Oncogenic Aspects HPV Infections of the Female Genital Tract

Humani papilomavirus (HPV) glavni je etiološki čimbenik zloćudne preobrazbe vrata maternice. Najvećim dijelom zloćudna preobrazba stidnice i rodnice također je inducirana ovim virusom. Humani papilomavirusi odlično su prilagođeni svom prirodnom domaćinu, epitelnim stanicama kože i sluznica, koristeći se njihovim staničnim mehanizmima za svoje potrebe. U prvom koraku nastaje mikrotrauma i infekcija bazalnog sloja višeslojnoga pločastog epitela genitalnog trakta. Virus se veže za staničnu membranu, ulazi u stanicu i razmnožava se u jezgri. Ključnu ulogu u replikaciji virusa imaju virusni proteini E6 i E7. Vezanje onkoproteina E7 za protein Rb aktivira transkripcijski faktor E2F, koji je odgovoran za ekspresiju proteina potrebnih za replikaciju DNK. Nepravilnosti u tijeku S-faze staničnog ciklusa u fi ziološkim uvjetima dovode do apoptoze posredovane proteinom p53. Međutim, u stanicama inficiranim HPV-om taj je proces onemogućen djelovanjem proteina E6, koji dovodi do proteolitičke razgradnje p53. Stalna aktivnost virusnih proteina E6 i E7 dovodi do nestabilnosti genoma, nakupljanja mutacija, gubitka kontrole staničnog rasta i na kraju do razvoja karcinoma. Putem prirođenog i stečenog imunosnog odgovora organizam prepoznaje i suzbija strane agense, ali u slučaju HPV-infekcije taj je odgovor ponekad nedovoljan. Nadalje, HPV-infekcija dovodi do gubitka ekspresije citokina djelovanjem E6 i E7- onkoproteina, posebice suprimiranjem ekspresije gena interferona. U oko 10% zaraženih nastaje perzistentna infekcija HPV-om što donosi značajan rizik od nastanka prekursorskih ("premalignih") lezija, kao i od nastanka invazivnog karcinoma.The causal role of human papilloma virus (HPV) in all cancers of the uterine cervix has been fi rmly established biologically and epidemiologically. Most cancers of the vulva and vagina are also induced by HPV. Papillomaviruses are perfectly adapted to their natural host tissue, the differentiating epithelial cell of skin or mucosae, and exploit the cellular machinery for their own purposes. The infectious cycle is initiated when infectious particles reach the basal layer of the epithelium, where they bind to and enter into cells. The critical molecules in the process of virus replication are the viral proteins E6 and E7, which interact with a number of cellular proteins. In experimental system these interactions have been shown to induce proliferation and eventually immortalization and malignant transformation of cells. Binding of E7 to pRb activates the E2F transcription factor, which triggers the expression of proteins necessary for DNA replication. Unscheduled S-phase would normally lead to apoptosis by the action of p53. However, in HPV-infected cells, this process is counteracted by the viral E6 protein, which targets p53 for proteolytic degradation. As an aberration of virus infection, constant activity of the viral proteins E6 and E7 leads to increasing genomic instability, accumulation of oncogene mutations, further loss of cell-growth control and ultimately cancer. The immune system uses innate and adaptive immunity to recognize and combat foreign agents that invade the body, but these methods are sometimes ineffective against human papillomavirus. HPV has several mechanisms for avoiding the immune system. Furthermore, HPV infections disrupt cytokine expression with the E6 and E7 oncoproteins, particularly targeting the expression of interferon genes. Approximately 10% of individuals develop a persistent infection, and it is this cohort who are at risk of cancer progression, with the development of high-grade precursor lesions and eventually invasive carcinoma

Human Papillomavirus-Related Diseases of the Female Lower Genital Tract: Oncogenic Aspects and Molecular Interaction

