THE IMPLICATIONS OF SMOKING IN PATIENTS WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE AND LUNG CANCER

45
O iginal pape s
TI S PHE MPLICATIONS OF MOKING IN ATIENTS WITH
CO P DHRONIC BSTRUCTIVE ULMONARY ISEASE AND
LCUNG ANCER
And eea-Nicole a Mălăescu , An onio-And ei Co ea , And eea Tî no eanu ,
1,2,6 1,6 4,6
Lucia-Ma ia Lo ean , Ma ius E emia , Ancua-Alina Cons an in , Flo in-Dumi u Mihălan ,
5,6 6 1,2 1,2,6
And eea-Roxana Flo escu1,3,6
1. Na ional Ins i u e o Pneumoph isiology "Ma ius Nas a", Bucha es ;
2. "Ca ol Da ila" Uni e si y o Medicine and Pha macy, Bucha es ;
3. “Vic o Babeș” Uni e si y o Medicine and Pha macy, Timișoa a;
4. G igo e T. Popa Uni e si y o Medicine and Pha macy, Iași, Romania;
5. "Iuliu Haieganu" Uni e si y o Medicine and Pha macy o Cluj-Napoca;
6. Ae Pu Romania, Bucha es , Romania.
Abs ac
Ch onic smoking emains one o he mos significan public heal h conce ns wo ldwide, se ing
as a majo isk ac o o espi a o y and ca dio ascula diseases, as well as a ious ypes o
cance . This s udy explo es he impac o smoking on ch onic obs uc i e pulmona y disease
(COPD) and lung cance , ocusing on aspec s such as p e alence, symp om se e i y, and
epidemiological co ela ions be ween hese condi ions. This s udy was conduc ed on a coho
o 164 pa ien s moni o ed a he Na ional Ins i u e o Pneumoph hisiology "Ma ius Nas a" in
Bucha es , iden i ying a significan associa ion be ween smoking and pulmona y disease
se e i y.
The findings sugges ha COPD may con ibu e o an inc eased isk o lung cance , possibly due
o sha ed pa hogenic mechanisms such as ch onic inflamma ion, oxida i e s ess, and issue
hypoxia. Conside ing he p o ound impac o hese diseases on pa ien s' quali y o li e and
mo ali y, he s udy highligh s he u gen need o effec i e p e en i e s a egies, including
smoking cessa ion p og ams, lung cance sc eening, and a mul idisciplina y app oach o COPD
managemen .
Keywo ds: Tobacco smoking, ch onic obs uc i e pulmona y disease, COPD, lung cance
Rezuma
Tabagismul ămâne una din e cele mai impo an e p obleme de sănă a e publică la ni el
mondial, se ind ca un ac o de isc majo pen u bolile espi a o ii și ca dio ascula e, p ecum și
pen u di e i e ipu i de cance . Aces s udiu explo ează impac ul uma ului asup a bolii
pulmona e obs uc i e c onice (BPOC) și cance ului pulmona , concen ându-se pe aspec e
p ecum p e alena, se e i a ea simp omelo și co elaiile epidemiologice din e aces e a eciuni.
In e nal Medicine 20 4 ol. X I No. 4 - www.s mi. o2X
/inmed-20 4-030610.2478 2
46
O iginal Pape s
In oduc ion
Smoking is conside ed a ch onic, elapsing
condi ion, wi h nico ine being i s p ima y
e iological ac o , one o he main
[1]
componen s o obacco. Nico ine is
esponsible o he pe sis en , olun a y
exposu e o he isks o smoking due o he
high le el o dependence i induces.
