Benjamin Namdarian

Immunohistochemical study of the cavernous nerves in the periprostatic region

Study Type – Therapy (case series)u2028Level of Evidenceu20034

Snail expression is an independent predictor of tumor recurrence in superficial bladder cancers

BACKGROUNDnEpithelial-mesenchymal transition (EMT) is known to play an important role in the development of tumor invasion and progression in tumors of epithelial origin.nnnOBJECTIVESnOur aim was to investigate the role of Snail transcription repressor family members in human bladder pathogenesis.nnnMATERIAL AND METHODSnWe evaluated levels of Snail and Slug in 87 patients who received transurethral resection of a transitional cell carcinoma at our institution during the period from June 1999 until November 2003. Immunohistochemistry was performed on tissue microarrays, and expression correlated with pathological variables and clinical outcomes. Degree and intensity of Snail and Slug staining was quantified by immunohistochemistry.nnnRESULTSnThere was no apparent enrichment in strong vs. weak staining for either Snail (43.7% vs. 56.3%) or Slug (46% vs. 54%) in the superficial bladder tumors. Univariate analysis determined that tumor focality and Snail expression were significantly associated with tumor recurrence (P < 0.05). Only for tumor focality did such a relationship exist when assessing tumor progression. Multivariate analysis using the Coxs proportional hazards model revealed similar results to that of the univariate analysis. Snail expression (P = 0.038) and tumor focality (P = 0.011) were independent and significant prognostic factors for tumor recurrence in all patients. However, only tumor focality was an independent predictor of tumor progression (P = 0.034).nnnCONCLUSIONSnHigh expression of Snail in superficial bladder tumors is a strong predictor of tumor recurrence enhancing risk stratification and prognostication.

Prostate tumour volume is an independent predictor of early biochemical recurrence in a high risk radical prostatectomy subgroup

Aims: To assess if accurately determined tumour volume variables could serve as independent predictors of early biochemical recurrence in high risk prostate cancer patients who underwent radical prostatectomy. Methods: Tumour volume variables were calculated by digital planimetry in 269 prostatectomy specimens of patients with high risk prostate cancer. The associations to biochemical progression of tumour volume and clinicopathological variables, including age, pre-operative prostate specific antigen (PSA) levels, final Gleason score, pathological T stage, and surgical margins, were examined using univariate and multivariate Cox proportional hazards analyses. Results: Median tumour volume was 3.7 ml [interquartile range (IQR) 2.1–6.1 mL] and median follow-up time was 12 months (IQR 6–24 months). Biochemical recurrence occurred in 64 men (24%) during this period, with a median time to recurrence of 7.5 months (IQR 3.0–15.5 months). On univariate analysis all of the tumour volume variables were strongly correlated with the clinicopathological variables, as well as biochemical recurrence (p < 0.001). On multivariate analysis, we found that tumour volume variables served as independent predictors of PSA progression whilst other routinely reported pathological variables did not. Conclusion: Accurately assessing tumour volume in the high risk setting may aid in identifying patients at greatest risk of developing early biochemical recurrence and most in need of adjuvant therapy.

Paraneoplastic syndromes in prostate cancer.

Prostate cancer is the second most common urological malignancy to be associated with paraneoplastic syndromes after renal cell carcinoma. These syndromes tend to occur in the setting of late stage and aggressive tumors with poor overall outcomes. Recognition of these syndromes is clinically important as it might lead to the detection of underlying malignancy and impact on the treatment options available. The literature features around 100 cases of paraneoplastic syndromes associated with prostate cancer and these include endocrine manifestations, neurological entities, dermatological conditions, and other syndromes. Over 70% of cases document the syndrome as the initial clinical manifestation of prostate cancer, while in just under 20% the syndrome was an initial sign of disease progression to the castrate-resistant state. The vast majority of cases involved advanced metastatic malignancy. The syndromes generally resolve upon institution of treatment for the underlying prostate cancer, but some syndromes require specific therapies. Some syndromes are associated with serum markers that are readily detectable and demonstration of these putative markers within prostate cancer tissue at an individual level would firmly link the paraneoplastic syndrome with its underlying prostatic malignancy. The causes of paraneoplastic syndromes in prostate cancer are incompletely understood, and further research into their biology might shed more light on the complex molecular mechanisms that underpin prostate cancer and its lethal potential.

