Post cardiotomy extracorporeal membrane oxygenation in pediatric patients: Results and neurodevelopmental outcomes.

BACKGROUND: The increasing complexity of congenital cardiac surgery has led to greater utilization of extracorporeal membrane oxygenation (ECMO) support for children post-surgery. This study aims to identify risk factors for mortality and brain injury in pediatric patients requiring post-cardiotomy ECMO and to evaluate their neurological outcomes. METHODS: This retrospective study includes pediatric patients with congenital heart diseases who required ECMO after surgery. Risk factors for in-hospital mortality and brain injury were assessed. Neurodevelopmental status was determined using the Pediatric Cerebral Performance Category (PCPC) Scale at discharge and during follow-up. RESULTS: Between October 2014 and May 2021, 2651 pediatric patients underwent cardiac surgery, with 90 (3.4%) requiring ECMO. The mean age was 0.6 years, ranging from 1 day to 13 years and 7 months. ECMO was implemented for 45 patients due to CPB weaning failure (NW-CPB), 24 due to postoperative low-cardiac output syndrome (LCOS), and 21 for extracorporeal cardiopulmonary resuscitation (E-CPR). ECMO weaning was achieved in 73 patients (81%), with an overall mortality rate of 36%. Pre-implant lactate levels (OR: 1.13, 95% CI: 1.03-1.25; p = 0.009) and peak bilirubin levels (OR: 1.04, 95% CI: 0.87-1.24; p = 0.69) were risk factors for in-hospital mortality. Survival rates were 79% for LCOS, 60% for NW-CPB, and 48% for E-CPR. Brain injury incidence was 33%, with E-CPR being a significant risk factor (p = 0.006) and NW-CPB being protective (p = 0.001). Follow-up in November 2023 showed significant improvement in neurodevelopmental status (p < 0.001). CONCLUSION: Elevated pre-implant lactate and elevated bilirubin levels during ECMO are major risk factors for mortality. E-CPR is the primary risk factor for brain injury. Follow-up revealed significant improvements in neurodevelopmental outcomes.

Sclerosing Pneumocytoma: A Host for a Typical Carcinoid With Pleural Metastasis-A Wolf in Sheep`s Clothing.

Sclerosing pneumocytoma (SP) is a rare primary lung tumor. Typical carcinoids (TCs) count for 2% of lung malignancies. A description of a combined neoplasm of SP with a nodal and pleural metastasized TC has, to our knowledge, never been published. A 57-year-old actively smoking woman received a diagnosis of a lesion in the left lower lobe via a screening CT scan for rheumatoid arthritis. A fluorodeoxyglucose-PET scan confirmed a 21 × 26 × 16 mm (standardized uptake maximum value, 3.0), well-circumscribed round lesion with calcification, which was thought to be most probably benign. No mediastinal lymph node enlargement or fluorodeoxyglucose uptake was detected. The results of routine laboratory tests, respiratory function tests, and physical examination were unremarkable. In diagnostic thoracoscopy pleural, diaphragmatic, and pericardial lesions were discovered and biopsied in addition to a wedge resection. After diagnosis of a pleural metastasized TC mixed with SP, radical resection and systemic lymph node dissection were performed. The patient is in remission after 36 months of follow-up.

Exploring mobility in Italian Neolithic and Copper Age communities.

As a means for investigating human mobility during late the Neolithic to the Copper Age in central and southern Italy, this study presents a novel dataset of enamel oxygen and carbon isotope values (δ18Oca and δ13Cca) from the carbonate fraction of biogenic apatite for one hundred and twenty-six individual teeth coming from two Neolithic and eight Copper Age communities. The measured δ18Oca values suggest a significant role of local sources in the water inputs to the body water, whereas δ13Cca values indicate food resources, principally based on C3 plants. Both δ13Cca and δ18Oca ranges vary substantially when samples are broken down into local populations. Statistically defined thresholds, accounting for intra-site variability, allow the identification of only a few outliers in the eight Copper Age communities, suggesting that sedentary lifestyle rather than extensive mobility characterized the investigated populations. This seems to be also typical of the two studied Neolithic communities. Overall, this research shows that the investigated periods in peninsular Italy differed in mobility pattern from the following Bronze Age communities from more northern areas.

