Analysis of morphological and functional heterogeneity in ct perfusion images of lung tumours

Questa tesi si propone di innovare lo stato dell’arte dei metodi di analisi dell’eterogeneità in lesioni polmonari attualmente utilizzati, affiancando l’analisi funzionale (emodinamica) a quella morfologica, grazie allo sviluppo di nuove feature specifiche. Grazie alla collaborazione tra il Computer Vision Group (CVG) dell’Università di Bologna e l’Unità Operativa di Radiologia dell’IRCCS-IRST di Meldola (Istituto di Ricovero e Cura a Carattere Scientifico – Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori), è stato possibile analizzare un adeguato numero di casi reali di pazienti affetti da lesioni polmonari primitive, effettuando un’analisi dell’eterogeneità sia su sequenze di immagini TC baseline sia contrast-enhanced, consentendo quindi un confronto tra eterogeneità morfologica e funzionale. I risultati ottenuti sono infine discussi sulla base del confronto con le considerazioni di natura clinica effettuate in cieco da due esperti radiologi dell’IRCCS-IRST.

A method for automated generation of radiotherapy treatment plans for lung cancer

La radioterapia è una tecnica molto impiegata per la cura del cancro. Attualmente la somministrazione avviene principalmente attraverso la intensity modulated radiotherapy (IMRT, sovrapposizione di campi ad intensità modulata), un cui sviluppo recente è la volumetric modulated arc therapy (VMAT, irradiazione continua lungo un arco ininterrotto). La generazione di piani richiede esperienza ed abilità: un dosimetrista seleziona cost functions ed obiettivi ed un TPS ottimizza la disposizione dei segmenti ad intensità modulata. Se il medico giudica il risultato non soddisfacente, il processo riparte da capo (trial-and-error). Una alternativa è la generazione automatica di piani. Erasmus-iCycle, software prodotto presso ErasmusMC (Rotterdam, The Netherlands), è un algoritmo di ottimizzazione multicriteriale di piani radioterapici per ottimizzazione di intensità basato su una wish list. L'output consiste di piani Pareto-ottimali ad intensità modulata. La generazione automatica garantisce maggiore coerenza e qualità più elevata con tempi di lavoro ridotti. Nello studio, una procedura di generazione automatica di piani con modalità VMAT è stata sviluppata e valutata per carcinoma polmonare. Una wish list è stata generata attraverso una procedura iterativa su un gruppo ristretto di pazienti con la collaborazione di fisici medici ed oncologi e poi validata su un gruppo più ampio di pazienti. Nella grande maggioranza dei casi, i piani automatici sono stati giudicati dagli oncologi migliori rispetto ai rispettivi piani IMRT clinici generati manualmente. Solo in pochi casi una rapida calibrazione manuale specifica per il paziente si è resa necessaria per soddisfare tutti i requisiti clinici. Per un sottogruppo di pazienti si è mostrato che la qualità dei piani VMAT automatici era equivalente o superiore rispetto ai piani VMAT generati manualmente da un dosimetrista esperto. Complessivamente, si è dimostrata la possibilità di generare piani radioterapici VMAT ad alta qualità automaticamente, con interazione umana minima. L'introduzione clinica della procedura automatica presso ErasmusMC è iniziata (ottobre 2015).

CCK2 receptor splice variant with intron 4 retention in human gastrointestinal and lung tumours

The wild-type cholecystokinin type 2 (CCK(2)) receptor is expressed in many gastrointestinal and lung tumours. A splice variant of the CCK(2) receptor with retention of intron 4 (CCK(2)Ri4sv) showing constitutive activity associated with increased tumour growth was described in few colorectal, pancreatic and gastric cancers. Given the potential functional and clinical importance of this spliceoform, its occurrence was quantitatively characterized in a broad collection of 81 gastrointestinal and lung tumours, including insulinomas, ileal carcinoids, gastrointestinal stromal tumours (GIST), gastric, colorectal and pancreatic ductal adenocarcinomas, cholangiocellular and hepatocellular carcinomas, small cell lung cancers (SCLC), non-SCLC (nSCLC) and bronchopulmonary carcinoids, as well as 21 samples of corresponding normal tissues. These samples were assessed for transcript expression of total CCK(2) receptor, wild-type CCK(2) receptor and CCK(2)Ri4sv with end-point and real-time RT-PCR, and for total CCK(2) receptor protein expression on the basis of receptor binding with in vitro receptor autoradiography. Wild-type CCK(2) receptor transcripts were found in the vast majority of tumours and normal tissues. CCK(2)Ri4sv mRNA expression was present predominantly in insulinomas (incidence 100%), GIST (100%) and SCLC (67%), but rarely in pancreatic, colorectal and gastric carcinomas and nSCLC. It was not found in wild-type CCK(2) receptor negative tumours or any normal tissues tested. CCK(2)Ri4sv transcript levels in individual tumours were low, ranging from 0.02% to 0.14% of total CCK(2) receptor transcripts. In conclusion, the CCK(2)Ri4sv is a marker of specific gastrointestinal and lung tumours. With its high selectivity for and high incidence in SCLC and GIST, it may represent an attractive clinical target.