Cadaveric Analysis of Periprostatic Nerve Distribution: An Anatomical Basis for High Anterior Release During Radical Prostatectomy?

PURPOSEnAn accurate, complete understanding of the prostate neuroanatomy is required to optimize nerve sparing techniques during radical prostatectomy. However, the precise topography and function of the periprostatic nerves remain contentious and there is uncertainty about which nerve sparing technique is most optimal. We accurately quantified the distribution, precise localization and cross-sectional area of periprostatic neural tissue using cadaveric specimens.nnnMATERIALS AND METHODSnWe analyzed 13 cadaveric hemipelves using hematoxylin and eosin stained sections from the base, mid zone and apex of each prostate. Each section was digitized and divided into 6 sectors numbered clockwise. Analysis was performed using National Institutes of Health ImageJ software to calculate the total periprostatic neural cross-sectional area per sector.nnnRESULTSnCalculating the total neural cross-sectional area highlighted a decrease from prostate base to mid zone to apex of 24.7, 19.7 and 13.7 mm(2), respectively. Most neural tissue was located in the posterolateral region. However, the proportion surrounding the anterior part of the prostate increased toward the apex with a median of 6.0% and 7.6% at the base and mid zone regions, respectively, increasing to 11.2% at the apex.nnnCONCLUSIONSnSimple numerical nerve quantification may be insufficient to accurately describe the periprostatic neural distribution. Calculating nerve bundle cross-sectional area confirmed that most neural tissue is in the posterolateral region, although the proportion located anterior increases from base to apex. Thus, higher release of the periprostatic fascia may be indicated toward the apex.

Circulating endothelial cells as biomarkers of prostate cancer.

Prostate cancer has a wide spectrum of biological aggressiveness, and where an individual tumor lies within this spectrum can be difficult to characterize at diagnosis. The degree of tumor vascularization in prostate cancer correlates with disease progression and, thus, markers of angiogenesis are potential indicators of clinical outcome. Identification of improved prognostic markers would have a substantial effect on patient outcomes. Such markers would also be invaluable in assessments of the effectiveness of experimental chemotherapeutic regimens and antiangiogenic drugs that are currently under investigation. Bone-marrow-derived circulating endothelial progenitors (CEPs) and circulating endothelial cells (CECs) play an integral part in neovascularization and their levels in the circulation correlate with disease progression and therapeutic response in various settings. Although CECs and CEPs are yet to be thoroughly investigated in prostate cancer, the evidence suggests that these markers may be of use in the prostate-cancer setting. We review current understanding of the contributions of CEPs and CECs to tumor progression, and discuss their potential as prognostic markers.

Extraprostatic Extension into Periprostatic Fat is a More Important Determinant of Prostate Cancer Recurrence than an Invasive Phenotype

PURPOSEnAlthough micrometastasis development correlates closely with the depth of invasion of many tumor types, it is unclear whether invasion into but not through the prostatic pseudocapsule has a negative impact on prognosis, similar to extraprostatic extension. We defined the impact of pseudocapsular invasion on the risk of post-prostatectomy biochemical recurrence.nnnMATERIALS AND METHODSnPatients with pT2-3a prostate cancer were identified from a prospectively recorded database. Those with pT2 disease were categorized according to pseudocapsular invasion presence or absence. The impact of pseudocapsular invasion on biochemical recurrence was determined by univariable and multivariable Cox regression analysis.nnnRESULTSnIn a cohort of 1,338 patients we identified 595 with organ confined cancer positive for pseudocapsular invasion. Compared to tumors without evidence of invasion, pseudocapsular invasion was positively associated with higher Gleason grade and tumor volume (1.2 vs 1.9 cc, each p<0.001). On univariable analysis there was no difference in biochemical recurrence-free survival between patients with vs without pseudocapsular invasion, although those with extraprostatic extension had significantly lower biochemical recurrence-free survival (p<0.001). This was confirmed on multivariable analysis, which revealed that extraprostatic extension was a significant independent predictor of biochemical recurrence (HR 1.53, p=0.018). The presence of pseudocapsular invasion had no effect (HR 0.81, p=0.33).nnnCONCLUSIONSnPseudocapsular invasion is not a pathological feature associated with an adverse outcome after prostatectomy. Thus, the depth of tumor invasion is not a continuum of risk and access to periprostatic adipose tissue is a more important determinant of disease behavior than an invasive phenotype.

