Adverse effects of fibrin sealants in thoracic surgery: the safety of a new fibrin sealant: multicentre, randomized, controlled, clinical trial.

OBJECTIVES: The safety of fibrin sealants (FS) has been questioned in the light of recent reports of adverse effects. We evaluated the safety of a new FS in a randomized controlled trial (RCT). METHODS: Multicentre, open-label Phase II/III RCT to evaluate the safety of the new FS. The trial was approved by the Ethic Committee of each three participating Centre. FS includes two components (component 1: fibrinogen; component 2: thrombin), each of them subjected to two viral inactivation procedures. Out of 200 screened patients, 185 eligible patients (49 females, 136 males), aged between 18 and 75 years, undergoing major thoracic surgery were randomized to receive FS (#91 patients) as an adjuvant for air leak control or no treatment (#94 patients, control group). Safety variables were: percentage of subjects with adverse events associated with the therapy; formation of antibodies against bovine aprotinin; vital signs (blood pressure, body temperature, heart and respiratory rate); laboratory parameters. RESULTS: Overall operative mortality was 3.2% (6/185), 1.1% in the FS group and 5.3% in the control group, respectively. Twenty patients (22%) had adverse events in the FS group and 22 (23.4%) in the control group. Atrial fibrillation (five patients in the FS group and four in the control group) and hyperpyrexia (five and seven patients, respectively, in the two groups) were the most common adverse events. No patient reported thromboembolic events (pulmonary embolism or deep vein thrombosis) during the in hospital stay or within 1 month from discharge. None of the adverse events was considered as treatment related. The formation of bovine aprotinin antibodies was reported in a total of 34 patients (37.4%) in the FS group and was not related to any adverse effect. CONCLUSIONS: The present RCT did not show any increased risk of adverse events, and of surgical complications, related to the use of the new FS.

Safety and effectiveness of a new fibrin pleural air leak sealant: a multicenter, controlled, prospective, parallel-group, randomized clinical trial.

BACKGROUND: This study evaluated the sealing capacity and safety of a new fibrin sealant (FS) to reduce alveolar air leaks (AALs) after pulmonary resections in a randomized controlled clinical trial conducted in 3 Italian centers. METHODS: The study randomized (1:1) 185 patients with an intraoperative AAL graded 1 to 3 according to the Macchiarini scale: 91 received FS and 94 had standard lung closure. The primary outcomes were the length of postoperative AAL duration and the mean time to chest drain removal. Other end points included the percentage of patients without AAL, the development of serum antibodies against bovine aprotinin, and any adverse event related to FS. Chest drains were removed when fluid output was 100 mL/day or less, with no air leak. RESULTS: The study groups were comparable with respect to demographic variables and surgical procedures. The FS group showed a statistically significant reduction in duration of postoperative AALs (9.52 vs 35.8 hours; p < 0.005) and in the percentage of patients with AALs at wound closure (81.11% vs 100%; p < 0.001); the difference in time to chest drain removal was not significant. Pleural empyema developed in 1 patient with FS treatment vs in 4 with standard treatment, and antibodies against bovine aprotinin were found in 34 of 91 FS-treated patients. CONCLUSIONS: The present study showed that the new FS is safe and effective in preventing AALs after lung resections and in shortening the duration of postoperative AALs.

Malignant primary chest-wall tumours: techniques of reconstruction and survival.

OBJECTIVES: We analysed our experience in primary malignant chest-wall tumours (PMCWTs) with an emphasis on a new reconstruction technique and on survival. METHODS: From 1998 to 2008, 41 patients (23 (56%) male, mean age 48 years) with PMCWT were operated in our unit: chondrosarcoma n=25; osteosarcoma n=8; Ewing's sarcoma n=2; other n=6. We performed nine sternectomies and 32 lateral chest-wall resections (median number of ribs resected=3.5). Resections were extended to the lung (n=2), diaphragm (n=3), vertebral body (n=3), scapula (n=1) and upper limb (n=1). Stability was obtained by a prosthetic material, rigid and non-rigid and a muscular flap. As non-rigid material, we mostly used a polytetrafluoroethylene patch (n=24). In the past 2 years, two patients (one total sternectomy and one wide anterior chest-wall resection) were reconstructed with a rigid system composed of mouldable titanium connecting bars and rib clips (Strasbourg Thoracic Osteosyntheses System--STRATOS, MedXpert GMbH, Heitersheim, Germany). A muscular flap was added in 12 patients (29.3%). RESULTS: There was no perioperative mortality or significant morbidity and all patients were extubated within first 24h. At a mean follow-up of 60.5 months (range 4-130 months), the overall 5- and 10-year survival was 61% and 47%, respectively. In the chondrosarcoma group, 5- and 10-year survival was 80%. CONCLUSIONS: Wide resection with tumour-free margins is necessary in PMCWT to minimise local recurrence and to contribute to long-term survival. The STRATOS system, developed for chest-wall replacement, allows a firm reconstruction, simple to handle and to fix, avoiding instability or paradoxical movement also in wide chest-wall resections.

