Introdução: A quimiorradioterapia (QRT) concomitante baseada em cisplatina é uma opção de tratamento empregada para os pacientes com carcinoma epidermoide de cabeça e pescoço (CECCP) localmente avançado e com bom performance status, seja em caráter adjuvante ou definitivo. O ganho de sobrevida com esta modalidade de tratamento é acompanhado de aumento das toxicidades agudas em comparação com a radioterapia isolada. A ocorrência de toxicidades tardias é menos reportada na literatura e incluem xerostomia, disfagia, hipotireoidismo, ototoxicidade, fístula/necrose cutânea, dentre outras. Tais sequelas tardias podem comprometer a qualidade de vida do sobrevivente ao CECCP. Objetivos: Verificar a prevalência de toxicidades tardias em sobreviventes ao CECCP tratados com QRT baseada em cisplatina. Métodos: Estudo transversal, uni-institucional, que incluiu de forma sequencial pacientes acima de 18 anos, tratados para CECCP (sítios primários: nasofaringe, orofaringe, cavidade oral, hipofaringe e laringe) e que haviam recebido QRT adjuvante ou definitiva, baseada em cisplatina. Estes pacientes estavam em seguimento há pelo menos 2 anos, sem evidência de doença. Os pacientes realizaram audiometria, endoscopia digestiva alta (EDA), nasofibrolaringoscopia da deglutição (NFL), exames laboratoriais (toxicidade tireoidiana e renal). Os pacientes incluídos também foram examinados clinicamente e as toxicidades apresentadas foram graduadas de acordo com a escala de toxicidades tardias do RTOG/EORTC. Os sobreviventes foram ainda avaliados quanto à percepção das toxicidades através de um inventário de sintomas e responderam questionários de qualidade de vida. Resultados: De janeiro de 2014 a fevereiro de 2017, 120 pacientes assinaram o TCLE. A idade mediana dos pacientes é 59 anos (21-78), com predomínio do sexo masculino (73%) e da cor branca (58%). Antecedente de tabagismo foi referido por 80% da amostra e de etilismo por 63%. Referente ao sítio primário, a maioria dos pacientes apresenta tumor em orofaringe (42%), seguido por laringe (23%) e cavidade oral (19%). O tempo de seguimento mediano é 42 meses (24-125). Há predomínio de pacientes com doença localmente avançada, tumores T3/T4 em 75% da amostra e N+ em 72%. A dose mediana de cisplatina recebida durante a concomitância foi 300 mg/m² (100-300) e de radioterapia foi 70 Gy (60-70,4). A QRT foi oferecida em caráter adjuvante em 49% da amostra. As toxicidades mais relatadas pelos pacientes foram: xerostomia (83%), alteração na voz (74%), saliva pegajosa (73%) e disfagia (73%). Ao se graduar as toxicidades conforme escala do RTOG/EORTC, verificou-se que a maioria das toxicidades apresentadas eram de graus leves, 1 ou 2. EDA encontrou estenose faríngea em 10% dos pacientes e NFL identificou fibrose em 37% dos sobreviventes. Dos pacientes submetidos a audiometria, 42% apresentaram perda auditiva de possível causa ototóxica. Cerca de 14% dos sobreviventes apresentam clearance de creatinina estimado < 60 mL/min/1,73m². Conclusões: Toxicidades tardias foram frequentemente reportadas pelos sobreviventes ao CECCP após QRT, porém, na maioria das vezes, de intensidade leve (graus 1 ou 2). Após a QRT, um seguimento cuidadoso é essencial para diagnóstico precoce e reabilitação a essas toxicidades, a fim de preservar a funcionalidade e qualidade de vida dos pacientes / Background: Cisplatin based CRT is the standard therapy for patients with locally advanced HNSCC with good performance status either as adjuvant or as definitive treatment. The survival gain with this treatment modality is accompanied by an increase in acute toxicities in comparison with isolated radiotherapy. The occurrence of LT is less reported in the literature and includes xerostomia, dysphagia, hypothyroidism, ototoxicity, cutaneous fistula / necrosis, among others. Such late sequelae may compromise the survivor\'s quality of life. Endpoints: To verify the prevalence of late toxicities in HNSCC survivors treated with cisplatin based CRT. Methods: A cross-sectional study that sequentially included patients over 18 years of age who were previously treated for HNSCC (primary sites: nasopharynx, oropharynx, oral cavity, hypopharynx and larynx) and who had received either adjuvant or definitive cisplatin based CRT. These patients were in follow-up for at least 2 years, with no evidence of disease. The patients underwent audiometry, upper GI endoscopy, nasopharyngolaryngoscopy (NPL), laboratory tests (thyroid and kidney toxicity). The included patients were also clinically assessed for mucous membrane, skin, subcutaneous tissue, salivary gland, larynx and esophagus LT according to the RTOG/EORTC Late Radiation