Addi ionally, he ha m ul effec s o smoking
a ise om inhaling o he subs ances ound in
obacco, including ca cinogens, oxic
chemicals, and ca bon monoxide . Some
[2]
ad e se heal h effec s associa ed wi h
smoking include malignan diseases in
a ious loca ions, ch onic condi ions such as
ch onic obs uc i e pulmona y disease,
ca dio ascula diseases, s oke, ype II
diabe es, and diso de s affec ing he
ep oduc i e sys em, immune sys em, eyes,
and pe iodon al heal h . A gene al
[3]
classifica ion o smoking s a us iden ifies
daily smoke s, cha ac e ized by he use o
obacco p oduc s e e y day o a leas h ee
mon hs; occasional smoke s, who use
obacco bu no daily; o me smoke s,
indi iduals who ha e abs ained om obacco
o a leas six mon hs; and, las ly, non-
smoke s, defined as hose who ha e smoked
ewe han 100 ciga e es o e hei
li e ime .
[1]
The s udy o he implica ions o ch onic
smoking on o e all heal h emains a p io i y
opic o global in e es , gi en he impac
smoking has on he pa hogenesis o
espi a o y, ca dio ascula , and a ious
malignan diseases. Ex ensi e esea ch on
he epidemiology o smoking suppo s his
claim by documen ing he significan ly high
p e alence o mo bidi y and mo ali y among
obacco use s.
Aces s udiu a os ealiza pe o coho ă de 164 de pacieni moni o izai la Ins i u ul Naional de
Pneumo iziologie „Ma ius Nas a” din Bucu eș i, iden ificând o asocie e semnifica i ă în e uma
și se e i a ea bolii pulmona e. Descope i ile suge ează că BPOC poa e con ibui la un isc c escu
de cance pulmona , posibil din cauza mecanismelo pa ogene comune, cum a fi inflamaia
c onică, s esul oxida i și hipoxia isula ă. A ând în ede e impac ul p o und al aces o boli
asup a cali ăii ieii și mo ali ăii pacienilo , s udiul e ideniază ne oia u gen ă de s a egii
p e en i e eficien e, inclusi p og ame de enuna e la uma , sc eening pen u cance ul
pulmona și o abo da e mul idisciplina ă a managemen ului BPOC.
Cu in e cheie: uma ul de u un, boală pulmona ă obs uc i ă c onică, BPOC, cance
pulmona .
47
O iginal pape s
Globally, ou o a popula ion o 8.1 billion
people, 1.3 billion a e smoke s, esul ing in a
smoking p e alence o 18% wo ldwide in he
pas yea . Romania anks 18 h in Eu ope, wi h
a smoking p e alence o 27.9%. Up o hal o
obacco use s die om a smoking- ela ed
condi ion . Smoking anked second in 2021
[4]
among he leading isk ac o s influencing he
global bu den o disease, ollowing ele a ed
blood p essu e . Ex ensi e s udies ha e
[5]
illus a ed he in ol emen o smoking in he
leading causes o p e en able dea h. One
indica o o smoking's influence on a
popula ion is lung cance , wi h 70-90% o lung
cance dea hs occu ing among smoke s.
O he smoking- ela ed condi ions ha impac
mo ali y include COPD in bo h sexes, la yngeal
and esophageal cance in women, and ao ic
aneu ysm in men . Fu he mo e, he main
[6]
diseases discussed in his s udy, COPD and
lung cance , a e among he op causes o
dea h, anking 4 h and 9 h globally in 2021 .
[5]
Ch onic Obs uc i e Pulmona y Disease
Ch onic obs uc i e pulmona y disease is a
long- e m lung condi ion p ima ily
cha ac e ized by dyspnea and cough, wi h o
wi hou spu um p oduc ion, esul ing om
he p og essi e obs uc ion o he ai ways
due o b onchi is, b onchioli is, and/o
emphysema. I is diagnosed h ough
spi ome y, whe e a pos -b onchodila o
Tiffeneau index o less han 0.7 confi ms he
condi ion. The leading en i onmen al ac o
con ibu ing o COPD de elopmen is
smoking; howe e , o he con ibu ing ac o s
include en i onmen al pollu ion, abno mal
lung de elopmen , and gene ic ac o s, such
as he SERPINA1 gene mu a ion, which
causes -1 an i ypsin deficiency .α [7]
Tobacco inhala ion dis up s pulmona y
homeos asis, leading o bo h s uc u al and
unc ional al e a ions.