Alternative splicing variants of carbonic anhydrase IX in human non-small cell lung cancer.

In human cancers, carbonic anhydrase IX (CAIX) contributes to maintain intracellular and extracellular pH under hypoxic conditions, but also influences regulation of cell proliferation and tumor progression. CaIX was previously indicated as an independent prognostic marker in non-small cell lung carcinoma (NSCLC). Very recently a CAIX alternative splicing isoform, generating a transcript lacking of exons 8-9, was detected in cancer cells independently from the levels of hypoxia. This alternative splicing (AS) generates a truncated protein lacking the transmembrane region, the intracellular tail and the C-terminal of the catalytic domain and competes with the full-length (FL) isoform in the regulation of the extracellular pH, mainly in a mild hypoxic status. In the present study we measured the mRNA expression of FL and AS CAIX isoforms in 101 NSCLC and in paired not affected tissues. The two isoforms were coexpressed in all NSCLC and normal tissues but while AS mRNA was prevalent in normal tissues (66+/-3%), the FL isoform was higher in NSCLC (58+/-2%, p=0.001). FL mRNA, but not AS, was statistically increased in NSCLC (p=0.01) and showed a statistical association with lymphnode involvement (p=0.009) and tumor stage (p=0.04). Global survival analysis of cancer/related death showed that high levels of FL mRNA were predictive of unfavorable outcome (p<0.0001) and shorter disease-free survival (p<0.0001). Multivariate analysis indicated that FL is an independent prognostic factor for overall survival and higher levels of mRNA in NSCLC sensibly increase hazard ratio ( approximately sixfold). In conclusion, our results seems to indicate that, at least in NSCLC, FL CAIX is the most accurate surrogate of hypoxic stress and represents the only variant with a prognostic role. These data indicate the importance of a separate measurement of the two isoforms in cancer and the need of an accurate re-evaluation of most studies on the clinical role of CAIX in cancer diagnosis.

Prognostic variability in completely resected pN1 non-small-cell lung cancer.

We used the Tuscan Cancer Registry archives to retrieve records of 2,896 patients with a histological diagnosis of lung tumor from January 1996 to December 2000. Of 2,410 patients with non-small-cell lung cancer, 767 (31.8%) underwent complete resection. The following variables were analyzed for their influence on survival in the 157 patients with pathologic N1 status: sex, age, cell type, pathologic tumor status, number and level of involved lymph nodes, tumor grade, and type of surgery. Overall 5-year survival rates were 43.9% for 417 patients with pN0 disease, 10.8% for 176 with pN2 disease, and 31.6% for those with pN1 disease. In pN1 disease, the overall 5-year survival rates for patients with hilar and non-hilar lymph node involvement were 27.4% and 39.6%, respectively. Univariate analysis demonstrated that pathological T status and level of N1 involvement were significant prognostic factors. Cox proportional hazards analysis indicated that hilar lymph node involvement was an independent prognostic factor. N1 lymph node status was identified as an independent prognostic factor in a combination of subgroups with different prognoses.

Thoracoscopic localization techniques for patients with solitary pulmonary nodule: hookwire versus radio-guided surgery.

