Is extended biopsy protocol justified in all patients with suspected prostate cancer?

Objective: To determine the significance of an extended 10-core transrectal biopsy protocol in different categories of patients with suspected prostate cancer using digital guidance.Materials and Methods: We studied 125 men who were being evaluated for prostate cancer. They all had an extended 10-core digitally guided transrectal prostatic biopsy done for either an elevated serum prostate-specific antigen (PSA) or an abnormal digital rectal examination finding or both. Sextant biopsy samples were collected first, followed by additional four lateral biopsies in all patients. Both groups of specimens were analyzed separately. The cancer detection rates of both sextant and extended 10-core biopsy protocols at different PSA levels and digital rectal examination (DRE) findings were determined and compared. The level of significance of difference in cancer detection was determined using Pearson’s Chi square test with level of significance set at <0.05.Results: The overall cancer detection by the extended technique was 61 (48.8%) cases while the sextant protocol detected cancer in 52 cases. The 10-core extended protocol yielded an increase in cancer detection rate of 14.8% but the improvement in detection rate was only statistically significant in the sub-set of patients with PSA between 4.1 and 10 ng/mL, with or without abnormality on DRE, with an overall increase detection rate of 33%.(P=0.04).Conclusion: Our study has shown that a 10-core prostate biopsy protocol significantly improves cancer detection in patients with suspected early cancer. It should therefore be the optimum biopsy protocol for patients with gray-zone PSA value, with or without abnormal DRE

Deficiency of Thioredoxin Binding Protein-2 (TBP-2) Enhances TGF-β Signaling and Promotes Epithelial to Mesenchymal Transition

Transforming growth factor beta (TGF-β) has critical roles in regulating cell growth, differentiation, apoptosis, invasion and epithelial-mesenchymal transition (EMT) of various cancer cells. TGF-β-induced EMT is an important step during carcinoma progression to invasion state. Thioredoxin binding protein-2 (TBP-2, also called Txnip or VDUP1) is downregulated in various types of human cancer, and its deficiency results in the earlier onset of cancer. However, it remains unclear how TBP-2 suppresses the invasion and metastasis of cancer.In this study, we demonstrated that TBP-2 deficiency increases the transcriptional activity in response to TGF-β and also enhances TGF-β-induced Smad2 phosphorylation levels. Knockdown of TBP-2 augmented the TGF-β-responsive expression of Snail and Slug, transcriptional factors related to TGF-β-mediated induction of EMT, and promoted TGF-β-induced spindle-like morphology consistent with the depletion of E-Cadherin in A549 cells.Our results indicate that TBP-2 deficiency enhances TGF-β signaling and promotes TGF-β-induced EMT. The control of TGF-β-induced EMT is critical for the inhibition of the invasion and metastasis. Thus TBP-2, as a novel regulatory molecule of TGF-β signaling, is likely to be a prognostic indicator or a potential therapeutic target for preventing tumor progression

c-Met activation leads to the establishment of a TGFβ-receptor regulatory network in bladder cancer progression

Treatment of muscle-invasive bladder cancer remains a major clinical challenge. Aberrant HGF/c-MET upregulation and activation is frequently observed in bladder cancer correlating with cancer progression and invasion. However, the mechanisms underlying HGF/c-MET-mediated invasion in bladder cancer remains unknown. As part of a negative feedback loop SMAD7 binds to SMURF2 targeting the TGFβ receptor for degradation. Under these conditions, SMAD7 acts as a SMURF2 agonist by disrupting the intramolecular interactions within SMURF2. We demonstrate that HGF stimulates TGFβ signalling through c-SRC-mediated phosphorylation of SMURF2 resulting in loss of SMAD7 binding and enhanced SMURF2 C2-HECT interaction, inhibiting SMURF2 and enhancing TGFβ receptor stabilisation. This upregulation of the TGFβ pathway by HGF leads to TGFβ-mediated EMT and invasion. In vivo we show that TGFβ receptor inhibition prevents bladder cancer invasion. Furthermore, we make a rationale for the use of combinatorial TGFβ and MEK inhibitors for treatment of high-grade non-muscle-invasive bladder cancers