Anti-Factor Xa-Based Anticoagulation during Extracorporeal Membrane Oxygenation: Potential Problems and Possible Solutions.

Choices for monitoring of unfractionated heparin (UFH) anticoagulation in extracorporeal membrane oxygenation (ECMO) patients include activated clotting time, activated partial thromboplastin time, reaction times of viscoelastic tests, and anti-factor Xa activity (between 0.3 and 0.7 IU/mL). Recent studies propose the anti-factor Xa to be the gold standard for monitoring UFH anticoagulation in ECMO. However, many extraneous factors combined question the utility of anti-factor Xa as the sole method of monitoring of UFH effects in ECMO. Anti-factor Xa is a chromogenic assay, which may be biased by the frequently elevated values of bilirubin and free hemoglobin in ECMO patients. The test may alternatively underestimate UFH effects in cases of low antithrombin values. More importantly, the anti-factor Xa assay is a plasma-based test which does not take into account the role of platelets and fibrinogen in forming a stable clot. Thrombocytopenia and platelet dysfunction are common features in ECMO patients, and underestimating their role may lead to over-anticoagulation, should only anti-factor Xa guiding be used to adjust the UFH dose. Conversely, fibrinogen is an acute phase protein, and some patients may experience high levels of fibrinogen during the ECMO course. In this case, an UFH monitoring based on anti-factor Xa is insensitive to this condition, although it may potentially be associated with thrombotic complications. Finally, the generally suggested range of 0.3 to 0.7 IU/mL is a somewhat arbitrary estimate, based on the desired range for treating and preventing thrombotic events in non-ECMO patients. In conclusion, anti-factor Xa may offer useful information on the real effects of UFH only when combined with a whole blood test capable of assessing the relative contribution of platelets and fibrinogen to clot formation.

Surveillance and control of African Swine Fever in free-ranging pigs in Sardinia.

African swine fever (ASF) is a notifiable infectious disease, caused by the ASF virus (ASFV), which is a DNA virus belonging to the family Asfarviridae, genus Asfivirus. This disease has gained importance in the last decade after its spread in several countries in Eastern and Central Europe, and more recently, in China. Despite the efforts made to eradicate it, ASF is still present on the Mediterranean island of Sardinia (Italy) and has been since 1978. ASF risk factors on the island have been analysed in previous studies; the role of free-ranging pigs in virus persistence has been suggested, but has not been fully elucidated. The most recent eradication plan provides more stringent measures to combat free-ranging pigs and any kind of illegality in the pig sector. From December 2017 to June 2018, a total of 29 depopulation actions were performed in 13 municipalities in central Sardinia, during which 2,281 free-ranging pigs were culled and more than 50% of them were tested for ASFV and antibody presence (1,218 and 1,416, respectively). A total of 651 pigs were seropositive, with a mean seroprevalence of 53.4% (CI 95% = 50.6-56.3), and 38 were ASFV positive (virus prevalence = 2.6%; CI 95% = 2.1-3.0). To the best of our knowledge, the present study is the first to provide a complete evaluation of this millennial system of pig farming and ASFV prevalence in free-ranging pigs. Furthermore, it has emphasised the necessity of combining the maintenance of an epidemiological surveillance program with continuous education of farmers and other people involved in pig husbandry, based on cultural and economic aspects.

Atypical outbreak of acute coenurosis by Taenia multiceps in a sheep flock.

Herein, we examined the brain of adult ewes and lambs less than 30 days old which were found affected by neurological signs in a flock located in Sardinia (Italy). Gross anatomo-pathological examination of all brains of the animals revealed multiple linear reddish-yellow foci of necrotic purulent inflammation due to oncosphere migration. Histologically, we confirmed a multifocal pyo-granulomatous meningo-encephalitis both in ewes and in lambs, confirming acute coenurosis. Morphological examination and DNA sequencing identified the Taenia multiceps we isolated as Tm1 strain. This report describes for the first time a natural acute coenurosis infection in suckling lambs under 30 days of age.

