S-p-bromobenzyl-glutathione cyclopentyl diester (BBGC) as novel therapeutic strategy to enhance trabectedin anti-tumor effect in soft tissue sarcoma preclinical models.

Trabectedin, approved for the treatment of soft tissue sarcoma (STS), interferes with cell division and genetic transcription processes. Due to its strong anti-tumor activity in only certain histotypes, several studies on trabectedin combinations are currently ongoing to improve its efficacy. In this study, we aimed to investigate novel potential therapeutic strategies to enhance the anti-tumor effect of trabectedin using integrated in silico, in vitro, and in vivo approaches. For in silico analysis, we screened two public datasets, GSEA M5190 and TCGA SARC. Fibrosarcoma, leiomyosarcoma, dedifferentiated, and myxoid liposarcoma cell lines were used for in vitro studies. For in vivo experiments, fibrosarcoma orthotopic murine model was developed. In silico analysis identified Glo1 as the only druggable target upregulated after trabectedin treatment and correlated with poor prognosis. The specific Glo1 inhibitor, S-p-bromobenzylglutathione cyclopentyl diester (BBGC), increased trabectedin cytotoxicity in STS cells, and restored drug sensitivity in myxoid liposarcoma cells resistant to trabectedin. Moreover, the combined treatment with BBGC and trabectedin had a synergistic antitumor effect in vivo without any additional toxicity to mice. Based on these results, we believe that BBGC warrants further investigation to evaluate its potential clinical use in combination with trabectedin.

Enhancing the activity and stability of carbon-supported platinum-gadolinium nanoalloys towards the oxygen reduction reaction.

The activity/stability towards the ORR of Pt x Gd/C nanoalloys has been enhanced by controlling the atmosphere during the dealloying process. By minimising the formation of porous nanoarchitectures, the ORR activity is increased, and is accompanied by higher activity retention and attenuation of metal dissolution on cycling to high voltage.

Management of post-intubation tracheal stenoses using the endoscopic approach.

BACKGROUND AND AIM: Tracheal stenosis is a common complication of intubation with or without subsequent tracheotomy whose management remains poorly defined. Over 600 post-intubation tracheal stenoses have been treated in our centre since 1982: the aim of this study was to determine the safety and efficacy of our endoscopic approach. METHODS: This retrospective study includes 113 new cases treated between 1998 and 2001. We chose this period to have a standardised technique and a significant number of cases with a sufficiently long follow up (28-78 months). Forty patients who did not meet the criteria for "true stenosis" (granulomas, pseudoglottic stenosis, etc.) were excluded from the study. RESULTS: 73 patients (50+/-21 years) entered the study: 13 (18%) web-like and 60 (82%) complex stenoses. Most web-like stenoses were successfully treated with Laser Assisted Mechanical Dilation (LAMD) alone; among complex stenoses LAMD was sufficient to treat 13 patients (22%), whereas 47 patients (78%) required stent placement: 22 had their stent removed after one year and did not require any further therapy, 13 inoperable patients required permanent stent and 12 were referred to surgery after failure of multiple endoscopic treatments. No permanent complications secondary to endoscopic treatment were observed. 48 patients (66%) obtained a stable, good result with the endoscopic procedure, 13 (18%) required a permanent stent while 12 patients (16%) were referred to surgery. CONCLUSIONS: Our results indicate that the endoscopic treatment of post-intubation tracheal stenoses performed in an expert setting can be considered a safe first-line therapy, leaving some selected cases and the relapsing stenoses, for surgical resection.

Autofluorescence bronchoscopy with white light bronchoscopy compared with white light bronchoscopy alone for the detection of precancerous lesions: a European randomised controlled multicentre trial.

BACKGROUND: The potential of autofluorescence bronchoscopy (AFB) to detect precancerous lesions in the central airways and its role in lung cancer screening is uncertain. A study was undertaken to evaluate the prevalence of moderate/severe dysplasia (dysplasia II-III) and carcinoma in situ (CIS) using a newly developed AFB system in comparison with conventional white light bronchoscopy (WLB) alone. METHODS: In a prospective randomised multicentre trial, smokers > or = 40 years of age (> or = 20 pack-years) were stratified into four different risk groups and investigated with either WLB+AFB (arm A) or WLB alone (arm B). RESULTS: 1173 patients (916 men) of mean age 58.7 years were included. Overall (arms A and B), preinvasive lesions (dysplasia II-III and CIS) were detected in 3.9% of the patients. The prevalence of patients with preinvasive lesions in the WLB arm was 2.7% compared with 5.1% in the WLB+AFB arm (p = 0.037). For patients with dysplasia II-III, WLB+AFB increased the detection rate by a factor of 2.1 (p = 0.03), while for CIS the factor was only 1.24 (p = 0.75). The biopsy based sensitivity of WLB alone and WLB+AFB for detecting dysplasia II-III and CIS was 57.9% compared with 82.3% (1.42-fold increase). The corresponding specificity was 62.1% compared with 58.4% (0.94-fold decrease). CONCLUSIONS: This first randomised study of AFB showed that the combination of WLB+AFB was significantly superior to WLB alone in detecting preneoplastic lesions. Our findings do not support the general use of AFB as a screening tool for lung cancer, but suggest that it may be of use in certain groups. The precise indications await further study.

