Jacques Cerrina

Angiogenesis: An indicator of metastasis in non-small cell lung cancer invading the thoracic inlet

We have attempted to identify a biologic rationale for the local aggressiveness and late treatment failure of resected non-small cell lung cancer involving the thoracic inlet. Tumor specimens from 28 patients who underwent a new transcervical approach were analyzed for the expression of tumor proliferative activity, suppressor-gene p53, intratumoral and peritumoral blood vessel invasion by tumor cells, the presence and degree of angiogenesis (induction of new capillaries and venules), and other biologic variables. Eighty-nine percent of the neoplasms were moderately or poorly differentiated, 89% expressed either an intermediate or high proliferative activity, 39% showed p53 aberrations, 71% exhibited induction of angiogenesis, and 39% had tumors that were positive for blood vessel invasion. With a median follow-up time of 3.5 years (range, 8 to 145+ months), the overall projected 5-year survival was 29% and the median disease-free interval was 23 months. Results of univariate and multivariate analysis of survival and the disease-free interval identified the degree of angiogenesis (density less than 1 versus more than 1 and number of neovessels less than 6 versus more than 6) as the only independent and significant predictors of the disease-free interval. Patients whose tumor showed a density of angiogenesis of 1 or greater and a number of neovessels of 6 or greater faced a significantly (p = 0.0001) higher relative risk of suffering systemic recurrence of their primary tumor than did their low-risk counterparts. Results demonstrate that angiogenesis significantly correlates with late treatment failure (metastasis), and this is acquired at a critical density and number of vessels.

Long-term outcome of double-lung and heart–lung transplantation for pulmonary hypertension: a comparative retrospective study of 219 patients

OBJECTIVE Whether double-lung transplantation (DLT) or heart-lung transplantation (HLT) is the best option in patients with pulmonary hypertension (PH) remains unclear. At our institution, patients with severe right ventricular dysfunction or congenital systemic-to-pulmonary shunt (CSPS) are preferentially treated with HLT. We sought to determine whether the outcomes warrant continuing this policy. METHODS We retrospectively reviewed cases of DLT (n=67) or HLT (n=152) performed for end-stage PH between 1986 and 2008 at our institution. According to the new clinical classification of PH, 147 patients were group I (pulmonary arterial hypertension group, of which 30 had CSPS), 24 were group III (PH associated with lung disease and/or hypoxaemia), 20 were group IV (chronic thrombo-embolic PH) and 20 were group V (sarcoidosis or histiocytosis X). RESULTS Compared with the HLT group, the DLT group had less severe disease as reflected by a higher preoperative cardiac index (2.5 + or - 0.8 vs 2.0 + or - 0.4; P=0.0006), lower New York Heart Association (NYHA) functional class (3.4 + or - 0.4 vs 3.8 + or - 0.5; P<0.0001), lower rates of kidney failure (31% vs 66%; P<0.0001) and liver failure (13% vs 38%; P=0.0003) and less need for preoperative inotropic support (10% vs 25%; P=0.014). Nevertheless, survival after 1, 5, 10 and 15 years was not significantly different between the two groups (HLT group: 70%, 50%, 39% and 26%; and DLT group: 79%, 52%, 43% and 30%; respectively; P=0.932). Freedom from obliterative bronchiolitis-related death was significantly greater in the HLT group (100% at 1 year, 84% at 5 years and 74% at 10 years; compared with 98%, 70%, and 59%, respectively, in the DLT group; P=0.035). CONCLUSIONS In patients with end-stage PH, good long-term survival rates were obtained using either DLT or HLT. However, these results were achieved with preferential use of HLT in patients with right heart failure or CSPS. Obliterative bronchiolitis-related death was less common with HLT than with DLT.

