Michele Rusca

Management of postintubation membranous tracheal rupture

BACKGROUND Postintubation tracheobronchial laceration is a rare complication of general anesthesia. A renewed interest in this disorder induced us to review our experience on its treatment, focusing on the evolution of the surgical approach, and describing a technical variation of the transcervical approach. METHODS From January 1994 to December 2002 we treated 13 patients with diagnosis of postintubation tracheobronchial laceration. The treatment was nonsurgical in 3 patients (1-cm-long tear) and surgical in the other cases. Two lesions extending to the main bronchi were repaired through a right thoracotomy as well as four lesions limited to the trachea observed before January 2001. After this date we used the transcervical approach for entirely intratracheal lesions: in three cases we performed an anterior transverse tracheotomy and in one case a transverse and midline vertical incision (T tracheotomy). RESULTS Both conservative and surgical therapy were successful in all the cases. Two patients in the thoracotomy group had a transient right vocal cord palsy. No morbidity was observed with the cervical approach. Normal healing of the sutures was evidenced by an endoscopic follow-up 30 days later. CONCLUSIONS In our experience nonsurgical treatment is advisable in small (length < 2 cm) uncomplicated tears. Concerning surgery, thoracotomy is indicated in tracheal lacerations extending to the main bronchi, whereas the transcervical approach is preferred for intratracheal tears because of its efficacy in reaching and suturing the lesions extending to the carina and for its limited invasiveness.

Grading the neuroendocrine tumors of the lung: an evidence-based proposal.

Lung neuroendocrine tumors are catalogued in four categories by the World Health Organization (WHO 2004) classification. Its reproducibility and prognostic efficacy was disputed. The WHO 2010 classification of digestive neuroendocrine neoplasms is based on Ki67 proliferation assessment and proved prognostically effective. This study aims at comparing these two classifications and at defining a prognostic grading system for lung neuroendocrine tumors. The study included 399 patients who underwent surgery and with at least 1 year follow-up between 1989 and 2011. Data on 21 variables were collected, and performance of grading systems and their components was compared by Cox regression and multivariable analyses. All statistical tests were two-sided. At Cox analysis, WHO 2004 stratified patients into three major groups with statistically significant survival difference (typical carcinoid vs atypical carcinoid (AC), P=0.021; AC vs large-cell/small-cell lung neuroendocrine carcinomas, P<0.001). Optimal discrimination in three groups was observed by Ki67% (Ki67% cutoffs: G1 <4, G2 4-<25, G3 ≥25; G1 vs G2, P=0.021; and G2 vs G3, P≤0.001), mitotic count (G1 ≤2, G2 >2-47, G3 >47; G1 vs G2, P≤0.001; and G2 vs G3, P≤0.001), and presence of necrosis (G1 absent, G2 <10% of sample, G3 >10% of sample; G1 vs G2, P≤0.001; and G2 vs G3, P≤0.001) at uni and multivariable analyses. The combination of these three variables resulted in a simple and effective grading system. A three-tiers grading system based on Ki67 index, mitotic count, and necrosis with cutoffs specifically generated for lung neuroendocrine tumors is prognostically effective and accurate.

Comparison Between Epidermal Growth Factor Receptor (EGFR) Gene Expression in Primary Non-small Cell Lung Cancer (NSCLC) and in Fine-Needle Aspirates from Distant Metastatic Sites

