S. Keshavjee

Adenoid cystic carcinoma of the airway: Thirty-two-year experience

METHODS We have reviewed our experience in 38 patients with adenoid cystic carcinoma of the upper airway seen between 1963 and 1995. The mean age was 44.8 years (15 to 80 years) with a male/female ratio of 1:1.1. Thirty-two of the 38 patients were treated by resection and reconstruction (primary anastomosis 28; Marlex mesh prosthesis 4). Twenty-six of the 32 patients undergoing resection received adjuvant radiotherapy. Six patients with unresectable tumors were treated primarily with radiotherapy only. RESULTS Pathologic examination revealed local invasion beyond the wall of the trachea in all patients. In a majority, microscopic extension was found in submucosal and perineural lymphatics, well beyond the grossly visible or palpable limits of the tumor. Lymphatic metastases were relatively uncommon, occurring in only five of 32 (19%) patients undergoing resection. Metachronous hematogenous metastases occurred in 17 of 38 patients (44%). Thirteen of these 38 patients (33%) had pulmonary metastases. Sixteen of 32 resections were complete and potentially curative. There were two deaths within 30 days of operation. The mean survival in the 14 patients undergoing complete resection was 9.8 years (12 months to 29 years). Sixteen of 32 resections were incomplete (residual tumor at the airway margin on final pathologic examination), with one operative death occurring in this group. The mean survival in the 15 surviving patients was 7.5 years (4 months to 21 years). Six patients were treated with primary radiation only and had a mean survival of 6.2 years (2 months to 14.3 years). In the patients with pulmonary metastases, mean survival was 37 months (4 months to 7 years) from the time of diagnosis of the pulmonary metastasis until their death. CONCLUSION Adenoid cystic carcinoma of the upper airway is a rare tumor, which is locally invasive and frequently amenable to resection. Although late local recurrence after resection is a feature of this tumor (up to 29 years), excellent long-term palliation is commonly achieved after both complete and incomplete resection. There was a small difference in survival between patients having complete and incomplete resection. Long periods of control can be obtained with radiotherapy alone. The best results, in this series of patients, were obtained by resection. Adjuvant radiotherapy is assumed to favorably influence survival.

Transbronchial administration of adenoviral-mediated interleukin-10 gene to the donor improves function in a pig lung transplant model

Interleukin-10 (IL-10) gene transfection of donor lungs prior to transplantation is an attractive strategy to reduce ischemia–reperfusion induced lung injury. However, experimental data with gene therapy in large animal models of lung transplantation are generally lacking. We have developed a simple clinically applicable technique for adenoviral-mediated gene delivery of human IL-10 to the lung of large animals that provides homogenous gene expression after 12–24 h of transfection. Using this technique of gene delivery, we have studied the dynamics of adenoviral gene delivery to the lung in the setting of lung transplantation. Although there is a persistent inflammatory response to the adenoviral vector, we achieved significant expression of human IL-10 in lung tissue before lung retrieval to obviate the deleterious impact of the adenoviral vector on the donor lung. The administration of adenoviral-mediated human IL-10 to the donor lung reduced ischemia–reperfusion injury and improved graft function after lung transplantation in this pig lung transplantation model. Transfection of adenoviral-mediated human IL-10 to the donor lung prevented the release of inflammatory cytokines such as IL-6 in lung tissue and plasma. We have demonstrated that IL-10 gene therapy has significant potential to prevent or treat the inflammatory response associated with ischemia–reperfusion injury in lung transplantation. In the future, IL-10 gene therapy could also be used for immunomodulation or tolerance induction.

Pretransplant Aspergillus colonization of cystic fibrosis patients and the incidence of post-lung transplant invasive aspergillosis.

Background Invasive aspergillosis (IA) is an important cause of morbidity and mortality among patients undergoing lung transplant. Cystic fibrosis-lung transplant recipients (CF-LTRs) may be at greater risk of IA following lung transplantation because of the presence of Aspergillus in their airways before transplantation. This study evaluated the impact of pretransplant Aspergillus colonization on the risk for IA among CF-LTRs. Methods A single-center retrospective cohort study of CF-LTRs was conducted between 2006 and 2010. Respiratory tract cultures before transplantation were reviewed to identify patients with pretransplant Aspergillus colonization. Patients with positive Aspergillus sputum culture or positive bronchoalvelolar lavage (BAL) galactomannan after transplantation were classified as having colonization or disease according to the International Society of Heart and Lung Transplantation criteria. Results A total of 93 CF patients underwent lung transplantation. Seventy percent (65/93) of CF-LTRs had pretransplant Aspergillus colonization. Thirty-six patients had positive intraoperative Aspergillus culture from the native lung BAL. Overall, 22.5% (20/93) of CF-LTRs developed IA. Median time to IA was 42 days following transplantation. Positive intraoperative Aspergillus culture (OR 4.36, 95% CI 1.35–14.05, P=0.01) and treatment for acute cellular rejection within 90 days after transplantation (OR 3.53, 95% CI 1.03–12.15, P=0.05) were independent risk factors for IA. Antifungal prophylaxis was administered to 61% (57/93) of CF-LTRs. One-year mortality rate was 16% (15/93). IA was not associated with increased risk of death (OR 2.10, 95% CI 0.62–7.06, P=0.23). Conclusion Pretransplant Aspergillus colonization is frequent among CF-LTRs and a positive intraoperative Aspergillus culture produced a fourfold higher risk of developing IA.