Screening renal artery angiography in hypertensive patients undergoing coronary angiography and 6-month follow-up after ad hoc percutaneous revascularization

OBJECTIVE: To determine the prevalence and independent predictors of significant atherosclerotic renal artery stenosis (RAS) in unselected hypertensive patients undergoing coronary angiography and to assess the 6-month outcome of those patients with a significant RAS. METHODS: One thousand, four hundred and three consecutive hypertensive patients undergoing drive-by renal arteriography were analyzed retrospectively. Univariate and multivariate logistic regression analyses were performed to identify independent predictors of RAS. In patients with significant RAS (>or=50% luminal narrowing), 6-month follow-up was assessed and outcome was compared between patients with or without renal revascularization. RESULTS: The prevalence of significant RAS was 8%. After multivariate analysis, coronary [odds ratio 5.3; 95% confidence interval (CI) 2.7-10.3; P < 0.0001], peripheral (odds ratio 3.3; 95% CI 2.0-5.5; P < 0.0001), and cerebral artery (odds ratio 2.8; 95% CI 1.5-5.3; P = 0.001) diseases, and impaired renal function (odds ratio 2.9; 95% CI 1.8-4.5; P < 0.0001) were found as independent predictors. At least one of these predictors was present in 96% of patients with RAS. In 74 patients (66%) with significant RAS, an ad hoc revascularization was performed. At follow-up, creatinine clearance was significantly higher in revascularized than in nonrevascularized patients (69.2 vs. 55.5 ml/min per 1.73 m, P = 0.029). By contrast, blood pressure was comparable between both groups, but nonrevascularized patients were taking significantly more antihypertensive drugs as compared with baseline (2.7 vs. 2.1, follow-up vs. baseline; P = 0.0066). CONCLUSION: The prevalence of atherosclerotic RAS in unselected hypertensive patients undergoing coronary angiography was low. Coronary, peripheral, and cerebral artery diseases, and impaired renal function were independent predictors of RAS. Ad hoc renal revascularization was associated with better renal function and fewer intake of antihypertensive drugs at follow-up.

Percutaneous access of the epicardial space for mapping ventricular and supraventricular arrhythmias in patients with and without prior cardiac surgery

There is a paucity of data on the success rates of achieving percutaneous epicardial access in different groups of patients.

Oxidative stress and inflammation response after nanoparticle exposure: differences between human lung cell monocultures and an advanced three-dimensional model of the human epithelial airways

Combustion-derived and manufactured nanoparticles (NPs) are known to provoke oxidative stress and inflammatory responses in human lung cells; therefore, they play an important role during the development of adverse health effects. As the lungs are composed of more than 40 different cell types, it is of particular interest to perform toxicological studies with co-cultures systems, rather than with monocultures of only one cell type, to gain a better understanding of complex cellular reactions upon exposure to toxic substances. Monocultures of A549 human epithelial lung cells, human monocyte-derived macrophages and monocyte-derived dendritic cells (MDDCs) as well as triple cell co-cultures consisting of all three cell types were exposed to combustion-derived NPs (diesel exhaust particles) and to manufactured NPs (titanium dioxide and single-walled carbon nanotubes). The penetration of particles into cells was analysed by transmission electron microscopy. The amount of intracellular reactive oxygen species (ROS), the total antioxidant capacity (TAC) and the production of tumour necrosis factor (TNF)-alpha and interleukin (IL)-8 were quantified. The results of the monocultures were summed with an adjustment for the number of each single cell type in the triple cell co-culture. All three particle types were found in all cell and culture types. The production of ROS was induced by all particle types in all cell cultures except in monocultures of MDDCs. The TAC and the (pro-)inflammatory reactions were not statistically significantly increased by particle exposure in any of the cell cultures. Interestingly, in the triple cell co-cultures, the TAC and IL-8 concentrations were lower and the TNF-alpha concentrations were higher than the expected values calculated from the monocultures. The interplay of different lung cell types seems to substantially modulate the oxidative stress and the inflammatory responses after NP exposure.

Variability of lung function predicts loss of asthma control following withdrawal of inhaled corticosteroid treatment

BACKGROUND One aspect of a multidimensional approach to understanding asthma as a complex dynamic disease is to study how lung function varies with time. Variability measures of lung function have been shown to predict response to beta(2)-agonist treatment. An investigation was conducted to determine whether mean, coefficient of variation (CV) or autocorrelation, a measure of short-term memory, of peak expiratory flow (PEF) could predict loss of asthma control following withdrawal of regular inhaled corticosteroid (ICS) treatment, using data from a previous study. METHODS 87 adult patients with mild to moderate asthma who had been taking ICS at a constant dose for at least 6 months were monitored for 2-4 weeks. ICS was then withdrawn and monitoring continued until loss of control occurred as per predefined criteria. Twice-daily PEF was recorded during monitoring. Associations between loss of control and mean, CV and autocorrelation of morning PEF within 2 weeks pre- and post-ICS withdrawal were assessed using Cox regression analysis. Predictive utility was assessed using receiver operator characteristics. RESULTS 53 out of 87 patients had sufficient PEF data over the required analysis period. The mean (389 vs 370 l/min, p<0.0001) and CV (4.5% vs 5.6%, p=0.007) but not autocorrelation of PEF changed significantly from prewithdrawal to postwithdrawal in subjects who subsequently lost control, and were unaltered in those who did not. These changes were related to time to loss of control. CV was the most consistent predictor, with similar sensitivity and sensitivity to exhaled nitric oxide. CONCLUSION A simple, easy to obtain variability measure of daily lung function such as the CV may predict loss of asthma control within the first 2 weeks of ICS withdrawal.

