KRAS G12C mutation and risk of disease recurrence in stage I surgically resected lung adenocarcinoma.

KRAS G12C mutations are found in about 12-13% of LUAD samples and it is unclear whether they are associated with worse survival outcomes in resected, stage I LUAD. We assessed whether KRAS-G12C mutated tumours had worse DFS when compared to KRAS-nonG12C mutated tumours and to KRAS wild-type tumours in a cohort of resected, stage I LUAD (IRE cohort). We then leveraged on publicly available datasets (TCGA-LUAD, MSK-LUAD604) to further test the hypothesis in external cohorts. In the stage I IRE cohort we found a significant association between the KRAS-G12C mutation and worse DFS in multivariable analysis (HR: 2.47). In the TCGA-LUAD stage I cohort we did not find statistically significant associations between the KRAS-G12C mutation and DFS. In the MSK-LUAD604 stage I cohort we found that KRAS-G12C mutated tumours had worse RFS when compared to KRAS-nonG12C mutated tumours in univariable analysis (HR 3.5). In the pooled stage I cohort we found that KRAS-G12C mutated tumours had worse DFS when compared to KRAS-nonG12C mutated tumours (HR 2.6), to KRAS wild-type tumours (HR 1.6) and to any other tumours (HR 1.8); in multivariable analysis, the KRAS-G12C mutation was associated with worse DFS (HR 1.61). Our results suggest that patients with resected, stage I LUAD with a KRAS-G12C mutation may have inferior survival outcomes..

Fatty thymic involution uptake mimicking a thymic epithelial tumour in a 18F-FDG PET/CT study / Captura de involución tímica grasa imitando un tumor epitelial tímico en un estudio 18F-FDG PET/TC

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The Third Italian Consensus Conference for Malignant Pleural Mesothelioma: State of the art and recommendations.

Malignant Pleural Mesothelioma (MPM) remains a relevant public health issue, and asbestos exposure is the most relevant risk factor. The incidence has considerably and constantly increased over the past two decades in the industrialized countries and is expected to peak in 2020-2025. In Italy, a standardized-rate incidence in 2011 among men was 3.5 and 1.25 per 100,000 in men and women, respectively, and wide differences are noted among different geographic areas. The disease remains challenging in terms of diagnosis, staging and treatment and an optimal strategy has not yet been clearly defined. The Third Italian Multidisciplinary Consensus Conference on Malignant Pleural Mesothelioma was held in Bari (Italy) in January 30-31, 2015. This Consensus has provided updated recommendations on the MPM management for health institutions, clinicians and patients.

Synchronous triple thymoma and true thymic hyperplasia simultaneously detected by 18F FDG PET-CT / Timoma triple sincrónico e hiperplasia tímica verdadera detectada mediante PET/TAC con 18F-FDG

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Protumorigenic effects of mir-145 loss in malignant pleural mesothelioma.

We identified a discrete number of microRNAs differentially expressed in benign or malignant mesothelial tissues. We focused on mir-145 whose levels were significantly downregulated in malignant mesothelial tissues and malignant pleural mesothelioma (MPM) cell lines as compared to benign tissues (pleura, peritoneum or cysts). We show that promoter hyper-methylation caused very low levels in MPM cell lines and specimens. Treatment of MPM cell lines with mir-145 agonists negatively modulated some protumorigenic properties of MPM cells, such as clonogenicity, cell migration and resistance to pemetrexed treatment. The main effector mechanism of the clonogenic death induced by mir-145 was that of accelerated senescence. We found that mir-145 targeted OCT4 via specific binding to its 3'-UTR. Increased intracellular levels of mir-145 decreased the levels of OCT4 and its target gene ZEB1, thereby counteracting the increase of OCT4 induced by pemetrexed treatment which is known to favor the development of chemoresistant cells. In line with this, reintroduction of OCT4 into mimic-145 treated cells counteracted the effects on clonogenicity and replicative senescence. This further supports the relevance of the mir-145-OCT4 interaction for the survival of MPM cells. The potential use of mir-145 expression levels to classify benign vs malignant mesothelial tissues and the differences between pemetrexed-induced senescence and that induced by the re-expression of mir-145 are discussed.