Purpose: Epidermal growth factor receptor (EGFR) gene copy number obtained by fluorescence in situ hybridization (FISH) has been recently found to predict treatment outcome in non-small cell lung cancer (NSCLC) patients receiving EGFR tyrosine kinase inhibitors. However, it is still unknown whether EGFR status differs in metastases compared with primary NSCLC. In all studies FISH have been performed on histologic material. The possibility to perform FISH analysis on cytologic material obtained by fine-needle aspiration from superficial and visceral metastases would allow us to know the real EGFR status avoiding invasive diagnostic procedures. Methods: EGFR gene copy number was analyzed by FISH on fine-needle aspirates obtained from 31 patients with metastatic NSCLC and the results were compared with those obtained on corresponding paraffin histologic sections from the primary tumor. Results: The feasibility of EGFR FISH on cytology was 90% (28 of 31 patients). EGFR FISH was positive in 61% (17 of 28 patients) of the metastases and in 36% (10 of 28 patients) of the primary tumors. Nine of the 28 cases (32%) were EGFR positive on both primary tumor and metastatic site and 10 (36%) were negative on both primary tumor and metastasis. Nine of the 28 cases (32%) showed discordance of primary tumor versus metastasis (McNemar test; p = 0.041). Conclusions: EGFR FISH can be reliably assessed on fine-needle aspirates obtained from NSCLC metastases. We found that EGFR gene copy number is discordant between primary NSCLC and the corresponding distant metastatic sites in a significant proportion of cases. These findings should be considered in future studies designed to elucidate the predictive role of EGFR FISH in NSCLC.

Lung metastasis resection of adenoid cystic carcinoma of salivary glands

BACKGROUND Adenoid cystic carcinoma is a rare tumour originating from the exocrine mucous glands, known for its high propensity for distant metastases. The value of lung metastasis resection from adenoid cystic carcinoma of salivary glands origin is evaluated. METHODS A retrospective study was conducted on patients undergoing surgery for primary adenoid cystic carcinoma of the salivary glands between 1982 and 2006. Patients were excluded who had primary tumour macroscopic incomplete resection or were lost at follow-up. From a database of 50 eligible patients, 27 were identified as having presented a tumour recurrence during follow-up; in 20 it was first diagnosed in the form of distant metastases, and in 7 in the form of loco-regional recurrence. Nine patients who presented isolated lung recurrence underwent complete lung metastasectomy. Demographic data, pathologic characteristics and operative and postoperative record were reviewed, as well as updated survival. RESULTS Twenty-six men and 24 women with a median age of 57 years (range 33-79) underwent radical surgery for adenoid cystic carcinoma during the study period. In 20 patients, at a median free interval time of 3 years (range 1-12), a distant metastasis relapse was observed. Nine patients with a median free interval time of 5 years (range 1-12) underwent lung metastasectomy: five had single metastasis resection, one multiple mono-pulmonary and three multiple and bilateral. In six of these patients a new disease recurrence was noted: four patients underwent further lung metastasectomy, but in all of them progression of the disease was observed. Mean survival of the population as a whole resulted as being 16 years (SE=1.4) with an actuarial survival of 77% at 5 years, 66% at 10 years and 56% at 15 years. Mean survival of patients having presented with distant metastases resulted as being 11 years (SE=2.2). Mean survival after appearance of distant metastases resulted as being 72 months (SE=15.8) in the 9 patients treated by metastasectomy, and 62 months (SE=15.1) in the 11 who did not have metastasis resection. CONCLUSIONS Patients with adenoid cystic carcinoma could be frequently encountered with disease recurrence confined to the lung. The impact of complete lung metastasis resection on the course of the disease, however, is yet to be determined.

Dose-dependent effect of FHIT-inducible expression in Calu-1 lung cancer cell line

Abnormalities in the expression of the tumour suppressor fragile histidine triad (FHIT) gene have been reported in a variety of human tumours, including lung cancer and restoration of its expression in cancer cell lines resulted in the inhibition of proliferation and apoptosis induction. Most of the studies that have assigned a proapoptotic role to the FHIT gene were performed in adenoviral-FHIT-transduced cancer cells expressing high levels of the Fhit protein. The present work was the first study designed to investigate the effects of FHIT gene replacement in a human FHIT-negative non-small-cell lung cancer (NSCLC) cell line (Calu-1) by using a hormone-inducible expression system that allows tight modulation of the transgene expression. Through this approach, we demonstrated that a prolonged induction was required to accumulate the Fhit protein at levels adequate to promote a significant decrease of cell proliferation. Analysis of cell-cycle phase distribution showed an accumulation of cells in the G0/G1 phase and a concomitant decrease in the S phase. Moreover, an upregulation of p21waf1 transcript was found, which could account for the alteration of the cycling properties of the cells. The growth-inhibitory effects observed were not associated with apoptosis appearance, and although in these conditions the Fhit protein content was higher than in normal bronchial human epithelial cells (NHBE), it was still significantly lower than the level capable of inducing apoptosis in Calu-1 cells after adenoviral-mediated FHIT gene transfer. These results indicate that the tumour suppressor properties of Fhit are strictly related to its expression level and show that the Fhit protein has a dose-dependent antiproliferative effect on the Fhit-negative Calu-1 lung cancer cell line.