The causal role of human papillomavirus (HPV) in all cancers of the uterine cervix has been firmly established biologically and epidemiologically. Most cancers of both the vulva and the vagina are also induced by HPV. Papillomaviruses are perfectly adapted to their natural host tissue, the differentiating epithelial cell of skin or mucosae, and exploit the cellular machinery for their own purposes. The infectious cycle is initiated once the infectious particles reach the basal layer of the epithelium, where they bind to and enter the cells. The critical molecules in the process of virus replication are the viral proteins E6 and E7, which interact with a number of cellular proteins. In experimental system these interactions have been shown to induce proliferation and eventually immortalization and malignant transformation of cells. Binding of E7 to pRb activates the E2F transcription factor, which then triggers the expression of proteins necessary for DNA replication. Unscheduled S-phase would normally lead to apoptosis by the action of p53. However, in HPV-infected cells, this process is counteracted by the viral E6 protein, which targets p53 for proteolytic degradation. Besides blocking p53 function in regulation of apoptosis, high-risk HPV proteins interact with both extrinsic and intrinsic apoptotic pathways. As an aberration of virus infection, constant activity of the viral proteins E6 and E7 leads to increasing genomic instability, accumulation of oncogene mutations, further loss of cell-growth control and ultimately cancer. The immune system uses innate and adaptive immunity to recognize and combat foreign agents that invade the body, but these methods are sometimes ineffective against human papillomavirus. HPV has several mechanisms for avoiding the immune system. Furthermore, HPV infections disrupt cytokine expression with the E6 and E7 oncoproteins, particularly targeting the expression of interferon genes. Approximately 10% of individuals develop a persistent infection, and it is this cohort who is at risk of cancer progression, with the development of high-grade precursor lesions and eventually invasive carcinoma

Prädiktoren zur Gewichtsbestimmung bei Neugeborenen

Recent observations that there is a secular variation in newborn weight and length call for their continuous assessment, as well as evaluating factors that influence them. The influence of maternal age, weight and height, as well as the number of previous deliveries, abortions and the number of cigarettes smoked per day on newborn weight and length was examined. Data were collected from 181 healthy pregnant women from Zagreb, Croatia, who delivered healthy newborns in term. Multiple regression, correlation coefficients and variance analysis were performed to assess the significance of tested variables on observed fetal features. Maternal age has no significant influence on birth weight, even though mothers younger than 20 and older than 30 tend to have lighter children. Both the numbers of previous deliveries and abortions showed no significant correlation to newborn weight. The number of cigarettes smoked per day during pregnancy and maternal pre-pregnancy weight were found to have significant correlation to newborn weight and length. Maternal height correlated significantly with newborn weight and length, but when multiple regression was performed, controlling for other parameters, no significant influence on newborn weight was found. These results indicate that smoking cessation and im-provement in maternal nutritional status (expressed as body weight) are the two modifiable factors that play a significant role in the reduction of low birth weight children, and thus the reduction of perinatal mortality.Novija zapažanja da postoje sekularna odstupanja u težini i duljini novorođenčadi zahtijevaju stalnu provjeru, kao i vrijednosti koje na njih utječu.Stoga se ispitivao utjecaj majčine dobi, težine i visine, kao i broj prijašnjih poroda, abortusa te broj popušenih cigareta na dan, na težinu i duljinu novorođene djece.Podaci su prikupljani od 181 zdrave trudnice iz Zagreba, Hrvatske, koje su rodile zdravu novorođenčad u terminu.Izvedene su regresijska analiza, korelacija koeficijenata i analiza varijance kako bi se utvrdila značajnost provjeravanih varijabli na opažanim karakteristikama fetusa.Majčina dob ne utječe značajno na težinu novorođenog djeteta, premda su majke mlađe od dvadeset godina i starije od 30 sklone rađanju djece s manjom porođajnom težinom.Broj prijašnjih poroda kao i prekida trudnoće nije značajno povezan s težinom novorođenčeta. Međutim, broj dnevno popušenih cigareta tijekom trudnoće te težina majki prije trudnoće bile su značajno korelirane s težinom i duljinom novorođenog djeteta.Visina majki također je bila značajno povezana s težinom i duljinom djeteta, ali nakon regresijske analize, kontrolom ostalih parametara, nije zamijećen značajan utjecaj na djetetovu težinu.Ovi nalazi pokazuju da su prestanak pušenja i poboljšanje majčine prehrane (izražene u tjelesnoj težini) dva modificirajuća faktora koji imaju važnu ulogu u smanjivanju broja djece s niskom porođajnom tjelesnom težinom te tako smanjuju i perinatalni mortalitet.Jüngsten Beobachtungen zufolge gibt es unter Neugeborenen außerordentlich große Schwankungen in Körpergewicht und Größe. Dies wie auch die Umstände, die dazu führen, erfordern eine ständige Kontrolle. Die vorliegende Untersuchung galt daher den Auswirkungen, die das Alter der Mutter, deren Körpergewicht und Größe, die Zahl der früheren Geburten und Abtreibungen, die Zahl der pro Tag gerauchten Zigaretten auf das Körpergewicht und die Größe von Neugeborenen haben. Die ermittelten Angaben stammen von 181 Schwangeren aus Zagreb, Kroatien, die innerhalb des Geburtstermins gesunde Babys zur Welt brachten. Es wurden eine Regressionsanalyse, eine Koeffizienten-Korrelation und eine Varianzanalyse angewandt, um die Auswirkung der geprüften Variablen auf die an den Föten beobachteten Charakteristiken zu untersuchen. Das Gewicht des Neugeborenen wird nur unwesentlich durch das Alter der Mutter beeinflußt, auch wenn Frauen unter 20 sowie Frauen über 30 Jahren dazu neigen, Kinder mit geringerem Körpergewicht zu gebären. Ebensowenig steht die Zahl früherer Geburten und Schwangerschaftsabbrüche in einem wesentlichen Zusammenhang mit dem Körpergewicht des Neugeborenen. Dafür erwies sich jedoch, daß die tägliche Zahl der während der Schwangerschaft gerauchten Zigaretten sowie das Körpergewicht der Mutter vor der Schwangerschaft in wesentlichem Bezug zu Körpergewicht und Größe des Neugeborenen stehen. Dasselbe gilt für die Körpergröße der Mutter, doch konnte – nach angewandter Regressionsanalyse und einer Kontrolle der übrigen Parameter – kein ausschlaggebender Einfluß auf das Körpergewicht des Säuglings nachgewiesen werden. Diese Angaben zeigen, daß die Einstellung des Rauchens und eine verbesserte Ernährungsweise der Mutter (ausgedrückt im Körpergewicht) zwei modifizierende Faktoren darstellen, die nachhaltig dazu beitragen können, die Zahl der untergewichtigen Neugeborenen und somit das Ausmaß der Säuglingssterblichkeit einzudämmen