Tracheal Sleeve Pneumonectomy for Bronchogenic Carcinoma: Report of 55 Cases

From 1966 to 1986, a total of 55 patients underwent a tracheal sleeve pneumonectomy (53 right and 2 left) for bronchogenic carcinoma. Preoperative radiotherapy was given in only 5 patients. The overall operative death rate was 10.9%, but no patient has died since 1975 (32 survivors). Seven patients had a postoperative empyema (12.7%); 4 of these patients had a bronchopleural fistula. Twenty-five patients had postoperative radiotherapy, 5 of whom also had chemotherapy. The actuarial survival rate, after exclusion of the 6 operative deaths, was 38% at 3 years and 23% at 5 years. Survival was correlated to regional lymph node involvement. The actuarial survival rate among patients with tumoral spread to bronchial lymph nodes was 43% at 3 years. Among the 13 patients with only subcarinal involvement, the actuarial survival rate was 34% at 3 years. None of the 8 patients with paratracheal lymph node involvement survived more than 30 months. These results indicate that tracheal sleeve pneumonectomy for bronchogenic carcinoma with extension to the carina is now fully justified considering the low operative mortality and the good results observed when lateral tracheal lymph nodes were not involved.

Intrapulmonary production of RANTES during rejection and CMV pneumonitis after lung transplantation.

RANTES (regulated upon activation, normally T expressed and secreted) is a chemoattractant for macrophages, memory T lymphocytes, and eosinophils. We investigated whether intrapulmonary production of the chemokine RANTES contributes to the recruitment of immune cells during lung transplantation complications. RANTES concentration was measured in bronchoalveolar lavage (BAL) fluids using an ELISA assay. It was significantly higher during CMV pneumonitis (36.2 +/- l6 pg/ml, n=12, P=0.031) and allograft rejection (31.1 +/- 8.5 pg/ml, n=27, P=0.013) than in patients without complications (9.1 +/- 2.3 pg/ml, n=22). At least some of the RANTES was produced by lung macrophages: BAL macrophages cultured for 24 hr spontaneously released larger amount of RANTES during CMV pneumonitis (140 +/- 53 pg/ml, n=8, P=0.002) and allograft rejection (84 +/- 44 pg/ml, n=11, P=0.037) than in control patients (15.2 +/- 6.5 pg/ml, n=21). Moreover, macrophages in transbronchial biopsies were labeled by an anti-RANTES mAb. RANTES production by BAL macrophages was followed in 2 patients with CMV pneumonitis. It remained high as long as CMV-induced cytopathic effects or clinical symptoms were present, but it returned to baseline as the infection was controlled. These results suggest that the intrapulmonary production of the chemokine RANTES by activated macrophages contributes to the intrapulmonary accumulation of immune cells during complications of lung transplantation.

Factors affecting long-term survival after en-bloc resection of lung cancer invading the chest wall.

OBJECTIVE Several reports emphasize the importance of en-bloc resection as the optimal surgical treatment of lung cancer with chest wall invasion. We investigated possible factors which could affect long-term survival following radical resection of these tumors. METHODS Between 1981 and 1998, 100 patients (90 male; ten female), with a median age of 60 years (36-84), underwent radical en-bloc resection of non-small cell lung cancer (NSCLC) with chest wall involvement. Patients with superior sulcus tumors invading the thoracic inlet were excluded from this series. There were 43 squamous and 57 non-squamous tumors. The median number of resected ribs was three (1-5). Lung resection included 73 lobectomies, two bilobectomies, 18 pneumonectomies and seven segmentectomies. Chest wall resection also extended to the sternum in one patient, the transverse process in one, the costotransverse foramen and hemivertebrae in two. All patients had a complete resection. Sixty-three patients received postoperative radiotherapy and 12 received chemotherapy. Histological data, including differentiation and depth of chest wall invasion, were carefully reviewed. The effect of various factors on survival were studied. RESULTS There were four in-hospital deaths. Lymph node involvement was negative on surgical specimens in 65 patients, and 28 patients had positive N1 nodes; the final histology revealed seven N2 diseases. Chest wall invasion was limited to the parietal pleura in 29 patients and included intercostal muscles, bones and extrathoracic muscles in 67, 24 and seven cases, respectively. The overall 2-year survival rate was 41%. The 5-year survival for patients with N0, N1 and N2 disease was 22, 9 and 0%, respectively. A local recurrence occurred in 13 patients, with four having a new resection and 45 patients developing systemic metastases. The nodal status (N0-1 vs. N2; P=0. 026) and the number of resected ribs(<2 vs. >2; P=0.03) were survival predictors in univariate analysis. By multivariate analysis, the two independent factors affecting long-term survival were the histological differentiation (well vs. poorly differentiated; P=0. 01) and the depth of chest wall invasion (parietal pleura vs. others; P=0.024). CONCLUSIONS Histological differentiation and depth of chest wall involvement were the main factors affecting long-term survival in this series. The role of induction chemotherapy for tumors with poor prognosis should be investigated.