Tracheocoele in a Duchenne muscular dystrophy patient. Case report.

Tracheocoele, a congenital or acquired lesion, is rarely detected radiologically and even more rarely diagnosed clinically. This tracheal lesion is characterised by the presence of a single cystic lesion filled with air or a mixture of liquid and air, of extremely variable size, occurring in almost all cases, in a locus minoris resistentiae situated in the right posterolateral portion of the trachea. The rare case is described of a voluminous tracheocoele located in the left paratracheal region, extending from the cricoid to sternal notch, manifesting clinically, 3 months prior to evaluation in our hospital in a 27-year-old male suffering from Duchenne muscular dystrophy since the age of 5 years. For 10 years, the patient had been treated with intermittent positive pressure ventilation via nasal mask, due to progressive deterioration of respiratory function. Diagnosis of tracheocoele, initially made at computed axial tomography scan, was confirmed by flexible laryngotracheoscopy under local anaesthesia. Due to severe comorbidity associated with the clinical picture described, the absence of a significant set of symptoms, and the problems concerning anaesthesiological management of the patient, palliative treatment was the only choice. This consisted in cervical compression bandaging during assisted nasal ventilation. Close follow-up was performed in order to monitor any progression of the lesion or onset of related complications. This is the second case of tracheocoele originating in the left paratracheal region reported in the literature, and the first associated with Duchenne muscular dystrophy and prolonged use of a positive pressure respirator. The aetiopathogenic mechanisms that may have determined the formation of this rare lesion are then taken into consideration.

Cardiac arrest due to ventricular fibrillation as a complication occurRing during rigid bronchoscopic laser therapy.

Laser bronchoscopy is a usually well tolerated procedure for the treatment of obstructive lesions on the tracheobronchial tree, with a very low morbidity and mortality rate. Cardiovascular complications, including atrial and ventricular arrhythmias, and myocardial ischemia, have only rarely been reported during laser bronchoscopy. Cardiac arrhythmias during such a procedure are usually well tolerated but occasionally may be life threatening. Here we report a case of a young, female patient affected by Pulmonary Tuberculosis with a cicatricial stenosis of the left main bronchus who developed an episode of prolonged cardiac arrest due to ventricular fibrillation (and no signs of acute myocardial ischemia) during rigid broncoscopic laser-therapy. Underlying Coronary Artery Disease and other cardiac abnormalities were also excluded by subsequent cardiovascular examination. The clinical implications are also discussed.

Acute respiratory acidosis does not increase plasma potassium in normokalaemic anaesthetized patients. A controlled randomized trial.

BACKGROUND AND OBJECTIVE: Few and conflicting data are available regarding the changes of plasma potassium concentration during acute respiratory acidosis in human beings. This study compares the acute changes in plasma potassium concentration in acutely hypercapnic patients and in non-hypercapnic patients during general anaesthesia. METHODS: Thirty-three patients undergoing interventional rigid bronchoscopy were studied. Ventilation of the lungs was randomly conducted using either spontaneous-assisted ventilation or intermittent negative-pressure ventilation. All patients received the same anaesthetic protocol. Arterial blood gases and osmolality, and plasma concentrations of glucose, sodium, potassium and chloride were measured. RESULTS: Intraoperatively, PaCO2 was higher during spontaneous-assisted ventilation than during intermittent negative-pressure ventilation (9 +/- 1.8 vs. 5.4 +/- 1.2 kPa, P < 0.001) and the pH was also lower during spontaneous-assisted ventilation than during intermittent negative-pressure ventilation (7.24 +/- 0.07 vs. 7.4 +/- 0.08, P < 0.001). Plasma potassium concentration remained similar in both groups (3.8 +/- 0.2 mmol L(-1) with spontaneous-assisted ventilation vs. 3.7 +/- 0.4 mmol L(-1) with intermittent negative-pressure ventilation). CONCLUSION: Acute respiratory acidosis does not affect plasma potassium concentration.

