The proposal of a new norisk screening method

The proposal of a new no-risk screening method for lung cancer Svetlana Žunić

Lung cancer is the most common cause of death from cancer worldwide Available from: ttp: //globocan. iarc. fr/Pages/fact_sheets_cancer. aspx Doctors predict global cancer rates will increase by 75% over the next two decades.

Standardized cancer mortality rates per 100. 000 population, males, Central Serbia, 1990 - 2012 From: CANCER INCIDENCE AND MORTALITY IN CENTRAL SERBIA 2012. CANCER REGISTRY OF CENTRAL SERBIA. REPORT No. 14 Beograd, 2014. ISBN 86 -7358 -030 -7

Standardized cancer mortality rates per 100. 000 population, females, Central Serbia, 1990 - 2012 From: CANCER INCIDENCE AND MORTALITY IN CENTRAL SERBIA 2012. CANCER REGISTRY OF CENTRAL SERBIA. REPORT No. 14 Beograd, 2014. ISBN 86 -7358 -030 -7

We live in a polluted world stars – conflicts (DU ammunition) 2010

DU particles transferred up to 2400 miles from Iraqi battlefields The square contour schematically represents 2400 miles around Serbia, teritory of Former Yugoslavia and exposed area after 10 tones 1495 miles is the of distance from Belgrade The square contour schematically represents DU used in 1999 bomb attack Airport, Serbia to Baghdad Airport, Iraq ; square 2400 miles around Bosnia & Herzegovina, contour schematically represents 2400 miles territory of Former Yugoslavia and exposed area around Persian Gulf and exposed area after 286 after 15 tones of DU used in 1994 -1995 conflict tones of DU used in the First Gulf War Schematical interpretation of data given by: Moret’s reported data. L. U. S. Weapons Poison Europe. Radiation From Iraq War Detected in UK Atmosphere. 2006; Online access: www. americanfreepress. net/html/weapons_poison_europe. html Busby C, Morgan S. 2006. Did the Use of Uranium Weapons in Gulf War 2 Result in Contamination of Europe? Evidence from the Measurements of the Atomic Weapons Establishment, Aldemastron, Aberystwyth, Green Audit

Cigarette smoke is the main cause of lung cancer • Carcinogenic effect of tobacco smoke may act synergically with radionuclides in tobacco, mostly alpha-emitters which induce cumulative doses at bifurcations. • Besides tobacco, radioactive particles may be inhaled from environmental sources, as it is contaminated air-pollution, including depleted uranium particles. • After inhalation, radioactive particles may be embedded into the tissue. (Martell, EA. Proc Nat Acad Sci USA, 1983; 80(5): 1285– 89).

Prevention is better than cure (when something has ultimately/no curable) https: //fr. slideshare. net/lahin 95/tqmprevention-is-better-than-cure

The Facts • 3. 7 million cancer deaths could have been avoided by life-style changes, such as quitting smoking, reducing alcohol intake and maintaining a healthy weight. http: //www. embracinghealthblog. com/2014/02/05/prevention-is-better-than-cure/

Lung cancer screening prolongs survival • The chest radiograph is a routine procedure, easy to perform, and well accepted by patients, but it is not sensitive enough as computerized tomography (CT) scan. • The use of CT scan as a screening tool is highly rational! But… overall cancer incidence was 24% greater for exposed than for unexposed people. The mean length of follow-up was 9. 5 years after exposure. Mathews, JD, et al. BMJ. 2013 May 21; 346: f 2360. doi: 10. 1136/bmj. f 2360.

Radionuclides from air pollution and tobacco smoke in the bronchoalveolar space ⋆ ⋆ ⋆ ● ● ●● ⋆ ⋆ ⋆ ●● ⋆ nonsmokers ⋆ ⋆ ● ● ● ●● ●● ●● ● smokers ⋆ ⋆ ⋆ Adopted from: Mosby's Medical Dictionary, 9 th edition. © 2009, Elsevier. http: //medicaldictionary. thefreedictionary. com/_/viewer. aspx? path =Mosby. MD&name=alveolus. jpg&url=http%3 A%2 F%2 Fmedical-dictionary. thefreedictionary. com%2 Falveolus

Schematic presentation of the interaction of , , and - radiation emitted by α-emitting particle with tissue From: Zunic and Rakic, 2016 A range of local energies (local dose) has little effect (A), a genetic effect (B) or a killing effect (C) on the tissue exposed to embedded DU particle. According to: Busby, C. , 2013. Random and irregular tissue damage and repair changes oxygen diffusion limit and proliferating cells change their metabolic phenotype from glycolytic to lipogenic. According to: Menendez and Lupu (2007).

