A dosimetric retrospective planning study comparing volumetric arc therapy (VMAT) and stereotactic body radiotherapy (SBRT) treatment plans for non-small cell lung cancer (NSCLC)

Purpose A retrospective planning study comparing volumetric arc therapy (VMAT) and stereotactic body radiotherapy (SBRT) treatment plans for non-small cell lung cancer (NSCLC). Methods and materials Five randomly selected early stage lung cancer patients were included in the study. For each patient, four plans were created: the SBRT plan and three VMAT plans using different optimisation methodologies. A total of 20 different plans were evaluated. The dose parameters of dose conformity results and the target dose constraints results were compared for these plans. Results The mean planning target volume (PTV) for all the plans (SBRT and VMAT) was 18·3 cm3, with a range from 15·6 to 20·1 cm3. The maximum dose tolerance to 1 cc of all the plans was within 140% (84 Gy) of the prescribed dose, and 95% of the PTV of all the plans received 100% of the prescribed dose (60 Gy). In all the plans, 99% of the PTV received a dose >90% of the prescribed dose, and the mean dose in all the plans ranged from 67 to 72 Gy. The planning target dose conformity for the SBRT and the VMAT (0°, 15° collimator single arc plans and dual arc) plans showed the tightness of the prescription isodose conformity to the target. Conclusions SBRT and VMAT are radiotherapy approaches that increase doses to small tumour targets without increasing doses to the organs at risk. Although VMAT offers an alternative to SBRT for NSCLC and the potential advantage of VMAT is the reduced treatment times over SBRT, the statistical results show that there was no significant difference between the SBRT and VMAT optimised plans in terms of dose conformity and organ-at-risk sparing.

Lung cancer risk of airborne particles for Italian population

Airborne particles, including both ultrafine and supermicrometric particles, contain various carcinogens. Exposure and risk-assessment studies regularly use particle mass concentration as dosimetry parameter, therefore neglecting the potential impact of ultrafine particles due to their negligible mass compared to supermicrometric particles. The main purpose of this study was the characterization of lung cancer risk due to exposure to polycyclic aromatic hydrocarbons and some heavy metals associated with particle inhalation by Italian non-smoking people. A risk-assessment scheme, modified from an existing risk model, was applied to estimate the cancer risk contribution from both ultrafine and supermicrometric particles. Exposure assessment was carried out on the basis of particle number distributions measured in 25 smoke-free microenvironments in Italy. The predicted lung cancer risk was then compared to the cancer incidence rate in Italy to assess the number of lung cancer cases attributed to airborne particle inhalation, which represents one of the main causes of lung cancer, apart from smoking. Ultrafine particles are associated with a much higher risk than supermicrometric particles, and the modified risk-assessment scheme provided a more accurate estimate than the conventional scheme. Great attention has to be paid to indoor microenvironments and, in particular, to cooking and eating times, which represent the major contributors to lung cancer incidence in the Italian population. The modified risk assessment scheme can serve as a tool for assessing environmental quality, as well as setting up exposure standards for particulate matter.

Pharmacists' role in lung health

Breathing is important. In fact, most people take on average 23,000 breaths each day. However, most of us probably take this for granted and do not notice these breaths – unless of course maybe when we are exercising, or huffing and puffing because we are running late for the bus...

Omega-hydroxylation of acyclic monoterpene alcohols by rat lung microsomes

Rat lung microsomes were shown to ω-hydroxylate acyclic monoterpene alcohols in the presence of NADPH and O2. NADH could neither support hydroxylation efficiently nor did it show synergistic effect. The hydroxylase activity was greater in microsomes prepared from β-naphthoflavone (BNF)-treated rats than from phenobarbital (PB)-treated or control microsomal preparations. Hydroxylation was specific to the C-8 position in geraniol and has a pH optimum of 7.8. The inhibition of the hydroxylase activity by SKF-525A, CO, N-ethylmaleimide, ellipticine, α-naphthoflavone, cyt. Image and p-CMB indicated the involvement of the cyt. P-450 system. However, NaN3 stimulated the hydroxylase activity to a significant level. Rat kidney microsomes were also capable of ω-hydroxylating geraniol although the activity was lower than that observed with lungs.