Efficacy and safety of fibrin sealant patch in the treatment of air leakage in thoracic surgery.

AIM: Air leakage represents a major problem in lung surgery. Absorbable fibrin sealant patch (AFSP), a collagen sponge coated with human fibrinogen and thrombin, can be used as an adjunct to primary stapling or suturing. This study compared the efficacy of AFSP with manual suturing after primary stapling. METHODS: This was a prospective, multicenter, randomized study. Patients undergoing lobectomy, bilobectomy, anatomical segmentectomy for lung cancer or wedge resection for pulmonary metastasis with air leakage grade 1 or 2 according to Macchiarini scale after stapler suture were randomized to receive AFSP or standard surgical treatment (ST). The primary endpoint was the reduction of intraoperative air leakage intensity. Duration of postoperative air leakage and number of days until removal of last chest drain were secondary endpoints. Safety was recorded for all patients. RESULTS: A total of 346 patients were enrolled in 14 centres, 179 of whom received AFSP and 167 ST. Intraoperative air leak intensity was reduced in 90.5% of AFSP patients and 82% of ST patients (P=0.03). A significant reduction in postoperative air leakage duration was observed in the AFSP group (P=0.0437). The median number of days until removal of last drainage was 6 (3-37) in the AFSP group and 7 (2-27) in the ST (P=0.38). Occurrence of adverse events was comparable in both groups. CONCLUSION: AFSP was more efficacious than standard ST as an adjunct to primary stapling in reducing intraoperative air leakage intensity and duration of postoperative air leakage in patients undergoing pulmonary surgery. AFSP was well tolerated.

SASP mediates chemoresistance and tumor-initiating-activity of mesothelioma cells.

Here we show that pemetrexed-treated mesothelioma cells undergo accelerated senescence. This is characterized by the secretion of proinflammatory and mitogenic cytokines, reminiscent of an SASP (senescence-associated secretory phenotype). Conditioned media from senescent MPM (malignant pleural mesothelioma) cells trigger the emergence of EMT (epithelial-to-mesenchymal)-like, clonogenic and chemoresistant cell subpopulations, expressing high levels of ALDH (aldehyde dehydrogenase) activity (ALDH(bright) cells). We show by fluorescence-activated cell sorting of purified ALDH(bright) and ALDH(low) cells, that both cell-autonomous and cell-non-autonomous mechanisms converge to maintain the SASP-induced, EMT-like cell subpopulations. Chemoresistant ALDH(bright) cells exist within primary MPM specimens and enrichment for ALDH(bright) cells correlates with an earlier tumor onset into NOD/SCID mice. We show that RAS(v12) expression induces SASP-like changes in untransformed human mesothelial cells, and that p53 ablation increases the effect of RAS(v12) expression. We identify STAT3 activation as a crucial event downstream to SASP signaling. In fact, small hairpin RNA-mediated ablation of STAT3 deeply attenuates the induction of EMT genes and the increase of ALDH(bright) cells induced by SASP-cytokines. This strongly affects the chemoresistance of MPM cells in vitro and leads to anticancer effects in vivo.

Nuclear and cytoplasmic cellular distribution of survivin as survival predictor in resected non-small-cell lung cancer.