Experimental Tracheal Transplantation Using a Cryopreserved Aortic Allograft

Background: The tracheal reconstruction after wide resections remains a critical surgical problem. Our aim was to replace trachea with a tissue easy to vascularize, which allows a simple reconstruction and does not require an immunosuppressive regimen. Materials and Methods: A segment of cryopreserved aorta was used in order to verify its adequacy as tracheal substitute. In phase 1, the thoracic aorta of 10 rabbits was excised, obtaining 20 segments that were cryopreserved. Ten segments were implanted in the omentum of 10 rabbits that were sacrificed on postoperative days 7, 14 and 21, and the grafts were examined histologically. In phase 2, a segment of cryopreserved aorta arranged with a silicone prosthesis was transplanted in 10 rabbits and wrapped with omentum. The animals were sacrificed on postoperative days 7, 14 and 21. Results: In phase 1, the neovascularization of the grafts was present after 7 days, and after 14 days the fibroblasts invaded the lumen of the aorta. In phase 2, 8 rabbits survived and the histologic examination after 7, 14 and 21 days showed neovascularization, the absence of rejection and the proliferation of fibroblasts inside the lumen of the aorta; this growth has been restrained by an endoluminal prosthesis. Conclusions: Our study demonstrated that replacing the trachea with cryopreserved aorta is technically feasible and does not evoke immunologic reactions. It requires, however, a silicone tube inside the allograft to limit the colonization of fibroblasts.

Exercise capacity assessment in patients undergoing lung resection

BACKGROUND The value is examined of preoperative functional assessment, including exercise capacity measurement by a cycloergometric maximal exercise test, in the prediction of postoperative cardio-pulmonary complication after lobar resection. METHODS In a prospective study over a 3-year period, all patients who were candidates for lung resection underwent preoperative functional evaluation by means of resting pulmonary function tests, measurement of the lung diffusing capacity for carbon monoxide and cardio-pulmonary exercise test. Patients who had had pneumonectomy or less than anatomical segmentectomy were excluded. The study population consisted of 73 patients. The postoperative morbidity and mortality record was collected. RESULTS Sixty-four patients underwent lobectomy, five bilobectomy and four segmentectomy. Indication for surgery was NSCLC in 71 cases. Two postoperative deaths were recorded (2.7%). A pulmonary (n=19) and/or cardiac (n=17) complication was scored in 30 patients (41%). Mean preoperative FEV(1) and VO(2)max of patients who developed pulmonary complications were significantly lower (p=0.013 and p=0.043 respectively) than those of patients without pulmonary complications. Logistic regression analysis found FEV(1) to be an independent factor in pulmonary complication (p=0.002). With regard to pulmonary complication occurrence, the receiver operating characteristic curve showed an area of 0.69 with VO(2)max expressed in ml/kg min and of 0.62 when VO(2)max was expressed as a percentage of the predicted value. The widest point of the curve was found at a VO(2)max value of 18.7 ml/kg min. Six out of the 14 patients (43%) with a preoperative VO(2)max equal to or lower than 15 ml/kg min had a pulmonary complication. No functional preoperative identifiers were found for the 16 patients who presented with postoperative new onset atrial fibrillation. The mean preoperative value of carbon monoxide lung diffusing capacity was significantly lower (p=0.037) in the 30 patients who had postoperative cardio-pulmonary complications than in the complication-free population. CONCLUSIONS Preoperative exercise capacity assessment helps in stratifying patients at risk for postoperative pulmonary complication. However, it does not appear to be an independent prognostic factor for postoperative outcome.