Mathematical modelling approaches have become increasingly abundant in cancer research…

Many models of low-dose radiation risk assessment exist, with possibility of their combining • Depending on what is emphasized, epidemiological data, or biological mechanisms, there are contradictory conclusions regarding dose-response relationship • Change in apoptotic regulation is one of earliest responses to radiation events leading to radioadaptive/radioprotective tissue response • (Zunic, S. Cytological characteristics of lung washings from children in depleted uranium stroked region. J Biol Regul Homeost Agents, 2013; 27(4): 961 -7. • Zunic, S. Lupus erythematosus cell phenomenon in pediatric bronchoalveolar lavages: possible manifestation of early radioadaptive response in radiation induced alveolitis. J Biol Regul Homeost Agents. 2013; 27(2): 389 -98. 2013 -1).

The aim… • Among different models of low-dose radiation risk assessment that were tested, the aim of present study is to introduce a neural network model for dose-response relationship based on apoptotic parameters.

Method

Change in apoptotic regulation is one of earliest responses to radiation events leading to radioadaptive/radioprotective tissue response Apoptotic detection in cytocentrifuge preparations of bronchoalveolar lavage cell suspensions was evaluated by light microscopy using TUNEL in situ cytochemical method (Zunic et al, 2004).

Apoptotic parameters • Apoptotic capacity (AC) - the score is a numerical equivalent of tissue ability for apoptosis and removal of apoptotic bodies • Apoptotic index (AI) - a relative per-cent of apoptotic cells in relation to all cells observed Smoking exposure Nonsmokers 0 AC AI (%) 218. 29 56. 24 0. 07 0. 03 AC AI Smokers 1. 80± 1. 60 289. 55 50. 77 0. 15 0. 08 ↑ ↑ NSCLC 44. 81± 21. 33 150. 37 40. 61 0. 28 0. 04 ↓ ↑ Nonsmokers vs. smokers p<0. 05 Nonsmokers vs. NSCLC p<0. 05 p<0. 001 p<0. 05 p<0. 01 Smokers vs. NSCLC p<0. 001

Neural network design Smoking exposure (pack-years formula): Non-smokers: 0 Smokers: <2 Smokers with NSCLC: > 40 Adopted from Zunic, S; Rakic, Lj; Zunic-Bozinovski, S; Minic, N. Cytochemical and Apoptotic Markers of Tissue Remodeling. In: Frontiers In Cell Apoptosis Research. Editor: Scott R. Erlich, Nova Publishers, New York, 2007; 37 -104.

Response Dose response relationship ldr – low dose radiation Dose (~smoking & ldr exposure)

The model fits with hormesis/threshold model of tissue response to low-doses of ionizing radiation ● The method represents a step toward individualized screening and lung cancer risk assessment; ● Proposed model does not require an exact measuring of tissue doses in conditions of exposure to low doses of radiation, especially alpha emitting radioisotopes; ● This method enables quick orientation about the extent of damage of complex tissue regulatory mechanisms in situ, and indirectly, it may indicate the existence of adaptive, premalignant or malignant lesions.

Hormesis-Threshold Model There is no linearity expected due to bystander effect at low-doses of ionizing radiation • A threshold model would imply no effects of radiation up to certain level, after which risk rises linearly with dose – cumulative smoking & lowdoses of ionizing radiation exposure. • The radiation hormesis model, in contrast, shows beneficial effect at low levels of exposure; bimodal: AC↑, AI↑ → AC↓, AI↑.

The under-funding of health care • Long smoking history of patients with NSCLC is the reason why we believe that all smokers who undergo bronchology unit should be included in the fast screening procedure that we presented as an initial step in clinical examination. • Simplicity and low cost are advantages of this method (Žunić and Rakić, 2016).

Conclusion • Smoking exposure values are not informative enough for estimation of lung cancer risk in smokers. Inclusion of some parameters which represent apoptotic ability of tissue, using neural network model, make possible to represent tissue regulation under the influence of tobacco smoke and radiation effects at low doses. • Proposed model can be used for the purposes of screening and it is a step towards personalized medicine approach in the diagnosis of lung cancer.

The appeal • Declaration against use of any kind of nuclear weapons, including Depleted Uranium; • To start with multi-centric collaboration project on Lung Cancer Screening under ERASUMMIT Scientific Committee! • First results evaluation during next ERASUMMIT! • Expected conclusions may be implemented in tobacco induced diseases campaign.

Thank you for your attention! • Svetlana Žunić – Mob: +381 65 2208958 – E-mail: svetlana. zunic@gmail. com • Clinical Center of Serbia – Adress: Clinical Center of Serbia Center of Nuclear Medicine Visegradska 26, 11000 Belgrade, Serbia