Negative pressure ventilation vs external high-frequency oscillation during rigid bronchoscopy. A controlled randomized trial.

STUDY OBJECTIVES: To compare the effectiveness of two modalities of external ventilation during rigid bronchoscopy: intermittent negative pressure ventilation (INPV) and external high-frequency oscillation (EHFO). DESIGN: Prospective, controlled, randomized, nonblinded study. SETTING: University-affiliated hospital. PATIENTS: Seventy patients undergoing interventional rigid bronchoscopy for tracheobronchial lesions were enrolled into the study. INTERVENTIONS: Mechanical ventilation was performed by INPV or EHFO. When pulse oximetry was < 90%, manually assisted ventilation was delivered. MEASUREMENTS AND RESULTS: Arterial blood gases were sampled preoperatively and intraoperatively. Most patients in both groups had normal intraoperative PaCO(2) (mean, 43. 6 +/- 11.8 mm Hg under EHFO and 37.4 +/- 8.2 mm Hg under INPV; p = 0.012), and acidemia occurred in 9 of 35 patients of EHFO group and in 2 of 35 patients of INPV group (p = 0.049). Hypercapnia (PaCO(2) > 50 mm Hg) was observed in 10 patients under EHFO and in 2 with INPV (p = 0.026). Intraoperative mean PaO(2) was similar (101.4 +/- 52.9 mm Hg with EHFO and 124.2 +/- 50.3 mm Hg with INPV; p = 0.07), but O(2) supply was different (3.5 +/- 2.3 L/min during INPV and 8.5 +/- 6.2 L/min during EHFO; p < 0.001). Intraoperative hypoxemia (PaO(2) < 60 mm Hg) occurred in five patients with EHFO and two with INPV (p = 0.426). Three EHFO patients required manually assisted ventilation (mean, 0.2 +/- 0.9), but no INPV patient did (p = 0.142). CONCLUSIONS: External negative pressure ventilation appears to be a suitable choice during rigid bronchoscopy: both EHFO and INPV ensure effective ventilation and comfortable operating conditions in the majority of patients. Some patients may receive inadequate ventilation with EHFO, developing respiratory acidosis and requiring manually assisted ventilation. In comparison with INPV, EHFO requires a higher fraction of inspired oxygen.

[Pleomorphic adenoma: a case treated by laryngotracheal resection and reconstruction]. / Un caso di adenoma pleomorfo trattato con resezione e ricostruzione laringo-tracheale.

Benign Pleomorphic Adenoma (PA) is a tumor rarely found in tracheal and laryngotracheal sites. A review of the literature published since 1922 has revealed only 30 certain cases of which 3 presented simultaneous involvement of both larynx and trachea. The present work describes the thirty-first case (the fourth with a laryngotracheal localization), diagnosed in a white, 40-year-old male who had been complaining of acute dyspnea for the last three years. Initially these symptoms had been interpreted as asthmatic crises. During one of these episodes, the patient underwent emergency tracheotomy and a laryngotracheoscopy revealed a rounded cricotracheal lesion with smooth surface and approximately 4 cm in cranio-caudal diameter. The mass occupied 90% of the air space and originated from the posterolateral right portion of the cricoid, and from the first 3 tracheal rings. CT and esophagoscopy ruled out its transmural invasion into the esophagus. Under rigid bronchoscopy, assisted NdYAG laser debulking was performed for biopsy purposes. The histological diagnosis was benign AP. For this reason a Grillo cricotracheal resection was performed with exeresis of the cricoid arch, mucosa of the cricoid plate and the first 4 tracheal rings. Reconstruction of the respiratory tract was achieved through termino-terminal cricothyrotracheal anastomosis. The initial diagnosis was confirmed and the resection edges were without evidence of neoplasm. Post-operative recovery proceeded without complications and the patient was discharged 7 days after surgery. Endoscopic and radiological follow-up after 30 months is still negative for any neoplastic recurrences. The laryngo-tracheal lumen is within the norm and cord motility has been preserved. The authors then describe the clinical, anatomopathological and radiological elements which prove useful in evaluating tracheal neoplasms and they underline the problems of differential diagnosis between benign AP and adenoid-cystic carcinoma. In addition, the various therapeutic options are discussed with special attention being focused on surgery through external approaches. Given the location of the AP described, the Grillo procedure-most commonly used in cases of inflammatory cricotracheal stenoses-proved well suited to the loco-regional control of the neoplasm. Stringent respect for some parts of this surgical technique make it possible to reduce post-operative complications to a minimum.