AIM: Survivin is a member of the inhibitors of apoptosis (IAP) gene family that acts through pathways different from those involving the bcl-2 family. Largely undetectable in normal adult tissues, survivin is deregulated in most human cancers including non-small-cell lung cancer (NSCLC) and may represent a tumor marker with prognostic and therapeutic implications. Aim of our study was to determine the prognostic role of survivin as an apoptosis-related biomarker in a series of resected NSCLC patients. METHODS: A retrospective series of resected NSCLC patients were retrieved from the files of the Regina Elena National Cancer Institute. Survivin was detected by immunohistochemistry (IHC) using a polyclonal antibody. Survivin displayed two kinds of immunoreactivity: (i) a diffuse cytoplasmic staining and (ii) a distinct nuclear staining. A score-scale to distinguish positive (score 1-2) vs. negative (score 0) pattern was applied. Clinical and biological (nuclear and cytoplasmic survivin staining) covariables were screened for a prognostic relationship with overall survival (OS) and disease-free survival (DFS) into the univariate and multivariate analyses. RESULTS: Data referring to 116 NSCLC patients who underwent surgery for stage I-IIIA NSCLC were collected. Multivariate analyses identified tumor size, nodal status and nuclear, but not cytoplasmic, expression of survivin as significant independent predictors of OS, with a hazard ratio of 2.40 (95% CI 1.44, 3.99, p=0.001), 2.03 (95% CI 1.26, 3.26, p=0.003) and 1.83 (95% CI 1.01, 3.30, p=0.044), respectively. Median OS for nuclear survivin positive (score 1-2) and negative (score 0) patients were 23 months (95% CI 15, 31) and 36 months (95% CI 1, 76), respectively (p=0.01); five-year survival for score 1-2 and score 0 patients were 20% and 44.5%, respectively. Conversely, no significant impact on survival is found when patients are stratified according to cytoplasmic survivin expression. CONCLUSIONS: Data presented herein open the issue that prognosis of stage I-IIIA NSCLC can be linked to the cellular pattern of distribution of survivin.

Expression of autoimmune regulator gene (AIRE) and T regulatory cells in human thymomas.

Expression of the autoimmune regulator gene (AIRE) and the presence of CD25(+)/forkhead box p3 (FoxP3)(+) T regulatory (T(reg)) cells were investigated in histologically normal adult thymi and in thymomas using immunohistochemistry and quantitative real-time polymerase chain reaction (PCR). In the normal thymus staining for AIRE was detected in the nucleus of some epithelial-like cells located in the medulla; in thymomas AIRE-positive cells were extremely rare and could be detected only in the areas of medullary differentiation of two B1 type, organoid thymomas. RNA was extracted from 36 cases of thymoma and 21 non-neoplastic thymi obtained from 11 myasthenic (MG(+)) and 10 non-myasthenic (MG(-)) patients. It was found that AIRE is 8.5-fold more expressed in non-neoplastic thymi than in thymomas (P = 0.01), and that the amount of AIRE transcripts present in the thymoma tissue are not influenced by the association with MG, nor by the histological type. A possible involvement of AIRE in the development of MG was suggested by the observation that medullary thymic epithelial cells isolated from AIRE-deficient mice contain low levels of RNA transcripts for CHRNA 1, a gene coding for acetylcholine receptor. Expression of human CHRNA 1 RNA was investigated in 34 human thymomas obtained from 20 MG(-) patients and 14 MG(+) patients. No significant difference was found in the two groups (thymoma MG(+), CHRNA1 = 0.013 +/- 0.03; thymoma MG-, CHRNA1 = 0.01 +/- 0.03). In normal and hyperplastic thymi CD25(+)/Foxp3(+) cells were located mainly in the medulla, and their number was not influenced by the presence of MG. Foxp3(+) and CD25(+) cells were significantly less numerous in thymomas. A quantitative estimate of T(reg) cells revealed that the levels of Foxp3 RNA detected in non-neoplastic thymi were significantly higher (P = 0.02) than those observed in 31 cases of thymomas. Our findings indicate that the tissue microenvironment of thymomas is defective in the expression of relevant functions that exert a crucial role in the negative selection of autoreactive lymphocytes.

Tracheotomy-related posterior tracheal wall rupture, trans-tracheal repair.

Laceration of the membranous part of the tracheo-bronchial tree is a rare complication that can occur after single lumen intubation, double-lumen intubation, percutaneous and surgical tracheotomy. The case of a 76-year-old male is presented in whom a posterior tracheal wall laceration, related to tracheotomy, was diagnosed and immediately treated at the end of a head and neck operation. A 6 cm long laceration started 1.5 cm below the tracheotomy level and ended 2 cm above the carina. The tear was closed from distal to proximal area via the tracheotomy opening with PDS 4/0 interrupted sutures using a thoracoscopic needle-holder. This original surgical technique is described in detail. In tracheotomy related tears, the fact that an opening in the trachea already exists and that the lesion rarely extends beyond the carina, should guide the surgeon to make every effort to repair the laceration through this already existing access.