Vulvovaginal Candidiasis

Vulvovaginalna je mikoza, nakon bakterijske, najčešća vaginalna infekcija. Česta je bolest mladih žena i nalazi se u 15-30% simptomatskih žena koje posjećuju liječnika. Prevalencija u općoj populaciji iznosi 5-15%. Najčešći uzročnik je Candida albicans i odgovorna je za 80-92% epizoda vulvovaginalne mikoze. Vulvovaginalna kandidoza nije spolno prenosiva bolest. Candida spp. čini dio fiziološke flore rodnice u 20-50% zdravih asimptomatskih žena. Glavni simptom je svrbež, s malo vaginalnog sekreta ili bez njega koji je tipično bijel, grudast i sirast. Mogu biti prisutni i bolnost, nadražaj, pečenje, disurija i dispareunija. Dijagnoza se postavlja nalazom gljive na mokrom preparatu iscjetka s dodatkom 10%-tnog kalijeva hidroksida. Mikroskopija je lažno negativna u 50% bolesnica s potvrđenom vulvovaginalnom kandidozom. Potrebno je napraviti kulturu bolesnicama s karakterističnim simptomima i negativnom mikroskopijom. Asimptomatska kolonizacija nije indikacija za liječenje. Vrsta i trajanje liječenja simptomatske bolesti određuju se temeljem osnovne podjele na nekomplicirani i komplicirani oblik bolesti. Nekomplicirani se oblik podjednako uspješno liječi lokalnim i sistemskim lijekovima. Optimalno je liječenje jednokratna primjena oralnog flukonazola (Zenafluk®, PLIVA) u dozi od 150 mg. Komplicirane infekcije liječe se dulje.Following bacterial, vulvovaginal mycosis is the most common vaginal infection. It is a common disease in young women, found in about 15% to 30% of symptomatic women visiting a clinician. The overall prevalence of the disease is estimated at 5% to 15%. The most common causative agent is Candida albicans, responsible for 80% to 92% of episodes. Vulvovaginal mycosis is not considered a sexually transmitted disease. Candida spp. form part of normal vaginal flora in 20% to 50% of healthy asymptomatic women. The dominant symptom is pruritus with little or no discharge. When present, vaginal discharge is characteristically white, clumpy and curdlike. Other possible symptoms include pain, irritation, vulvar burning, dysuria and dyspareunia. Diagnosis is made by finding yeast on a wet mount of the discharge, adding 10% potassium hydroxide. Microscopy is negative in up to 50% of patients with confirmed vulvovaginal candidiasis. A culture is necessary in patients with characteristic symptoms and negative microscopy. Asymptomatic colonisation is not an indication for treatment. We differentiate between uncomplicated and complicated forms of the disease, and the type and duration of treatment are based on this classification. Uncomplicated forms are equally well treated by vaginal and oral preparations. The optimal treatment is oral fluconazole (Zenafluk®, PLIVA) in a single 150 mg dose. Complicated infections require longer courses of treatment