Remifentanil vs. fentanyl during interventional rigid bronchoscopy under general anaesthesia and spontaneous assisted ventilation.

The treatment of tracheo-bronchial diseases with rigid bronchoscopy requires general anaesthesia without tracheal intubation. Spontaneous assisted ventilation is a safe modality of ventilation. In this study the use of remifentanil and fentanyl is compared during rigid bronchoscopy with spontaneous assisted ventilation. Ninety high-risk patients received fentanyl or remifentanil with propofol for general anaesthesia. During the maintenance fentanyl was delivered at 6.1 +/- 4.6 micrograms kg-1 h-1 and remifentanil at 0.15 +/- 0.07 microgram kg-1 min-1. The same degree of intra-operative respiratory acidosis with similar good operating conditions resulted in both groups. Patients treated with remifentanil recovered more quickly compared with those in the fentanyl group (3.8 +/- 2 vs. 10.4 +/- 9.2 min, P < 0.001). In conclusion, the use of remifentanil during rigid bronchoscopy under general anaesthesia with spontaneous assisted ventilation is safe and assures good operating conditions. Moreover, remifentanil permits a more rapid recovery than fentanyl. The dose of remifentanil is higher than previously described for spontaneously breathing patients.

[Tracheal stenosis due to metastatic adenopathic compression from breast carcinoma]. / Stenosi tracheale per compressione adenopatica metastatica da carcinoma della mammella.

Paratracheal lymph-nodal metastases secondary of breast cancer aren't frequent in this kind of cancer. Here is described the case of a 76-years-old woman come to our note for ingravescent dyspnoea caused by metastatic adenopathy compression of the tracheal lumen. After excluding other treatments, a tracheal stent is put on. The obstruction gets better right away, the initial severe respiratory symptoms are improved and the ventilation is almost normal.

[Bronchial laser: techniques, indications, and results]. / Laser bronchique: techniques, indications et résultats.

Laser emits a light characterised by being monochromatic, phased and collimated. Since the beginning of the '80s the fibers ND-YAG laser, whose energy may be transmitted by quartz fibres, is the type principally used for therapeutic bronchoscopy. It may be used to coagulate or to vaporize endoluminal lesions. The effect looked for depends on the level of density of power selected. During rigid bronchoscopy, YAG laser is usually applied in the coagulation mode, with a weak liberation of energy. Further resection is then achieved mechanically with the rigid tube or forceps. For malignant lesions the laser has a palliative action in eliminating endoluminal tumour mass. Its use has overturned the management of progressive tracheal or bronchial asphyxia. Outside emergencies, its action can be combined with radio and chemotherapy. For benign lesions its action may be curative. The laser is however poorly adapted for extrinsic compression and for infiltrating lesions where other more appropriate endoscopic methods should be used.

Negative pressure ventilation vs. spontaneous assisted ventilation during rigid bronchoscopy. A controlled randomised trial.

BACKGROUND: Ventilation during interventional rigid bronchoscopy (IRB) under general anaesthesia (jet ventilation, positive pressure ventilation and spontaneous assisted ventilation) may offer some difficulties. This study compares the effectiveness during IRB of intermittent negative pressure ventilation (INPV) and spontaneous assisted ventilation (SAV). METHODS: Thirty-eight patients submitted to IRB were randomised into two groups: SAV or INPV. All patients received a total intravenous anaesthesia; INPV patients were paralysed. Pre- and intra-operative arterial blood gases and O2 flow through a rigid bronchoscope were assessed. The endoscopist applying a subjective score evaluated the operating conditions. RESULTS: Patients of the INPV group, as compared to the SAV group, required a lower dosage of fentanyl (2.6 +/- 1.8 micrograms.kg-1.h-1 vs. 6.6 +/- 4.8 micrograms.kg-1.h-1), a lower O2 supply (3.3 +/- 2.8 l/min vs. 11.6 +/- 3.4 l/min), a shorter recovery time (5.4 +/- 2.9 min vs. 9.8 +/- 7.1 min) and no manually assisted ventilation (0 +/- 0 vs. 1 +/- 1.1 n degree/procedure). Intraoperative PaCO2 was higher in the SAV (8.1 +/- 1.3 kPa) than in the INPV group (5.0 +/- 1.6 kPa) and intraoperative pH differed in the two groups (7.26 +/- 0.05, SAV vs. 7.47 +/- 0.08, INPV). Operating conditions, as assessed by a subjective score, were considered better with INPV than with SAV (4.9 vs. 4.3). CONCLUSIONS: As compared to SAV, INPV in paralysed patients during IRB reduces administration of opioids, shortens recovery time, prevents respiratory acidosis, excludes the need for manually assisted ventilation, reduces O2 need and affords optimal surgical conditions. INPV appears a safe, non-invasive and effective ventilatory management during IRB.