Ch onic smoking induces oxida i e s ess,
ai way inflamma ion, cellula senescence,
and cell dea h, all o which play a ole in he
pa hophysiology o COPD .
[8]
Reac i e oxygen species (ROS) play
physiological oles in mic obial de ense,
mi ochond ial espi a ion, and in e cellula
signaling. Oxida i e s ess occu s when ee
adical exposu e exceeds he an ioxidan
de ense sys em's capaci y, damaging
p o eins, lipids, and deoxy ibonucleic acid
(DNA) . This imbalance be ween oxidan s
[9]
and an ioxidan s p omo es inflamma ion by
up egula ing he exp ession o inflamma ion-
ela ed genes, inc easing mucus sec e ion,
and inac i a ing an ip o eases . The lungs
[8]
a e especially p one o oxida i e s ess due o
hei high oxygen concen a ion, ich blood
supply, and cons an exposu e o ex e nal
oxins. Rema kably, ciga e e smoke con ains
mo e han 10¹⁵ ee adicals in a single
inhala ion .
[9]
When i i an s, such as hose ound in ciga e e
smoke, en e he ai ways, hey ec ui and
ac i a e cells such as neu ophils, eosinophils,
mac ophages, lymphocy es, and epi helial
cells, eleasing chemo ac ic ac o s ha
ini ia e o in ensi y inflamma ion. I has been
shown ha inflamma ion in he small ai ways
o COPD can p og ess o many yea s be o e
symp oms appea . Al hough inflamma ion
affec s all a eas o he ai ways, ai flow
obs uc ion is p ima ily caused by damage o
he small ai ways. The e o e, he symp oms
a e p eceded by b onchioli is wi h small ai way
obs uc ion, pe iphe al dis ibu ion o goble
cells, pe ib onchiola fib osis, and hickening o
he b onchial smoo h muscle issue, wi h
emphysema possibly also de eloping.
Addi ionally, he numbe o submucosal glands
inc eases, and cilia ed epi helial cells a e
eplaced by goble cells, leading o mucus
hype sec e ion. The in ol emen o he
In e nal Medicine 20 4 ol. X I No. 4 - www.s mi. o2X
48
O iginal Pape s
inflamma o y esponse in he pa hogenesis o
COPD has he apeu ic implica ions o he use
o inhaled co icos e oids, which ha e also
been shown o educe mo ali y . Beyond
[10]
localized inflamma ion in he lungs and
ai ways, sys emic in ol emen o he
inflamma o y esponse has also been
documen ed, wi h ele a ed le els o C- eac i e
p o ein (CRP), fib inogen, and leukocy es. This
inflamma ion pe sis s sub ly e en a e
smoking cessa ion .
[11]
Lung Cance
The mos common loca ion o cance
associa ed wi h obacco use is he lungs .
[13]
The isk o lung cance is 10 o 30 imes
highe among smoke s, while smoking
cessa ion significan ly educes his isk o e
ime . Al hough nico ine is he well-known
[14]
subs ance in ciga e e smoke, i is p ima ily
in ol ed in addic ion, and he e a e
p edominan ly s udies ha ha e denied i s
in ol emen in he pa hogenesis o lung
cance .
The e a e o e 5,000 componen s in ciga e e
smoke, 73 o which a e conside ed
ca cinogenic . These include polycyclic
[12]
a oma ic hyd oca bons, obacco-specific
ni osamines, a oma ic amines, benzene,
o maldehyde, and ace aldehyde, all o which
ha e di ec effec s on DNA in eg i y. In
addi ion o hese ca cinogenic subs ances,
an impo an ole in he e iology o lung
cance is played by he inflamma o y
changes in he lungs associa ed wi h he
ac i a ion o nuclea ac o kappa B (NF-kB)
and he p omo ion o pulmona y g ow h and
de elopmen . Tobacco exposu e leads o
[13]
an inc eased numbe o soma ic mu a ions,
wi h he a e age being se e al housand
mu a ions in a b onchial cell .