Human Papillomavirus-Related Diseases of the Female Lower Genital Tract: Oncogenic Aspects and Molecular Interaction

The causal role of human papillomavirus (HPV) in all cancers of the uterine cervix has been firmly established biologically and epidemiologically. Most cancers of both the vulva and the vagina are also induced by HPV. Papillomaviruses are perfectly adapted to their natural host tissue, the differentiating epithelial cell of skin or mucosae, and exploit the cellular machinery for their own purposes. The infectious cycle is initiated once the infectious particles reach the basal layer of the epithelium, where they bind to and enter the cells. The critical molecules in the process of virus replication are the viral proteins E6 and E7, which interact with a number of cellular proteins. In experimental system these interactions have been shown to induce proliferation and eventually immortalization and malignant transformation of cells. Binding of E7 to pRb activates the E2F transcription factor, which then triggers the expression of proteins necessary for DNA replication. Unscheduled S-phase would normally lead to apoptosis by the action of p53. However, in HPV-infected cells, this process is counteracted by the viral E6 protein, which targets p53 for proteolytic degradation. Besides blocking p53 function in regulation of apoptosis, high-risk HPV proteins interact with both extrinsic and intrinsic apoptotic pathways. As an aberration of virus infection, constant activity of the viral proteins E6 and E7 leads to increasing genomic instability, accumulation of oncogene mutations, further loss of cell-growth control and ultimately cancer. The immune system uses innate and adaptive immunity to recognize and combat foreign agents that invade the body, but these methods are sometimes ineffective against human papillomavirus. HPV has several mechanisms for avoiding the immune system. Furthermore, HPV infections disrupt cytokine expression with the E6 and E7 oncoproteins, particularly targeting the expression of interferon genes. Approximately 10% of individuals develop a persistent infection, and it is this cohort who is at risk of cancer progression, with the development of high-grade precursor lesions and eventually invasive carcinoma

Uloga citologije u otkrivanju preinvazivnih i invazivnih promjena stidnice ovisno o načinu uzimanja uzorka