Morbidity Scoring Schema. All patients answered a questionnaire about their perception of LT through a symptoms inventory and also answered QoL questionnaires. Results: From January 2014 to February 2017, 120 patients signed the informed consent form. The mean age of the patients is 59 years (21-78), predominantly male (73%) and white (58%). Previous smoking habits were reported by 80% of the sample and alcohol consumption by 63%. Most common primary sites were oropharynx (42%), followed by larynx (23%) and oral cavity (19%). The median follow-up time is 42 months (24-125). There was a predominance of locally advanced disease, T3 / T4 tumors in 75% of the sample and N + in 72%. The median cisplatin dose during concomitance was 300 mg/m² (100-300) and the median radiotherapy delivered dose was 70Gy (60-70.4). CRT was delivered as an adjuvant treatment in 49% of the sample. The most frequently selfreported LT were xerostomia (83%), voice disorders (74%), sticky saliva (73%) and dysphagia (73%). Assessing the toxicities according to the RTOG / EORTC scale most of them were mild, grade 1-2. Upper GI endoscopy diagnosed stenosis in 10% of the patients and NPL identified fibrosis in 37% of the survivors. Audiometry identified ototoxic hearing loss in 42% of the sample. About 14% of the survivors present chronic kidney disease (an estimated creatinine clearance < 60 mL/min/1.73m²). Conclusion: High rates of self-reported LT were detected although most of them seem to be mild. After CRT, a close follow-up of HNSCC patients is essential for early diagnosis, treatment of these late sequelae and rehabilitation, in order to preserve QoL and functionality and to avoid lifethreatening conditions and social reclusion

Head and neck cancer is the fifth most common cancer worldwide with an estimated annual global incidence of over 500 000 cases. These malignant tumours develop in the mucosal linings of the upper respiratory tract or in the salivary glands. The most common sites are in the oral cavity and larynx. Treatment modalities comprising surgery and chemoradiotherapy have improved significantly during the last 20 years, but not the long-term survival of patients. The aim of this thesis was to study the different factors affecting tumour growth in head and neck cancer that may have clinical implications in the future. Factors involving apoptosis, cell cycle activity, inflammation, and enzyme activity were of special interest. The results of the thesis indicate that patients with malignant salivary gland tumours having the lowest level of actively replicating cells have the best prognosis. The largest amount of replicating cells in tongue cancer specimens was found in the peripheral areas of tumour nests. Metallothionein, a protein that can hinder apoptosis, was found in excess in the same areas, whereas apoptosis activity was considerably lower. Taken together, these results indicate that the most aggressive cancer cells are found in the peripheral areas of tumours where apoptosis may be hindered. The expression of the death receptor Fas was higher in tongue cancer specimens than in normal mucosa. The expression of this receptor was studied further in two cell lines established from oral cancers. When a low dose of cisplatin was added to cell cultures, the Fas expression was enhanced in both cell lines and, furthermore, the Fas-induced apoptosis was increased in one of the cell lines. The results show that a common chemotherapeutic drug given in a low, less toxic dose may enhance receptor-mediated apoptosis of cancer cells. Malignant solid tumours are often distinguished by an increased proteolytic activity resulting in invasive growth, neo-angiogenesis, and metastases. This activity is conducted by enzymes that are secreted from tumour cells, or from normal cells in the tumour microenvironment. The regulation of enzyme secretion may be mediated by cytokines, small signalling molecules also present in cancer tissue. The results of this thesis show that two cytokines can synergistically induce enzyme secretion (matrix metalloproteinase-1 and -9) from oral cancer cells. Cytokine tumour necrosis factor-alpha and hepatocyte growth factor added alone to cell cultures strongly stimulated secretion of these enzymes. Thus, the tested cytokines, which are commonly secreted by fibroblasts and immune cells, may promote tumour growth. This thesis has contributed to an increased understanding of factors affecting tumour growth in head and neck cancer. The upcoming cancer therapies will be based on the increasing knowledge of these and other aberrant cellular mechanisms that may vary between different cancer forms.

