Gastro-esophageal reflux disease was the most commonly observed complication (22.9%), followed by inflammatory or infectious colitis (20.5%) and gastroparesis (10.7%). Major GI complications (Dindo/Clavien III-V) were observed in 83 (40.5%) patients and were fatal in 4 patients (2.0%). Multivariate analysis identified double-lung transplantation (p = 0.012) and early (1993-1998) transplantation period (p = 0.008) as independent risk factors for developing major GI complications. Forty-three (21%) patients required surgery such as colectomy, cholecystectomy, and fundoplication in 6.8, 6.3, and 3.9% of the patients, respectively. Multivariate analysis identified Charlson comorbidity index of ≥3 as an independent risk factor for developing GI complications requiring surgery (p = 0.015). CONCLUSION: GI complications after lung transplantation are common. Outcome was rather encouraging in the setting of our transplant center.