Is 18F-fluorodeoxyglucose positron emission tomography/computed tomography useful to discriminate metachronous lung cancer from metastasis in patients with oncological history?

BACKGROUND: Solitary pulmonary nodules detected during follow-up in patients with previous cancer history have a high probability of malignancy being either a metachronous lung cancer or a metastasis. This distinction represents a crucial issue in the perspective of "personalized medicine," implying different treatments and prognosis. Aim, to evaluate the role of 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) in distinguishing whether solitary pulmonary nodules are metachronous cancers or metastases and the relationship between the nodule's characteristics and their nature. METHODS: From a single-institution database, we retrospectively selected all patients with a previous cancer history who performed 18F-FDG PET/CT to evaluate pulmonary nodules detected during follow-up, ranging from 5 mm to 40 mm, and histologically diagnosed as malignant. RESULTS: Between September 2009 and August 2017, 127 patients (80 males; mean age=70.2±8.5years) with 127 malignant nodules were included: 103/127 (81%) metachronous cancers, 24/127 (19%) metastases. In both groups, PET/CT provided good and equivalent detection rate of malignancy (81% vs. 83%). No differences between metachronous cancers and metastases were found in: patient's age (70.3±8.1 years vs. 69.5±9.7years), gender (males=63.1% vs. 62.5%), interval between previous cancer diagnosis and nodules' detection (median time=4years vs. 4.5years), location (right-lung=55% vs. 54%; upper-lobes=64% vs. 67%; central-site=31% vs. 25%), size (median size=17mm vs. 19.5mm), 18F-FDG standardized uptake value (median SUVmax=5.2 vs. 5.9). CONCLUSIONS: In oncological patients, despite its high detection rate, 18F-FDG PET/CT, as well as any other clinico-anatomical features, cannot distinguish whether a malignant solitary pulmonary nodule is a metachronous lung cancer or a metastasis, supporting the need of histological differential diagnosis.

Hybrid treatment of T3 chest wall lung cancer lobectomy.

Nowadays the treatment of patients with non-small cell lung cancer (NSCLC) that invades the chest wall is still questioned. The classic approach is a lobectomy that requires chest wall resection through thoracotomy, but thanks to the progress in the field of thoracoscopic surgery, this procedure can be performed by video-assisted thoracoscopic surgery (VATS). Major advances have been made in recent years both in the surgical technique associated with thoracoscopy and in the instrumentation available today. This has allowed the use of thoracoscopic technique even in advanced disease. To choose to perform complex surgery in assisted video surgery, considerable experience is needed to avoid making mistakes and giving up a better approach for the patient only for any technical difficulties. Thoracoscopy is not currently the preferred intervention for patients with chest wall invasion because there are insufficient studies on the feasibility of lobectomy with thoracoscopic wall resection, although the thoracoscopic approach has reduced mortality and morbidity in lung cancer cases not in advanced stage. We discuss our experience in three patients using hybrid approach with assisted video thoracoscopic lobectomy and a chest wall en-block resection with an alternative method of estimating thoracic wall resection that uses assisted video surgery and hypodermic needles (minimally invasive posterior approach).

ß2-Agonist clenbuterol hinders human monocyte differentiation into dendritic cells.

Clenbuterol (CLB) is a beta2-adrenergic agonist commonly used in asthma therapy, but is also a non-steroidal anabolic drug often abused in sport doping practices. Here we evaluated the in vitro impact of CLB on the physiology and function of human monocytes and dendritic cells (DCs), instrumental in the development of immune responses. We demonstrate that CLB inhibits the differentiation of monocytes into DCs and this effect is specific and dependent on ß2-adrenergic receptor (AR) activation. We found that CLB treatment reduced the percentage of CD1a(+) immature DCs, while increasing the frequency of monocytes retaining CD14 surface expression. Moreover, CLB inhibited tumor necrosis factor-alpha (TNF-alpha) enhanced IL-(interleukin)-10 and IL-6 production. In contrast, CLB did not modulate the phenotypic and functional properties of monocytes and DCs, such as the surface expression of HLA-DR, CD83, CD80 and CD86 molecules, cytokine production, immunostimulatory activity and phagocytic activity. Moreover, we found that CLB did not modulate the activation of NF-kB in DCs. Moreover, we found that the differentiation of monocytes into DCs was associated with a significant decrease of ß2-ARs mRNA expression. These results provide new insights on the effect of CLB on monocyte differentiation into DCs. Considering the frequent illegal use of CLB in doping, our work suggests that this drug is potentially harmful to immune responses decreasing the supply of DCs, thus subverting immune surveillance.

