Intratumoral Chemotherapy for Lung Cancer: Re-challenge Current Targeted Therapies

Strategies to enhance the already established doublet chemotherapy regimen for lung cancer have been investigated for more than 20 years. Initially, the concept was to administer chemotherapy drugs locally to the tumor site for efficient diffusion through passive transport within the tumor. Recent advances have enhanced the diffusion of pharmaceuticals through active transport by using pharmaceuticals designed to target the genome of tumors. In the present study, five patients with non-small cell lung cancer epidermal growth factor receptor (EGFR) negative stage IIIa–IV International Union Against Cancer 7 (UICC-7), and with Eastern Cooperative Oncology Group (ECOG) 2 scores were administered platinum-based doublet chemotherapy using combined intratumoral-regional and intravenous route of administration. Cisplatin analogues were injected at 0.5%–1% concentration within the tumor lesion and proven malignant lymph nodes according to pretreatment histological/cytological results and the concentration of systemic infusion was decreased to 70% of a standard protocol. This combined intravenous plus intratumoral-regional chemotherapy is used as a first line therapy on this short series of patients. To the best of our knowledge this is the first report of direct treatment of involved lymph nodes with cisplatin by endobronchial ultrasound drug delivery with a needle without any adverse effects. The initial overall survival and local response are suggestive of a better efficacy compared to established doublet cisplatin–based systemic chemotherapy in (higher) standard concentrations alone according to the UICC 7 database expected survival. An extensive search of the literature was performed to gather information of previously published literature of intratumoral chemo-drug administration and formulation for this treatment modality. Our study shows a favorable local response, more than a 50% reduction, for a massive tumor mass after administration of five sessions of intratumoral chemotherapy plus two cycles of low-dose intravenous chemotherapy according to our protocol. These encouraging results (even in very sick ECOG 2 patients with central obstructive non-small cell lung cancer having a worse prognosis and quality of life than a non-small cell lung cancer in ECOG 0 of the same tumor node metastasis [TNM]-stage without central obstruction) for a chemotherapy-only protocol that differs from conventional cisplatin-based doublet chemotherapy by the route, target site, and dose paves the way for broader applications of this technique. Finally, future perspectives of this treatment and pharmaceutical design for intratumoral administration are presented

