Alessandro Calarco

Epigenetic silencing of SOCS3 identifies a subset of prostate cancer with an aggressive behavior

Chronic inflammation and subsequent tissutal alterations may play a key role in prostate carcinogenesis. In this way, molecular alterations of the suppressor of cytokine signaling 3 (SOCS3), one of the most important inhibitory molecule of inflammatory signal transduction circuitries, could contribute to explain the pleiotropic role of interleukin‐6 (IL‐6) in this type of cancer.

Imaging in prostate cancer diagnosis: present role and future perspectives

Prostate cancer (PCa) remains a major health concern for the male population. Detection and primary diagnosis of PCa are based on digital rectal examination, serum prostate-specific antigen levels, and transrectal ultrasound (TRUS)-guided random biopsy. Moreover, the gold standard for detecting PCa, systematic biopsy, lacks sensitivity as well as grading accuracy. This review summarizes recent developments of ultrasonography modalities and functional magnetic resonance imaging (MRI) in the diagnosis of PCa. A comparison between the different methods is presented, including their clinical value and usefulness. It is concluded that innovative ultrasound techniques (including ultrasound contrast agents, 3-D and 4-D sonography, elastography and harmonic sonography) promise benefits in comparison to standard TRUS to accurately diagnose PCa. Promising advances have been made in the detection of PCa with multiparametric MRI. The combination of conventional and functional MRI techniques (including diffusion-weighted imaging, dynamic contrast-enhanced MRI, and MR spectroscopy) can provide information for differentiating PCa from noncancerous tissue and can be used for MRI-guided biopsies, especially in patients with persistent elevation of serum prostate-specific antigen and previous negative TRUS-guided biopsies. However, functional MRI technique and MRI-guided biopsy remain expensive and complex tools presenting inherent challenges.

Imaging in prostate cancer staging: present role and future perspectives.

Despite recent improvements in detection and treatment, prostate cancer continues to be the most common malignancy and the second leading cause of cancer-related mortality. Thus, although survival rate continues to improve, prostate cancer remains a compelling medical health problem. The major goal of prostate cancer imaging in the next decade will be more accurate disease characterization through the synthesis of anatomic, functional, and molecular imaging information in order to plan the most appropriate therapeutic strategy. No consensus exists regarding the use of imaging for evaluating primary prostate cancer. However, conventional and functional imaging are expanding their role in detection and local staging and, moreover, functional imaging is becoming of great importance in oncologic management and monitoring of therapy response. This review presents a multidisciplinary perspective on the role of conventional and functional imaging methods in prostate cancer staging.

Role of SOCS3 evaluated by immunohistochemical analysis in a cohort of patients affected by prostate cancer: preliminary results

Background Chronic inflammation may play a role in prostate carcinogenesis. Molecular alterations of the Suppressor of Cytokine Signaling (SOCS)-3 can contribute to explain the pleiotropic role of interleukin (IL)-6 in this type of cancer. Recently, the methylation of SOCS3 gene has been demonstrated to cause the non-expression of the protein, being involved in the pathogenesis of prostate cancer (PC) and identifying a subset of aggressive tumors. We evaluated the expression of SOCS3 protein in patients (pt) with bioptically-diagnosed PC by immunohistochemical analysis, which is easier to perform, cheaper and more reproducible compared to DNA analysis. Methods We analyzed the protein expression of SOCS3 by immunohistochemistry in 44 patients (pt) with PC diagnosed after biopsy. Slides were incubated with monoclonal antibody SOCS3 (1E4, 1.5 μg/mL; Abnova, Taiwan). The SOCS3 staining intensity was evaluated by two pathologists (FP and LML) in three different ways: positive (+), negative (-) and weak (+/-). Colonic mucosa was used as positive control. 36/44 patients underwent radical prostatectomy (RP). Results Biopsy Gleason score (Gs) was: <7 in 8 pt, 7 in 33 pt (3 + 4 pattern in 21 pt, 4 + 3 pattern in 12 pt), >7 in 3 pt. 8/8 (100%) pt with Gs <7 and 7/33 (21%) with Gs 7 were SOCS+. 15/33 (45%) pt with Gs 7 and 3/3 (100%) pt with Gs >7 were negative. In 11/33 pt (33%) Gs 7 a weak intensity was found so they were classified as SOCS3 +/-. 25/36 (69%) patients who underwent RP were SOCS3– (15 pt with Gs 7(3 + 4), 7 pt with Gs 7(4 + 3), 3 pt with Gs 8) and 11/36 (30%) SOCS3+ (8 pt with Gs 6 and 3 pt with Gs 7(3 + 4)) (Tab 2). 12/25 (48%) SOCS3– pt had an organ-confined disease (≤pT2), whereas 13/25 (52%) had an extra prostatic neoplasm (5 pT3a (one was N+), 6 pT3b, 1 pT4). All SOCS3+ patients (8/8 (100%)) had an organ-confined disease. 3/3 (100%) SOCS3+/- pt had an extra prostatic neoplasm (>pT2). Conclusions SOCS3– pt turned out to have a more aggressive disease compared with SOCS3+. In particular, also SOCS3+/- patients seemed to have an aggressive behavior. The non-expression of SOCS3 protein may identify PC with more aggressive behavior and can be evaluated with immunohystochemical analysis, which is a relatively easy and cheap procedure in clinical practice. These results, if confirmed by a wider population and a longer follow-up, may encourage the research on the use of this molecular family as a prognostic marker and a target for therapy with demethylating agents.