Iron excretion in iron dextran-overloaded mice.

BACKGROUND: Iron homeostasis in humans is tightly regulated by mechanisms aimed to conserve iron for reutilisation, with a negligible role played by excretory mechanisms. In a previous study we found that mice have an astonishing ability to tolerate very high doses of parenterally administered iron dextran. Whether this ability is linked to the existence of an excretory pathway remains to be ascertained. MATERIALS AND METHODS: Iron overload was generated by intraperitoneal injections of iron dextran (1 g/kg) administered once a week for 8 weeks in two different mouse strains (C57bl/6 and B6D2F1). Urinary and faecal iron excretion was assessed by inductively coupling plasma-mass spectrometry, whereas cardiac and liver architecture was evaluated by echocardiography and histological methods. For both strains, 24-hour faeces and urine samples were collected and iron concentration was determined on days 0, 1 and 2 after iron administration. RESULTS: In iron-overloaded C57bl/6 mice, the faecal iron concentration increased by 218% and 157% on days 1 and 2, respectively (p<0.01). The iron excreted represented a loss of 14% of total iron administered. Similar but smaller changes was also found in B6D2F1 mice. Conversely, we found no significant changes in the concentration of iron in the urine in either of the strains of mice. In both strains, histological examination showed accumulation of iron in the liver and heart which tended to decrease over time. CONCLUSIONS: This study indicates that mice have a mechanism for removal of excess body iron and provides insights into the possible mechanisms of excretion.

ß-Blockers promote angiogenesis in the mouse aortic ring assay.

Recent results indicate that the reduction of ß-adrenergic signaling impairs angiogenesis under ischemic conditions. Because angiogenesis may occur in the absence of ischemia, it remains to be determined whether and how ß-adrenergic signaling regulates angiogenesis, which develops under normoxic conditions. The effect of ß-adrenergic ligands on angiogenesis was investigated using 3-dimensional cultures of mouse aortic rings embedded in collagen type I, in which luminized microvessels develop in response to vascular endothelial growth factor (VEGF). Under normoxic conditions, both isoproterenol, a ß-adrenergic receptor (ß-AR) agonist, and forskolin, an adenylate cyclase activator, were unable to influence aortic microvessel sprouting. On the contrary, treatment with propranolol, a ß-AR antagonist, caused an approximately 70% increase in VEGF-mediated microvessel sprouting. This effect was abolished in rings from both double ß-AR and ß1-AR knockout mice, but not in rings from ß2-AR knockout mice. Significant increases in microvessel sprouting were also observed when mouse aortic rings from C57BL/6 mice were treated with the ß1-AR-selective antagonists metoprolol and bisoprolol or with the ß2-AR-selective antagonist ICI 118,551. Conversely, carvedilol, a nonselective ß-AR antagonist, was unable to affect aortic sprouting. These findings suggest that some ß-blockers display proangiogenic activity through a mechanism that is independent of their ability to antagonize catecholamine action. The present results also identify a new function for ß-AR signaling as a facilitator for VEGF-mediated angiogenesis and have implications for understanding the mechanisms that regulate angiogenic responses under normoxic conditions.

The C57BL/6 genetic background confers cardioprotection in iron-overloaded mice.

