Nikola Knezevic

The Transcriptional Co-Activator cAMP Response Element-Binding Protein-Binding Protein Is Expressed in Prostate Cancer and Enhances Androgen- and Anti-Androgen-Induced Androgen Receptor Function

Progression of human prostate cancer toward therapy resistance occurs in the presence of wild-type or mutated androgen receptors (ARs) that, in some cases, exhibit aberrant activation by various steroid hormones and anti-androgens. The AR associates with a number of co-activators that possess histone acetylase activity and act as bridging molecules to components of the transcription initiation complex. In previous reports, it was shown that the transcriptional co-activator CREB (cAMP response element-binding protein)-binding protein (CBP) enhances AR activity in a ligand-dependent manner. In the present study, we have investigated whether CBP modifies antagonist/agonist balance of the nonsteroidal anti-androgens hydroxyflutamide and bicalutamide. In prostate cancer DU-145 cells, which were transiently transfected with CBP cDNA, hydroxyflutamide enhanced AR activity to a greater extent than bicalutamide in the presence of either wild-type or the mutated AR 730 val-->met. In two sublines of LNCaP cells that contain the mutated AR 877 thr-->ala and overexpressed CBP, increase in AR activity was observed after treatment with hydroxyflutamide but not with bicalutamide. Anti-androgens did not influence AR expression in cells transfected with CBP cDNA, as judged by Western blot analysis. Endogenous CBP protein was detected by Western blot in nuclear extracts from the three prostate cancer cell lines, LNCaP, PC-3, and DU-145, all derived from therapy-resistant prostate cancer. In addition, CBP was expressed in both basal and secretory cells of benign prostate epithelium, high-grade prostate intraepithelial neoplasia, and prostate cancer clinical specimens, as evidenced by immunohistochemical staining. Taken together, our findings demonstrate the selective enhancement of agonistic action of the anti-androgen hydroxyflutamide by the transcriptional co-activator CBP, which is a new, potentially relevant mechanism contributing to the acquisition of therapy resistance in prostate cancer.

Laparoscopic Adrenalectomy: Lessons Learned from 306 Cases

INTRODUCTION Laparoscopic adrenalectomy has become the standard of care for the surgical treatment of benign adrenal pathology. We present the following case series documenting our experience in refinement of this approach. PAIENTS AND METHODS Analysis of patient records identified those in whom laparoscopic adrenalectomy was performed from January 1997 through February 2010. Study variables included indications, operative time, blood loss, length of hospital stay, histopathological evaluation, and complications. RESULTS Laparoscopic adrenalectomy was performed in 306 patients using the transperitoneal lateral approach. No major operative complications were noted, and postoperative complications included a pulmonary embolism and 2 cases of pneumonia. Conversion to the open approach was necessitated in two cases. The median operative time was 95±29 minutes (range, 45-145 minutes). Estimated blood loss was 60 mL (range, 30-150 mL). The mean size of the removed gland was 5.9±1.6 cm (range, 3-13 cm). The mean size of the tumor was 5±2 cm (range, 0.5-12 cm). The median hospitalization was 4±3.7 days (range, 2-22 days). Adrenal pathology included adenoma (n=164), pheochromocytoma (n=79), hyperplasia (n=35), metastatic carcinoma (n=22), cyst (n=9), myelolipoma (n=9), hemangioma (n=3), ganglioneuroma (n=3), and melanoma (n=2). CONCLUSION Laparoscopic adrenalectomy is a safe and feasible approach to adrenal pathology, providing the patients with all the benefits of minimally invasive surgery.

Correlation between retroperitoneal lymph node size and presence of metastases in nonseminomatous germ cell tumors

Eighty-five patients had staging laparoscopic retroperitoneal lymph node dissection (L-RPLND) for nonseminomatous germ cell tumors at our institution. The largest lymph node size was measured and presence or absence of metastatic disease was determined. A total of 1139 lymph nodes have been removed and in 27 (31.8%) patients, metastases in one or more lymph nodes were detected. There were 338 (29.7%) hilar, 259 (22.7%) paraaortic, 221 (19.4%) interaortocaval, 171 (15%) paracaval, 133 (11.7%) preaortic and 17 (1.5%) precaval lymph nodes. The total number of lymph nodes with metastases was 74 (6.5%), and 1065 (93.5%) nodes did not have any metastases. The average size of a lymph node with metastases was 1.05 (0.3-3), and without metastases it was 0.55 (0.1-2.5) cm, (p<0.001). If we use > 1 cm size of a lymph node as a “cut-off” value for enlargement and presence of metastases, 60% of metastatic lymph nodes would be missed since they were all ≤ 1 cm. Our results have shown that decreasing size of lymph nodes which are considered positive from > 1 cm to 0.7 -0.8 cm can be recommended, with specificity and sensitivity equal 70%.

Laparoscopic partial nephrectomy with diode laser: a promising technique

OBJECTIVE The aim of this study was to evaluate application of diode laser in laparoscopic partial nephrectomy (LPN), and to question this technique in terms of ease of tumor excision and reduction of warm ischemia time (WIT). BACKGROUND DATA LPN is the standard operative method for small renal masses. The benefits of LPN are numerous, including preserving renal function and prolonging overall survival. However, reduction of WIT remains main challenge in this operation. In order to shorten WIT, many techniques have been developed, with variable results. PATIENTS AND METHODS We performed a prospective collection and analysis of health records for patients who were operated on between March 2011 and August 2012. Inclusion criteria were single tumor ≤ 4 cm, predominant exophytic growth and intraparenchymal depth ≤ 1.5 cm, with a minimum distance of 5 mm from the urinary collecting system. RESULTS We operated on 17 patients. Median operative time was 170 min. In all but two patients, we had to perform hilar clamping. Median duration of WIT was 16 min. Pathohistological evaluation revealed clear cell renal cancer and confirmed margins negative for tumor in all cases. Median size of the tumor was 3 cm. Median postoperative hospitalization was 5 days. Average follow up was 11.5 months. There were no intraoperative complications. One postoperative complication was noted: perirenal hematoma. CONCLUSIONS Laser LPN is feasible, and offers the benefit of shorter WIT, with effective tissue coagulation and hemostasis. With operative experience and technical advances, WIT will be reduced or even eliminated, and a solution to some technical difficulties, such as significant smoke production, will be found.

OCT 4 immunohistochemistry in postpubertal cryptorchidism

Patients with cryptorchidism are at an increased risk for germ cell testicular cancer. OCT 4 has been shown to be a sensitive and specific marker for some types of germ cell testicular cancer. We undertook this study to establish whether OCT 4 immunohistochemistry is a useful tool in the pathohistologic evaluation of postpubertal patients with cryptorchidism. Seventeen postpubertal patients underwent orchidectomy for cryptorchidism at our center since 1997. Immunohistochemical staining with OCT 4 was performed on these samples. Characteristic OCT 4 nuclear staining was positive in two patients. One patient was correctly diagnosed on previous pathohistological evaluation, while OCT4 immunohistochemical staining revealed previously unidentified intratubular germ cell neoplasia in the other patient. OCT 4 immunohistochemistry can be useful in diagnosing a testicular germ cell tumor in patients with cryptorchidism. If we consider a low number of postpubertal patients with cryptorchidism a benefit of immunohistochemical staining with OCT4, this could favor the use of OCT 4 staining in work-up of cryptorchidism.