Integrin involvement in freeze resistance of androgen-insensitive prostate cancer.

Cryoablation has emerged as a primary therapy to treat prostate cancer. Although effective, the assumption that freezing serves as a ubiquitous lethal stress is challenged by clinical experience and experimental evidence demonstrating time-temperature-related cell-death dependence. The age-related transformation from an androgen-sensitive (AS) to an androgen-insensitive (AI) phenotype is a major challenge in the management of prostate cancer. AI cells exhibit morphological changes and treatment resistance to many therapies. As this resistance has been linked with alpha6beta4 integrin overexpression as a result of androgen receptor (AR) loss, we investigated whether alpha6beta4 integrin expression, as a result AR loss, contributes to the reported increased freeze tolerance of AI prostate cancer. A series of studies using AS (LNCaP LP and PC-3 AR) and AI (LNCaP HP and PC-3) cell lines were designed to investigate the cellular mechanisms contributing to variations in freezing response. Investigation into alpha6beta4 integrin expression revealed that AI cell lines overexpressed this protein, thereby altering morphological characteristics and increasing adhesion characteristics. Molecular investigations revealed a significant decrease in caspases-8, -9, and -3 levels in AI cells after freezing. Inhibition of alpha6beta4 integrin resulted in increased caspase activity after freezing (similar to AS cells) and enhanced cell death. These data show that AI cells show an increase in post-freeze susceptibility after inhibition of alpha6beta4 integrin function. Further understanding the role of androgen receptor-related alpha6beta4 integrin expression in prostate cancer cells responses to freezing might lead to novel options for neo-adjunctive treatments targeting the AR signaling pathway.

Issues critical to the successful application of cryosurgical ablation of the prostate.

The techniques of present-day cryosurgery performed with multiprobe freezing apparatus and advanced imaging techniques yield predictable and encouraging results in the treatment of prostatic and renal cancers. Nevertheless, and not unique to cryosurgical treatment, the rates of persistent disease demonstrate the need for improvement in technique and emphasize the need for proper management of the therapeutic margin. The causes of persistent disease often relate to a range of factors including selection of patients, understanding of the extent of the tumor, limitations of the imaging techniques, and failure to freeze the tumor periphery in an efficacious manner. Of these diverse factors, the one most readily managed, but subject to therapeutic error, is the technique of freezing the tumor and appropriate margin to a lethal temperature [Baust, J. G., Gage, A. A. The Molecular Basis of Cryosurgery. BJU Int 95, 1187-1191 (2005)]. This article describes the recent experiments that examine the molecular basis of cryosurgery, clarifies the actions of the components of the freeze-thaw cycle, and defines the resultant effect on the cryogenic lesion from a clinical perspective. Further, this review addresses the important issue of management of the margin of the tumor through adjunctive therapy. Accordingly, a goal of this review is to identify the technical and future adjunctive therapeutic practices that should improve the efficacy of cryoablative techniques for the treatment of malignant lesions.

Sacral stress fracture in a female collegiate distance runner: a case report.

OBJECTIVE: To present the case of a 19-year-old collegiate distance runner diagnosed with a unilateral sacral stress fracture. BACKGROUND: Low back and sacroiliac joint pain are common in female athletes but are often difficult to differentiate. Although sacral stress fractures in young female athletes are rarely reported, they are a potential cause of low back pain. DIFFERENTIAL DIAGNOSIS: Acute lumbosacral strain, disc disease, gluteus maximus strain, idiopathic low back pain, low back strain, sacroiliac joint sprain, or congenital anomaly. TREATMENT: Six weeks of active rest and nutritional counseling followed by an incremental 8-week running program. The athlete returned to symptom-free competitive running within 4 months. UNIQUENESS: This young athlete presented with a unilateral sacral stress fracture with components of the female athlete triad and a vigorous exercise regime. CONCLUSIONS: Sacral stress fractures are rare in the young female athletic population. Because stress fractures in female runners have various etiologies, a thorough patient history and diagnostic imaging are necessary in the evaluation. Athletes can return to their normal activity once a successful management strategy has addressed all components of the female athlete triad while providing adequate rest. Prevention strategies, such as screening for the components of the female athlete triad, may help to decrease injuries and promote healthier lifestyles among this population.