| Abstract | Zbog relativno niske stope odgovora i skromnih ishoda primjene imunoterapije inhibitorima
kontrolnih točaka u recidivirajućem ili metastatkom karcinomu grkljana, potrebna je bolja
selekcija pacijenata, uz učinkovitije prediktivne i prognostičke biomarkere. Retrospektivna
analiza epidemioloških podataka provedena je na populaciji pacijenata koji su prema
uključujućim kriterijima dijagnosticirani, liječeni ili praćeni u KBC-u Split u razdoblju od 1.
siječnja 2015. do 31. prosinca 2018. godine. Rezultati istraživanja na 91 pacijentu su pokazali
visok udio pacijenata s primarnim sijelom područja glotisa (oko 80 %) te uznapredovalim
stadijima (oko 50 %) bolesti pri dijagnozi koji su većinom liječeni kirurški (više od 60 %),
nakon čega je kod oko 60 % pacijenata, a ovisno o faktorima rizika, provedena adjuvantna
terapija. Stope povrata bolesti kao i udaljene diseminacije bile su niske (4,4 % i 5,5 %), za
razliku od učestalosti pojave drugog primarnog tumora kod 23,1 % pacijenata. Mjesto
primarnog tumora (glotis), stadij III i IV te N2 i N3 su značajno utjecali na ukupno preživljenje.
Stadij N2 i N3 su neovisno značajno utjecali na ukupno preživljenje, uz 7,0 puta (p=0,0004)
viši rizik od smrti, kao i preživljenje bez znakova bolesti, uz 5,3 puta (p=0,0011) viši rizik za
pojavu bolesti. Kod uznapredovalih stadija bolesti (stadij III i IV) kirurškim se liječenjem u
odnosu na protokol očuvanja organa postiglo značajno dulje ukupno preživljenje (p=0,0290),
kao i preživljenje bez znakova bolesti (p=0,0388). Medijani petogodišnjeg kao i ukupnog
preživljenja nisu dosegnuti. Medijan preživljenja bez znakova bolesti iznosio je 7 godina.
Imunohistokemijska analiza ekspresije proteina STING, cGAS i imunološkog infiltrata
provedena je na uzorcima tumorskog tkiva 59 pacijenata koji su liječeni kirurški. Povišena
ekspresija proteina STING u tumorskim stanicama pozitivno je korelirala sa stadijem IV, pT3,
pT4, pN+, kao i slabijim stupnjem diferencijacije tumora (G2 i G3). Povišena ekspresija
proteina STING značajno je korelirala samo s nemetastatskim stadijem IV u modelu višestruke
logističke regresije (β=1,849, SE=±0,8643, p=0,0324). Rezultati ovog istraživanja su pokazali
da postoji povišena ekspresija proteina STING specifična za tumorske stanice u uzorcima tkiva
karcinoma grkljana u uznapredovalim stadijima bolesti što razlikuje karcinome grkljana od
drugih zloćudnih tumora podrijetla glave i vrata, a što bi moglo biti važno za razvoj i uvođenje
novih terapijskih mogućnosti u liječenju ovih pacijenata. |
| Abstract (english) | Due to the relatively low response rate and modest outcomes of immunotherapy targeting
checkpoint inhibitors in recurrent or metastatic laryngeal cancer, we need more precise patient
selection, along with more efficient predictive and prognostic biomarkers. A retrospective
analysis of epidemiological data was conducted on the population of patients who were
diagnosed, treated, or monitored at the University Hospital Split from January 1 2015, to
December 31 2018. Total of 91 patients were included in the analysis. The results showed a
high proportion of patients with primary lesions of the glottic area (approximately 80%) and
advanced stages (approximately 50%) of the disease at diagnosis. In most cases, patients were
treated surgically (> 60%). Approximately 60% of patients were treated adjuvantly, depending
on the risk factors. The recurrence rates and dissemination of the disease rates were low (4.4%
and 5.5%, respectively), in contrast to the occurrence of a second primary tumor in 23.1% of
patients. The location of the primary tumor (glottis), stage of the disease (stages III and IV),
and lymph node status (N2 and N3) had a statistically significant effect on overall survival.
Only N stage independently had a significant effect on overall survival, with a 7.0-fold
(p=0.0004) higher risk of death in N2 and N3 disease, as well as disease-free survival, with a
5.3 times (p=0.0011) higher risk of the disease recurrence. In advanced disease stages (stages
III and IV), surgical treatment compared to the organ preservation protocol resulted in a
significantly longer overall survival (p=0.0290) as well as survival without signs of disease
(p=0.0388). Despite the advanced stage of the disease at diagnosis, the median five-year
survival as well as overall survival were not reached. The median disease-free survival was 7
years. Fifty-nine tumor tissue samples from surgically treated patients were
immunohistochemically stained for STING, cGAS expression, and immune infiltration.
Elevated tumor cell-intrinsic STING expression was positively associated with stage IV, pT3,
pT4, and pN+ laryngeal cancers, and with higher histological grades (G2 and G3). Elevated
STING expression was significantly associated with stage IV cancer in a multiple logistic
regression model (β=1.849, SE=±0.8643, P=0.0324). The results of this study showed that there
is an elevated expression of the STING protein specific to tumor cells in tissue samples of
laryngeal carcinoma in advanced stages of the disease, which distinguishes laryngeal carcinoma
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from other malignant tumors of head and neck origin. This could be important for the
development and introduction of new therapeutic options for treating these patients. |