[15]
Lung cance o igina es in basal epi helial
cells and includes non-small cell lung cance
(NSCLC), which accoun s o 85% o cases,
and small cell lung cance (SCLC), bo h o
which a e closely linked o smoking. The main
ypes o NSCLC a e adenoca cinoma in 40%
o cases, la ge cell ca cinoma in 10% o cases,
and squamous cell ca cinoma in he
emaining 30% o pa ien s .
[16]
The T iad o Mo ali y (Smoking – COPD –
Lung Cance )
Aside om he sha ed e iology o obacco
use, COPD is ecognized as an independen
isk ac o o lung cance , pa icula ly o
squamous cell ca cinoma. This finding mos
likely a ises om he common mechanisms in
hei pa hogenesis, which in ol e he
accele a ed unc ional and mo phological
deg ada ion o he lungs in smoke s, gene ic
p edisposi ion, oxida i e s ess wi h di ec
effec s on DNA deg ada ion, o indi ec
effec s h ough he ini ia ion o main enance
o inflamma ion, epigene ic changes, and
g ow h ac o s .
[16]
49
O iginal pape s
Ch onic obs uc i e pulmona y disease is a
di ec isk ac o o lung cance , p ima ily
h ough i s in ol emen in inflamma ion. In
he pa hological p ocess leading om COPD
o cance , he exagge a ed exp ession o NF-
kB leads o he supp ession o he p o ein 53
kilodal ons (p53) gene, while he
phosphoinosi ide 3-kinase (PI3K) pa hway
d i es cell p oli e a ion and supp esses
apop osis. Addi ionally, he abe an
exp ession o g ow h ac o s in ol ed in
issue emodeling plays a ole . Besides he
[16]
ch onic inflamma ion in COPD, ano he
mechanism in ol ed in ca cinogenesis is
ini ia ed by hypoxia gene a ed by pulmona y
hype infla ion and b onchial obs uc ion,
which ac i a es a ansc ip ion ac o known
as hypoxia-inducible ac o 1-alpha (HIF- ).α
This ac o affec s mo e han 200 genes and
can inhibi apop osis .
[17]
Lung cance mo ali y is among he highes
due o la e diagnosis and limi ed ea men
efficacy. This si ua ion could be imp o ed
h ough imaging sc eening o COPD pa ien s
o lung cance using compu ed omog aphy .
[18]
Addi ionally, seconda y p ophylaxis wi h
a ge ed he apies could be used in he u u e
o educe he isk o lung cance de elopmen .
One such ini ia i e would be educing oxida i e
s ess h ough he adminis a ion o i amin E,
C, o NAC (N-ace ylcys eine), al hough u he
s udies a e needed o documen hei
effec i eness .
[16]
Al hough he exac mechanisms h ough
which COPD influences he de elopmen o
lung cance a e no ye ully unde s ood, i is
ce ain ha hese wo pa hologies a e
equen ly associa ed. Fu he analysis is
needed o de e mine whe he COPD is an
indi idual isk ac o o lung cance o i he
wo pa hologies a e complica ions o he
same disease, namely ch onic smoking .
[19]
Me hods
The epidemiological s udy p esen ed is a
desc ip i e, c oss-sec ional analysis
designed o assess he associa ion be ween
ch onic smoking and he p esence o
como bidi ies, specifically lung cance and
ch onic obs uc i e pulmona y disease. The
s udy included 164 pa ien s unde medical
supe ision a he Na ional Ins i u e o
Pneumoph hisiology "Ma ius Nas a",
Bucha es . Pa ien selec ion was based on
medical eco ds, and he s udy g oups we e
defined acco ding o he ollowing inclusion
c i e ia:
lG oup 1: Pa ien s diagnosed wi h lung
cance wi hou a COPD diagnosis.
lG oup 2: Pa ien s diagnosed wi h COPD
wi hou an oncological diagnosis.
lG oup 3: Pa ien s diagnosed wi h bo h
COPD and lung cance .