The impact was assessed of clinical and nutritional factors on prognosis of 107 oesophageal cancer patients treated with neoadjuvant chemoradiotherapy (CHRT) and surgery. Individualised nutritional support, according to grade of dysphagia was carried out in all the patients. Serum leptin, soluble leptin receptors (SLR), TNF, IGF and fatty acid (FA) profiles in plasma phosphatidylcholine (PC) were studied as well. Addition of paclitaxel to carboplatin and continual fluorouracil significantly increased toxicity without influencing efficacy of the treatment. Post-operative node negativity, grade of dysphagia, weight loss and serum albumin were proved to be prognostic factors of survival and time to progression. CHRT led to decrease of SLR, palmitoleic and oleic acid and increase of n-3 polyunsaturated FA in PC. Lower concentrations of SLR were associated with improved survival of the patients. Key words: oesophageal cancer, neoadjuvant chemoradiotherapy, weight loss, paclitaxel, albumin, soluble leptin receptor, fatty acids

<p>Karcinom bronha je danas u svetu najče&scaron;ći uzrok smrti povezanih sa malignim bolestima. U XX veku je registrovan značajan porast kako incidence, tako i mortaliteta karcinoma bronha u većini zemalja. Medijana&nbsp; preživljavanja u svim stadijumima bolesti se značajno pobolj&scaron;ala poslednjih godina XX veka, ali nedovoljno u odnosu na očekivano. U najvećem broju slučajeva, bolest se otkriva u uznapredovalom stadijumu, kada je radikalno hirur&scaron;ko lečenje kao optimalan vid lečenja nemoguće. Određivanje stadijuma bolesti (stejdžing) je najbitniji segment u evaluaciji svakog bolesnika s karcinomom bronha. Utvrđivanje zahvaćenosti medijastinalnih&nbsp; limfnih čvorova karcinomom je od posebne važnosti, jer je u velikom broju slučajeva upravo nodalni status faktor koji određuje svsishodnost primene hirur&scaron;kog lečenja, radioterapije i hemioterapije, a samim tim i jedan od bitnih faktora prognoze bolesnika sa nemikrocelularnim karcinomom bronha NSCLC. Bolesnici sa dokazanom zahvaćeno&scaron;ću N2 medijastinalnih limfnih čvorova se svrstavaju u IIIA stadijum NSCLC koji je potencijalno resektabilan, dok se bolesnici sa dokazanom zahvaćeno&scaron;ću N3 medijastinalnih limfnih čvorova svrstavaju u IIIB stadijum NSCLC, koji se smatra neresektabilnim. Cilj ove doktorske disertacije je bio da se utvrdi da li postoje prognostički značajni faktori za rezultat lečenja medijastinoskopski dokazanog N2 i N3 stadijuma NSCLC. Studija je bila nerandomizovana, delom retrospektivnog, a delom prospektivnog karaktera. U ispitivanje je uključeno 60 bolesnika lečenih u Institutu za plućne bolesti Vojvodine tokom&nbsp; 2006., 2007. i 2008. godine. Kod svih uključenih bolesnika medijastinoskopijom je dokazana propagacija NSCLC u medijastinalne limfne čvorove. U radu su analizirani sledeći faktori: pol, starost, ECOG performans status, pridružena hronična opstruktivna bolest pluća (HOBP), pridruženo kardiovaskularno oboljenje sa simtomatologijom klasifikovanom prema NYHA, T faktor, lokalizacija i broj medijastinoskopski dokazanih metastatski zahvaćenih