Predictive factors of diagnostic accuracy of CT-guided transthoracic fine-needle aspiration for solid noncalcified, subsolid and mixed pulmonary nodules

Purpose. The aim of this study was to analyse factors predicting the diagnostic accuracy of computed tomography (CT)-guided transthoracic fine-needle aspiration (TTFNA) for solid noncalcified, subsolid and mixed pulmonary nodules, with particular attention to those responsible for false negative results with a view to suggesting a method for their correction.PurposeThe aim of this study was to analyse factors predicting the diagnostic accuracy of computed tomography (CT)-guided transthoracic fine-needle aspiration (TTFNA) for solid noncalcified, subsolid and mixed pulmonary nodules, with particular attention to those responsible for false negative results with a view to suggesting a method for their correction.Materials and methodsFrom January 2007 to March 2010, we retrospectively reviewed the CT images of 198 patients of both sexes (124 males and 74 females; mean age, 70 years; range age, 44–90) used for the guidance of TTFNA of pulmonary nodules. Aspects considered were: lesion size and density, distance from the pleura, and lesion site. Multiplanar reformatted images (MPR) were retrospectively obtained in the sagittal and axial oblique planes relative to needle orientation.ResultsThe overall diagnostic accuracy of TTFNA CTguided biopsy was 86% for nodules between 0.7 and 3 cm, 83.3% for those between 0.7 and 1.5 cm, and 92% for those between 2 and 3 cm. Accuracy was 95.1% for solid pulmonary nodules, 84.6% for mixed nodules, and 66.6% for subsolid nodules. The diagnostic accuracy of CT-guided TTFNA in relation to the distance between the nodule and the pleural plane was 95.6% for lesions adhering to the pleura and 83.5% for central ones. The diagnostic accuracy was 84.2% for the pulmonary upper lobe nodules, 85.3% for the lower lobe and 90.9% for those in the lingula and middle lobe. In 75% of false negative and inadequate/insufficient cases the needle was found to lie outside the lesion, after reconstruction of the needle path by MPR.ConclusionsThe positive predictive factors of CT-guided TTFNA are related to the nodule size, density and distance from the pleural plane. The most common negative predictive factor of CT-guided TTFNA is the wrong position of the needle tip, as observed in the sagittal and axial oblique sections of the MPR reconstructions. The diagnostic accuracy of CT-guided TTFNA can therefore be improved by using the MPR technique to plan the needle path during the FNA procedure.RiassuntoObiettivoScopo del presente lavoro è stato individuare ed analizzare i fattori che predicono l’accuratezza diagnostica dell’ago-biopsia trans-toracica (TTFNA) guidata da tomografia computerizzata (TC) dei noduli polmonari solidi non calcifici, subsolidi e misti, con particolare attenzione ai fattori responsabili di falsi negativi, proponendo un metodo per la loro correzione.Materiali e metodiTra il 2007 ed il 2010 sono state analizzate retrospettivamente le immagini TC del torace di 198 pazienti di entrambi i sessi (124 maschi e 74 femmine, età media 70 anni, range età 44–90) utilizzate per l’esecuzione di TTFNA TC-guidata di noduli polmonari. I criteri analizzati sono stati: dimensione, densità, distanza dal piano pleurico e sede dei noduli polmonari. Sono state ottenute retrospettivamente immagini in ricostruzioni multiplanari (MPR) sui piani sagittali ed asssiali obliqui in relazione all’orientamento dell’ago.RisultatiL’accuratezza complessiva della TTFNA TC-guidata per noduli polmonari compresi tra 0,7 e 3 cm è stata 86%. L’accuratezza per i noduli polmonari compresi tra 7 e i 15 mm è stata del 83,3%, per quelli compresi tra 20 e 30 mm del 92%. L’accuratezza per i noduli polmonari solidi è stata del 95%, per i noduli misti 84,6% e per noduli subsolidi 66,6%. L’accuratezza per i noduli adesi al piano pleurico è stata del 95,6% e per quelli centrali 83,5%. Per i noduli dei lobi superiori è stata 84,2%, per quelli dei lobi inferiori 85,3%, per quelli della lingula e del lobo medio 90,9%. Nel 75% dei casi falsi negativi, inadeguati o insufficienti, la punta dell’ago dopo ricostruzione MPR era localizzata all’esterno o in periferia del nodulo polmonare.ConclusioniI fattori diagnostici predittivi positivi della TTFNA TC-guidata sono correlati con le dimensioni, la densità e la distanza del nodulo polmonare con il piano pleurico. Il fattore predittivo negativo ricorrente della TTFNA TC-guidata è l’errata localizzazione della punta dell’ago, mal evidente nelle scansioni assiali native, osservata retrospettivamente nelle sezioni sagittali ed assiali oblique MPR. Il ricorso alle immagini MPR sagittali e assiali oblique durante l’agoaspirazione è utile per il corretto planning della traiettoria dell’ago, quest’ultimo aspetto cruciale che influenza l’accuratezza diagnostica della procedura.