Soluble E-cadherin and IL-6 serum levels in patients affected by prostate cancer before and after prostatectomy

Prostate specific antigen (PSA) is still the best available tumour marker in prostate cancer (PCa), but presents some limits. Therefore, there is a need for novel markers in the detection and management of PCa. The 80-kDa soluble form of E-cadherin (sE-cad) and the cytokine IL-6 are being discussed as supplemental serum markers for PCa. In this study, sE-cad and IL-6 serum levels were determined in patients with pathological localized or locally advanced PCa without any previous treatment. These patients underwent radical retropubic prostatectomy (RRP) in accordance with the EAU Guidelines on Prostate Cancer. The molecules were determined via immunoenzymatic assays in samples collected before and after surgery. Statistical analysis was performed by Students t-test and Pearsons correlation test. sE-cad levels were 6.0 ± 2.7 and 4.6 ± 2.3 µg/ml, before and after RRP, respectively. A highly statistically significant decrease in sE-cad concentrations after RRP was observed (p<0.0001), in 50/61 patients (82%). sE-cad levels before and after surgery were correlated (Pearsons correlation coefficient, r=0.6993, p<0.0001). sE-cad values detected after surgery were higher in patients with PSA levels >10 ng/ml (p<0.05). sE-cad levels before RRP were significantly higher in patients with G3 tumours compared to those with G2 tumours (p<0.02). Finally, sE-cad concentrations both before and after surgery were higher in tumours with Gleason score =7 compared to those with Gleason score <7 (p<0.002 and p<0.05, respectively). Preliminary data from 20 patients indicated a statistically significant increase in IL-6 levels after RRP (11.2 vs. 7.2 pg/ml, p<0.001). This is the first study on the reduction in sE-cad levels after RRP in PCa patients. Moreover, it shows that preoperative sE-cad concentrations are higher in patients with less differentiated PCa. Promising findings of this pilot study may lead to investigation of sE-cad in a larger study with follow-up.

High-intensity focused ultrasound in prostate cancer: Today's outcomes and tomorrow's perspectives

Abstract High-intensity focused ultrasound (HIFU) is a minimally invasive therapy applied for prostate cancer that capitalizes on the coagulation necrosis that occurs at temperatures greater than 60°C. Owing to a lack of long-term follow-up data the procedure is still considered experimental treatment. As primary therapy, HIFU is indicated in patients aged ≥70 years with clinical organ-confined disease, although it has also been used, with encouraging results, as first line salvage therapy after definitive treatment, and in locally advanced (T3–4) and non-metastatic hormone-resistant prostate cancer. Morbidity associated with this treatment method appears to be low and includes urinary retention (1–9%), urethral stricture (4–14%), incontinence (1–15%), erectile dysfunction (13–53%) and rectourethral fistulae (0–3%). The risk of complications increases with repeated treatments. A few studies have recently been published on HIFU as focal therapy. HIFU technology can be enhanced using means such as ultrasound microbubble contrast agents for assessment of therapy efficacy, magnetic resonance imaging to guide the enhancement of heat rate, and localized drug and gene delivery.

Doping and urologic tumors

Several substances such as growth hormone (GH), erythropoietin (Epo), and anabolic steroids (AS) are improperly utilized to increase the performance of athletes. Evaluating the potential cancer risk associated with doping agents is difficult since these drugs are often used at very high doses and in combination with other licit or illicit drugs. The GH, via its mediator, the insulin-like growth factor 1 (IGF-1), is involved in the development and progression of cancer. Animal studies suggested that high levels of GH/IGF-1 increase progression of androgen-independent prostate cancer. Clinical data regarding prostate cancer are mostly based on epidemiological studies or indirect data such as IGF-1 high levels in patients with prostate cancer. Even if experimental studies showed a correlation between Epo and cancer, no clinical data are currently available on cancer development related to Epo as a doping agent. Androgens are involved in prostate carcinogenesis modulating genes that regulate cell proliferation, apoptosis and angiogenesis. Most information on AS is anecdotal (case reports on prostate, kidney and testicular cancers). Prospective epidemiologic studies failed to support the hypothesis that circulating androgens are positively associated with prostate cancer risk. Currently, clinical and epidemiological studies supporting association between doping and urological neoplasias are not available. Nowadays, exposure to doping agents starts more prematurely with a consequent longer exposition period; drugs are often used at very high doses and in combination with other licit or illicit drugs. Due to all these elements it is impossible to predict all the side effects, including cancer; more detailed studies are therefore necessary.