BACKGROUND: Chronic transfusion therapy causes a progressive iron overload that damages many organs including the heart. Recent evidence suggests that L-type calcium channels play an important role in iron uptake by cardiomyocytes under conditions of iron overload. Given that beta-adrenergic stimulation significantly enhances L-type calcium current, we hypothesised that beta-adrenergic blocking drugs could reduce the deleterious effects of iron overload on the heart. METHODS: Iron overload was generated by intraperitoneal injections of iron dextran (1g/kg) administered once a week for 8 weeks in male C57bl/6 mice, while propranolol was administered in drinking water at the dose of 40 mg/kg/day. Cardiac function and ventricular remodelling were evaluated by echocardiography and histological methods. RESULTS: As compared to placebo, iron injection caused cardiac iron deposition. Surprisingly, despite iron overload, myocardial function and ventricular geometry in the iron-treated mice resulted unchanged as compared to those in the placebo-treated mice. Administration of propranolol increased cardiac performance in iron-overloaded mice. Specifically, as compared to the values in the iron-overloaded group, in iron-overloaded animals treated with propranolol left ventricular fractional shortening increased (from 31.6% to 44.2%, P =0.01) whereas left ventricular end-diastolic diameter decreased (from 4.1 ± 0.1 mm to 3.5 ± 0.1 mm, P =0.03). Propranolol did not alter cardiac systolic function or left ventricular sizes in the placebo group. CONCLUSIONS: These results demonstrate that C57bl/6 mice are resistant to iron overload-induced myocardial injury and that treatment with propranolol is able to increase cardiac performance in iron-overloaded mice. However, since C57bl/6 mice were resistant to iron-induced injury, it remains to be evaluated further whether propranolol could prevent iron-overload cardiomyopathy.

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.

Signaling pathway-focused gene expression profiling in pressure overloaded hearts.

The ß-blocker propranolol displays antihypertrophic and antifibrotic properties in the heart subjected to pressure overload. Yet the underlying mechanisms responsible for these important effects remain to be completely understood. The purpose of this study was to determine signaling pathway-focused gene expression profile associated with the antihypertrophic action of propranolol in pressure overloaded hearts. To address this question, a focused real-time PCR array was used to screen left ventricular RNA expression of 84 gene transcripts representative of 18 different signaling pathways in C57BL/6 mice subjected to transverse aortic constriction (TAC) or sham surgery. On the surgery day, mice received either propranolol (80 mg/kg/day) or vehicle for 14 days. TAC caused a 49% increase in the left ventricular weight-to-body weight (LVW/BW) ratio without changing gene expression. Propranolol blunted LVW/BW ratio increase by approximately 50% while causing about a 3-fold increase in the expression of two genes, namely Brca1 and Cdkn2a, belonging to the TGF-beta and estrogen pathways, respectively. In conclusion, after 2 weeks of pressure overload, TAC hearts show a gene expression profile superimposable to that of sham hearts. Conversely, propranolol treatment is associated with an increased expression of genes which negatively regulate cell cycle progression. It remains to be established whether a mechanistic link between gene expression changes and the antihypertrophic action of propranolol occurs.

Primary neuroendocrine tumours of the thymus: a clinicopathologic and prognostic study in 19 patients.

BACKGROUND: We sought to evaluate factors influencing long-term survival in 19 patients with primary neuroendocrine tumours of the thymus. METHODS: From January 1990 to December 2004, 19 patients (14 males, 5 females; mean age 48.6 years) were surgically treated for a primary neuroendocrine tumour of the thymus. RESULTS: All patients underwent radical R0 thymomectomy and were followed up for a total of 1,459 months (median: 69 months; range: 8-180). Nine patients had associated paraneoplastic syndrome. No operative mortality occurred. Two patients underwent re-do surgery because of local recurrence, respectively, 25 and 35 months after surgery. Five patients died of disease, respectively, 51, 70, 95, 131 and 153 months after surgery. One patient died of myocardial infarction with no evidence of disease. Thirteen patients are alive, of which 10 are free from disease and three with disease. The overall 5-year and 10-year actuarial survival rates were 91.6% and 69.8%, respectively (median survival: 153 months). The 10-year survival was evaluated according to histology (typical carcinoid 100%; atypical carcinoid: 66.6%; large cell neuroendocrine tumours: 0%), Masaoka staging (stage I: 100%; stage II: 50%; stage III: 66.6%; stage IV: 0%), presence of paraneoplastic syndrome (no: 87.5%; yes: 0%) and postoperative radiotherapy (yes: 40%; no: 83.3%). CONCLUSIONS: The prognosis of primary neuroendocrine tumours of the thymus is related to the grading of the neoplasm, the presence of a paraneoplastic syndrome and to the Masaoka staging but not to the postoperative radiotherapy.