Circulating endothelial cells and progenitors: potential biomarkers of renal cell carcinoma.

To compare the levels of circulating endothelial cells (CECs) and progenitors (CEPs) between tumour‐bearing mice and healthy controls, in human renal cell carcinoma (RCC) xenograft models. The secondary objective was to correlate CEC and CEP levels with tumour variables such as tumour volume, weight and vascularity, indicators of disease severity.

Loss of APKC expression independently predicts tumor recurrence in superficial bladder cancers

OBJECTIVESnEpithelial-mesenchymal transition (EMT) is known to play an important role in the development of tumor invasion and progression in tumors of epithelial origin. Our aim was to investigate the role of tight junction proteins, Par3/Par6/atypical protein kinase C (APKC), Discs large (Dlg), and Scribble in human bladder pathogenesis.nnnMETHODSnWe evaluated levels of APKC, Dlg, and Scribble in 92 superficial bladder tumors using tissue microarrays and immunohistochemistry, and correlated expression with pathologic variables and clinical outcomes.nnnRESULTSnThere was a slight apparent enrichment in strong vs. weak staining for APKC (54.9% vs. 45.1%), Dlg (65.7% vs. 34.3%), and a marked enrichment for Scribble (75% vs. 25%) in the superficial bladder tumors. Univariate analysis determined that both tumor focality and APKC expression were significantly associated with tumor recurrence (P < 0.05). Multivariate analysis using the Coxs proportional hazards model revealed that only APKC (P = 0.025) as well as tumor focality (P = 0.018) were independent and significant prognostic factors for tumor recurrence in all patients. We found that no immunohistochemical staining of any of the cell polarity proteins significantly predicted for tumor progression on either univariate or multivariate analysis.nnnCONCLUSIONSnLoss of APKC expression in superficial bladder tumors is a strong predictor of tumor recurrence.

Levels of a subpopulation of platelets, but not circulating endothelial cells, predict early treatment failure in prostate cancer patients after prostatectomy

Background:Angiogenesis is one of the hallmarks of cancer driving tumour growth and ultimately metastasis. Circulating endothelial cells (CECs) and circulating endothelial progenitor (CEPs) cells have been reported as candidate surrogate markers for tumour vascularisation. Our aim was to investigate the potential use of these circulating cells levels as predictors of prostate cancer treatment failure and metastasis.Methods:We examined the levels of CD31+CD45− cells (CECs) and CD31+CD45−CD117+ (CEPs) in s.c. and orthotopic models of human prostate cancers and correlated measurements with tumour size, volume and microvessel density (MVD). We then performed a prospective cohort study in 164 men with localised prostate cancer undergoing prostatectomy. The CD31+CD45−, CD31+CD45−CD146+ (CECs) and CD31+CD45intermediateCD133+ (CEPs) populations were quantified and subsequently enriched for further characterisation.Results:In preclinical models, levels of CD31+CD45− cells, but not CEPs, were significantly elevated in tumour-bearing mice and correlated with tumour size, volume and MVD. In our human prospective cohort study, the levels of CD31+CD45− cells were significantly higher in men who experienced treatment failure within the first year, and on logistic regression analysis were an independent predictor of treatment failure, whereas neither levels of CECs or CEPs had any prognostic utility. Characterisation of the isolated CD31+CD45− cell population revealed an essentially homogenous population of large, immature platelets representing <0.1% of circulating platelets.Conclusion:Elevated levels of a distinct subpopulation of circulating platelets were an independent predictor for early biochemical recurrence in prostate cancer patients within the first year from prostatectomy.