Off-label use of thoracic aortic endovascular stent grafts to simplify difficult resections and procedures in general thoracic surgery.

OBJECTIVES: Tumour infiltration, or gross infectious involvement of the thoracic aortic wall, poses a significant intraoperative risk for fatal bleeding and therefore could compromise adequate resection or efficient surgical management of pleural infection in a considerable amount of cases. We present 3 successful cases of off-label thoracic aortic endografting to safeguard thoracic aortic wall integrity. METHODS: After all patients received thoracic stent grafts through femoral access into the descending aorta, the first patient underwent a resection of a locally advanced squamous cell carcinoma of the left inferior lobe cT4cN0-1cM0 after neoadjuvant chemoradiation, which had infiltrated the descending aortic wall. The second case was video-assisted thoracoscopic bilateral pleural decortication for empyema with aortic ulcers of the distal thoracic aorta in a patient with pancreatic intrathoracic fistula in a necrotizing pancreatitis. The third patient was operated for a locally advanced squamous cell carcinoma of the left inferior lobe initial stage cT4 cN1-2 cM0 after neoadjuvant chemoradiation, which had broad contact to the descending aorta at the level of thoracic vertebrae 7 and 8 on a circumference of circa 180°. Regional ethics committee approval according the Swiss Federal Human Research Act was obtained according to regulations. RESULTS: Preventive stent graft placement resulted in complication-free resection and significantly minimized the risk of fatal intraoperative bleeding. Patients were thus not exposed to complications associated with aortic cross-clamping, possible prosthetic replacement and extracorporeal circulation techniques. CONCLUSIONS: In carefully selected patient populations, the resection of locally advanced tumours or infectious processes involving the aortic wall can be facilitated by thoracic endovascular aortic repair prior to resection.

Carbon dioxide production during cardiopulmonary bypass: pathophysiology, measure and clinical relevance.

Carbon dioxide production during cardiopulmonary bypass derives from both the aerobic metabolism and the buffering of lactic acid produced by tissues under anaerobic conditions. Therefore, carbon dioxide removal monitoring is an important measure of the adequacy of perfusion and oxygen delivery. However, routine monitoring of carbon dioxide removal is not widely applied. The present article reviews the main physiological and pathophysiological sources of carbon dioxide, the available techniques to assess carbon dioxide production and removal and the clinically relevant applications of carbon dioxide-related variables as markers of the adequacy of perfusion during cardiopulmonary bypass.

Coagulation monitoring in postcardiotomy ECMO: conventional tests, point-of-care, or both?

BACKGROUND: The aim of this study was to assess the association of the coagulation point-of-care (POC) tests activated clotting time (ACT) and thromboelastography-derived parameters reaction time (R-time) and maximum amplitude (MA) with the standard coagulation tests during postcardiotomy extracorporeal membrane oxygenation (ECMO), finding adequate values predictive for the target range of the standard coagulation tests. METHODS: Thirty-one patients undergoing postcardiotomy ECMO with heparin anticoagulation were analyzed. Paired data of the POC tests and standard coagulation tests were analyzed for association and positive predictive value (PPV). RESULTS: The following target range values for standard coagulation test were settled: activated partial thromboplastin time (aPTT) 50-70 seconds; international normalized ratio (INR) 1.5-2.5; platelet count >50,000 cells/µL; fibrinogen >150 mg/dL. The best predictor for the desired aPTT range was an ACT of 162-185 seconds. A combination of an ACT<162 seconds with an R-time <10 minutes had an 83% PPV for a short aPTT. A combination of an ACT>185 seconds with an R-time >27 minutes had a 71% PPV for a long aPTT. No predictive ability of the POC tests was found in terms of the optimal INR range. An MA value <41 mm had a 75% PPV for a low platelet count or fibrinogen level. CONCLUSIONS: Diagnostic-therapeutic algorithms based on coagulation POC-tests may be useful to manage anticoagulation during postcardiotomy ECMO. The best PPV for prompting therapeutic decision is provided by a combination of ACT and visco-elastic tests.