Adenoviral gene therapy for non-small cell lung cancer

Adenoviral gene therapy is an experimental approach to cancer refractory to standard cancer therapies. Adenoviruses can be utilized as vectors to deliver therapeutic transgenes into cancer cells, while gene therapy with oncolytic adenoviruses exploits the lytic potential of viruses to kill tumor cells. Although adenoviruses demonstrate several advantages over other vectors - such as the unparalleled transduction efficacy and natural tropism to a wide range of tissues - the gene transfer efficacy to cancer cells has been limited, consequently restricting the therapeutic effect. There are, however, several approaches to circumvent this problem. We utilized different modified adenoviruses to obtain information on adenovirus tropism towards non-small cell lung cancer (NSCLC) cells. To enhance therapeutic outcome, oncolytic adenoviruses were evaluated. Further, to enhance gene delivery to tumors, we used mesenchymal stem cells (MSCs) as carriers. To improve adenovirus specificity, we investigated whether widely used cyclooxygenase 2 (Cox-2) promoter is induced by adenovirus infection in nontarget cells and whether selectivity can be retained by the 3 untranslated region (UTR) AU-rich elements. In addition, we investigated whether switching adenovirus fiber can retain gene delivery in the presence of neutralizing antibodies. Our results show that adenoviruses, whose capsids were modified with arginine-glycine-aspartatic acid (RGD-4C), the serotype 3 knob, or polylysins displayed enhanced gene transfer into NSCLC cell lines and fresh clinical specimens from patients. The therapeutic efficacy was further improved by using respective oncolytic adenoviruses with isogenic 24bp deletion in the E1A gene. Cox-2 promoter was also shown to be induced in normal and tumor cells following adenovirus infection, but utilization of 3 UTR elements can increase the tumor specificity of the promoter. Further, the results suggested that use of MSCs could enhance the bioavailability and delivery of adenoviruses into human tumors, although cells had no tumor tropism per se. Finally, we demonstrated that changing adenovirus fiber can allow virus to escape from existing neutralizing antibodies when delivered systemically. In conclusion, these results reveal that adenovirus gene transfer and specificity can be increased by using modified adenoviruses and MSCs as carriers, and fiber modifications simultaneously decrease the effect of neutralizing antibodies. This promising data suggest that these approaches could translate into clinical testing in patients with NSCLC refractory to current modalities.

Metabolism of geraniol and linalool in the rat and effects on liver and lung microsomal enzymes

1. Metabolites isolated from the urine of rats after oral administration of geraniol (I) were: geranic acid (II), 3-hydroxy-citronellic acid (III), 8-hydroxy-geraniol (IV), 8-carboxy-geraniol (V) and Hildebrandt acid (VI). 2. Metabolites isolated from urine of rats after oral administration of linalool (VII) were 8-hydroxy-linalool (VIII) and 8-carboxy-linalool (IX). 3. After three days of feeding rats with either geraniol or linalool, liver-microsomal cytochrome P-450 was increased. Both NADH- and NADPH-cytochrome c reductase activities were not significantly changed during the six days of treatment. 4. Oral administration of these two terpenoids did not affect any of the lung-microsomal parameters measured.

Hanging drop: An in vitro air toxic exposure model using human lung cells in 2D and 3D structures

Using benzene as a candidate air toxicant and A549 cells as an in vitro cell model, we have developed and validated a hanging drop (HD) air exposure system that mimics an air liquid interface exposure to the lung for periods of 1 h to over 20 days. Dose response curves were highly reproducible for 2D cultures but more variable for 3D cultures. By comparing the HD exposure method with other classically used air exposure systems, we found that the HD exposure method is more sensitive, more reliable and cheaper to run than medium diffusion methods and the CULTEX (R) system. The concentration causing 50% of reduction of cell viability (EC50) for benzene, toluene, p-xylene, m-xylene and o-xylene to A549 cells for 1 h exposure in the HD system were similar to previous in vitro static air exposure. Not only cell viability could be assessed but also sub lethal biological endpoints such as DNA damage and interleukin expressions. An advantage of the HD exposure system is that bioavailability and cell concentrations can be derived from published physicochemical properties using a four compartment mass balance model. The modelled cellular effect concentrations EC50(cell) for 1 h exposure were very similar for benzene, toluene and three xylenes and ranged from 5 to 15 mmol/kg(dry weight) which corresponds to the intracellular concentration of narcotic chemicals in many aquatic species, confirming the high sensitivity of this exposure method. (C) 2013 Elsevier B.V. All rights reserved.