Correlation between tumor necrosis factor-alpha and D-dimer levels in non-small cell lung cancer patients.

The present study was designed to investigate whether a correlation exists between IL-6, TNF-alpha and coagulation (Thrombin-antithrombin, TATc) or fibrinolysis (D-dimer) activation in non-small cell lung cancer (NSCLC) patients. One hundred thirty patients with NSCLC (n=65, 53 males, mean age 65 +/- 8, adenocarcinoma n=32, squamous cancer n=33) or chronic obstructive pulmonary disease (COPD) (n=65, 51 males, mean age 67 +/- 9) were studied. As control group 65 healthy donors (51 males, mean age 61 +/- 14) were also evaluated. The results obtained showed that median D-dimer levels were higher in NSCLC patients (3.0 microg/ml) compared either to COPD patients (1.1 microg/ml, P<0.05) or controls (0.3 microg/ml, P<0.0001). Positive TNF-alpha levels (>10 pg/ml) were found in 26% of NSCLC compared to 3% of COPD (P<0.002) and 5% of controls (P<0.0005). On the other hand, positive (>8.5 pg/ml) IL-6 levels were found in 53% of NSCLC and 21% of COPD patients, compared to 5% of control subjects (P<0.001). Median TATc levels were elevated in either NSCLC (6.9 microg/l) or COPD (5.7 microg/l) patients compared to controls (1.8 microg/l, P<0.0001). Elevated D-dimer levels were significantly associated to positive TNF-alpha levels in patients without distant metastasis (F=4.3, P<0.05). Moreover, TNF-alpha levels (P<0.01) were independently related to the presence of positive D-dimer levels in patients with non-metastatic NSCLC. These results suggest that increased levels of TNF-alpha might be responsible for an activation of fibrinolysis in patients with NSCLC.

The combination of carboplatin and weekly paclitaxel: a safe and active regimen in advanced non small-cell lung cancer patients. A phase I-II study.

The combination of carboplatin and paclitaxel given every three weeks is a tolerated and reasonably active regimen in advanced non-small cell lung cancer (NSCLC). This study was designed to evaluate the maximum tolerated dose (MTD) of a fixed dose of carboplatin with an area under the curve (AUC) of 6 and escalating doses of weekly paclitaxel with an initial dose of 50 mg/m2 with 10 mg/m2 increments at each level in untreated NSCLC patients (phase I study). The study continued with a phase II study. Thirty patients entered the phase I study. The MTD was: carboplatin AUC = 6 on days 1 and 28 plus paclitaxel 100 mg/m2 (1 hour) on days 1, 8,15, 28. The dose-limiting toxicity (DLT) was severe neutropenia and cardiological toxicity. Subsequently, 42 patients entered the phase II study with the same treatment schedule. The 2-drug combination was globally well tolerated. The overall response rate (RR) was 42% [CI 95%: 26.3-57.7], stable disease (SD) 29% and progression (PD) 29%. The median duration of response was 8.0 mos (range: 1.0-19.0). The median time to progression was 8.0 mos (range: 7.0-19.0) and the median survival was 14.0 months (range: 9.0-19.0). The association of carboplatin AUC = 6 and weekly paclitaxel 100 mg/m2 proved to be manageable, active and extremely safe even in elderly patients (one third of all patients in our cohort). The survival results were interesting: the median survival time was 14 months (9-19 months) and the 1- and 2-year survival was 59% and 16%, respectively.

Long-term follow-up of video-assisted talc pleurodesis in malignant recurrent pleural effusions.

