SHH-N non-canonically sustains androgen receptor activity in androgen-independent prostate cancer cells.

Prostate cancer is the second most frequent cancer diagnosed in men worldwide. Localized disease can be successfully treated, but advanced cases are more problematic. After initial effectiveness of androgen deprivation therapy, resistance quickly occurs. Therefore, we aimed to investigate the role of Hedgehog-GLI (HH-GLI) signaling in sustaining androgen-independent growth of prostate cancer cells. We found various modes of HH-GLI signaling activation in prostate cancer cells depending on androgen availability. When androgen was not deprived, we found evidence of non-canonical SMO signaling through the SRC kinase. After short-term androgen deprivation canonical HH-GLI signaling was activated, but we found little evidence of canonical HH-GLI signaling activity in androgen-independent prostate cancer cells. We show that in androgen-independent cells the pathway ligand, SHH-N, non-canonically binds to the androgen receptor through its cholesterol modification. Inhibition of this interaction leads to androgen receptor signaling downregulation. This implies that SHH-N activates the androgen receptor and sustains androgen-independence. Targeting this interaction might prove to be a valuable strategy for advanced prostate cancer treatment. Also, other non-canonical aspects of this signaling pathway should be investigated in more detail and considered when developing potential therapies.

PROGNOSTIC IMPACT OF LOW ESTROGEN AND PROGESTERONE POSITIVITY IN LUMINAL B (HER2 NEGATIVE) BREAST CANCER.

- Luminal B (HER2 negative) subtype is the most diversiform type of breast cancers, with a high Ki-67 proliferation index (>20%) or/and low progesterone (PR; <20%) with various intensity and distribution of hormone receptors. Considerable difference has also been noticed in disease outcome, wherefore there is the need for a more detailed classification of this tumor subtype. The clinical and pathologic parameters of 147 luminal B (HER2 negative) breast cancers were examined. The expression of hormone receptors in correlation with other prognostic factors and disease outcome was analyzed by Kaplan-Meier curves and multivariate Cox regression analysis. The Kaplan-Mayer analysis showed that low positivity of estrogen (ER) and PR receptors in tumors was associated with a significantly worse disease outcome (overall survival (ER), p=0.020; disease free survival (ER), p=0.019; overall survival (PR), p=0.026; disease free survival (PR), p=0.038)), unlike Ki-67, which did not show a statistically significant connection (overall survival, p=0.343; disease free survival, p=0.322). The intensity of receptor staining and Ki-67 relative to other histopathologic prognostic factors showed a statistically significant correlation solely with histologic grade of tumor. By using the Cox regression model, PR proved to be an independent prognostic factor for overall survival (p=0.004) and disease free survival (p=0.029). The luminal B (HER2 negative) breast cancer with low expression of hormone receptors, independent of the Ki-67 proliferation index, and in correlation with a higher histologic grade, could be a unique subtype of cancer.

Coexistence of Condylomata Acuminata with Warty Squamous Cell Carcinoma and Squamous Cell Carcinoma.

INTRODUCTION: Condyloma acuminatum has previously been considered to be a benign growth with no malignant potential, but a review of the literature supports the concept that condylomata acuminata may precede or be associated with invasive squamous cell carcinoma (ISCC) or warty squamous cell carcinoma (WSCC). CASE REPORT: We present a clinical case of a 58-year old woman with large, slow-growing, exophytic tumor of external genitalia shaped like a cauliflower with the propagation to both legs and behind. We performed multiple biopsies to detect potential malignancy but malignancy was not confirmed histologically. The presence of HPV (human papilloma virus) low and high risk was discovered. Inguinal lymph nodes were enlarged both sides, but cytologic examination identified no malignant cells. The patient was initially treated by the loop electro surgical excision procedure (LEEP) and podophilin solution on the rest of the condylomas. Condyloma acuminatum was confirmed histologically. Later, we performed a wide surgical excision of the rest of the condylomas. The new changes on the previously treated region were removed using LEEP. WSCC and ISCC were confirmed histologically so were radical vulvectomy and inguinal lymphadenectomy performed. The patient was advised to remain under close follow-up.

Expression of proinflammatory cytokine interleukin-6 in tissue samples of human prostate obtained by needle biopsy.