The diagnosis o COPD in pa ien eco ds was
ini ially suspec ed due o symp oms o
ch onic b onchi is and was la e confi med
h ough spi ome y. Lung cance was
diagnosed based on medical documen a ion,
including discha ge summa ies om
pulmonology o oncology depa men s o
o he medical uni s whe e he diagnosis was
es ablished.
The s udy Objec i es include:
1. Analyze demog aphic and clinical
cha ac e is ics o pa ien s wi h COPD
and/o lung cance , including sex, age,
and place o esidence.
2. Iden i y key isk ac o s o bo h diseases,
wi h a ocus on smoking and occupa ional
exposu e o espi a o y haza ds.
3. Assess he ole o COPD as an independen
isk ac o o lung cance .
4. In es iga e he associa ion be ween
obacco use and he p e alence o COPD
and lung cance .
5. E alua e COPD se e i y in ela ion o
In e nal Medicine 20 4 ol. X I No. 4 - www.s mi. o2X

50
O iginal Pape s
smoking his o y, pa icula ly he impac
o cumula i e obacco exposu e (pack-
yea index) on disease p og ession.
6. Iden i y he mos common symp oms
associa ed wi h COPD and lung cance .
7. Examine he ole o ch onic inflamma ion
as a po en ial sha ed mechanism in he
pa hogenesis o bo h condi ions.
8. Analyze ele an biological pa ame e s
linked o COPD and lung cance .
9. Assess he p e alence o common
como bidi ies, such as b onchiec asis,
ischemic hea disease, hype ension,
and diabe es melli us, which may also
ha e smoking as a isk ac o .
10.Suppo he de elopmen o sc eening
and p e en ion p og ams and p omo e a
mul idisciplina y app oach o he
diagnosis and managemen o COPD and
lung cance .
Exclusion c i e ia we e es ablished o ensu e
he alidi y and accu acy o he s udy esul s.
Pa ien s we e excluded i hey had:
lIncomple e smoking his o y da a;
lIn e s i ial lung diseases ha could affec
lung unc ion and influence cance isk;
lAc i e o sequelae pulmona y ube culosis,
o p e en in e e ence be ween ube -
culosis- ela ed lung lesions and COPD/lung
cance ;
lO he obs uc i e pulmona y diseases
(e.g., b onchial as hma), o main ain a
clea dis inc ion be ween COPD and
simila condi ions;
lSe e e ca dio ascula diseases (acu e
myoca dial in a c ion, ad anced hea
ailu e, significan a hy hmias) ha could
impac clinical se e i y;
lO he ypes o cance ;
lDeclined o p o ide in o med consen .
The da a collec ed o he s udy we e
ex ac ed om pa ien eco ds and included
demog aphic ac o s (age, sex, place o
esidence, occupa ional exposu e), smoking
his o y (smoking s a us — e e -smoke ,
ne e -smoke ), pack-yea s index, and clinical
cha ac e is ics (COPD se e i y based on he
Global Ini ia i e o Ch onic Obs uc i e Lung
Disease (GOLD) classifica ion, his ological
ype o lung cance , symp oms, weigh , BMI –
body mass index, and blood es esul s). A
ne e -smoke is an indi idual who has ne e
smoked o , a mos , has expe imen ed wi h
smoking occasionally bu ne e on a daily
basis and has no consumed mo e han 100
ciga e es in o al. In ou s udy, he e m e e -
smoke includes bo h cu en smoke s —
indi iduals who had been smoking o a leas
six mon hs a he ime o ques ioning — and
o me smoke s, defined as hose who had
comple ely qui smoking o a leas six
mon hs. These da a we e en e ed in o an
Excel da abase and subjec ed o s a is ical
analysis o gene a e a desc ip i e o e iew
51
O iginal pape s In e nal Medicine 20 4 ol. X I No. 4 - www.s mi. o2X
Table 1. Socio-demog aphical and clinical cha ac e is ics
52
O iginal Pape s
o he pa ien coho s. S a is ical analysis was
pe o med using IBM SPSS e sion 26.0. We
conduc ed equencies es s, independen -
es , chi-squa e es and co ela ion analyses.