Modern ECMO: why an ECMO programme in a tertiary care hospital.

Extracorporeal Membrane Oxygenation (ECMO) represents a useful tool to support the lungs and the heart when all conventional therapies failed and the patients are at risk of death. While the Extracorporeal Life Support Organization (ELSO) collects data from different institutions that joined the Registry and reports overall outcome, individual centres often collide with results below expectations, either in adults and in paediatric population. Some authors suggest that poor outcomes could be overcome with a programme dedicated to ECMO, with specialized professionals adequately trained on ECMO and with a consistent number of procedures. In 2012, The IRCCS PSD ECMO Programme was instituted with the specific aim of achieving better results than hitherto obtained. After only 1 year of activity, the results justified the programme, with a better survival rate for each group investigated, particularly in adults, but surprisingly in paediatrics too, where the results were better than what reported by ELSO. Although the number of patients treated with ECMO is still growing up, the effects of the ECMO programme continue to exert a positive action on outcome even now. The present article reports data on survival, blood loss, and blood consumption during ECMO in the last few years at our institution.

Exposure to 915 MHz radiation induces micronuclei in Vicia faba root tips.

The increasing use of mobile phones and wireless networks raised a great debate about the real carcinogenic potential of radiofrequency-electromagnetic field (RF-EMF) exposure associated with these devices. Conflicting results are reported by the great majority of in vivo and in vitro studies on the capability of RF-EMF exposure to induce DNA damage and mutations in mammalian systems. Aimed at understanding whether less ambiguous responses to RF-EMF exposure might be evidenced in plant systems with respect to mammalian ones, in the present work the mutagenic effect of RF-EMF has been studied through the micronucleus (MN) test in secondary roots of Vicia faba seedlings exposed to mobile phone transmission in controlled conditions, inside a transverse electro magnetic (TEM) cell. Exposure of roots was carried out for 72h using a continuous wave (CW) of 915 MHz radiation at three values of equivalent plane wave power densities (23, 35 and 46W/m(2)). The specific absorption rate (SAR) was measured with a calorimetric method and the corresponding values were found to fall in the range of 0.4-1.5W/kg. Results of three independent experiments show the induction of a significant increase of MN frequency after exposure, ranging from a 2.3-fold increase above the sham value, at the lowest SAR level, up to a 7-fold increase at the highest SAR. These findings are in agreement with the limited number of data on cytogenetic effects detected in other plant systems exposed to mobile phone RF-EMF frequencies and clearly show the capability of radiofrequency exposure to induce DNA damage in this eukaryotic cell system.

Hemodilution on cardiopulmonary bypass as a determinant of early postoperative hyperlactatemia.

OBJECTIVE: The nadir hematocrit (HCT) on cardiopulmonary bypass (CPB) is a recognized independent risk factor for major morbidity and mortality in cardiac surgery. The main interpretation is that low levels of HCT on CPB result in a poor oxygen delivery and dysoxia of end organs. Hyperlactatemia (HL) is a marker of dysoxic metabolism, and is associated with bad outcomes in cardiac surgery. This study explores the relationship between nadir HCT on CPB and early postoperative HL. DESIGN: Retrospective study on 3,851 consecutive patients. MEASUREMENTS AND MAIN RESULTS: Nadir HCT on CPB and other potential confounders were explored for association with blood lactate levels at the arrival in the Intensive Care Unit (ICU), and with the presence of moderate (2.1 - 6.0 mMol/L) or severe (> 6.0 mMol/L) HL. Nadir HCT on CPB demonstrated a significant negative association with blood lactate levels at the arrival in the ICU. After adjustment for the other confounders, the nadir HCT on CPB remained independently associated with moderate (odds ratio 0.96, 95% confidence interval 0.94-0.99) and severe HL (odds ratio 0.91, 95% confidence interval 0.86-0.97). Moderate and severe HL were significantly associated with increased morbidity and mortality. CONCLUSIONS: Hemodilution on CPB is an independent determinant of HL. This association, more evident for severe HL, strengthens the hypothesis that a poor oxygen delivery on CPB with consequent organ ischemia is the mechanism leading to hemodilution-associated bad outcomes.