Microbiological follow-up of nosocomial infections in a single urological center

Background To analyze data from the cultural examinations of different biological fluids, obtained from urologic patients from January 2007 to April 2010, in order to describe the incidence of infections in our setting. Methods In the period of reference a urine culture was carried out for every patient admitted, in case of suspected urinary tract infection, a blood culture in case of suspected sepsis, and a wound culture in case of wound infection. Results In the period of investigation 321 patients developed some kind of infection: 589 positive isolations obtained from cultural examinations have been diagnosed in urine (63%), blood (6%), surgical wound (6%), venous central catheter (7%) and other sites (18%) (tip of ureteral and bladder catheters). The most commonly isolated pathogenic agent for all the sites of infection has been Escherichia coli (22.5%). In urine, the most frequently isolated species have been Escherichia coli (27.8%), Enterococcus (12.5%), and Candida spp (9.3%). Escherichia coli (22.9%), Pseudomonas (5.7%), and Staphylococcus aureus (3.5%) were the most frequently found pathogenic agents responsible for sepsis, compared to others. In the period of investigation we have recorded 35 episodes of sepsis. Conclusions Empiric antibiotic therapy is frequent in cases of clinical evidence of infection, before the identification of the causative microorganism is available; therefore, it is important to know which are the bacterial species mainly responsible for these specific infections. We need continuous surveillance of infections and the improvement in the use of antibiotic therapy in order to limit the antimicrobial resistance.

Brachytherapy in men with prostate cancer: update on indications and outcomes

Brachytherapy (BT), using either a low-dose-rate (LDR) or mostly high-dose-rate (HDR) technique, is the device able to deliver the highest dose-rate in the most conformal way It is used as monotherapy or in combination with external beam radiotherapy (EBRT). LDR-BT is mostly used as monotherapy; HDR-BT is combined with EBRT +/– adjuvant hormone therapy In patients with low-risk disease and in selected intermediate-risk patients, LDR-BT ensures long-term good disease control rates and HDR-BT shows similar results, even if with shorter follow-up. In patients with intermediate/high risk disease the combination therapy (EBRT + HDR-BT) provides better oncological outcomes compared to EBRT monotherapy, even if the role of adjuvant hormone therapy is still unclear. Literature shows variable efficacy of BT in case of local recurrence after EBRT and radical prostatectomy even if few cases have been reported with short follow-up. Side effects are acceptable (urogenital toxicity, urinary incontinence, sexual function) and comparable with the other treatment modalities. So far, randomized controlled trials comparing the different treatment modalities are necessary to clarify indications and real efficacy.

[Regenerative medicine: applications and development in urology].

PURPOSE. Congenital abnormalities and acquired disorders can lead to organ damage and loss. Nowadays, transplantation represents the only effective treatment option. However, there is a marked decrease in the number of organ donors, which is even yearly worsening due to the population aging. The regenerative medicine represents a realistic option that allows to restore and maintain the normal functions of tissues and organs. This article reviews the principles of regenerative medicine and the recent advances with regard to its application to the genitourinary tract. RECENT FINDINGS. The field of regenerative medicine involves different areas of technology, such as tissue engineering, stem cells and cloning. Tissue engineering involves the field of cell transplantation, materials science and engineering in order to create functional replacement tissues. Stem cells and cloning permit the extraction of pluripotent, embryonic stem cells offering a potentially limitless source of cells for tissue engineering applications. Most current strategies for tissue engineering depend upon a sample of autologous cells from the patients diseased organ. Biopsies from patients with extensive end-stage organ failure, however, may not yield enough normal cells. In these situations, stem cells are envisaged as being an alternative source. Stem cells can be derived from discarded human embryos (human embryonic stem cells), from fetal tissue or from adult sources (bone marrow, fat, skin). Therapeutic cloning offers a potentially limitless source of cells for tissue engineering applications. Regenerative medicine and tissue engineering scientists have increasingly applied the principles of cell transplantation, materials science and bioengineering to construct biological substitutes that will restore and maintain normal function in urological diseased and injured tissues such as kidney, ureter, bladder, urethra and penis. CONCLUSIONS. Regenerative medicine offers several applications in acquired and congenital genito-urinary diseases. Tissue engineering, stem cells and, mostly, cloning have been applied in experimental studies with excellent results. Few preliminary human applications have been developed with promising results.