Pathophysiology of orthopnea in patients with congestive heart failure

The aim of this study was the investigation of respiratory system function and mechanics, between sitting and supine position, among patients with orthopnea due to congestive heart failure. We also investigated if orthopnea score correlated with lung function tests, mechanical properties of respiratory system assessed with impulse oscillometry technique or cardiac function parameters. We studied 40 congestive heart failure patients (mean age 70±8 years) and 15 control subjects (mean age 63±6 years) who were matched for gender, height and weight. All underwent spirometry, measurement of diffusion capacity and IOS both in sitting and supine position. We assessed orthopnea using Borg scale. In a subgroup of 22 patients isosorbide dinitrate was administered sublingually and IOS was performed in the supine position. All patients underwent echocardiography and ejection fraction of left ventricle was measured. No patient reported dyspnea while seated and orthopnea score was 2.9±1.4 in the supine position. Left ventricular ejection fraction was 43±10% in the group of patients. Patients demonstrated restrictive spirometric pattern in the sitting position (FEV₁/FVC>70%, TLC, FVC, IC were decreased) while FRC was comparable with the control group. In the supine position all pulmonary volumes decreased, except IC that increased. Volume changes % were not different between patients and control group. Xrs was much higher in patients both in sitting (421.8 ±630.6 %pred versus 147.2±72.8 %pred, p=0.01) and supine position (699.8 ±699.9 %pred vs 251.2 ±151.6 %pred, p≤0.001). Resistance, as measured between 5-35 Hz, was similar between patients and controls for both positions. Parameters of respiratory mechanics (Rrs 5, Xrs 5 and AX) were improved after isosorbide dinitrate administration. Orthopnea score was correlated with FEV₁ (p=0,006, r=-0,426) and MMEF (p=0,004, r=-0,45) change% between sitting and supine position, as well as SRrs 5 in the supine position (p=0,036, r=0,33). In conclusion, patients with congestive heart failure demonstrate restrictive spirometric pattern, while pulmonary volumes changes % after adopting the supine position are not different compared with normal subjects. Xrs 5 is a respiratory mechanics parameter that could separate patients with congestive heart failure from normal subjects. Nitrates improve all respiratory mechanics parameters. Degree of orthopnea correlates with FEV₁, MMEF change % and SRrs 5 in the supine position.Σκοπός της εργασίας ήταν η διερεύνηση των µεταβολών της µηχανικής του αναπνευστικού συστήµατος, από την καθιστή στην ύπτια θέση, σε ασθενείς µε ορθόπνοια στα πλαίσια συµφορητικής καρδιακής ανεπάρκειας. ∆ιερευνήσαµε επίσης κατά πόσο ο βαθµός της ορθόπνοιας σχετίζεται µε αντικειµενικές παραµέτρους της αναπνευστικής λειτουργίας, µε µηχανικές ιδιότητες του αναπνευστικού συστήµατος όπως αυτές υπολογίζονται µε τη µέθοδο των εξαναγκασµένων ταλαντώσεων ή µε παραµέτρους της καρδιακής λειτουργίας. Μελετήθηκαν συνολικά 40 ασθενείς (µέσης ηλικίας 70±8 ετών) και 15 φυσιολογικά άτοµα (µέσης ηλικίας 63±6 ετών) αντίστοιχα ως προς το φύλο, ύψος και βάρος. Όλοι υποβλήθηκαν σε σπιροµέτρηση, προσδιορισµό της διαχυτικής ικανότητας και δοκιµασία IOS τόσο σε καθιστή όσο και σε ύπτια θέση. Ο βαθµός ορθόπνοιας εκτιµήθηκε βάση της κλίµακας Borg. Σε υποοµάδα 22 ασθενών χορηγήθηκε δινιτρικός ισοσορβίτης υπογλωσσίως και στη συνέχεια υποβλήθηκαν σε δοκιµασία IOS στην ύπτια θέση. Όλοι οι ασθενείς υποβλήθηκαν σε υπερηχογραφική εκτίµηση της καρδιακής λειτουργίας. Κανένας ασθενής δεν ανέφερε δύσπνοια στην καθιστή θέση, ενώ ο βαθµός ορθόπνοιας ήταν 2,9 ±1,4 στην ύπτια θέση. Το κλάσµα εξώθησης της αριστερής κοιλίας ήταν 43±10% για την οµάδα των ασθενών. Οι ασθενείς παρουσίαζαν περιοριστικού τύπου διαταραχή στην καθιστή θέση (FEV₁/FVC>70%, ελαττωµένη TLC, FVC, IC) µε FRC συγκρίσιµη µε την οµάδα ελέγχου. Στην ύπτια θέση όλοι οι πνευµονικοί όγκοι µειώθηκαν, εκτός από την IC η οποία αυξήθηκε. Οι ποσοστιαίες µεταβολές των όγκων, µεταξύ καθιστής και ύπτιας θέσης, δεν διέφεραν µεταξύ ασθενών και φυσιολογικών ατόµων. Η Xrs 5 διέφερε σε στατιστικά σηµαντικό βαθµό µεταξύ ασθενών και οµάδας ελέγχου τόσο στην καθιστή (421,8 ±630,6 %pred έναντι 147,2 ±72,8 %pred, p=0,01) όσο και στην ύπτια θέση (699,8 ±699,9 %pred έναντι 251,2 ±151,6 %pred, p≤0,001). Οι αντιστάσεις σε όλο το εύρος των εφαρµοζόµενων συχνοτήτων ήταν παρόµοιες µεταξύ των δύο οµάδων και στις δύο θέσεις. Η χορήγηση δινιτρικού ισοσορβίτη υπογλωσσίως βελτίωσε τη µηχανική του αναπνευστικού συστήµατος (Rrs 5, Xrs 5 και ΑΧ) σε στατιστικά σηµαντικό βαθµό. Ο βαθµός ορθόπνοιας σχετίστηκε µε την ποσοστιαία µεταβολή του FEV₁ (p=0,006, r=-0,426) και της µεσοεκπνευστικής ροής (p=0,004, r=-0,45) µεταξύ καθιστής και ύπτιας θέσης, καθώς και µε τη SRrs στα 5 Hz στην ύπτια θέση (p=0,036, r=0,33). Συµπερασµατικά, οι ασθενείς µε ΣΚΑ παρουσιάζουν περιοριστικού τύπου διαταραχή σπιροµετρικά ενώ οι ποσοστιαίες µεταβολές των όγκων µετά την κατάληψη της ύπτιας θέση δε διαφέρουν συγκριτικά µε τα φυσιολογικά άτοµα. Η Xrs 5 αποτελεί σαφή διαχωριστικό παράγοντα της µηχανικής του αναπνευστικού µεταξύ ασθενών µε ΣΚΑ και φυσιολογικών ατόµων. Η χορήγηση νιτρώδους βελτιώνει τις παραµέτρους της µηχανικής του αναπνευστικού συστήµατος. Ο βαθµός ορθόπνοιας σχετίζεται µε την ποσοστιαία µεταβολή του FEV₁ και της µεσοεκπνευστικής ροής, καθώς και µε τη SRrs στα 5 Hz στην ύπτια θέση

Electronic Cigarettes and Asthma: What Do We Know So Far?