Acute Kidney Injury and Hemodilution During Cardiopulmonary Bypass: A Changing Scenario.

BACKGROUND: Severe hemodilution during cardiopulmonary bypass (CPB) is a risk factor for acute kidney injury (AKI) after heart operations. Many improvements to CPB technology have been proposed during the past decade to limit the hemodilution-related AKI risk. The present study is a retrospective analysis of the relationship between hemodilution during CPB and AKI in cardiac operations in the setting of different interventions applied over 14 years. METHODS: We retrospectively analyzed 16,790 consecutive patients undergoing heart operations from 2000 to 2013. Various risk factors for AKI were collected and analyzed, together with a number of interventions as possible modifiers of the relationship between a nadir hematocrit (HCT) value during CPB and AKI. RESULTS: The relationship between the nadir HCT value during CPB and AKI was confirmed in a multivariable analysis, with the relative risk of AKI increasing by 7% per percentage point of decrease of the nadir HCT value during CPB. The relative risk of AKI decreased by 8% per year of observation (p = 0.001) despite a significantly increased risk of AKI (p = 0.001). A sensitivity analysis based on differences before and after different interventions demonstrated a beneficial effect of the application of goal-directed perfusion (aimed at preserving oxygen delivery during CPB), with a reduction in the AKI rate from 5.8% to 3.1% (p = 0.001). A policy restricting angiographic examination on the day of operation was also useful (reduction of AKI rate from 4.8% to 3.7%; p = 0.029). CONCLUSIONS: A bundle of interventions mainly aimed at limiting the renal impact of hemodilution during CPB is effective in reducing the AKI rate.

Heparin-like effect in postcardiotomy extracorporeal membrane oxygenation patients.

INTRODUCTION: Unfractionated heparin (UFH) is the anticoagulant of choice for extracorporeal membrane oxygenation (ECMO), but bivalirudin can be used as an alternative. The purpose of the present study is to investigate the existence of a heparin-like effect (HLE) during heparin-free ECMO. METHODS: This is a retrospective study on patients treated with ECMO and receiving bivalirudin as the sole anticoagulant. Thromboelastography (TEG) tests with and without heparinase were recorded during the ECMO duration. A total of 41 patients (22 pediatrics and 19 adults) treated with ECMO after cardiac surgery procedures and receiving only bivalirudin-based anticoagulation were studied. Based on the presence of a different reaction time (R-time) between the TEG test with heparinase or without heparinase we defined the presence of a HLE. Survival to hospital discharge, liver failure, sepsis, bleeding and transfusion rate were analyzed for association with HLE with univariate tests. RESULTS: HLE was detected in 56.1% of the patients. R-times were significantly shorter in tests done with heparinase versus without heparinase during the first seven days on ECMO. Patients with HLE had a significantly (P = 0.046) higher rate of sepsis (30%) than patients without HLE (5.6%) at a Pearson's chi-square test. CONCLUSIONS: A heparin-like effect is common during ECMO, and most likely due to a release of heparinoids from the glycocalyx and the mast cells, as a consequence of sepsis or of the systemic inflammatory reaction triggered by the contact of blood with foreign surfaces.

An unusual case of mediastinal mass and bilateral nodules.

