Joseph Ischia

The role of heat shock proteins in bladder cancer

Heat shock proteins (HSPs) and clusterin (another chaperone protein with HSP-like properties) are present in normal cells and are upregulated by cellular stressors such as hyperthermia, hypoxia, and cytotoxic agents. HSPs are overexpressed in a wide range of cancers. Cancer cells are in a constant state of proteotoxic stress and exploit the HSPs to protect themselves against the toxic effects of aberrant oncoproteins, genomic instability, hypoxia, and acidosis. In many patients with cancer, high levels of HSPs are associated with poor prognosis and treatment resistance as these proteins protect tumour cells from therapeutic stressors such as androgen or oestrogen withdrawal, radiation, and cytotoxic chemotherapy. Differences in the expression levels of HSPs in bladder cancers compared with normal urothelium have led to HSPs being investigated as diagnostic and prognostic biomarkers. Evidence suggests that HSPs are important modulators of the immune system and have a role in BCG-stimulated regression of urothelial cancers. New bladder cancer treatment strategies that target HSPs are being investigated and could have a synergistic role with modern radiotherapy and chemotherapy regimens. A combination of OGX-427 (an antisense oligonucleotide that targets HSP27), gemcitabine, and cisplatin is currently being investigated in a phase II trial of patients with advanced bladder cancer.

Gastrin‐releasing peptide: Different forms, different functions

All forms of the neuropeptide gastrin‐releasing peptide (GRP) are derived from the precursor proGRP1‐125. Amidated GRP18‐27, which together with amidated GRP1‐27 was long thought to be the only biologically relevant product of the GRP gene, is involved in a multitude of physiological functions and acts as a mitogen, morphogen, and proangiogenic factor in certain cancers. Recently, GRP has been implicated in several psychiatric conditions, in the maintenance of circadian rhythm, in spinal transmission of the itch sensation, and in inflammation and wound repair. The actions of GRP are mediated by the GRP receptor. Over the last decade, nonamidated peptides derived from proGRP, such as the glycine‐extended form GRP18‐28 and recombinant and synthetic fragments from proGRP31‐125, have been shown to be biologically active in a range of tissues and in cancer cell lines. While GRP18‐28 acts via the GRP receptor, the identity of the receptor for proGRP31‐125 and its fragments has not yet been established. Nonamidated fragments are also present in normal tissues and in various cancers. In fact, proGRP31‐98 is the most sensitive serum biomarker in patients with small cell lung cancer and is a significant predictor of poor survival in patients with advanced prostate cancer.

Active surveillance for prostate cancer: an Australian experience.

•  To assess the patient and cancer characteristics as well as outcomes of a large cohort of Australian men who chose active surveillance (AS) as initial management of their low‐risk prostate cancer.

Guideline of guidelines: follow‐up after nephrectomy for renal cell carcinoma

The purpose of this article was to review and compare the international guidelines and surveillance protocols for post‐nephrectomy renal cell carcinoma (RCC). PubMed database searches were conducted, according to the PRISMA statement for reporting systematic reviews, to identify current international surveillance guidelines and surveillance protocols for surgically treated and clinically localized RCC. A total of 17 articles were reviewed. These included three articles on urological guidelines, three on oncological guidelines and 11 on proposed strategies. Guidelines and strategies varied significantly in relation to follow‐up, specifically with regard to the frequency and timing of radiological imaging. Although there is currently no consensus within the literature regarding surveillance protocols, various guidelines and strategies have been developed using both patient and tumour characteristics.

The promise of heat shock protein inhibitors in the treatment of castration resistant prostate cancer.

Purpose of review To present the recent advances in novel agents that target heat shock proteins (Hsps) to treat or delay the development of castration resistant prostate cancer (CRPC). Recent findings Multiple preclinical studies have shown that silencing Hsp27, Hsp90, or clusterin sensitizes prostate cancer cells to modern chemotherapy and radiation treatments; and overexpression of these chaperones confers resistance to these therapies. Antisense oligonucleotides targeting Hsp27 and clusterin have shown good biological activity in human phase II trials and phase III studies are ongoing. Despite promising preclinical efficacy, a number of phase I/II human trials with various Hsp90 inhibitors have been disappointing with negligible anticancer activity and dose-limiting toxicity profiles. Newer Hsp90 inhibitors with better toxicity profiles, and inhibitors that target Hsp90 cofactors, such as FKBP52, are currently being investigated in human studies. Summary Many Hsp chaperone client proteins are key components of alternative growth factor pathways upregulated in CRPC and are involved in key resistance pathways to current chemotherapy and radiotherapy regimes. New treatments that inhibit Hsps are attractive anticancer strategies as they have the ability to simultaneously target multiple pathways involved in CRPC.

HIF1α Expression under Normoxia in Prostate Cancer— Which Pathways to Target?