Role of basic fibroblast growth factor in revascularization of rabbit tracheal autografts

Despite omentopexy of the bronchial anastomosis, donor airway ischemia remains a problem after lung transplantation. This study examined the hypothesis that surface abrasion and topical application of basic fibroblast growth factor (bFGF) would enhance omental revascularization of trachea in a rabbit heterotopic autograft model. Tracheal segments were excised, primary tracheal anastomoses performed, and the segments placed in the peritoneal cavity wrapped in omentum. Animals were randomized to one of six groups according to tracheal segment treatment: control, surgical abrasion, Surgicel wrap with topical bFGF, Surgicel wrap with bFGF vehicle, Gelfoam wrap with bFGF, and topical bFGF alone. One week later, animals were heparinized, perfused with Aquablak dye, and killed. Tracheal segments were excised and sectioned for light microscopic quantitative assessment of viability and dye perfusion. There was no significant improvement in viability or perfusion between abraded tracheal segments or segments treated with bFGF/Gelfoam or bFGF alone when compared with control segments. Airways wrapped in Surgicel had significantly greater ischemic injury compared with the control group, regardless of bFGF application. Neither surgical abrasion nor topical bFGF increased omental revascularization of transplanted tracheal segments after 7 days.

Simultaneous single-lung transplantation and lung volume reduction

We report our experience with 2 cases of simultaneous single-lung transplantation and lung volume reduction for emphysema. The lung volume reduction was undertaken electively in an attempt to improve overall lung function above that to be expected from single-lung transplantation alone. There were no postoperative problems related to the addition of lung volume reduction. The pulmonary function at 3 months was greater than that seen in a retrospective group of bilateral lung transplants previously reported from our institution.

Survival of Burkholderia cepacia sepsis following lung transplantation in recipients with cystic fibrosis

E.F. Nash, A. Coonar, R. Kremer, E. Tullis, M. Hutcheon, L.G. Singer, S. Keshavjee, C. Chaparro. Survival of Burkholderia cepacia sepsis following lung transplantation in recipients with cystic fibrosis.
Transpl Infect Dis 2010: 12: 551–554. All rights reserved

Rate of cyp51A mutation in Aspergillus fumigatus among lung transplant recipients with targeted prophylaxis

OBJECTIVES The most common mechanism of azole (itraconazole and voriconazole) resistance in Aspergillus fumigatus is a mutation at the cyp51A locus. The aim of our study was to determine the rate of cyp51A mutations in lung transplant recipients (LTR) undergoing targeted antifungal prophylaxis with 12 weeks of voriconazole. METHODS We conducted a prospective study that included 22 LTR with A. fumigatus between October 2008 and November 2011. Of those, 10 LTR were colonized with A. fumigatus and 12 had invasive pulmonary aspergillosis. RESULTS Four patients were found to have A. fumigatus isolates with a cyp51A mutation, two had colonization and two had invasive pulmonary aspergillosis. The remaining 18 LTR had WT cyp51A A. fumigatus isolates. All A. fumigatus isolates (except one due to mixed growth) were tested for antifungal susceptibility. A total of nine LTR were exposed to azoles prior to A. fumigatus isolation for a median duration of 249 (IQR 99-524) days. Azole exposure preceded the isolation of two mutant isolates and seven WT isolates. None of the cyp51A mutant isolates conferred phenotypic resistance to azoles. CONCLUSIONS Targeted antifungal prophylaxis in LTR did not lead to cyp51A resistance mutations in this cohort. Data on larger cohorts who receive universal antifungal prophylaxis are needed.