OBJECTIVE: Our aim was to evaluate the best intrathoracoscopic localization technique between hookwire and radio-guided surgery, in patients with pulmonary nodule. METHODS: From January 2000 to January 2005 we enrolled in this study 50 patients with a solitary pulmonary nodule, prospective randomized in two groups, well matched for diameter and depth of the pulmonary lesion. In 25 patients we performed the hookwire technique (Group A), whereas in the other 25 patients radio-guided localization was adopted (Group B). In both groups the localization technique was compared with finger palpation. In Group A, 9 lesions were in the left and 16 in the right lung; in Group B, 14 nodules were in the left lung and 11 in the right one. In both groups, the distance of the nodule from the pleural surface with lung inflated was 2.5 cm (1.5-2.5 cm in 12 patients, and >2.5 cm for the remaining 13). The mean size of the nodules in both groups was 1.1, range 0.6-1.9 (1 cm n=7 patients). RESULTS: All patients underwent thoracoscopic wedge resection, and 23 patients with a primary pulmonary lesion underwent thoracotomy for lobectomy and radical mediastinal lymphadenectomy. In Group A the hookwire technique localized the nodule in 21 of 25 patients (84%) whereas finger palpation localized it in 7 of 25 patients (28%). In Group B, radio-guided surgery localized the nodule in 24 of 25 patients (96%) whereas finger palpation localized it in 6 of 25 (24%). In Group A we registered 6 cases of pneumothorax compared to 1 case observed in the radio-guided group. Postoperative hospital stay required an average of 4 days in both groups. CONCLUSIONS: In our experience radio-guided surgery has therefore been proven efficacious in the diagnosis of solitary pulmonary nodule and video-assisted thoracoscopic surgery allows the removal of pulmonary nodules without complications. Hookwire was also shown to be efficacious but demonstrated complications linked primarily to external technical factors.

Prognostic variability among nonsmall cell lung cancer patients with pathologic N1 lymph node involvement. Epidemiological figures with strong clinical implications.

BACKGROUND: Patients who have nonsmall cell lung cancer with N1 lymph node status are an intermediate group of patients who have a variable prognosis. Differences in lymph node level (hilar or pulmonary lymph nodes) may influence patient survival. The authors retrospectively analyzed the factors that influenced prognosis, including the level of N1 lymph node involvement. METHODS: The authors used the Tuscan Cancer Registry archives to retrieve records on 2523 patients who had lung tumors diagnosed during the period from 1996 and 1998 in the provinces of Florence and Prato, central Italy. To analyze the survival of patients according to the level of lymph node involvement, the prognoses of patients with nonsmall cell lung cancer who had N1 lymph node status were compared in a population-based case series. Among 112 patients with pathologic N1 status, the following variables were analyzed for their influence on postoperative survival: gender, age, cell type, pathologic tumor status, the number of metastatic lymph nodes, the level of metastatic lymph nodes (hilar or pulmonary), and the type of surgical resection. RESULTS: The 5-year survival rates for patients who had involvement of pulmonary and hilar lymph nodes were 41.2% and 21.8%, respectively (P =.005). A Cox proportional hazards model analysis indicated that the presence of hilar lymph node involvement was an independent prognostic factor. CONCLUSIONS: N1 pathologic lymph node status was identified in a combination of subgroups with different prognoses, and the presence of hilar lymph node disease had prognostic significance. This difference in survival may lead to the use of different therapies for these subgroups of patients with pathologic N1 non-small cell lung cancer.

Quantitative analysis of carbonic anhydrase IX mRNA in human non-small cell lung cancer.

Hypoxia is associated with malignant progression and poor outcome in human cancers. The effects of hypoxia are mediated by a series of genomic changes that enable tumor cells to survive or escape their oxygen deficient environment. Recent studies indicated that carbonic anhydrase IX (CA IX) is an intrinsic marker of hypoxia. In the present study we investigated with quantitative RT-PCR the expression of CA IX mRNA in 93 non-small cell lung carcinomas (NSCLC) and in their paired not affected tissues. CA IX mRNA was expressed in 100% NSCLC and in 76% of paired not affected tissues, even if tumoral CA IX expression was found constantly higher (p < 0.02) than that found in normal tissues. The increase of CA IX mRNA expression in cancer tissues was significantly correlated to the increase of corresponding protein, as determined with conventional immunoblotting (p = 0.027). In addition the expression of CA IX mRNA in NSCLC samples was significantly correlated to VEGF (p = 0.002) and MMP-9 (p = 0.002) mRNAs. Whereas CA IX mRNA expression was not associated to any clinical-pathological parameters in our patients, global survival analysis of cancer-related death revealed that high expression of CA IX mRNA predicted unfavorable outcome (p = 0.001) and shorter disease free survival interval (p = 0.004). A multivariate analysis showed that CA IX expression was the strongest prognostic parameter (p = 0.000) in comparison to other conventional predictive markers. In addition, differences emerged on the basis of clinical-pathological parameters: in fact separate Kaplan-Meyer analyses of patients indicated that whereas high levels of CA IX mRNA expression were not predictive of worse prognosis in early NSCLC (G1, T1, Stage 1 and pN- patients), this parameter appeared highly significant in advanced NSCLC (G2-G3, T2-T3, Stage 2-3 and pN+ patients). Finally we demonstrated that CA IX expression was not able to discriminate different survival probability in adenocarcinomas, whereas the same parameter was highly predictive in squamous (p = 0.03) and adenosquamous cell carcinomas (p = 0.001).