PURPOSE HIF1α over expression correlates with poor prognosis in a number of cancers. Although it is widely accepted that hypoxia induces HIF1α expression up-regulation by a reduction in oxygen dependent degradation, HIF1α up-regulation under normoxic conditions is noted with increasing frequency in many cancers. We reviewed the current knowledge of mechanisms of normoxic and hypoxic HIF1α up-regulation, and its therapeutic implications with a particular focus on its role as a potential biomarker in prostate cancer. MATERIALS AND METHODS Although the literature on the role of HIFs in cancer development and progression has been reviewed extensively, few publications have specifically considered the role of HIFs in prostate cancer. Therefore, we searched PubMed® and Google® with the key words prostate cancer, castration resistance, metastasis, hypoxia, HIF1α, HIF2α and regulation. Relevant articles, including original research studies and reviews, were selected based on contents and a synopsis was generated. RESULTS Normoxic expression of HIF1α has an important role in the development of prostate cancer chemoresistance, radioresistance and castrate resistance. Thus, HIF1α could serve as a potential biomarker. Furthermore, agents that target HIF1α could be used as adjuvant therapy to decrease resistance to conventional treatment modalities. HIF1α over expression in prostate cancer can be regulated at 3 levels, including transcription, translation and protein stability, by a number of mechanisms such as gene amplification, single nucleotide polymorphism, increased transcription of HIF1α mRNA, expression of truncated isoforms of HIF1α and stabilization of HIF1α. However, there is no definitive consensus and the intriguing question of how HIF1α is up-regulated in prostate cancer is still unanswered. CONCLUSIONS HIF1α over expression under normoxia could serve as a biomarker for chemoresistance, radioresistance and castrate resistance in prostate cancer. There is an urgent need to identify the cause of HIF1α over expression in castrate resistant prostate cancer cells and tumors to guide the choice of HIF inhibitors (transcription or translation based) that are best suited for treating castrate resistant prostate cancer.

Radical prostatectomy in high‐risk prostate cancer

One consistent finding in the studies regarding treating men with prostate cancer is that men with high‐risk disease have the most to gain from treatment with curative intent. Men with high‐risk or locally‐advanced prostate cancer require treatment to the primary cancer or risk dying prematurely from their disease. Increasingly, combined androgen deprivation therapy + radiation treatment is seen as the standard treatment as a result of prospective studies in this space, and the perceived increased morbidity of radical prostatectomy in the setting of a “low” cure rate as monotherapy. In the absence of a well‐conducted randomized trial, there is no definite evidence that one treatment is superior to the other. The advantages of radical prostatectomy are that it provides excellent local control of the primary tumor without an increase in morbidity, accurately stages the disease to guide further therapy, and removes benign sources of prostate‐specific antigen so that failures can be promptly identified and subsequent treatment can be initiated in a timely manner. Although several guidelines recommend radiation treatment over radical prostatectomy as first‐line treatment, there is no evidence that surgery is inferior and radical prostatectomy should remain part of any informed discussion regarding treatment options for men with high‐risk prostate cancer.

Holmium Laser Enucleation of the Prostate: Comparison of Immediate Postoperative Outcomes in Patients with and without Antithrombotic Therapy.

Objective: To compare the immediate postoperative outcomes of patients with benign prostatic hyperplasia undergoing Holmium laser enucleation of the prostate (HOLEP) with and without full anticoagulation or antiplatelet therapy at the time of surgery. Materials and Methods: A retrospective review was performed on a series of consecutive patients undergoing HOLEP at our institution by a single surgeon from February 2004 to September 2010. Demographic, surgical, pathological and outcome data were collected. Two cohorts were identified on the basis of antithrombotic therapy at the time of surgery. Patients who continued on aspirin, aspirin/dipyridamole, clopidogrel and warfarin throughout the surgery were included in the antithrombotic cohort. Univariate analysis was performed to determine differences in outcomes between the 2 cohorts. Results: Total 125 consecutive patients underwent HOLEP with 52 patients on antithrombotic therapy at the time of surgery and 73 patients were not on antithrombotic therapy during surgery. Patients in the antithrombotic group were older (75.1 ±7.5 vs. 71.7 ± 8.3 years; p = 0.02) and had a higher median ASA physical status (3 (3-3) vs. 2 (2-3), p < 0.0001). The mean operating time and median specimen volume were not significantly different between the 2 cohorts. The median length of stay (2 (1-3) vs. 1 (1-2) d, p = 0.014) was longer in the antithrombotic cohort. The transfusion rate (7.7 vs. 0%, p = 0.028) was predictably higher in the antithrombotic cohort. No patients required re-operation for bleeding. Conclusions: The use of HOLEP in patients on antithrombotic therapy is safe despite the higher surgical risk profile of that particular patient population and the potential increased risk for significant bleeding.

Expression and function of gastrin-releasing peptide (GRP) in normal and cancerous urological tissues

Gastrin‐releasing peptide (GRP) acts as an important regulatory peptide in several normal physiological processes and as a growth factor in certain cancers. In this review we provide a comprehensive overview of the current state of knowledge of GRP in urological tissues under both normal and cancerous conditions. GRP and its receptor, GRP‐R, are expressed in the normal kidney and renal cancers. GRP can stimulate the growth of renal cancer cells. GRP and GRP‐R are expressed in prostate cancer and GRP can stimulate the growth of prostate cancer cell lines. Importantly, GRP is a key neuroendocrine peptide, which may be involved in the progression of advanced prostate cancer and in the neuroendocrine differentiation of prostate cancer. Recent animal studies have shown that GRP and GRP‐R are an integral part of male sexual function and play a crucial role in spinal control of erections and ejaculation.

Renal colic: current protocols for emergency presentations.

Flank pain caused by renal colic is a common presentation to emergency departments. This paper reviews the acute clinical assessment of these patients, outlines appropriate diagnostic strategies with labwork and imaging and updates the reader on conservative treatments, suitable choices for analgesia and indications for surgical intervention. Prompt diagnosis and appropriate treatment instituted in the Emergency Department can rapidly and effectively manage this excruciatingly painful condition.