Expression, regulation and clinical significance of soluble and membrane CD14 receptors in pediatric inflammatory lung diseases

BACKGROUND: Inflammatory lung diseases are a major morbidity factor in children. Therefore, novel strategies for early detection of inflammatory lung diseases are of high interest. Bacterial lipopolysaccharide (LPS) is recognized via Toll-like receptors and CD14. CD14 exists as a soluble (sCD14) and membrane-associated (mCD14) protein, present on the surface of leukocytes. Previous studies suggest sCD14 as potential marker for inflammatory diseases, but their potential role in pediatric lung diseases remained elusive. Therefore, we examined the expression, regulation and significance of sCD14 and mCD14 in pediatric lung diseases. METHODS: sCD14 levels were quantified in serum and bronchoalveolar lavage fluid (BALF) of children with infective (pneumonia, cystic fibrosis, CF) and non-infective (asthma) inflammatory lung diseases and healthy control subjects by ELISA. Membrane CD14 expression levels on monocytes in peripheral blood and on alveolar macrophages in BALF were quantified by flow cytometry. In vitro studies were performed to investigate which factors regulate sCD14 release and mCD14 expression. RESULTS: sCD14 serum levels were specifically increased in serum of children with pneumonia compared to CF, asthma and control subjects. In vitro, CpG induced the release of sCD14 levels in a protease-independent manner, whereas LPS-mediated mCD14 shedding was prevented by serine protease inhibition. CONCLUSIONS: This study demonstrates for the first time the expression, regulation and clinical significance of soluble and membrane CD14 receptors in pediatric inflammatory lung diseases and suggests sCD14 as potential marker for pneumonia in children.

Organ-specific eosinophilic disorders of the skin, lung, and gastrointestinal tract

Eosinophils are multifunctional leukocytes that increase in various tissues in patients with a variety of disorders. Locally, they can be involved in the initiation and propagation of diverse inflammatory responses. In this review the clinical association of eosinophils with diseases of the skin, lung, and gastrointestinal tract is summarized. An approach to determining the causal role of eosinophils in these diseases is presented. Recent findings concerning molecular diagnosis, cause, and treatment are discussed.

[The thoracoscopic talc pleurodesis with intraoperative pleural biopsy - a retrospective analysis in patients with malignant pleural effusion]

The thoracoscopic pleurodesis with talc is an established therapy in case of malignant pleural effusion. With the instillation of talc a -localised inflammation is induced. However, some-times it turns into a severe systemic reaction. In this study of the postoperative course, the -question is examined whether a pleural biopsy is an additional risk factor for morbidity and mortality after talc pleurodesis.

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.

Inflammatory myofibroblastic tumour of the lung in a five-year-old girl

The inflammatory myofibroblastic tumour of the lung is considered a rare diagnosis of lung masses. We report the case of a five-year-old girl who presented with recurrent pyrexia, dry cough, and shortness of breath. Chest X-ray and computed tomography showed a total atelectasis of the left lower lobe and a segmental atelectasis of the left upper lobe. The mass was removed in toto, histopathology revealed the diagnosis of an inflammatory myofibroblastic tumour of the lung. The patient is without any signs of relapse 30 months after surgery.

The lectin-like domain of tumor necrosis factor improves lung function after rat lung transplantation--potential role for a reduction in reactive oxygen species generation

To test the hypothesis that the lectin-like domain of tumor necrosis factor, mimicked by the TIP peptide, can improve lung function after unilateral orthotopic lung isotransplantation. Because of a lack of a specific treatment for ischemia reperfusion-mediated lung injury, accompanied by a disrupted barrier integrity and a dysfunctional alveolar liquid clearance, alternative therapies restoring these parameters after lung transplantation are required.

Four-arm robotic lobectomy for the treatment of early-stage lung cancer

We investigated the feasibility and safety of four-arm robotic lung lobectomy in patients with lung cancer and described the robotic lobectomy technique with mediastinal lymph node dissection.

Improvement of migraine headaches after percutaneous closure of patent foramen ovale for secondary prevention of paradoxical embolism

Patent foramen ovale (PFO) has been linked to migraine, and an improvement in migraine prevalence or frequency has been reported after PFO closure for other reasons. We sought to identify whether there is a specific patient population of migraineurs which may be more susceptible to benefiting from PFO closure.