Angioscopic video-assisted pulmonary endarterectomy for post-embolic pulmonary hypertension

OBJECTIVES To assess whether the use of video-assisted angioscopy would increase the outcome of pulmonary thromboendarterectomy (PTE). METHODS PTE included a median sternotomy, intrapericardial dissection of the superior vena cava, institution of cardiopulmonary bypass, deep hypothermia and sequential circulatory arrest periods. It was always performed through two separate arteriotomies on both main intrapericardial pulmonary arteries, into which a rigid 5 mm angioscope connected to a video camera was introduced to increase the visibility and endarterectomies. RESULTS From January 1996 to July 1998, 68 consecutive patients (35 males and 33 females) aged 54.3 +/- 13.5 years underwent PTE. Patients were in New York Heart Association (NYHA) class II (n = 2), III (n = 43) or IV (n = 23) with the following hemodynamics: mean pulmonary arterial pressure (PAP) 54 +/- 13 mmHg; cardiac output (CO): 3.8 +/- 0.8 l/min, and total pulmonary resistance (TPR): 1207 +/- 416 dyne x s x cm(-5). The cumulated circulatory arrest time was 23 +/- 12 min and postoperative length of ventilatory support 10 +/- 12 days. Nine patients died, for an overall in-hospital mortality of 13.2%. The functional outcome in surviving patients was significantly improved (P < 0.0001) both clinically (NYHA class 3.2 +/- 0.5 vs. 1.3 +/- 0.6) and hemodynamically (PAP (mmHg) 53.1 +/- 13 vs. 30.2 +/- 11.8, CI (l/min per m2) 2.1 +/- 0.5 vs. 2.8 +/- 0.6, TPR (dyne x s x cm(-5)) 1174 +/- 416 vs. 519 +/- 250). CONCLUSIONS Video-assisted angioscopy improves the quality and degree of pulmonary endarterectomy expanding the indications to include patients with previously inaccessible distal disease.

Extended operations after induction therapy for stage IIIb (T4) non-small cell lung cancer

Twenty-three patients with stage IIIb (T4) non-small cell lung cancer received induction chemotherapy (median, 2 cycles) with (n = 12) or without (n = 11) radiation (median, 45 Gy) before operation. Nine tumors involved the carina (n = 8) or lateral tracheal wall (n = 1), 11 were located centrally and invaded the proximal pulmonary artery (n = 6), veins (n = 3), or both (n = 2), three were apical tumors involving T4 structures, and six were associated with histologically diseased mediastinal nodes. Five complete and 18 partial responses were observed after induction treatment. Resection of all residual tumor at the primary site and involved vestiges was possible in 21 patients (91%); in two apical tumors, tumor was left behind. Nine right tracheal sleeve and 11 intrapericardial pneumonectomies and three resections of apical tumors were performed; 11 patients (48%) had radical mediastinal lymph node dissection. Complete sterilization of the primary tumor was observed in 3 patients (13%). Mean operating time was 209.3 +/- 86.8 minutes, and mean blood loss was 896.9 +/- 1031 mL. Major postoperative complications occurred in 6 patients (26%), including hemothorax requiring drainage (n = 1) or reoperation (n = 1), acute distress syndrome (n = 2), and bronchopleural fistula (n = 2), and their incidence was significantly higher (p = 0.0003) among patients receiving induction chemoradiation than among those receiving chemotherapy alone (42 versus 9%). Early (< 1 month) postoperative mortality was 8.6% (n = 2). With a median follow-up of 25 months (range, 12 to more than 39 months), the projected 3-year overall survival was 54%.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of diltiazem and other Ca2+ antagonists on guinea-pig tracheal muscle

The effects of diltiazem and 3 other Ca2+ antagonists (verapamil, nicardipine, bepridil) were studied on isolated guinea-pig tracheal preparations which were contracted with several agonists. Assessment of the contractile agonists was performed under physiological conditions as well as in Ca2+-depleted solutions. The order of potency of the contractile agonists was LTD4 greater than ACh greater than 5-HT greater than Hist greater than BaCl2 greater than TEA greater than KCl. The efficacy of the physiological agonists ACh, Hist and LTD4 was moderately depressed in Ca2+-free solutions while the responses to non-specific agonists and 5-HT were markedly reduced. Diltiazem and verapamil reduced basal tone at concentrations greater than or equal to 10(-4) M. Diltiazem displaced all agonist concentration-effect curves to the right. The four Ca2+ antagonists studied had a marked effect on non-physiological agonists as compared to that on physiological agents. Increasing Ca2+ concentration only partially reversed the inhibitory effect of diltiazem.