Mixture Effects of Benzene, Toluene, Ethylbenzene and Xylenes (BTEX) to Lung Carcinoma Cells via a Hanging Drop Air Exposure System

A recently developed hanging drop air exposure system for toxicity studies of volatile chemicals was applied to evaluate the cell viability of lung carcinoma A549 cells after 1 h and 24 h of exposure to benzene, toluene, ethylbenzene and xylenes (BTEX) as individual compounds and mixtures of 4 or 6 components. The cellular chemical concentrations causing 50% reduction of cell viability (EC50) were calculated use a mass balance model and came to 17, 12, 11, 9, 4 and 4 mmol/kg cell dry weight for benzene, toluene, ethylbenzene, m-xylene, o-xylene and p-xylene respectively after 1 h of exposure. The EC50 decreased by a factor of four after 24 h of exposure. All mixture effects were best described by the mixture toxicity model of concentration addition, which is valid for chemicals with the same mode of action. Good agreement with the model predictions were found for benzene, toluene, ethylbenzene and m-xylene at four different representative fixed concentration ratios after 1 h of exposure but lower agreement to mixture prediction was obtained after 24 h of exposure. A recreated car exhaust mixture, which involved the contribution of the more toxic p-xylene and o-xylene, yielded an acceptable but lower quality prediction as well.

Assessing the combined effect of asbestos exposure and smoking on lung cancer: a Bayesian approach

We review the literature on the combined association between lung cancer and two environmental exposures, asbestos exposure and smoking, and explore a Bayesian approach to assess evidence of interaction between the exposures. The meta-analysis combines separate indices of additive and multiplicative relationships and multivariate relative risk estimates. By making inferences on posterior probabilities we can explore both the form and strength of interaction. This analysis may be more informative than providing evidence to support one relation over another on the basis of statistical significance. Overall, we find evidence for a more than additive and less than multiplicative relation.

Microarrays in Lung Cancer Research: From Comparative Analyses to Verified Findings