OBJECTIVE: Recurrent pleural effusion is a common condition and often presents a challenge for treatment. The aim of this report is to evaluate the long-term follow-up of thoracoscopic management of malignant recurrent pleural effusions. METHODS: From July 1st, 1992 to February 28th, 2001, out of 2311 VATS procedures performed at our Institution, 690 patients (29.85%) underwent videothoracoscopy (VATS) for recurrent pleural effusion. Of these 611 (88.55%) were treated for a malignant pleural effusion. There were 374 male and 237 female, with a mean age of 61.2 years. In all patients VATS was performed under general anaesthesia. The pleural effusion was carefully aspirated; fibrinous adhesions were taken down while dense fibrous adhesions were selectively divided; some limited decortications were also performed. Multiple pleural biopsies were always performed. Pleurodesis was performed with 5 g of sterile purified talc insufflated through a talc atomizer. One chest tube was left in situ for 3-5 days. RESULTS: Operative mortality was 0.81% (five cases). Postoperative complications occurred in 19 cases (3.1%). Specific histologic diagnosis was obtained in all patients. Follow-up was available for 602 patients (98.5%). After a median follow-up of 64 months (range 5-105 months), talc pleurodesis was successful in controlling recurrence of effusion in 92.7% (558 out of 602) of patients. The success rate did not show any statistically significant difference between patients who underwent postoperative adjuvant therapy and patients who did not. In two patients with failure of talc pleurodesis a redo-VATS was performed. CONCLUSIONS: VATS represents the method of choice for both diagnosis and treatment of malignant recurrent pleural effusions. Talc poudrage is safe and effective in obtaining pleurodesis.

Recurrences following videothoracoscopic treatment of primary spontaneous pneumothorax: the role of redo-videothoracoscopy.

OBJECTIVE: There is very little experience regarding recurrences following videothoracoscopic (VATS) treatment of primary spontaneous pneumothorax. We report our experience with 19 patients who underwent redo-VATS to evaluate the feasibility of such surgical approach. METHODS: From July 1, 1992 to September 1, 2000, out of 2136 VATS procedures performed at our institution, 597 patients (27.94%) underwent VATS treatment of primary spontaneous pneumothorax with a recurrence rate of 3.85% (23 cases). Primary VATS treatment in these patients was: talc poudrage, three cases; subtotal pleurectomy, three cases; ligation of the bullae + subtotal pleurectomy, 12 cases; stapling of the bullae + subtotal pleurectomy, two cases; ligation of the bullae + talc poudrage, one case; stapling of the bullae + talc poudrage, one case. Treatment of the 23 recurrences included: 15 redo-VATS, four standard thoracotomy, three pleural drainage, one bed rest. Four additional redo-VATS were also performed in four patients operated on in different institutions. Redo-VATS showed residual bullae in nine cases and a minimal leaking area in one patient; in the remaining nine patients no lesion was found. Redo-VATS treatment was: stapling of the bullae + talc poudrage in nine patients; suture of the leaking area with a no-knife stapler + talc poudrage in one patient; isolated talc poudrage in the remaining nine patients with no-evidence of bullae or blebs. RESULTS: No mortality was reported; no major complications occurred. The conversion rate in the group of redo-VATS was 5.2% (one patient). At a mean follow-up of 32 months no patient showed recurrent pneumothorax. CONCLUSIONS: In the light of our initial experience, redo-VATS seems to be a promising tool for the surgical therapy of recurrences following VATS treatment of primary spontaneous pneumothorax.

Chest wall invasion in non-small cell lung carcinoma: a rationale for en bloc resection.

