Role of α- and ß-adrenergic signaling in phenotypic targeting: significance in benign and malignant urologic disease.

The urinary tract is highly innervated by autonomic nerves which are essential in urinary tract development, the production of growth factors, and the control of homeostasis. These neural signals may become dysregulated in several genitourinary (GU) disease states, both benign and malignant. Accordingly, the autonomic nervous system is a therapeutic target for several genitourinary pathologies including cancer, voiding dysfunction, and obstructing nephrolithiasis. Adrenergic receptors (adrenoceptors) are G-Protein coupled-receptors that are distributed throughout the body. The major function of α1-adrenoceptors is signaling smooth muscle contractions through GPCR and intracellular calcium influx. Pharmacologic intervention of α-and ß-adrenoceptors is routinely and successfully implemented in the treatment of benign urologic illnesses, through the use of α-adrenoceptor antagonists. Furthermore, cell-based evidence recently established the antitumor effect of α1-adrenoceptor antagonists in prostate, bladder and renal tumors by reducing neovascularity and impairing growth within the tumor microenvironment via regulation of the phenotypic epithelial-mesenchymal transition (EMT). There has been a significant focus on repurposing the routinely used, Food and Drug Administration-approved α1-adrenoceptor antagonists to inhibit GU tumor growth and angiogenesis in patients with advanced prostate, bladder, and renal cancer. In this review we discuss the current evidence on (a) the signaling events of the autonomic nervous system mediated by its cognate α- and ß-adrenoceptors in regulating the phenotypic landscape (EMT) of genitourinary organs; and (b) the therapeutic significance of targeting this signaling pathway in benign and malignant urologic disease. Video abstract.

Prostatic intraepithelial neoplasia: a risk factor for prostate cancer.

Prostatic Intraepithelial Neoplasia (PIN) is an increasingly common finding at ultrasound guided prostate biopsy, with the high grade form (HGPIN) thought to be "precancerous". With the more widespread use of extended biopsy protocols, taking sometimes up to 14 cores or more, the incidence of HGPIN can be up to 25%. Histologically, it has many features in common with cancer of the prostate and has been shown to be both associated with cancer at the time of its finding and predictive for the development of prostate cancer in the future. Basic science research has demonstrated genes common specifically to both prostate cancer and HGPIN and immunostaining studies of microvessel density may help to differentiate HGPIN from lower risk PIN. There are no active treatments for HGPIN although there are trials to assess the effectiveness of hormonal therapy and nutritional supplements. Currently most urologists recommend that patients should be followed at 6 monthly intervals with regular PSA and repeat biopsies as indicated.

Guglielmi detachable coiling for intracranial aneurysms: the story so far.

Spontaneous rupture of cerebral aneurysms typically results in subarachnoid hemorrhage. The primary goal of treatment of cerebral aneurysms is to prevent future rupture. Surgical clipping had been the mainstay of treatment of both ruptured and unruptured cerebral aneurysms. In 1991, Guglielmi detachable coil (GDC) embolization was introduced as an alternative method for treating selected patients with aneurysm. The goal of the treatment is prevent the flow of blood into the aneurysm sack by filling the aneurysm with coils and thrombus. Theoretically, there are several advantages of GDC over surgery. These procedures are performed under general anesthesia with the standard transfemoral approaches used in diagnostic angiography. Since its inception, GDC embolization has evolved as a result of both clinical experience and the introduction of technological improvements. We are now better at selecting aneurysms appropriate for coiling, which also have wide necks. Advances in GDC technology have also improved this method of treatment. Over the last several years, the number of coil sizes has been increased, multidimensional coils allowing safer initial coil placement have become available, and, more recently, softer coils have been introduced. Our current approach is to have both surgical and endovascular options for patients.

Surgery following endovascular coiling of intracranial aneurysms.

BACKGROUND: Surgery for intracranial aneurysms that have been treated by endovascular coiling is a new challenge for neurosurgeons and the need for it will undoubtedly continue to increase. The indications for, timing, and technique of surgery in our experience are described. METHODS: We have reviewed our experience with 11 patients who underwent surgery following endovascular coiling with Guglielmi detachable coils (GDCs) of an aneurysm. We analyzed the indications for surgery, surgical techniques used, and patient outcome. RESULTS: There were nine female and two male patients. The mean age was 49 years (range 13 to 67 years). The intervals between coiling and surgery were 1, 2, 3, 4, 7, 7, 10, and 14 days, 6 weeks, 2, 18, and 25 months. The indications for surgery were partial treatment (3), growth of residual neck (2), persistent mass effect of a giant aneurysm (1), mass effect from the coil ball (2), coil migration (2), and coil protrusion with embolic event (1). The coils were removed at the time of surgery from 9 of 11 aneurysms before clipping. In two cases it was possible to place a clip across the neck of the aneurysm without removing the coils, as the coils no longer occupied the neck. There were two permanent deficits directly related to the endovascular procedures. Two other patients who presented with subarachnoid hemorrhage had residual neurological deficits post surgery and one patient with a giant aneurysm had persistent visual loss. CONCLUSION: Surgery remains a viable option at any time for treating aneurysms that have been previously treated by GDC placement. The operative approach is determined by the need for coil removal and the duration since coiling.