Eksfolijativna citologija stidnice kao neinvazivna metoda koristi se u dijagnostici i praćenju promjena na stidnici, osobito onih kod kojih nije indicirana biopsija. Dosad se tradicionalno obrisak uzimao špatulom te su citološki uzorci često bili slabo celularni. Kako bi se poboljšala celularnost uveden je postupak uzimanja endocervikalnom četkicom. U retrospektivnoj studiji obuhvaćeno je 1866 uzoraka sa stidnice uzetih u razdoblju od 1. srpnja 2011. do 31. prosinca 2013. Analizirana je primjerenost uzoraka kao i omjer nalaza atipičnih pločastih stanica (ASC) prema nalazu pločaste intraepitelne lezije ili karcinoma (SIL+), ovisno o ambulanti u kojoj je uzorak uzet, te citohistološka korelacija. U onkološkoj ambulanti specijaliziranoj za bolesti stidnice u kojoj je većina uzoraka uzimana četkicom bilo je najmanje neprimjerenih uzoraka zbog oskudnosti (3,4%), kao i zadovoljavajućih, ali oskudnih uzoraka (5,6%), a najviše ovakvih uzoraka bilo je u ginekološkim ambulantama primarne zdravstvene zaštite (13,7% odnosno 25,3%) u kojima su obrisci uglavnom uzimani na tradicionalan način – špatulom. Usporedili smo omjer ASC:SIL+ nalaza kod potpuno zadovoljavajućih nalaza ovisno o ambulanti u kojoj su uzeti uzorci: u ambulanti specijaliziranoj za bolesti stidnice bio je 2,6:1, u ostalim onkološkim ambulantama 1,9:1, u ostalim ambulantama klinike 3,5:1, dok je u ambulantama primarne ginekologije bio 2,3:1. Kod zadovoljavajućih, ali oskudnih nalaza ovaj omjer ASC:SIL+ varirao je od 5:1 do 11:0 ovisno o ambulanti u kojoj su uzorci uzeti. Citohistološka korelacija 159 slučajeva pokazala je visoku osjetljivost u otkrivanju preinvazivnih (94,1%) i invazivnih (100,0%) promjena, ali nisku specifičnost (35,4%). Uzorci sa stidnice uzeti endocervikalnom četkicom značajno su celularniji od uzoraka uzetih špatulom i time bolji za citološku analizu te je manji omjer ASC:SIL+ nalaza. Citološka analiza uzoraka sa stidnice ne može zamijeniti biopsiju, ali kod klinički nejasnih lezija može pomoći u postavljanju indikacije za daljnji postupak, kao i u praćenju bolesnica s potvrđenom bolesti

THERAPY OF OVARIAN CANCER WITH PACLITAXEL Our Results

Cilj istraživanja. Standardna kemoterapija u bolesnica s lokalno uznapredovalim rakom jajnika stadija II do IVa je kombinacija paklitaksela s cisplatinom/karboplatinom. Više od 75% bolesnica javlja se upravo u tim stadijima bolesti. Početkom 90-tih godina prošlog stoljeća ova kombinacija lijekova koristila se u recidivima nakon incijalne kemo-terapije s cisplatinom/karboplatinom, u kombinaciji s ciklofosfamidom i/ili adriamicinom, da bi se nakon zadovoljavajućih rezultata nakon 1995. godine počela koristiti i u »prvoj« liniji liječenja. Metode. U Zavodu za ginekološku onkologiju Klinike za ženske bolesti i porode KBC-a Zagreb započeli smo primjenom paklitaksela 1994. godine. Od 1994.–1996. godine davali smo ga isključivo u slučaju recidiva da bismo 1996. godine prvi puta započeli liječenje spomenutom kombi-nacijom kao prvom linijom. Od 1994. do 2002. godine ukupno je liječeno 65 bolesnica; paklitaksel je ušao na listu lijekova Hrvatskog Zavoda za zdravstveno osiguranje (HZZO) za recidiv bolesti 1997. godine, a tek 1998. godine za prvu liniju uz posebne zamolbe HZZO-u. Svaka je bolesnica primila između 4–10 ciklusa kemoterapije te je ukupno primijenjeno preko 650 ciklusa kemoterapije. Rezultati. Tijekom primjene ni u jedne bolesnice nismo imali smrtni ishod, a samo kod dvije (3%) ozbiljnije alergijske reakcije koje su uspješno zbrinute, pa je nastavljeno s kemoterapijom. Zaključak. Na temelju našega iskustva možemo reći da je paklitaksel u kombinaciji s cisplatinom/karboplatinom vrlo učinkovit citostatik te da se naši rezultati liječenja ne razlikuju od rezultata objavljenih u svjetskoj literaturi.The aim of investigation. Standard chemotherapy in patients with locally advanced ovarian cancer stage II to stage IV is the combination of paclitaxel with cisplatin/carboplatin. More than 75% of patients are diagnosed at these stage of disease. At the begining of the 90’s of last century this combination of agents was used in recurrencies after initial chemotherapy with cisplatin/carboplatin with cyclophosphamide and/or adriamycin and has, proving to have satisfactory results, since 1995 been used in the first-line therapy. Methods. At Gynecologic Cancer Center, University Hospital Zagreb the use of paclitaxel started in 1994; from 1994 to 1996 paclitaxel was exclusively used for patients with recurrent disease. The use of paclitaxel plus cisplatin/carboplatin combination began as the first-line therapy in 1996. From 1994 to 2002 a total of 65 patients were treated with this combination. In 1997 paclitaxel was listed by the Croatian Health Insurance Agency (HZZO) as therapy for recurrent disease; in 1998 was the special request to HZZO for the first-line therapy and in 2002 separate funds were allocated for the treatment of patients with ovarian cancer stage II to IV with paclitaxel. From 1994 to 2001 paclitaxel was used in 23 patients, of which 5 in the first-line therapy and 18 after recurrencies as second-line therapy. In 2002, 42 patients were treated with paclitaxel – 32 in the first-line and 10 in the second-line therapy. Considering the fact that each patient was treated with between 4 to 10 cycles of chemoterapy, it has amounted to a total of more than 650 cycles of chemotherapy. Results. No treatment had a death outcome, only two patients (3%) experienced a serious allergic reaction but were successfully managed and chemotherapy was continued. Conclusion. Our experience confirms that paclitaxel in combination with cisplatin/carboplatin is a very effective drug and our results of chemotherapy do not differ from the results published in the world literature