A 23-year-old woman presented with a mediastinal paraganglioma and multiple pulmonary chondromas following antral gastric resection for gastrointestinal stromal tumor. These tumors form the Carney triad, a rare disorder of unknown genetic background. First described in 1977, approximately 120 cases have been documented in the literature. The tumors do not harbor the specific c-kit or PDGFRA gene mutations often found in sporadic gastrointestinal stromal tumor. In most cases, gastric gastrointestinal stromal tumor is the first tumor to be detected, with secondary tumors appearing years later. Even if it is rare, Carney triad should be suspected in young patients with history of gastrointestinal stromal tumor.

Effect of phrenic nerve palsy on early postoperative lung function after pneumonectomy: a prospective study.

BACKGROUND: The issue of phrenic nerve preservation during pneumonectomy is still an unanswered question. So far, its direct effect on immediate postoperative pulmonary lung function has never been evaluated in a prospective trial. METHODS: We conducted a prospective crossover study including 10 patients undergoing pneumonectomy for lung cancer between July 2011 and July 2012. After written informed consent, all consecutive patients who agreed to take part in the study and in whom preservation of the phrenic nerve during operation was possible, were included in the study. Upon completion of lung resection, a catheter was placed in the proximal paraphrenic tissue on the pericardial surface. After an initial phase of recovery of 5 days all patients underwent ultrasonographic assessment of diaphragmatic motion followed by lung function testing with and without induced phrenic nerve palsy. The controlled, temporary paralysis of the ipsilateral hemidiaphragm was achieved by local administration of lidocaine 1% at a rate of 3 mL/h (30 mg/h) via the above-mentioned catheter. RESULTS: Temporary phrenic nerve palsy was accomplished in all but 1 patient with suspected catheter dislocation. Spirometry showed a significant decrease in dynamic lung volumes (forced expiratory volume in 1 second and forced vital capacity; p < 0.05) with the paralyzed hemidiaphragm. Blood oxygen saturation levels did not change significantly. CONCLUSIONS: Our results show that phrenic nerve palsy causes a significant impairment of dynamic lung volumes during the early postoperative period after pneumonectomy. Therefore, in these already compromised patients, intraoperative phrenic nerve injury should be avoided whenever possible.

Cardiac catheterization and postoperative acute kidney failure in congenital heart pediatric patients.

BACKGROUND: Acute renal failure (ARF) is a severe complication of cardiac operations in pediatric patients. Angiography with the exposure to contrast media is a risk factor for ARF. In the present study, we explored the association between timing of angiography, dose of contrast media, and the incidence of ARF after cardiac operations in pediatric patients. METHODS: We performed a retrospective analysis of prospectively collected data. Angiographic data and other covariates were collected in 277 patients aged ≤12 years receiving angiography and cardiac operations during the same hospital stay. Renal outcome was assessed according to the pediatric Risk, Injury, Failure, Loss of function, End stage score (pRIFLE). RESULTS: One hundred seventy-seven (64%) patients suffered some degree of postoperative renal dysfunction, and 55 (20%) had ARF (pRIFLE stage Failure). Patients with ARF received a significantly (P < 0.001) larger dose of iodine contrast media (4.6 ± 2.6 g/kg) with respect to the other patients (2.8 ± 2.2 g/kg), with a relative risk increase for ARF of 31% per each incremental iodine dose of 1 g/kg at the univariate analysis. A multivariable risk model demonstrated that the risk for ARF is 20 times higher in patients aged younger than 2 years and 3 times higher in case of postoperative low cardiac output. Within this model, the iodine dose on angiography is confirmed as an independent risk factor for ARF, with a relative risk increase for ARF of 16% per each incremental iodine dose of 1 g/kg. CONCLUSIONS: Angiography before cardiac surgery is an important risk factor for ARF in pediatric patients. Being a modifiable risk factor, the contrast media dose should be limited to the lowest possible value, avoiding large doses of iodine which, together with other factors (age and postoperative low cardiac output), concur in the determinism of postoperative ARF.

Long term survival after trimodal therapy in malignant pleural mesothelioma.