OBJECTIVE: The choice of surgical approach to non-small cell lung cancer invading the chest wall, extrapleural resection versus en bloc chest wall resection, is much more related to the experience of the surgeon than to objective criteria. The aim of the present study is to help to establish a rationale for en bloc chest wall resection in lung cancer invading the chest wall. METHODS: From January 1990 to June 1999, of 1855 patients having major pulmonary resections for non-small cell lung carcinoma, 104 (5.6%) patients with neoplasms involving the chest wall underwent en bloc chest wall and lung resection plus radical mediastinal lymphadenectomy. RESULTS: All patients underwent complete resection with microscopically disease-free tissue margins. Depth of invasion was into the parietal pleura only in 28 (26.92%), into the pleura and soft tissue in 36 (34.62%), and into the pleura, soft tissue, and bone in 40 (38.46%). No operative mortality was reported. Follow-up was completed in 96 patients. One patient had a local recurrence. The overall 5-year estimated survival was 61.4%. Survival in the subsets T3 N0 and T3 N2 were, respectively, 67.3% and 17.9% (P =.007). The 5-year survival was 79.1% in involvement of parietal pleura only and 54.0% in involvement of soft tissue with or without bone invasion (P =.014). Five-year survival was 53.0% in adenocarcinoma versus 71.8% in squamous cell carcinoma (P =.329) and 74.1% in patients who did undergo radiation therapy versus 46.7% in patients who did not undergo radiation therapy (P =.023). CONCLUSIONS: En bloc resection of the chest wall and lung is the procedure of choice to obtain complete resection in lung carcinoma invading the chest wall. Survival is highly dependent on the completeness of resection, nodal involvement, and depth of chest wall invasion.

Videothoracoscopic treatment of primary spontaneous pneumothorax: a 6-year experience.

BACKGROUND: Timing and surgical approach in the treatment of primary spontaneous pneumothorax (PSP) are not well defined. The objective of this study is to propose a treatment protocol by videothoracoscopy (VATS) in PSP. METHODS: From July 1992 to May 1998, 432 patients underwent VATS treatment of PSP. Indications were: recurrent ipsilateral pneumothorax: 322 cases; persistent air leak following a first episode: 93 patients; recurrence following VATS: 16 cases; recurrence following thoracotomy: 1 patient. Vanderschueren's classification was used for staging. Surgical indications were: stages I and II, subtotal pleurectomy or talc poudrage; stages III and IV, stapling or ligation of the bullae and subtotal pleurectomy or talc poudrage. Differences in recurrence rates were calculated to compare the specific procedures. RESULTS: No postoperative deaths occurred. Complication rate was 4.16%. Conversion rate was 2.3%. Mean follow-up was 38 months (2 to 72 months). Overall recurrence rate was 4.4%. Specific recurrence rates following stapling and talc poudrage were, respectively, 1.27% and 1.79%. Talc poudrage and stapling of the bullae are respectively superior to subtotal pleurectomy (p < 0.0001) and ligation (p < 0.0001). CONCLUSIONS: Stapling of the bullae and talc poudrage by VATS represent the treatment of choice of PSP.

Localized (solitary) fibrous tumors of the pleura: an analysis of 55 patients.

BACKGROUND: Localized (solitary) fibrous tumors (LFTPs) of the pleura are rare, slow-growing neoplasms thought to originate from submesothelial connective tissue. The aim of this article is to present 55 new cases of LFTP, and to discuss the treatment of choice and the clinical behavior of such neoplasms. METHODS: From July 1990 to November 1999, 55 patients (32 male, 23 female) with an LFTP were surgically treated at our Institution. Neoplasms were considered to be malignant if one or more of the following histologic features were present: high cellularity with crowding and overlapping of nuclei; high mitotic activity; or mild, moderate, or marked pleomorphism. RESULTS: No operative mortality was reported. Forty-eight of the cases arose from the visceral pleura and seven arose from the parietal pleura. A local removal of the neoplasm with free surgical margins was accomplished by video-assisted thoracic surgery in 39 patients and by standard thoracotomy in 10 patients. Four patients underwent formal lung resections, 1 had thymectomy, and 1 had en bloc chest wall resection. Four malignant variants were identified. One patient developed local recurrence and underwent redo surgery with chest wall resection. One patient died of unrelated disease. The remaining patients are alive and disease free at a median follow-up of 53.2 months. CONCLUSIONS: LFTPs show a benign outcome in most of the cases. Video-assisted thoracic surgery, with intraoperative assessment of the surgical margins, represents the treatment of choice.