CLINICAL RECOMMENDATIONS FOR DIAGNOSING, TREATMENT AND MONITORING OF PATIENTS WITH OVARIAN CANCER – CROATIAN ONCOLOGY SOCIETY AND CROATIAN SOCIETY FOR GYNECOLOGY AND OBSTETRICS AS CROATIAN MEDICAL ASSOCIATION UNITS AND CROATIAN SOCIETY OF GYNECOLOGICAL ONCOLOGY

Rak jajnika i jajovoda po učestalosti je peta zloćudna bolest žena u Hrvatskoj. Histološki je rak jajnika najčešće epitelnog podrijetla, i to seroznog podtipa. Rjeđi su različiti neepitelni malignomi jajnika, a posebnu skupinu čine epitelni karcinomi niskoga zloćudnog potencijala karakterizirani neinvazivnošću, klinički indolentnim tijekom i dobrom prognozom te primarni rak potrbušnice i rak jajovoda. Klinički su ovi zloćudni tumori u ranim stadijima razvoja uglavnom asimptomatski, zbog čega se najčešće dijagnosticiraju u kasnijim stadijima bolesti. Dijagnoza se potvrđuje patohistološkim nalazom, a iznimno citološkim nalazom nakon provedene dijagnostičke obrade. O liječenju odlučuje multidisciplinarni tim uzimajući u obzir dob, opće stanje i komorbiditete bolesnice, kao i obilježja samog tumora uključujući stadij bolesti, histološki tip i gradus tumora. Principi liječenja primarnog raka potrbušnice i jajovoda temelje se na principima liječenja epitelnog raka jajnika koji obuhvaćaju primjenu kirurških zahvata, kemoterapije, imunoterapije i hormonske terapije, kao i suportivno-simptomatskih mjera tijekom cijelog liječenja. Razlikuje se terapijski pristup rjeđim, neepitelnim histološkim tipovima tumora koji se češće dijagnosticiraju u ranim stadijima bolesti, imaju indolentniji tijek pa se kod ovih bolesnica češće primjenjuju poštedni kirurški zahvati s ciljem očuvanja plodnosti. U tekstu koji slijedi predstavljene su kliničke upute s ciljem standardizacije postupaka i kriterija postavljanja dijagnoze, liječenja te praćenja bolesnica s rakom jajnika, jajovoda i potrbušnice u Republici Hrvatskoj.Ovarian cancer together with fallopian tube represents the fifth most common female cancer in the Republic of Croatia. Epithelial ovarian cancer, serous subtype, encompasses most of malignant ovarian neoplasms. Less common are various non-epithelial ovarian malignancies. A special group consists of epithelial carcinomas of low malignant potential with clinically indolent flow, good prognosis and no invasion, and primary cancer of the peritoneum and fallopian tube cancer. Clinically, these malignant tumors are generally asymptomatic in early stages, and usually diagnosed in advanced stages. The diagnosis is confirmed by pathological examination, and occasionally, cytological findings after completing diagnostic procedures. Multidisciplinary team makes treatment decisions, taking into account age, general condition and comorbidities of the patient and characteristics of the tumor itself, including disease stage, histological type and grade of the tumor. The principles of treatment of primary peritoneal and fallopian tube cancer are based on the principles of treatment of epithelial ovarian cancer involving surgery, chemotherapy, immune and hormone therapy, and symptomatic-supportive care throughout the treatment. Less common histological types have a different treatment approach being more frequently diagnosed in the early stages of the disease, have more indolent flow, so in these patients conservative surgeries with the goal of preserving fertility are more often employed. The following text presents the clinical guidelines in order to standardize the procedures and criteria for the diagnosis, management, treatment and monitoring of patients with ovarian carcinoma, fallopian tube and primary peritoneal cancer in the Republic of Croatia