Simultaneous measurement of MMP9 and TIMP1 mRNA in human non small cell lung cancers by multiplex real time RT-PCR.

Extracellular matrix (ECM) homeostasis is strictly maintained by a coordinated balance between the expression of matrix metalloproteinases (MMPs) and their specific inhibitors (TIMPs). Our study was focused on the simultaneous measurement of the expression profile of MMP9 mRNA and its principal inhibitor, TIMP-1, in 100 non small cell lung cancers (NSCLC) and in corresponding adjacent non malignant tissues. The measurement was performed with a multiplex quantitative RT-PCR assay based on TaqMan assay, using two probes labelled with different fluorocromes. We found that both MMP9 and TIMP-1 mRNAs were significantly higher in NSCLC (P < 0.0001) in comparison to corresponding controls as well as the MMP9/TIMP-1 ratio (P = 0.014). MMP9 and TIMP-1 mRNA expression was highly correlated in cancer samples (r = 0.73, P < 0.0001). The analysis in the two main histotypes revealed a significant increase of MMP9 mRNA in adenocarcinomas in comparison to normal tissues (P = 0.006) but not in squamous cell carcinomas, while TIMP-1 mRNA showed a significative increase both in adenocarcinomas and in squamous cell carcinoma samples (P = 0.02 and 0.01, respectively). Both MMP9 and TIMP-1 mRNAs were significantly correlated to lymphnode invasion and cancer stage. Survival analysis revealed that high levels of expression of MMP9 mRNA, but not of TIMP-1, were significantly associated to an unfavourable outcome in NSCLC patients in toto (P = 0.017). In addition our results showed that high levels of MMP9 expression are of independent prognostic impact in operable NSCLC. Our data seem to demonstrate a simultaneous and coordinated up-regulation of MMP9 and TIMP-1 expression at the mRNA level in NSCLC, even if this phenomenon seems variable according to the histotype. In addition, the increase of MMP9/TIMP-1 ratio may reflect an unbalance of their production in affected tissues. The increased expression of the two mRNAs, even not necessarily equate their enzymatic activities, seems to parallel a major cancer aggressiveness.

Pulmonary resection for inflammatory complications due to benign oesophageal disease.

Benign oesophageal disease is sometimes causes an irreversible damage to the pulmonary parenchyma. The earliest symptoms often occur when the respiratory tract is involved. Primary oesophageal disease can only be detected by taking an accurate and precise medical history of the patient, so that oesophageal contrast radiography can provide the correct diagnosis. In this article we present two cases in which it was necessary to carry out a diverticulectomy with pulmonary resection, left lower lobectomy and left pneumonectomy. Reports from the literature agree that diverticular disease of the oesophagus, if misdiagnosed, can have serious consequences for the pulmonary parenchyma, even if this is rare. In both cases we present the contrast radiographic study of the oesophagus together with a double endoscopic examination of the airways and upper digestive tract which played a crucial role in the diagnosis. We can therefore conclude that respiratory symptoms in an otherwise healthy patient may constitute the basis for the diagnosis of a benign oesophageal lesion.

Primary pulmonary meningioma: report of a case and review of the literature.

Primary pulmonary meningiomas are rare and their occurrence has been reported only sporadically. The diagnosis of such tumors should be accepted only after the presence of an intracranial or intraspinal meningioma has been excluded. The morphological and immunohistochemical features are similar to those of intracranial meningiomas. A case of primary pulmonary meningioma along with a review of the literature and discussion of other lesions in the differential diagnosis of this rare neoplasm are here presented.