Tamoxifen Ameliorates Cholestatic Liver Fibrosis in Mice: Upregulation of TGFß and IL6 Is a Potential Protective Mechanism.

The available treatments for cholestatic liver fibrosis are limited, and the disease often progresses to liver cirrhosis. Tamoxifen is a selective modulator of estrogen receptors, commonly used in breast cancer therapy. A recent in vitro study showed that tamoxifen deactivates hepatic stellate cells, suggesting its potential as an antifibrotic therapeutic, but its effects in vivo remain poorly investigated. In the present study, we show that tamoxifen protects against the cholestatic fibrosis induced by a diet supplemented with 0.025% 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC). Mice fed with a DDC-supplemented diet for four weeks and treated with tamoxifen developed a significantly milder degree of liver fibrosis than vehicle-treated mice, as evidenced by a lower percentage of Sirius red-stained area (60.4% decrease in stained area in male and 42% decrease in female mice, p < 0.001 and p < 0.01, respectively) and by lower hydroxyproline content. The finding was further confirmed by qPCR analysis, which showed a lower expression of genes for Col1a1, Acta2, Sox9, Pdgf, and Krt19, indicating the inhibitory effect on hepatic stellate cells, collagen production, and biliary duct proliferation. The degree of protection was similar in male and female mice. Tamoxifen per se, injected into standard-diet-fed mice, increased the expression of genes for Il6 (p < 0.01 and p < 0.001 in male and female mice, respectively) and Tgfß (p < 0.01 for both sexes), and had no adverse effects. We showed that tamoxifen sex-independently protects against cholestatic DDC-induced liver fibrosis. The increased expression of Il6 and Tgfß seems to be a plausible protective mechanism that should be the primary focus of further research.

Distribution of human papillomavirus genotypes in women with high-grade cervical intraepithelial lesions and cervical carcinoma and analysis of human papillomavirus-16 genomic variants.

AIM: To analyze the distribution of high-risk human papillomavirus (HR-HPV) genotypes and the diversity of HPV-16 genomic variants in Croatian women with high-grade squamous intraepithelial lesions (HSIL) and cervical carcinoma. METHODS: Tissue biopsy specimens were obtained from 324 women with histopathologically confirmed HSIL or cervical carcinoma, 5 women with low-grade SIL, and 49 women with negative histopathology. HR-HPV DNA was detected with Ampliquality HPV-type nucleic-acid hybridization assay, which identifies 29 different HPV genotypes. HPV-16 genomic variants were analyzed by an in-house sequencing. RESULTS: The most common HPV type in women with HSIL was HPV-16, detected in 127/219 (57.9%) specimens. HPV-16 was also the dominant type in squamous cell cervical carcinoma (46/69 or 66.7%) and in adenocarcinoma (18/36 or 50.0%). Out of 378 patients, 360 had HR-HPV (282 single infections and 79 multiple infections), 3 (0.8%) patients had low-risk HPV, and 15 (4%) tested negative. HPV-16 variants were determined in 130 HPV-16 positive specimens, including 74 HSIL and 46 carcinoma specimens. In HSIL specimens, 41 distinct variants were found, 98.6% belonging to the European branch and 1.4% belonging to the African branch. In cervical carcinoma specimens, 95% isolates grouped in 41 variants belonging to the European branch, one isolate (2.5%) belonged to the North American, and one (2.5%) to the Asian-American branch. CONCLUSION: HPV-16, mainly belonging to the European branch, was the most frequent HPV genotype in women from Croatia with histologically confirmed HSIL and cervical cancer.

Desmoplastic Small Round Cell Tumor of the Ovary: A Case Report with a New Modality of Treatment and Review of the Literature.

OBJECTIVE: Desmoplastic small round cell tumor (DSRCT) is a rare intraabdominal neoplasm that grows along serosal surfaces and is primarily found in young men. To date, only 16 cases of ovarian DSRCT have been previously reported in women in the English literature, and no large population-based studies on this topic exist. CASE REPORT: We report the case of a 19-year-old virgo with unremarkable past medical history, initially presented with abdominal fullness. After being treated with the optimal treatment modality (primary and secondary surgical debulking, unique chemotherapy, protocol and adjuvant radiotherapy), the patient has remained without tumor disease for 40 months. CONCLUSION: Although the best therapy for patients with DSRCT has yet to be determined, combining complete surgical resection, adjuvant chemotherapy, and radiotherapy is required to prolong survival and to achieve proper quality of life.

Fertility-sparing surgery for patients with malignant ovarian germ cell tumors: 10 years of clinical experience from a tertiary referral center.