CLINICAL RECOMMENDATIONS FOR DIAGNOSING, TREATMENT AND MONITORING OF PATIENTS WITH ENDOMETRIAL CANCER – CROATIAN ONCOLOGY SOCIETY AND CROATIAN SOCIETY FOR GYNECOLOGY AND OBSTETRICS AS CROATIAN MEDICAL ASSOCIATION UNITS AND CROATIAN SOCIETY OF GYNECOLOGICAL ONCOLOGY

Rak trupa maternice javlja se u većini slučajeva u poslijemenopauzalnih žena, a najčešće se očituje ginekološkim krvarenjem. Nakon raka jajnika i vrata maternice treći je uzrok smrti žena od raka spolnog sustava. Dijagnoza se postavlja patohistološkim pregledom kiretmana ili bioptata, a definitivni stadij bolesti utvrđuje se analizom uzoraka dobivenih histerektomijom i obostranom salpingoovariektomijom sa zdjeličnom i paraaortalnom limfadenektomijom. U tekstu koji slijedi sadržane su kliničke upute s ciljem standardizacije postupaka i kriterija postavljanja dijagnoze, liječenja i praćenja bolesnica s rakom trupa maternice u Republici Hrvatskoj.Uterine cancer occurs mainly in postmenopausal women, usually as vaginal bleeding. Following ovarian and cervical cancer it is the third most common cause of female reproductive system cancer death. Diagnosis is set by analyzing samples obtained via hysterectomy with salpingo-oophorectomy and pelvic / paraaortal lymphadenectomy. The following text presents the clinical guidelines in order to standardize the procedures and criteria for the diagnosis, treatment and monitoring of patients with uterine cancer in the Republic of Croatia

Human papillomavirus-related diseases of the female lower genital tract: oncogenic aspects and molecular interaction [Bolesti donjeg dijela ženskog spolnog sustava povezane s humanim papilomavirusom - onkogeni aspekti i molekularne interakcije]

The causal role of human papillomavirus (HPV) in all cancers of the uterine cervix has been firmly established biologically and epidemiologically. Most cancers of both the vulva and the vagina are also induced by HPV. Papillomaviruses are perfectly adapted to their natural host tissue, the differentiating epithelial cell of skin or mucosae, and exploit the cellular machinery for their own purposes. The infectious cycle is initiated once the infectious particles reach the basal layer of the epithelium, where they bind to and enter the cells. The critical molecules in the process of virus replication are the viral proteins E6 and E7, which interact with a number of cellular proteins. In experimental system these interactions have been shown to induce proliferation and eventually immortalization and malignant transformation of cells. Binding of E7 to pRb activates the E2F transcription factor, which then triggers the expression of proteins necessary for DNA replication. Unscheduled S-phase would normally lead to apoptosis by the action of p53. However, in HPV-infected cells, this process is counteracted by the viral E6 protein, which targets p53 for proteolytic degradation. Besides blocking p53 function in regulation of apoptosis, high-risk HPV proteins interact with both extrinsic and intrinsic apoptotic pathways. As an aberration of virus infection, constant activity of the viral proteins E6 and E7 leads to increasing genomic instability, accumulation of oncogene mutations, further loss of cell-growth control and ultimately cancer. The immune system uses innate and adaptive immunity to recognize and combat foreign agents that invade the body, but these methods are sometimes ineffective against human papillomavirus. HPV has several mechanisms for avoiding the immune system. Furthermore, HPV infections disrupt cytokine expression with the E6 and E7 oncoproteins, particularly targeting the expression of interferon genes. Approximately 10% of individuals develop a persistent infection, and it is this cohort who is at risk of cancer progression, with the development of high-grade precursor lesions and eventually invasive carcinoma