limfnih čvorova, vrsta primenjenog&nbsp; lečenja (hemioradioterapija, hemioterapija, operacija), rezultat lečenja (odgovor na terapiju i preživljavanje). Univarijantnom analizom je utvrđeno da su kod bolesnika sa medijastinoskopski dokazanim N2 i N3 stadijumom NSCLC prognostički faktori koji su imali uticaj na lo&scaron;ije preživljavanje bili: ECOG PS 2 (p=0,00000), pridruženo kardivaskularno oboljenja sa simptomatologijom klase NYHA II (p=0,00113), zahvaćenost kontralateralnih medijastinalnih medijastinalnih limfnih čvorova (N3 stadijum) (p=0,000003), dok je uticaj zahvaćenosti vi&scaron;e pozicija ipsilateralnih medijastinalnih limfnih čvorova (multi station N2) bio na granici statističke značajnosti (p=0,05385). Utvrđeno je da bolesnici sa N2 i N3 stadijumom NSCLC lečeni hemioradioterapijom imaju bolju stopu odgovora na primenjenu terapiju u odnosu na bolesnike lečene samo hemioterapijom (p=0,03118), kao i da operativno lečenje primenjeno kod bolesnika koji su imali dobar odgovor na sprovedenu terapiju ima statistički značajan uticaj u vidu boljeg preživljavanja (p=0,00121). Univarijantnom analizom nije utvrđen značajan uticaj sledećih faktora na preživljavanje bolesnika sa N2 i N3 stadijomom NSCLC: pol, starost, pridružena HOBP, skvamozni tip NSCLC i T faktor. Multivarijantnom analizom su kao nezavisni prognostički faktori na preživljavanje bolesnika sa N2 i N3 stadijumom NSCLC utvrđeni klinički N status (bolje preživljavanje ima N2 u odnosu na N3 stadijum) i sprovedena terapija (bolje preživljavanje ima hemioradioterapija u odnosu na hemioterapiju). Dobijeni rezultati navode nas na zaključak da su pozicija i broj zahvaćenih pozicija medijastinalnih limfnih čvorova, koji su utvrđeni medijastinoskopski, kao i sprovođenje multimodalnog lečenja ključni prognostički faktori za preživljavanje bolesnika sa N2 i N3 stadijumom NSCLC.</p> / <p>Lung&nbsp; cancer&nbsp; is&nbsp; the&nbsp; most&nbsp; common cause of cancer&nbsp; related mortality&nbsp; worldwide.&nbsp; Increase&nbsp; in&nbsp; both&nbsp; incidence&nbsp; and mortality&nbsp; of&nbsp; lung&nbsp; cancer&nbsp; was&nbsp; registered&nbsp; throughout&nbsp; 20th century. The median survival in every stage of lung cancer has been improved in last years of 20th century but it is still not satisfactory. In most cases, lung cancer is diagnosed in advanced&nbsp; stage&nbsp; when&nbsp; surgical&nbsp; treatment&nbsp; as&nbsp; the&nbsp; optimal approach&nbsp; is&nbsp; not&nbsp; possible. Staging&nbsp; is&nbsp; the&nbsp; most&nbsp; important element&nbsp; in&nbsp; the&nbsp; evaluation&nbsp; of&nbsp; every&nbsp; lung&nbsp; cancer&nbsp; patient. Mediastinal lymph node involvement is crucial, because in most of the cases nodal staging is factor which determines appropriate use of surgery, radiotherapy and chemotherapy and it is one of the important factors influencing prognosis of lung cancer patients. Patients with proven involvement of ipsilateral&nbsp; mediastinal&nbsp; lymph&nbsp; nodes&nbsp; (N2&nbsp; stage)&nbsp; are categorized&nbsp; in&nbsp; IIIA&nbsp; stage&nbsp; which&nbsp; is&nbsp; considered&nbsp; to&nbsp; be