Interleukin-6 (IL-6) has been associated with the development of prostate cancer. The aim of the study was to clarify whether IL-6 expression in prostate tissue could be a useful marker in differentiation of prostate diseases in small foci by pathologist visual scoring. Archival paraffin-embedded specimens of benign prostate hyperplasia (BPH), high-grade prostatic intraepithelial neoplasia (PIN), prostatitis and prostate adenocarcinoma were studied by immunohistochemistry with a mouse monoclonal antibody IL-6 using the streptavidin-biotin method. Significantly, lower IL-6 immunoreactivity was observed in normal epithelial cells (p=0.000) and basal cells (p=0.000) in the samples of prostate adenocarcinoma in comparison to the samples with BPH, PIN and prostatitis. There was no significant difference in IL-6 expression in malignant and premalignant cells (p=0.814) as well as in stromal cells among the four diagnoses (p=0.22). IL-6 was expressed in normal epithelial cells, premalignant epithelial cells and malignant epithelial cells as well as in stromal cells. However, in our research IL-6 was of limited utility as a single marker for differential diagnosis of the prostate diseases in small foci needle biopsy by pathologist visual scoring. The standardization of immunohistochemical (IHC) staining protocol for IL-6 is required to determine IL-6 expression in order to avoid possible misinterpretation of the IHC results.

Association of IL-1ß and IL-10 Polymorphisms with Prostate Cancer Risk and Grade of Disease in Eastern Croatian Population.

Single nucleotide polymorphisms (SNPs) in the promotor regions of cytokine genes included in angiogenesis may influence prostate cancer (PCa) development via regulation of the pathways of tumor angiogenesis. The aim of the present study was to investigate the association of IL-1 female +3954 (rs1143634) and IL-10-1082 (rs1800896) polymorphisms with PCa risk and aggressiveness in eastern Croatian patients. One hundred twenty PCa patients and 120 benign prostatic hyperplasia (BPH) controls were genotyped using real-time PCR (LightCycler Instrument, Roche Diagnostics) and the melting curve analysis method. There was no significant difference in the frequency of genotypes for the two polymorphisms between PCa patients and controls (Χ2 = 0.857, p = 0.355 for IL-female 1; Χ2 = 0.026, p = 0.872 for IL-10). Carriers of the IL-10-1082A>G variant were found to be associated with the Gleason score (GS) > 7 (AA versus GA+GG, OR = 3.47, 95% CI 1.11-10.88, p = 0.033). There was no significant difference in the frequency of genotypes for the two polymorphisms and the presence of metastatic disease in PCa patients. These results suggest that tested SNPs associated with differential production of IL-1 female and IL-10 are not risk factors for PCa and do not correlate with the presence of distant metastasis in eastern Croatians. We found that IL-10-1082 GA+/or GG carriers have a higher risk of developing PCa with GS > 7 in eastern Croatians.

Primary serous papillary adenocarcinoma of the fallopian tube.

Fallopian tube cancer is least common of all gynecologic tumors, with the mean age at onset between 54 and 63 years. This case report presents a 67-year-old female, gravida 1, para 1, with primary adenocarcinoma of the fallopian tube, detected and diagnosed preoperatively in clinical stage IIIc. The patient was asymptomatic, with only mild vaginal discharge of amber color and normal measured value of CA 125. The diagnosis was based on routine clinical and ultrasound examination, followed by surgery, surgical-pathological staging of the disease, and finally paclitaxel and platinum based chemotherapy. The patient has been in remission for nine years now.

Management of cervical ectopic pregnancy after unsuccesful methotrexate treatment.

BACKGROUND: Cervical pregnancy is rare and dangerous form of ectopic pregnancy which can be treated surgically or conservatively. Methotrexate is reasonable conservative option with high efficiency and acceptable level of side effects. Aim of this paper is to present possible treatment option in case of methotrexate failure, still keeping the postulates of minimal invasive surgery. CASE: We describe a case of cervical ectopic pregnancy in nulliparous female that was unsuccessfully treated with single dose, local, ultrasound guided intraamniotic methotrexate. Due to vaginal bleeding caused by remaining products of conception a hysteroscopic resection was performed. CONCLUSION: Despite the problems that can occur in methotrexate treatment, it is still by far, cheapest and most effective treatment of cervical pregnancies. If necessary, procedure can be combined with other minimal invasive surgical procedures leading to satisfactory results. Hysteroscopic resection has enabled us to remove the product of conception from cervix making the minimal damage to the local tissue, thus preserving fertility.

Comparison between clinical significance of serum proinflammatory protein interleukin-6 and classic tumor markers total PSA, free PSA and free/total PSA prior to prostate biopsy.