Structural insights into the catalysis and regulation of E3 ubiquitin ligases

Covalent attachment (conjugation) of one or more ubiquitin molecules to protein substrates governs numerous eukaryotic cellular processes, including apoptosis, cell division and immune responses. Ubiquitylation was originally associated with protein degradation, but it is now clear that ubiquitylation also mediates processes such as protein–protein interactions and cell signalling depending on the type of ubiquitin conjugation. Ubiquitin ligases (E3s) catalyse the final step of ubiquitin conjugation by transferring ubiquitin from ubiquitin-conjugating enzymes (E2s) to substrates. In humans, more than 600 E3s contribute to determining the fates of thousands of substrates; hence, E3s need to be tightly regulated to ensure accurate substrate ubiquitylation. Recent findings illustrate how E3s function on a structural level and how they coordinate with E2s and substrates to meticulously conjugate ubiquitin. Insights regarding the mechanisms of E3 regulation, including structural aspects of their autoinhibition and activation are also emerging

Original Articles Efficacy and Safety of Doxazosin (CARDURATM) in the Management of Benign Prostatic Hyperplasia

ObjectiveTo assess the efficacy and safety of the selective á -blocker doxazosin in black men with lower urinary tract symptoms (LUTS) suggestive of benign prostatic hyperplasia.Patients and MethodsAn open-label study involving consecutive patients with benign prostatic hyperplasia. They were asked to complete the International Prostate Symptom Score (IPSS), with its eighth question (bother score) and perform basic uroflowmetry. The study involved the use of doxazosin for the treatment of symptomatic benign prostatic hyperplasia in three phases. Phase 1 of washout period/enrolment, a two weekly interval titration phase and a maintenance phase for four weeks. The symptom score (IPSS), bother score and uroflowmetry were used to evaluate the severity of the condition and the efficacy of the drug.ResultsTwenty-four patients were enrolled into the study, only 18(75%) completed the eight-week study. The ages of the patients ranged between 46 years and 82 years with a mean of 66 years. (SD, 10.0). Fourteen patients were stabilized on 4mg doxazosin while the remaining 4 patients had 2mg. There was significant improvement of the symptoms, with a remarkable sharp decline after two weeks of medication in IPSS by 8 points from baseline. The improvement was sustained over the following six weeks period. The bother score (quality of life index) was similarly observed to decline from a mean of 4.7 at baseline to 1.3 at the end of the study. The clinical trial showed a significant increase in the urine flow rate with an improvement of 4mls/second from baseline and a 24.1% increase in voided volume. There was no adverse event recorded in all the patients to warrant discontinuation of the study.ConclusionDoxazosin is an effective and well tolerated drug in the treatment of symptomatic BPH in Nigerians.Key Words: BPH, LUTS, Quality of life, IPSS, a1-blocker, Doxazosin

Clinico-pathological Correlation of Digital Rectal Examination Findings Amongst Nigerian Men with Prostatic Diseases: A Prospective Study of 236 Cases

Aims and Objective: This study aims at correlating different digital rectal examination (DRE) abnormalities with histopathological results in patients with prostatic diseases. Materials and Methods: A prospective study of 236 patients who underwent prostate needle biopsy (PNB). Inclusion criteria were presence of abnormal DRE findings or elevated prostate specific antigen above 4 ng/ml or both. They all had 10.core extended transrectal biopsy and specimens were sentfor histopathological examination. Correlations were made between DRE findings and histopathology results. Two separate multivariate logistic regression models were created; the first evaluated the relationship of predictors (DRE findings) to the likelihood of detecting cancer and the second explored predictors of high.grade cancer on PNB.Results: Two hundred and thirty.six patients were enrolled with a mean age of 66.9 years and range of 43.90 years. Histopathology results were malignant in 102 (43.2%) and benign in 134 (56.8%). Ninety.one (38.6%) and 145 (61.4%) had normal DRE and abnormal DRE findings with cancer detection rates of 23.1% and 55.8% respectively. Nodular prostate is the most common abnormality in 63.4% patients with abnormal DRE. Each sign of DRE had different predictive value with enhanced positive predictive value when combinations of abnormalities are present. Abnormal DRE is an independent predictor of high.grade tumor. Mean Gleason scores were 4.7and 7.1 in patients with normal and abnormal DRE respectively.Conclusion: DRE is a useful and important tool in assessing patients with suspected prostate diseases who need prostate biopsy. An abnormal DRE correlated well with prostate cancer and independently predicted high.grade disease in these men. Keywords: Clinico-pathological correlation, digital rectal examination findings, prostate cancer, prostate needle biops

Impact of prostate size on cancer detection values of two different prostate biopsy strategies amongst Nigerian men

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