PRINCIPLES: Trimodal therapy results in long term survival in a small fraction of patients with malignant pleural mesothelioma, particularly in patients having epithelial histology, R0-resection and no nodal involvement. This study analyses the outcome after trimodal therapy including extrapleural pneumonectomy. METHODS: From 2000 to 2005 41 patients with histologically verified malignant pleural mesothelioma were included. Diagnosis and nodal status were confirmed by surgery. 21 patients (51%) underwent trimodal therapy with 655 days (63-2,567 days) of median follow-up. Postoperative complications, mortality, long term survival and recurrence rates were analysed retrospectively. RESULTS: Neoadjuvant chemotherapy consisted of a combination of platinum based agents (n = 19) with gemcitabine (n = 15) or pemetrexed (n = 4). Extrapleural pneumonectomy was the standard procedure for surgery. 13 patients (62%) had postoperative complications. 16 patients (76%) received postoperative adjuvant radiotherapy. There was a 30-day mortality of 4.8% in the trimodal group. Survival rates in the trimodal group were 71% after one, 28% after two and 10% after five years. There were no significant differences regarding age, tumour stage, cell type or lymph node involvement. Tumour recurrence occurred after one and two years in 44% and in 83% respectively. CONCLUSIONS: The majority of patients considered for surgical resection of malignant pleural mesothelioma have regionally advanced disease. In those receiving trimodal therapy long term survival is achieved only in a minority of patients. In view of the time consuming and intensive treatment it should be offered only in carefully selected patients as new surgical approaches such as pleurectomy/decortication have shown high efficacy rates regarding patients' survival.

Putative cancer stem cells in malignant pleural mesothelioma show resistance to cisplatin and pemetrexed.

Malignant pleural mesothelioma (MPM) is a lethal cancer of the mesothelium with high chemotherapeutic resistance via unknown mechanisms. A prevailing hypothesis states that cancer stem cells (CSCs) persist in tumors causing relapse after chemotherapy, thus, rendering these cells as critical targets responsible for tumor resistance and recurrence. We selected candidate CSC markers based on expansion under hypoxic conditions, a hallmark for the selection of chemoresistant cells; and investigated the expression of CSC markers: CD133, Bmi-1, uPAR and ABCG2 in three MPM cell lines and normal mesothelial cells by quantitative RT-PCR. Furthermore, we evaluated the chemotherapeutic resistance associated with each CSC marker by determining the change in CSC marker-mRNA levels as an index of drug-resistance following treatment with either cisplatin or pemetrexed. We demonstrate the expression of CSC markers: CD133, Bmi-1, uPAR and ABCG2 in both normal and MPM cell lines. Bmi-1+, uPAR+ and ABCG2+ cells show a distinct role in conferring chemoresistance to cisplatin and pemetrexed in the malignant setting. By contrast, these markers have no apparent participation in chemoresistance to drug treatments in normal mesothelial cells. Intriguingly, CD133 revealed chemoresistant properties in both normal mesothelial and malignant pleural mesothelioma cells. This study provides evidence of putative CSCs conferring drug-resistance to cisplatin and pemetrexed in MPM cell lines. Specific targeting of these drug-resistant cells, while considering the functional heterogeneity of the MPM subtypes, may contribute to more focused and effective chemotherapeutic regimens for malignant pleural mesothelioma.

Inhibition of tissue transglutaminase sensitizes TRAIL-resistant lung cancer cells through upregulation of death receptor 5.

Tissue transglutaminase (TG2) is implicated in cellular processes such as apoptosis and cell migration. Its acyl transferase activity cross-links certain proteins, among them transcription factors were described. We show here that the TG2 inhibitor KCC009 reversed resistance to tumor necrosis factor-related apoptosis-inducing factor (TRAIL) in lung cancer cells. Sensitization required upregulation of death receptor 5 (DR5) but not of death receptor 4. Upregulation of DR5 involved the first intron of the DR5 gene albeit it was independent from p53 and nuclear factor kappa B. In conclusion, inhibition of tissue transglutaminase provides an interesting strategy for sensitization to TRAIL-induced apoptosis in p53-deficient lung cancer cells.