The esul s we e p esen ed as mean ±
s anda d de ia ion (SD) and we conside ed a
p- alue lowe han 0.05 and R alues lowe
han 0.01 o be s a is ically significan .
The s udy was app o ed by he E hics
Commi ee o he Na ional Ins i u e o
Pneumoph hisiology "Ma ius Nas a".
Resul s
The s udy included 164 pa ien s, ca ego ized
in o h ee g oups: pa ien s wi h COPD, pa ien s
wi h lung cance , and pa ien s diagnosed wi h
bo h condi ions. The a e age age o all
pa ien s was 65.68 yea s, wi h no significan
diffe ences in mean age among he selec ed
g oups (Table 1).
Ch onic Smoking
When compa ing e e -smoke s and ne e -
smoke s, we obse ed a significan ly highe
p opo ion o males among e e -smoke s
(72.9%), whe eas emales p edomina ed
among ne e -smoke s (77.4%). Al hough
e e -smoke s had a lowe a e age BMI (27.53
Kg/m s. 30.73 Kg/m ), his diffe ence was
22
no s a is ically significan . Simila ly, he e
we e no no able diffe ences in blood
p essu e, hea a e, o oxygen sa u a ion in
ambien ai .
Al hough place o esidence heo e ically
influences exposu e o inhaled espi a o y
oxins, his ac o may ha e been influenced
by he ins i u e's u ban loca ion, whe e da a
collec ion ook place.
Lung cance cha ac e is ics we e also
analyzed based on smoking s a us. Among
e e -smoke s, lung cance was mo e
equen ly loca ed cen ally (62.5%),
whe eas in ne e -smoke s, cen al and
pe iphe al umo loca ions we e equally
dis ibu ed. In ne e -smoke s, he igh
hemi ho ax was he p edominan si e
(69.56%), while in e e -smoke s, he e was
no significan diffe ence in umo loca ion
ela i e o he midline o he ho ax.
Ch onic Obs uc i e Pulmona y Disease
The socio-demog aphic analysis e ealed a
significan gende diffe ence in COPD
p e alence, wi h a highe occu ence among
men (74%) compa ed o women (33%).
The p e alence o ch onic smoking among
COPD pa ien s was also assessed. O he 107
pa ien s wi h COPD, 93 we e e e -smoke s
(86.92%), while 14 we e ne e -smoke s
(13.08%) (Figu e 1). The se e i y o COPD,
assessed using GOLD s ages based on o ced
expi a o y olume in 1 second (FEV1) alues,
did no show s a is ically significan
diffe ences be ween e e -smoke s and
ne e -smoke s (p = 0.328). Howe e , e e -
smoke s had a highe p e alence o GOLD
s age III-IV compa ed o ne e -smoke s
53
O iginal pape s In e nal Medicine 20 4 ol. X I No. 4 - www.s mi. o2X
Figu e 1. P e alence o ch onic smoking based on COPD diagnosis
Figu e 2. Dis ibu ion o smoking p e alence by GOLD s ages
0
Non-COPD
Pe cen (%)
20
40
60
80
100
30.91%
69.09%
COPD
13.08%
86.92%
Ne e -smoke s
E e -smoke s
0
I
Pe cen (%)
10
20
30
40
50
21.43%
17.20%
Ne e -smoke s
E e -smoke s
II
42.86%
32.26%
14.29%
III
33.33%
IV
21.43%
17.20%
GOLD S ages
60
O iginal Pape s
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