Pulmonary Arteriography for the Assessment of Technical Feasibility of Sleeve Resection in Lung Cancer

BACKGROUND Pulmonary arteriography has been reported to be useful in the preoperative assessment of patients with lung cancer to determine the technical resectability and feasibility of pneumonectomy by imaging the main right and left pulmonary arteries. In this report, we describe the use of selective pulmonary arteriography in the assessment of lobar resectability. METHODS Selective pulmonary arteriography provides a detailed anatomic view of the lobar branches and has been used at our institution for the past 30 years to preoperatively investigate patients who are candidates for a sleeve lobectomy. RESULTS Three cases are described that demonstrate the usefulness of selective pulmonary arteriography in the assessment of the technical feasibility of sleeve resection in patients with lung cancer. CONCLUSIONS Arteriographic findings may accurately show whether a sleeve lobectomy is technically possible, that only a pneumonectomy is possible, or that the only safe way to ensure clearance of the pulmonary artery is to perform arterioplasty. This information may obviate an unnecessary thoracotomy in patients who are judged on the basis of a physiologic assessment to be unable to tolerate a pneumonectomy.

P2.01-76 The Impact of Concordance with a Lung Cancer Diagnosis Pathway Guideline on Treatment Access in Patients with Stage IV Lung Cancer

patients with non-surgical stage disease (n1⁄410); 2) imprinted cytological samples from positive mediastinoscopies during the intraoperative staging of patients with lung cancer (n1⁄411); 3) positive pleural fluid in patients with pulmonary nodule (n1⁄42). Then we performed FISH technique, evaluated the quality of the signal obtained, and compared the results with those obtained on paraffin sections. FISH technique on paraffin blocks was performed using 2XSSC/ proteinase K pretreatment as standardized by our lab. Cytology smears were destained and fixed in 10% methanol and incubated with FISH probe (ALK, ROS1 and MET). Result: All cytology cases had scorable signals and were easy to interpret. Also, as no pretreatment was required, assay time was shorter. Depending on cellularity, one same slide was useful for analysis of the three probes. When comparing with IHC and FISH studies, we obtained a 100% correlation with ALK (n1⁄423; positive1⁄42, negative1⁄421), ROS1 (n1⁄45, all negative) and MET (n1⁄45, all negative). Conclusion: This work allowed us to optimize the use of different cytology samples frequently available in advance stage NSCLC for FISH studies. The use of cytological material might improve turnaround time for results and can become a useful tool in pathology labs, in particular when paraffin included material is limited. Keywords: cytology, FISH

EARLY POST TRANSPLANT DENOVO HLA ANTIBODIES PREDICT DECLINE IN LUNG ALLOGRAFT FUNCTION AT 18 MONTHS POST TRANSPLANT: 1878

Introduction: Both pre-and post transplant HLA antibodies (HLAAb) in isolation have been correlated with bronchiolitis obliterans syndrome (BOS) and graft failure in lung transplant, but the temporal relationship of post transplant HLAAb to clinically relevant outcomes is not well described. Methods: We conducted a retrospective review of 98 consecutive lung transplant from 11/06 to 12/07 with 3 month survival, who had protocol post transplant HLAAb testing q3mo for one year (solid phase, Luminex TM platform).We examined the relationship of HLAAb development and presence to acute rejection (AR), diffuse alveolar damage (DAD), infections, radiographic findings, 6-minute walk, and pulmonary function tests at 3,6,9,12, and 18 months post transplant. C4d staining was not routinely performed in this cohort’s biopsies. Patients were divided into 3 groups for comparison: no HLAAb preor post-transplant (NoAb n=58), sensitized with HLAAb pre-tx (PreTxAb, n=18),and post-transplant de novo HLAAb (DNAb, n=22). The PreTxAb group received our standard high-risk protocol of perioperative plasma exchange, IVIg and MMF. Routine immunosuppression with CsA, azathioprine and prednisone was used for the remaining patients. Where appropriate, categorical variables were compared with Chi-squared or Fisher’s exact test, and continuous variables were compared using T-test, ANOVA, KruskalWallis or Rank-sum tests. Results: Of 22 DNAb, 18 developed Ab at 3-6 months and 4 at 9-12 months. 18 month survival between the three groups was not statistically different (NoAb 86.2%; PreTxAb 94.4%, DNAb 77.2%, p=NS log-rank) Immunosuppression therapy was comparable between NoAb and DNAb groups. There was no association between de novo HLAAb or pre-transplant HLAAb and AR, DAD, infection, 6 minute walk, or XR findings at any timepoint. Early de novo HLAAb, and to a lesser extent pre-transplant HLAAb, were associated with decreased FEV1 at 18 months post-transplant to <80% of best FEV1 achieved (BOS-1). (Table) After adjusting for AR and CMV infection in the first year, early DNAb remained a significant predictor of BOS at 18 months post-transplant (OR 7.68:2.28-25.8).