Pulmonary endothelial cell modifications after storage in solid-organ preservation solutions.

During lung preservation, the vascular endothelium is probably the first site of damage and these lesions are considered the main limiting factor in solid-organ preservation. In the present study, the ultrastructural changes in the endothelial cells of human pulmonary artery hypothermically stored (at 4 °C) for 6 and 12 h in Euro-Collins, University of Wisconsin and Ringer-lactate solutions were compared. The arteries obtained from three patients who underwent pneumonectomy were divided into 20 segments and preserved in the three solutions mentioned. The specimens, which were fixed in osmic acid, were examined using transmission electron microscopy. Transmission electron microscopy indicated that the cells stored in the University of Wisconsin solution either for 6 or 12 h were the best preserved, while the most severely damaged cells were those stored in Euro-Collins solution, even after just 6 h. The cells stored in Ringer-lactate showed an intermediate level of damage. The data from an ultrastructural grading scale, which quantified the damage to the cytoplasm, mitochondria and nucleus, were in broad agreement with the general transmission electron microscopy observations. Analysis of variance of the grading scale data showed that there were statistically significant differences between the groups after both 6 and 12 h storage (P < 0.05).

Biological variables in non-small cell lung cancer: comparison between immunocytochemical determination on fine needle aspirates from surgical specimens and immunohistochemical determination on tissue sections

A number of biological and predictive markers of non-small cell lung cancer (NSCLC) have been sought, but these have so far been mainly evaluated on surgically resected specimens. Given that fine needle aspiration biopsy (FNAB) is being increasingly used in the diagnosis of NSCLC, its application could be extended to the immunocytochemical detection of biological parameters at the time of diagnosis before surgery. In order to assess the reliability of estimating biological markers on fine needle aspirates (FNAs) from NSCLC, the aim of this study was to compare Ki67 growth fraction, p53 and bcl-2 protein expression as revealed by the immuncytochemical assessment of FNAs obtained from surgical samples with the immunohistochemical results obtained from the corresponding histological sections. FNAs were performed on surgical specimens obtained from 29 NSCLC patients. Ki67, p53 and bcl-2 were cytologically and histologically evaluable in respectively 25, 27 and 19 cases. Concordance between FNAs and corresponding paraffin sections was 84% for Ki67, 93% for p53 and 95% for bcl-2. All of the specimens whose biological parameters were studied by immunocytohistochemistry also underwent flow cytometric DNA analysis of FNAs taken from fresh surgical specimens. Of the 29 cases, 22 were aneuploid and seven diploid. The S-phase fraction (SPF) was evaluable in 62% of cases. Comparison of SPF results on FNAs with Ki67 values evaluated on the corresponding histologic and cytologic specimens, revealed a significant correlation only with histology. Good reproducibility was also found in relation to the immunocytochemical results obtained on FNAs from different areas of the same tumour, showing that tumour heterogeneity does not affect the method. The concordance between the immunocytochemical and immunohistochemical results suggests that FNAB may be a reliable procedure for the biological characterization of NSCLC. Given its limited invasiveness, FNAB could be used in vivo for the preoperative assessment of biological parameters in patients with operable or metastatic NSCLC.