Clamshell or sternotomy for double lung or heart-lung transplantation?

OBJECTIVE To evaluate the influence of either incision on the lungs and chest wall. METHODS Ninety-two double lung (DLT) or heart-lung (HLT) transplantations were done since January 1990. There were 22 (24%) hospital deaths, leaving 70 patients with complete data for evaluation. We did 38 DLT and 32 HLT for end-stage chronic respiratory failure (n = 22) and primary (n = 34) or secondary (n = 14) pulmonary hypertension, using 37 fourth or fifth interspace clamshell incisions and 33 median sternotomies. RESULTS The clamshell group included a higher percentage of DLTs (73 vs. 33%, P = 0.001) but recipient age, gender, preoperative diagnosis, bronchial anastomotic complications, number of cytomegalovirus infection, episode of acute rejection per patient-months and incidence of bronchiolitis obliterans were not statistically different between the two groups. At a follow-up time of 3.7 +/- 2 years, the overall 5-year survival of 57% was not influenced by the type of incision. The clamshell incision caused sternal over-riding in 12 (32%) patients, and eight surgical clamshell revision were necessary as compared with one median sternotomy (P = 0.02). The clamshell incision was associated with a significantly higher incidence of postoperative chronic pain (27 vs. 6%, P = 0.02). Postoperative mechanical properties of the chest wall were significantly (P < 0.0001) worse in the clamshell-group patients while the intrinsic properties of the airways were not different. CONCLUSIONS The clamshell incision results in more postoperative deformity, chronic pain, and impaired function as compared with median sternotomy. A bilateral anterolateral thoracotomy without division of the sternum is proposed for the sequential bilateral lung transplantation technique.

In situ production of interleukin-6 within human lung allografts displaying rejection or cytomegalovirus pneumonia.

Interleukin-6 (IL-6) is a pleiotropic cytokine that is a regulator of inflammation and immunity. As production of IL-6 may be an important mechanism by which local and systemic inflammatory processes are regulated during lung transplantation, we measured this cytokine concentration in the serum and bronchoalveolar lavage fluid (BALF) collected in 27 lung recipients. IL-6 bioactivity was analyzed using a B cell hybridoma proliferation assay (B9 cell line). Three groups of clinical situations were analyzed: control lung recipients, rejections, and CMV pneumonia. Serum IL-6 concentrations (mean +/- SEM) were 24.2 +/- 3.3 U/ml in the 26 control samples. In 20 allograft rejection episodes, the serum IL-6 concentration was higher than in control samples but the difference was not significant (59.3 +/- 20.5 U/ml, P > 0.05). IL-6 serum levels were significantly increased during the 14 CMV pneumonias (61.2 +/- 11.5 U/ml, P < 0.01). In BALF, IL-6 levels were increased during CMV pneumonia (52.4 +/- 21.9 U/ml BALF), and to a lesser extent during rejection events (14.1 +/- 3.7 U/ml BALF), as compared with controls (5.6 +/- 1.6 U/ml BALF, P < 0.005, and P < 0.05, respectively). Similar results were observed when IL-6/albumin and IL-6/urea ratios were determined so as to compensate for possible dilution effects in BALF. IL-6 in BALF was produced in situ during CMV pneumonia as shown by in situ hybridization experiments that revealed a significant number of IL-6 gene-expressing alveolar cells in this condition. IL-6 concentrations in the serum and in the BALF were compared. There was no correlation between serum and BALF IL-6 concentrations, showing that serum IL-6 levels do not accurately reflect intrapulmonary IL-6 levels do not accurately reflect intrapulmonary IL-6 production. Thus IL-6 is produced within lung transplants during CMV pneumonia, and to a lesser extent during allograft rejection.