potentially resectable, and patients with proven involvement of&nbsp; contralateral&nbsp; mediastinal&nbsp; lymph&nbsp; nodes&nbsp; (N3&nbsp; stage)&nbsp; are categorized&nbsp; in&nbsp; IIIB&nbsp; stage,&nbsp; which&nbsp; is&nbsp; considered&nbsp; to&nbsp; be nonresectable. The aim of this study was the determination of&nbsp; significant&nbsp; prognostic&nbsp; factors&nbsp; that&nbsp; have&nbsp; influence&nbsp; on treatment&nbsp; and&nbsp; survival&nbsp; of&nbsp; non-small&nbsp; cell&nbsp; lung&nbsp; cancer (NSCLC)&nbsp; patients&nbsp; in&nbsp; stage&nbsp; N2&nbsp; and&nbsp; N3.&nbsp; Study&nbsp; was nonrandomized,&nbsp;&nbsp; partially&nbsp;&nbsp; retrospective&nbsp;&nbsp; and&nbsp;&nbsp; partially prospective. It included 60 patients treated at the Institute for Pulmonary&nbsp; Diseases&nbsp; of&nbsp; Vojvodina&nbsp; during&nbsp; 2006,&nbsp; 2007&nbsp; and 2008. Cancer involvement of mediastinal lymph nodes was determined by mediastinoscopy in every patient. In study we analyzed following factors: gender, age, ECOG performance&nbsp;&nbsp; status,&nbsp;&nbsp; associated&nbsp;&nbsp; chronic&nbsp;&nbsp; obstructive pulmonary&nbsp; disease&nbsp; (COPD),&nbsp; associated&nbsp; cardiovascular disease with symptoms graded by NYHA classification, T status, position and number of involved mediastinal lymph nodes,&nbsp; applied&nbsp; treatment&nbsp; (surgery,&nbsp; chemoradiotherapy, chemotherapy alone), treatment result (response to treatment and&nbsp; survival).&nbsp; Prognostic&nbsp; factors&nbsp; for&nbsp; poorer&nbsp; survival&nbsp; on univariant analysis were ECOG PS 2 (p=0,0000), associated cardiovascular&nbsp;&nbsp; disease&nbsp;&nbsp; with&nbsp;&nbsp; symptoms&nbsp;&nbsp; NYHA&nbsp;&nbsp; II (p=0,00113)&nbsp; and&nbsp; involvement of&nbsp; contralateral&nbsp; mediastinal lymph nodes (N3 stage) (p=0,00003) while multi station N2 disease was borderline significant at level of p=0,05385. It was determined that patients treated with chemoradiotherapy achieved better response to treatment compared to patients treated&nbsp; with&nbsp; chemotherapy&nbsp; alone&nbsp; (p=0,03118).&nbsp; Univariant analyses&nbsp; did&nbsp; not&nbsp; confirm&nbsp; significance&nbsp; of&nbsp; gender,&nbsp; age, associate COPD, squamous cell lung cancer and T factor on survival. Multivariante&nbsp; analyses&nbsp; identified&nbsp; N&nbsp; status&nbsp; (better survival has N2 stage compared to N3 stage of NSCLC) and conducted treatment (better survival has&nbsp; chemoradiotherapy compared to chemotherapy alone) as independent prognostic factors.&nbsp; Our&nbsp; results&nbsp; suggest&nbsp; that&nbsp; position&nbsp; and&nbsp; number&nbsp; of cancer involved&nbsp; mediastinal lymph nodes position,&nbsp; proven by mediastinoscopy, as well as the conducted multimodality treatment are key prognostic factors which might influence the survival of patients with N2 and N3 stage of NSCLC.</p>