The aim of the study was to clarify whether serum levels of proinflammatory cytokine interleukin-6 (IL-6) could be a useful marker in prostate diseases. Serum IL-6 was determined prior to prostate biopsy procedure in 82 patients with prostate adenocarcinoma (PCa), 25 patients with benign prostatic hyperplasia (BPH), 24 patients with high-grade prostatic intraepithelial neoplasia (PIN) and 17 patients with chronic prostatitis. Serum IL-6 levels were compared with total PSA (tPSA), free PSA (fPSA) and the free/total ratio (f/tPSA) serum levels. Statistically significant difference was not found in serum IL-6 levels among the four groups (p = 0.088). However, the patients with poorly differentiated PCa with Gleason score (GS) 4 + 3 = 7 and > 7 had significantly higher serum IL-6 levels than the patients with moderately differentiated PCa with GS 3 + 4 = 7 and < 7 (p = 0.007). The findings suggest that serum IL-6 level might be a potentially useful marker for poorly differentiated PCa.

[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]. / Klinicke upute za dijagnostiku, lijecenje i pracenje bolesnica oboljelih od raka jajnika hrvatskoga onkoloskog drustva i hrvatskog drustva za ginekologiju i opstetriciju hrvatskoga lijetnickog zbora te hrvatskoga ginekoloskoonkoloskog drustva.

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.

Vascular endothelial growth factor and intratumoral microvessel density as prognostic factors in endometrial cancer.

The aim of this research was to determine the VEGF A expression in tumor cells and the intratumoral microvessel density and their prognostic significance in the survival of the subjects. 87 subjects were monitored retrospectively for a period of 60 to 132 months. The subjects were treated at the Department of Obstetrics and Gynecology of Osijek University Hospital Center, Croatia. We analysed standard clinical, pathohistological and therapeutical prognostic factors, intratumoral microvessel density and expression of VEGF A. Five-year survival was calculated by the life chart method and presented graphically by Kaplan-Meier curves. Reaching conclusions on statistical hypotheses in this paper was done with a reliability level p < 0.05. Of the analyzed clinical prognostic factors, those which proved to be statistically significant and independent prognostic factors were age and clinical stage of the disease, and of pathohistologic ones it was the depth of myometrial invasion and VEGF expression. An elevated VEGF expression is associated with deep myometrial invasion, poorly differentiated tumors, histologic type and intratumoral microvessel density to a statistically significant degree. Elevated VEGF expression, age, FIGO stage and depth of myometrial invasion play a significant prognostic role in patients with endometrial cancer. VEGF receptors could be a target for adjuvant therapy in VEGF positive endometrial cancer.

Numerical analysis of standard and modified osteosynthesis in long bone fractures treatment.

The fundamental problem in osteoporotic fracture treatment is significant decrease in bone mass and bone tissue density resulting in decreased firmness and elasticity of osteoporotic bone. Application of standard implants and standard surgical techniques in osteoporotic bone fracture treatment makes it almost impossible to achieve stable osteosynthesis sufficient for early mobility, verticalization and load. Taking into account the form and the size of the contact surface as well as distribution of forces between the osteosynthetic materials and the bone tissue numerical analysis showed advantages of modified osteosynthesis with bone cement filling in the screw bed. The applied numerical model consisted of three sub-models: 3D model from solid elements, 3D cross section of the contact between the plate and the bone and the part of 3D cross section of the screw head and body. We have reached the conclusion that modified osteosynthesis with bone cement resulted in weaker strain in the part of the plate above the fracture fissure, more even strain on the screws, plate and bone, more even strain distribution along all the screws' bodies, significantly greater strain in the part of the screw head opposite to the fracture fissure, firm connection of the screw head and neck and the plate hole with the whole plate and more even bone strain around the screw.

The case of asymptomatic primary actinomycosis of the greater omentum in the patient with intrauterine contraceptive device.

This paper describes a case of asymptomatic multifocal actinomycosis of the greater omentum which was detected accidentally in a patient who was suspected of uterus myoma. The patient was a 40 year old woman who had a copper intrauterine contraceptive device (IUCD) for three years. After the gynecological examination and pelvic ultrasound she was diagnosed with sub serous myoma of uterus. Since she did not give a birth it was suggested to have myoma enucleating. However during the surgery a dermoid teratoma of the right ovary was detected so it was removed together with tumor and there were two thickenings on the greater omentum, suspicious of inflammation, whereas one grew together with the front abdominal wall. Due to these conditions, she had partial omentectomy done and omentum was sent for path histological examination. The path histological examination confirmed it to be actinomycosis. The patient had an intensive antibiotic therapy prescribed (Penicillin) in order to prevent a disease relapse because we could not be sure whether the remaining part of omentum was affected by microscopic actinomycosis.