Electronic cigarettes (EC) are a novel product, marketed as an alternative to tobacco cigarette. Its effects on human health have not been investigated widely yet, especially in specific populations such as patients with asthma. With this review, we use the existing literature in order to answer four crucial questions concerning: (1) ECs’ role in the pathogenesis of asthma; (2) ECs’ effects on lung function and airway inflammation in patients with asthma; (3) ECs’ effects on asthma clinical characteristics in asthmatics who use it regularly; and (4) ECs’ effectiveness as a smoking cessation tool in these patients. Evidence suggests that many EC compounds might contribute to the pathogenesis of asthma. Lung function seems to deteriorate by the use of EC in this population, while airway inflammation alters, with the aggravation of T-helper-type-2 (Th2) inflammation being the most prominent but not the exclusive effect. EC also seems to worsen asthma symptoms and the rate and severity of exacerbations in asthmatics who are current vapers, whilst evidence suggests that its effectiveness as a smoking cessation tool might be limited. Asthmatic patients should avoid using EC

Smoking-Induced Disturbed Sleep. A Distinct Sleep-Related Disorder Pattern?

The relationship between smoking and sleep disorders has not been investigated sufficiently yet. Many aspects, especially regarding non-obstructive sleep apnea–hypopnea (OSA)-related disorders, are still to be addressed. All adult patients who visited a tertiary sleep clinic and provided information about their smoking history were included in this cross-sectional study. In total, 4347 patients were divided into current, former and never smokers, while current and former smokers were also grouped, forming a group of ever smokers. Sleep-related characteristics, derived from questionnaires and sleep studies, were compared between those groups. Ever smokers presented with significantly greater body mass index (BMI), neck and waist circumference and with increased frequency of metabolic and cardiovascular co-morbidities compared to never smokers. They also presented significantly higher apnea–hypopnea index (AHI) compared to never smokers (34.4 ± 24.6 events/h vs. 31.7 ± 23.6 events/h, p p = 0.13) did not differ between groups. Ever smokers, compared to never smokers, presented more frequent episodes of sleep talking (30.8% vs. 26.6%, p = 0.004), abnormal movements (31.1% vs. 27.7%, p = 0.021), restless sleep (59.1% vs. 51.6%, p p = 0.002) during sleep. Those were more evident in current smokers and correlated significantly with increasing AHI. These significant findings suggest the existence of a smoking-induced disturbed sleep pattern

Intratumoral chemotherapy for lung cancer: re-challenge current targeted therapies

Strategies to enhance the already established doublet chemotherapy regimen for lung cancer have been investigated for more than 20 years. Initially, the concept was to administer chemotherapy drugs locally to the tumor site for efficient diffusion through passive transport within the tumor. Recent advances have enhanced the diffusion of pharmaceuticals through active transport by using pharmaceuticals designed to target the genome of tumors. In the present study, five patients with non-small cell lung cancer epidermal growth factor receptor (EGFR) negative stage IIIa-IV International Union Against Cancer 7 (UICC-7), and with Eastern Cooperative Oncology Group (ECOG) 2 scores were administered platinum-based doublet chemotherapy using combined intratumoral-regional and intravenous route of administration. Cisplatin analogues were injected at 0.5%-1% concentration within the tumor lesion and proven malignant lymph nodes according to pretreatment histological/cytological results and the concentration of systemic infusion was decreased to 70% of a standard protocol. This combined intravenous plus intratumoral-regional chemotherapy is used as a first line therapy on this short series of patients. To the best of our knowledge this is the first report of direct treatment of involved lymph nodes with cisplatin by endobronchial ultrasound drug delivery with a needle without any adverse effects. The initial overall survival and local response are suggestive of a better efficacy compared to established doublet cisplatin-based systemic chemotherapy in (higher) standard concentrations alone according to the UICC 7 database expected survival. An extensive search of the literature was performed to gather information of previously published literature of intratumoral chemo-drug administration and formulation for this treatment modality. Our study shows a favorable local response, more than a 50% reduction, for a massive tumor mass after administration of five sessions of intratumoral chemotherapy plus two cycles of low-dose intravenous chemotherapy according to our protocol. These encouraging results (even in very sick ECOG 2 patients with central obstructive non-small cell lung cancer having a worse prognosis and quality of life than a non-small cell lung cancer in ECOG 0 of the same tumor node metastasis [TNM]-stage without central obstruction) for a chemotherapy-only protocol that differs from conventional cisplatin-based doublet chemotherapy by the route, target site, and dose paves the way for broader applications of this technique. Finally, future perspectives of this treatment and pharmaceutical design for intratumoral administration are presented