Breathing pattern and arterial blood gases during Nd-YAG laser photoresection of endobronchial lesions under general anesthesia: use of negative pressure ventilation: a preliminary study.

STUDY OBJECTIVE: To evaluate the efficacy of negative pressure ventilation (NPV) in avoiding or reducing apneas and related hypoxemia and respiratory acidosis during laser therapy (LT) of endobronchial lesions. DESIGN: A prospective, controlled, randomized study. SETTING: An operating theater of a respiratory endoscopy and laser therapy unit. POPULATION AND INTERVENTION: Twenty-seven consecutive patients referred to LT were entered into the study. Fourteen patients were randomly assigned to LT under general anesthesia and spontaneous assisted ventilation (control group) whereas in 13 cases, NPV by a poncho-wrap ventilator (NPV group) was added to the procedure. MEASUREMENTS AND RESULTS: The prevalence and the duration of apnea/hypopnea periods assessed by respiratory inductive plethysmography during LT were significantly reduced under NPV, compared to the control group. As compared to baseline, during LT, all control patients developed mild to severe hypercapnia (PaCO2 ranging from 55 to 76 mm Hg) and respiratory acidosis (pH from 7.33 to 7.19), whereas only three patients undergoing NPV (23%) developed hypercapnia (PaCO2 from 52 to 68 mm Hg) and related acidosis (pH from 7.29 to 7.21). Optimal oxygenation was achieved in all of the patients; nevertheless, patients under NPV needed a lower mean oxygen supply; five of them (38%) could be treated at a fraction of inspired oxygen of 0.21 for the whole procedure. CONCLUSION: NPV may be useful in reducing apneas during laser therapy under general anesthesia, thus reducing hypercapnia, related acidosis, and need of oxygen supplementation.

Inflammatory pseudotumour of the lung presenting as an airway obstructive syndrome.

The inflammatory pseudotumour of the lung is a rare and non-malignant neoplasm, which can be asymptomatic or characterized by variable clinical expressions. This report refers to a case occurring in a young woman and presenting as a persistent airway obstructive syndrome. With regard to histopathologic characterization, the present case can be classified as a fibrous histiocytic subtype.

Endoscopic treatment of malignant airway obstructions in 2,008 patients.

We report our 13-year experience with endoscopic treatment of malignant obstructions of the airway by Nd:YAG laser, stents, and intraluminal brachytherapy in 2,008 patients. We performed 2,610 laser resections in 1,838 patients, 66 high dose rate brachytherapies, and we placed 393 tracheobronchial silicone stents in 306 patients. We used the rigid bronchoscope in 96% of the laser procedures and in all cases requiring stent placement; general anesthesia was given to 90% of these patients. Endobronchial radiotherapy was performed under local, anesthesia. In 93% of patients undergoing laser resection, we obtained an immediate patency of the airway with consequent improvement of quality of life. The median time between the first and second laser treatment was 102 days, being longer in the case of stent placement (when required) or in association with brachytherapy. Even if endoscopic treatment should be considered only for palliation, laser vaporization could be curative in case of in situ carcinoma. Since 1983, we have treated 23 such lesions in 17 patients and up to now, none has recurred. Finally, endoscopic resection may allow a better assessment of the true extent of the tumor, shifting to surgery patients originally considered to have inoperable disease or allowing lung-sparing operations (21 and 18 patients of our series, respectively). The total mortality rate was 0.4% (12 patients over 2,798 treatments; 2,710 Nd:YAG laser + 151 stents without laser + 37 brachytherapies without laser) in the first week after the procedures, and was mainly related to cardiovascular problems and respiratory failure. In conclusion, endoscopic resection of lung malignancies is rapid, effective, repeatable, and complementary to other treatments; although it should be considered only palliative, laser resection could be curative in patients with in situ carcinomas and early cancers. Laser, stents, and endoluminal brachytherapy should be available in all centers with major experience; a well-trained team is mandatory to plan the most appropriate treatment and manage any possible complication.