Keuhkosyöpä on yleisimpiä syöpätauteja. Se jaetaan kahteen päätyyppiin: pienisoluiseen ja ei-pienisoluiseen keuhkosyöpään. Ei-pienisoluinen keuhkosyöpä jaetaan lisäksi alatyyppeihin, joista suurimmat ovat levyepiteeli-, adeno- ja suurisoluinen karsinooma. Keuhkosyövän tärkein riskitekijä on tupakointi, mutta muutkin työ- ja elinympäristön altisteet, kuten asbesti, voivat johtaa syöpään. Väitöstyössä tutkittiin kahdenlaisten keuhkosyöpäryhmien erityispiirteitä. Työssä kartoitettiin, onko löydettävissä muutoksia, jotka erottavat asbestikeuhkosyövät muista syövistä sekä luuytimeen varhaisessa vaiheessa leviävät keuhkosyövät leviämättömistä syövistä. Tutkimusten ensimmäisessä vaiheessa käytettiin mikrosirupohjaisia menetelmiä, jotka mahdollistavat jopa kaikkien geenien tarkastelun yhden kokeen avulla. Vertailevien mikrosirututkimusten avulla on mahdollista paikantaa geenejä tai kromosomialueita, joiden muutokset erottelevat ryhmät toisistaan. Asbestiin liittyvissä tutkimuksissa paikannettiin kuusi kromosomialuetta, joissa geenien kopiolukumäärän sekä ilmenemistason muutokset erottelivat potilaat altistushistorian mukaan. Riippumattomilla laboratoriomenetelmillä tehtyjen jatkoanalyysien avulla pystyttiin varmistamaan, että 19p-alueen häviämä oli yhteydessä asbestialtistukseen. Työssä osoitettiin myös, että 19p-alueen muutoksia voidaan indusoida altistamalla soluja asbestille in vitro. Tutkimuksessa saatiin lisäksi viitteitä asbestispesifisistä muutoksista signaalinvälitysreiteissä, sillä yhdessä toimivien geenien ilmentymisessä havaittiin eroja asbestille altistuneiden ja altistumattomien välillä. Vertailemalla luuytimeen syövän aikaisessa vaiheessa levinneiden ja leviämättömien keuhkoadenokarsinoomien muutosprofiileita toisiinsa, paikannettiin viisi aluetta, joilla geenien kopiolukumäärä- sekä ilmenemistason muutokset erottelivat ryhmät toisistaan. Jatkoanalyyseissä havaittiin, että 4q-alueen häviämää esiintyi adenokarsinoomien lisäksi levyepiteelikarsinoomiin, jotka olivat levinneet luuytimeen. Myös keuhkosyöpien aivometastaaseissa alue oli toistuvasti hävinnyt. Väitöstyön tutkimukset osoittavat, että vertailevien mikrosiruanalyysien avulla saadaan tietoa syöpäryhmien erityispiirteistä. Työssä saadut tulokset osoittavat, että 19p-alueen muutokset ovat tyypillisiä asbestikeuhkosyöville ja 4q-alueen muutokset luuytimeen aikaisessa vaiheessa leviäville keuhkosyöville.

Molecular Alterations in Asbestos-Related Lung Cancer

Background: Asbestos is a well known cancer-causing mineral fibre, which has a synergistic effect on lung cancer risk in combination with tobacco smoking. Several in vitro and in vivo experiments have demonstrated that asbestos can evoke chromosomal damage and cause alterations as well as gene expression changes. Lung tumours, in general, have very complex karyotypes with several recurrently gained and lost chromosomal regions and this has made it difficult to identify specific molecular changes related primarily to asbestos exposure. The main aim of these studies has been to characterize asbestos-related lung cancer at a molecular level. Methods: Samples from asbestos-exposed and non-exposed lung cancer patients were studied using array comparative genomic hybridization (aCGH) and fluorescent in situ hybridization (FISH) to detect copy number alterations (CNA) as well as microsatellite analysis to detect allelic imbalance (AI). In addition, asbestos-exposed cell lines were studied using gene expression microarrays. Results: Eighteen chromosomal regions showing differential copy number in the lung tumours of asbestos-exposed patients compared to those of non-exposed patients were identified. The most significant differences were detected at 2p21-p16.3, 5q35.3, 9q33.3-q34.11, 9q34.13-q34.3, 11p15.5, 14q11.2 and 19p13.1-p13.3 (p<0.005). The alterations at 2p and 9q were validated and characterized in detail using AI and FISH analysis in a larger study population. Furthermore, in vitro studies were performed to examine the early gene expression changes induced by asbestos in three different lung cell lines. The results revealed specific asbestos-associated gene expression profiles and biological processes as well as chromosomal regions enriched with genes believed to contribute to the common asbestos-related responses in the cell lines. Interestingly, the most significant region enriched with asbestos-response genes was identified at 2p22, close to the previously identified region showing asbestos-related CNA in lung tumours. Additionally, in this thesis, the dysregulated biological processes (Gene Ontology terms) detected in the cell line experiment were compared to dysregulated processes identified in patient samples in a later study (Ruosaari et al., 2008a). Commonly affected processes such as those related to protein ubiquitination, ion transport and surprisingly sensory perception of smell were identified. Conclusions: The identification of specific CNA and dysregulated biological processes shed some light on the underlying genes acting as mediators in asbestos-related lung carcinogenesis. It is postulated that the combination of several asbestos-specific molecular alterations could be used to develop a diagnostic method for the identification of asbestos-related lung cancer.