Abstract Tumor associated macrophages (TAMs) are linked to the invasion of oral tongue squamous cell carcinoma (OTSCC). We modified THP-1 leukemia cells to M1 (inflammatory), M2 (TAM-like) and R848 (imidazoquinoline-treated) type macrophages in order to examine their interactions with OTSCC-cells (HSC-3) by using different kinds of in vitro migration and invasion models. We observed that interaction of TAM-resembling M2-type macrophages with HSC-3 cells induced invasion and migration, whereas the influence of M1 macrophages reduced them. Patient response to chemoradiotherapy is highly reliant on the characteristics such as the aggressiveness and stage of the cancer. Therefore, new methods for treatment testing are needed in order to design personalized therapies. We tested the applicability and consistency of human TME mimicking tissue methods for analyzing the effects of chemoradiation using commercial OTSCC cell lines. Based on our trials, both our human uterine leiomyoma tissue -based matrix models provide viable platforms for future in vitro chemoradiotherapy testing. Conventionally pro-tumorigenic activities of matrix metalloproteinase (MMP)9 have been linked with oral squamous cell carcinoma, but recently its tumor-suppressor role has also been revealed. Our study provides strong evidence that MMP9 also has an anti-invasive effect in OTSCC and is a potential mediator of the protective effects of arresten in tongue cancer cells. / Tiivistelmä Makrofageilla on yhteys kielen levyepiteelikarsinooman invaasioon eli syöpäkasvaimen tunkeutumiseen ympäröivään kudokseen. Tutkimuksessamme muokkasimme ihmisen THP-1 leukemiasoluja kemiallisesti tulehdusreittejä aktivoiviksi M1-makrofageiksi, kasvaimeen liittyvien makrofagien kaltaisiksi M2-makrofageiksi sekä imidatsokinoliini-käsitellyiksi R848-makrofageiksi. Tarkoituksenamme oli tutkia makrofagien ja kielisyöpäsolujen vuorovaikutuksia erilaisilla in vitro migraatio- ja invaasiomalleilla. Anti-inflammatoristen, syövän etenemistä edesauttavien TAM-makrofagien kaltaisiksi erilaistetut M2-tyypin makrofagit lisäsivät HSC-3 kielikarsinoomasolujen invaasiota ja migraatiota, kun taas M1-tyypin makrofagien vaikutus oli päinvastainen. Potilaan vaste kemosädehoitoon riippuu syöpäkasvaimen ominaisuuksista, kuten syöpäsolujen aggressiivisuudesta ja syövän levinneisyysasteesta. Tämän vuoksi on tarve uusille menetelmille, joiden avulla voidaan ottaa huomioon potilaan sekä syöpätyypin yksilölliset ominaisuudet hoitoa suunniteltaessa. Testasimme syöpäkasvaimen mikroympäristöä mallintavien, ihmiskudokseen perustuvien menetelmien käyttökelpoisuutta ja luotettavuutta kemosädehoidon vaikutusten arvioimiseen. Testiemme perusteella myoomakudokseen pohjautuvat menetelmät voivat auttaa kemosädehoidon vaikutusten testauksessa. Matriksin metalloproteinaasi (MMP) 9:n on pitkään uskottu olevan yksinomaan syövän etenemistä edesauttava molekyyli. Viimeaikaisissa tutkimuksissa on myös havaittu, että MMP9:llä voi olla syövältä suojaavia vaikutuksia. Tutkimme MMP9:n vaikutusta kielisyöpäsoluihin ja havaitsimme, että MMP9:llä on myös invaasiota hillitseviä vaikutuksia. Lisäksi MMP9 saattaa toimia verisuonten muodostumista estävän arresten-molekyylin syövältä suojaavien mekanismien välittäjänä.

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