PURPOSE: To describe a case series of patients with malignant ovarian germ cell tumors (MOGCT) treated exclusively with fertility-sparing surgery (FSS) with or without adjuvant chemotherapy. METHODS: We retrospectively reviewed the records of 27 patients with MOGCT treated in the Department of Obstetrics and Gynecology, University Hospital Center Zagreb, Croatia, between January 2009 and July 2019. RESULTS: The median age at diagnosis was 22 years, and the main symptom was abdominal distension (57.0%). The most prevalent histological subtype was immature teratoma (n = 13, 48.1%). Twenty-three patients (85.2%) had laparotomy and 4 (14.8%) had laparoscopy, without conversions. Lymphadenectomy was performed in 16 (59.3%) patients, with 184 removed lymph nodes, and omentectomy was performed in 19 (70.4%) patients. The rate of chemotherapy administration was 81.5%. The follow-up length ranged between 6.30 and 115.1 months (median: 49.60 months). No patient experienced tumor recurrence. The rate of complete gross resection was 100%. At the time of analysis, all patients were alive and disease free. Fifty percent of patients who actively tried to conceive after FSS became pregnant, with 12 deliveries. CONCLUSION: This study suggests that FSS is a safe treatment option for MOGCT, regardless of tumor stage and histological type.

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, RARß2, 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.

Preventative valve-sparing aortic root replacement and pregnancy outcome in Marfan syndrome.

In Marfan syndrome, with dilatation of the aortic root secondary to an underlying connective tissue defect, pregnancy can cause hemodynamic stress leading to the development of an aortic aneurysm and even a fatal aortic dissection. In the presence of existing aortic root enlargement and a family history of aortic dissection, preventative elective surgery is suggested. Aortic root replacement with or without a valve-sparing procedure is superior to total aortic root replacement with prosthetic valve/tube graft. It provides excellent survival with low rates of aortic - valve related complications.

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. Themortality data were obtained from the World Health Organization (WHO) mortality database. Trends of incidence and mortality were analysed 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%. 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.

Cervical cancer as a public health issue--what next?

Cervical cancer is the second most common cancer in women worldwide. There are about 60,000 newly detected cases and 30,000 deaths annually in Europe, with the highest incidence reported from Eastern Europe countries. According to data from the National Institute of Public Health, in Croatia the incidence of cervical cancer was 14.9/100,000 in 2006, ranking eighth most common malignancy in women. Croatia has a lower incidence of the disease compared to many countries of Central and Southeast Europe. A large study carried out in 1995 by the International Agency for Research on Cancer, which included cervical cancer material collected from 22 countries all over the world revealed HPV genome in 99.7% of cases. Efficient methods of cervical cancer detection and screening methods for identification of precancerous lesions (conventional Pap smear) are available. Cervical cancer prevention programs should include education (of health care providers and women), stressing the benefits of screening, the age of the peak cervical cancer incidence, and the signs and symptoms of precancerous lesions and invasive disease. The aim of screening actions is to detect precancerous lesions that may lead to cancer if left untreated. Screening can only be effective if there is a well-organized system of follow up, diagnosis and treatment. Cervical cytology, or Papanicolaou (Pap) testing, has for decades been a cornerstone of cervical cancer screening. According to recent guidelines issued by the World Health Organization Regional Office for Europe, the primary task of the public health system is the introduction of secondary prevention through properly organized screening programs. Launching the national immunization program is only possible in the countries with well-organized secondary prevention programs and in those that can afford it.

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.

Management of Wolffian duct tumor recurrence without chemotherapy.

BACKGROUND: A female adnexal tumor of probable Wolffian origin (FATWO) is a rare neoplasm which is considered to have a low malignant potential. CASE: In 2006, a 60-year-old patient was admitted to hospital with solid tumor on the vaginal cuff confirmed by abdominal/pelvic CT, 6 years after her first FATWO was diagnosed and hysterectomy, bilateral adnexectomy, and omentectomia were done. No chemotherapy was administrated after her first surgery. Pelvic washings, lysis of adhesions, and excision of tumor mass were performed. Pathologic examination revealed malignant epithelial neoplasm of Wolffian origin with morphologic features similar to those of the patient's prior tumor. Immunohistochemical staining was positive for vimentin and partially low positive for cytokeratin 19. No chemotherapy was administrated. Two years after second surgery, the patient was asymptomatic and her clinical, laboratory, CT, and chest X-ray findings were unremarkable. CONCLUSION: Surgical debulking with hysterectomy and bilateral adnexectomy appears as the most successful initial treatment for FATWOs.

Laporovaginal surgery in cervical cancer: a Croatian experience.

With correct staging a large number of patients with cervical cancer FIGO stages IA2 and IB can be spared of unnecessary radiation therapy by laparoscopic assisted vaginal radical hysterectomy (LAVRH) as an option of radical surgical treatment in such patients. The development of laparovaginal surgery, indication and contraindication were presented. Also, the surgical technique was described in detail. Fifty-two patients were followed up in 2003 after LAVRH or open surgery, performed in our single center. Only 5 (14%) patients died from cervical cancer within 3 years following the treatment. They were all clinical stage IB treated with open surgery. There were 4 (11%) complications following treatment and they were all in patients with clinical stage IB, also treated with open surgery. There was no complication in LAVRH treated patients. The results and complications of the sole Croatian center performing LAVRH or open surgery in patients with cervical cancer FIGO stages IA and IB were similar to those in centers across the world.