Predictors of survival in patients with locally advanced thymoma and thymic carcinoma (Masaoka stages III and IVa).

OBJECTIVE: We sought to evaluate factors influencing long-term survival of patients with locally advanced thymoma/thymic carcinoma (Masaoka stages III and IVa) treated by immediate surgery or induction therapy plus surgery. METHODS: From January 1991 to April 2007, we surgically treated 61 patients with locally advanced thymoma/thymic carcinoma (Masaoka stages III and IVa). Staging included total body computed tomography (CT) scan in all patients, and chest magnetic resonance imaging (MRI) in 27 selected patients. All patients had histological confirmation before surgery. Thirty-one patients (group A) underwent induction chemotherapy followed by surgery. Thirty patients (group B) underwent immediate surgery. Thirty-four patients (group A: 13; group B: 17) received postoperative radiation therapy. RESULTS: No intra-operative mortality was reported. World Health Organization (WHO) histological classification included 19 AB, four B1, seven B2 and 13 B3 thymomas and 18 thymic carcinomas. Thirty-four patients were Masaoka stage III (group A: 18; group B: 16) and 27 patients were stage IVa (group A: 13; group B: 14). After a median follow-up of 77 months, six patients of group A and seven patients of group B died of disease. The overall 10-year survival rate was 50.6%. The 10-year survival rate was 57.9% in group A and 38.1% in group B (p=0.03). Multivariate analysis showed complete resection (p=0.02), Masaoka stage (III vs IVa) (p=0.02), induction chemotherapy (group A vs group B) (p=0.003) and histological WHO subtype (AB vs B1, B2 and B3) (p=0.01) to be statistically significant independent predictors of survival. Sex, age and adjuvant radiation therapy showed no statistically significant difference. CONCLUSIONS: Complete resection, Masaoka stage, induction chemotherapy and histological WHO classification showed to be independent predictors of survival in locally advanced thymoma/thymic carcinoma.

Tumor type M2-pyruvate-kinase levels in pleural fluid versus plasma in cancer patients: a further tool to define the need for invasive procedures.

OBJECTIVE: Pleural effusion is a common diagnostic problem and a challenge to the thoracic surgeon. The analysis of serum and body fluids for tumor markers is an established diagnostic procedure. Among various markers, tumors are linked to the overexpression of a glycolytic isoenzyme, M2-pyruvate-kinase (M2-PK). This preliminary study evaluated this enzyme as a tumor marker to differentiate malignant from benign pleural effusion. METHODS: The tumor M2-PK concentration was measured in the EDTA-plasma and pleural fluid of 34 patients with an established diagnosis of cancer, either primary of the chest (18) or secondary to chest (16) and in 34 controls with benign effusion. The concentration was quantitatively determined by an enzyme-linked immunosorbent assay. The cut-off level between negative and positive values of the tumor M2-PK was defined as the benign group's mean+2SD (95% percentile). True-positives, false-positives, true-negatives, and false-negatives, were determined with 'positive' referring to histologically proven malignant effusion and 'negative' referred to as nonmalignant effusions. Sensitivity, specificity, positive predictive value, and negative predictive value were assessed. RESULTS: The cut-off value was established at 7.61 U/ml for plasma and 32.9 U/ml for pleural fluid. Both plasma and pleural fluid levels of tumor M2-PK were significantly higher in patients with known chest malignancy, either primary or metastatic, compared to nonmalignant effusions (p<0.001). Sensitivity in pleural fluid was significantly higher compared to plasma (85.7% vs 76.2%; p<0.01). Moreover, negative predictive value was higher for pleural fluid compared to plasma (79.4% vs 70.8; p<0.01) CONCLUSIONS: Tumor M2-PK marker is useful in differentiating malignant from benign pleural effusions. Moreover, its sensitivity and NPV in pleural fluid are significantly higher compared to plasma. The usefulness of such a test is not strictly diagnostic but aims at excluding poorly performing patients from further invasive procedures. Thus, the inclusion of M2-PK within a panel of well-known tumor markers such as CEA, MCA, Ca 125 and Ca 19-9, may help in increasing the overall sensitivity and specificity.