Ante Ćorušić

Methylated Host Cell Gene Promoters and Human Papillomavirus Type 16 and 18 Predicting Cervical Lesions and Cancer

Change in the host and/or human papillomavirus (HPV) DNA methylation profile is probably one of the main factors responsible for the malignant progression of cervical lesions to cancer. To investigate those changes we studied 173 cervical samples with different grades of cervical lesion, from normal to cervical cancer. The methylation status of nine cellular gene promoters, CCNA1, CDH1, C13ORF18, DAPK1, HIC1, RARβ2, hTERT1, hTERT2 and TWIST1, was investigated by Methylation Specific Polymerase Chain Reaction (MSP). The methylation of HPV18 L1-gene was also investigated by MSP, while the methylated cytosines within four regions, L1, 5’LCR, enhancer, and promoter of the HPV16 genome covering 19 CpG sites were evaluated by bisulfite sequencing. Statistically significant methylation biomarkers distinguishing between cervical precursor lesions from normal cervix were primarily C13ORF18 and secondly CCNA1, and those distinguishing cervical cancer from normal or cervical precursor lesions were CCNA1, C13ORF18, hTERT1, hTERT2 and TWIST1. In addition, the methylation analysis of individual CpG sites of the HPV16 genome in different sample groups, notably the 7455 and 7694 sites, proved to be more important than the overall methylation frequency. The majority of HPV18 positive samples contained both methylated and unmethylated L1 gene, and samples with L1-gene methylated forms alone had better prognosis when correlated with the host cell gene promoters’ methylation profiles. In conclusion, both cellular and viral methylation biomarkers should be used for monitoring cervical lesion progression to prevent invasive cervical cancer.

Successful Laparoscopic Bipolar Coagulation of a Large Arteriovenous Malformation Due to Invasive Trophoblastic Disease: a Case Report

We report the case of an acquired large arteriovenous malformation due to invasive gestational trophoblastic tumor that was treated successfully with laparoscopic surgery. After 4 cycles of methotrexate chemotherapy, a vascular tangle (volume, 28 cm(3)) was noted that emerged from the right uterine horn, invading the broad ligament adjacent to the uterine artery. Doppler ultrasonography along with magnetic resonance arteriography confirmed the diagnosis. The location, size and relation of this arteriovenous malformation to the uterine vasculature demanded urgent intervention. Laparoscopy was performed, and bipolar coagulation of the ovarian and uterine artery feeding branches was achieved after surgical resection of the tumor. The defect in the uterine wall with an intact uterine cavity was reconstructed using sutures. There were no intraoperative or postoperative complications. The patient underwent chemotherapy, and at 2-month follow-up was cured and has since had regular menstrual cycles.

Breast and gynecological cancers in Croatia, 1988-2008.

Aim To analyze and interpret incidence and mortality trends of breast and ovarian cancers and incidence trends of cervical and endometrial cancers in Croatia for the period 1988-2008. Methods Incidence data were obtained from the Croatian National Cancer Registry. The mortality data were obtained from the World Health Organization (WHO) mortality database. Trends of incidence and mortality were analyzed by joinpoint regression analysis. Results Joinpoint analysis showed an increase in the incidence of breast cancer with estimated annual percent of change (EAPC) of 2.6% (95% confidence interval [CI], 1.9 to 3.4). The mortality rate was stable, with the EAPC of 0.3% (95% CI, -0.6 to 0.0). Endometrial cancer showed an increasing incidence trend, with EAPC of 0.8% (95% CI, 0.2 to 1.4), while cervical cancer showed a decreasing incidence trend, with EAPC of -1.0 (95% CI, -1.6 to -0.4). Ovarian cancer incidence showed three trends, but the average annual percent change (AAPC) for the overall period was not significant, with a stable trend of 0.1%. Ovarian cancer mortality was increasing since 1992, with EAPC of 1.2% (95% CI, 0.4 to 1.9), while the trend for overall period was stable with AAPC 0.1%. Conclusion Incidence trends of breast, endometrial, and ovarian cancers in Croatia 1988-2008 are similar to the trends observed in most of the European countries, while the modest decline in cervical cancer incidence and lack of decline in breast cancer mortality suggest suboptimal cancer prevention and control.

Pregnancy following the laparoscopic bipolar electrocoagulation of polycystic ovaries resistant to medicamentous ovulation induction – a case report

The case of a primarily infertile patient with polycystic ovaries (PCOS) resistant to medicamentous ovulation induction is presented. The preoperative condition, laparoscopic ovarian drilling using an original technique of bipolar electrocoagulation and consecutive spontaneous pregnancy and delivery are described. This case suggests that bipolar forceps with jaws 1 mm wide could be a useful instrument for laparoscopic ovarian drilling.

Onkogeni aspekti HPV-genitalnih infekcija kod žena

Genital human papillomavirus (HPV) infection is a most common sexually transmitted infection among women (Munoz et al., 2003). The immune system effectively repels most HPV infections, and is associated with strong localized cell mediated immune responses. However, approximately ten percent of individuals develop a persistent infection, with risk of development of high-grade precursor lesions and eventually invasive carcinoma (Stanley, 2006). The causal role of HPV in all cancers of the uterine cervix has been firmly established (zur Hausen, 1999; Walboomers et al., 1999; Bosch et al., 2008). Most cancers of the vulva and vagina are also induced by oncogenic HPV types. In precancerous lesions, most HPV genomes persist in an episomal state whereas, in many high-grade lesions and carcinomas, genomes are found integrated into the host chromosome. Two viral genes, E6 and E7, are invariably expressed in HPV-positive cancer cells. Their gene products are known to inactivate the major tumour suppressors, p53 and retinoblastoma protein (pRB), respectively. In addition, E6 oncoprotein is also capable to up regulate the expression of inhibitors of apoptosis, and E6 and E7 cooperate to effectively immortalise primary epithelial cells. Tumour formation is not an inevitable consequence of viral infection; it rather reflects the multi-step nature of oncogenesis where each step constitutes an independent (reversible or irreversible) genetic change that cumulatively contributes to deregulation of cell cycle, cell growth and survival.Genital human papillomavirus (HPV) infection is a most common sexually transmitted infection among women (Muñoz et al., 2003). The immune system effectively repels most HPV infections, and is associated with strong localized cell mediated immune responses. However, approximately ten percent of individuals develop a persistent infection, with risk of development of high-grade precursor lesions and eventually invasive carcinoma (Stanley, 2006). The causal role of HPV in all cancers of the uterine cervix has been firmly established (zur Hausen, 1999; Walboomers et al., 1999; Bosch et al., 2008). Most cancers of the vulva and vagina are also induced by oncogenic HPV types. In precancerous lesions, most HPV genomes persist in an episomal state whereas, in many high-grade lesions and carcinomas, genomes are found integrated into the host chromosome. Two viral genes, E6 and E7, are invariably expressed in HPV-positive cancer cells. Their gene products are known to inactivate the major tumour suppressors, p53 and retinoblastoma protein (pRB), respectively. In addition, E6 oncoprotein is also capable to up regulate the expression of inhibitors of apoptosis, and E6 and E7 cooperate to effectively immortalise primary epithelial cells. Tumour formation is not an inevitable consequence of viral infection; it rather reflects the multi-step nature of oncogenesis where each step constitutes an independent (reversible or irreversible) genetic change that cumulatively contributes to deregulation of cell cycle, cell growth and survival.