Combined 18F‐fluorocholine and 18F‐fluoride positron emission tomography/computed tomography imaging for staging of high‐risk prostate cancer

Study Type – Diagnosis (cohort) Level of Evidence 2a What's known on the subject? and What does the study add? Positron emission tomography/computed tomography (PET/CT) with choline and fluoride for the detection of metastases in patients with prostate cancer have each been evaluated, with mixed results. Choline PET/CT has been evaluated against pelvic lymphadenectomy, generally with a low sensitivity but a high specificity; however, the study populations have been heterogenous. Fluoride PET/CT has been evaluated against other imaging methods, such as bone scan, single photon emission CT and MRI, and has been shown to have high specificity as well as sensitivity for bone metastases, but there are no studies with biopsy verification. This is the first study that evaluates the clinical use of both choline and fluoride PET/CT on the same patients in a well‐defined population of patients with high‐risk prostate cancer.

OBJECTIVE

• ? To investigate how often positron emission tomography/computed tomography (PET/CT) scans, with both ¹⁸F‐fluorocholine and ¹⁸F‐fluoride as markers, add clinically relevant information for patients with prostate cancer who have high‐risk tumours and a normal or inconclusive planar bone scan.

PATIENTS AND METHODS

• ? Patients with prostate cancer with prostate specific antigen (PSA) levels between 20 and 99 ng/mL and/or Gleason score 8–10 tumours, planned for treatment with curative intent based on routine staging with a negative or inconclusive bone scan, were further investigated with a ¹⁸F‐fluorocholine and a ¹⁸F‐fluoride PET/CT.
• ? None of the patients received hormonal therapy before the staging procedures were completed.

RESULTS

• ? For 50 of the 90 included patients (56%) one or both PET/CT scans indicated metastases.
• ? ¹⁸F‐fluorocholine PET/CT indicated lymph node metastases and/or bone metastases in 35 patients (39%).
• ? ¹⁸F‐fluoride PET/CT was suggestive for bone metastases in 37 patients (41%).
• ? In 18 patients (20%) the PET/CT scans indicated widespread metastases, leading to a change in therapy intent from curative to non‐curative.
• ? Of the patients with positive scans, 74% had Gleason score 8–10 tumours. Of the patients with Gleason score 8–10 tumours, 64% had positive scans.

CONCLUSIONS

• ? PET/CT scans with ¹⁸F‐fluorocholine and ¹⁸F‐fluoride commonly detect metastases in patients with high‐risk prostate cancer and a negative or inconclusive bone scan.
• ? For 20% of the patients the results of the PET/CT scans changed the treatment plan.

     

The extent of pelvic lymph node dissection correlates with the biochemical recurrence rate in patients with intermediate- and high-risk prostate cancer

Study Type – Therapy (case series) Level of Evidence 4 What’s known on the subject? and What does the study add? Pelvic lymph‐node dissection during radical prostatectomy for prostate cancer is certainly a fundamental staging procedure but its therapeutic role is yet under debate. This retrospective study suggests that, in patients with intermediate‐ and high‐risk of prostate cancer, the greater the number of lymph‐nodes removed, the lower the risk of biochemical relapse, even in the presence of 1 or 2 lymph‐node metastasis. However, the Will Rogers phenomenon must be considered due to the retrospective nature of the present study.

OBJECTIVE

• ? To assess the impact of pelvic lymph node dissection (PLND) and of the number of lymph nodes (LNs) retrieved during radical prostatectomy (RP) on biochemical relapse (BCR) in pNX/0/1 patients with prostate cancer according to the clinical risk of lymph node invasion (LNI).

PATIENTS AND METHODS

• ? We evaluated 872 pT2‐4 NX/0/1 consecutive patients submitted to RP between October 1995 and June 2009, with the following inclusion criteria: (i) a follow‐up period ≥12 months; (ii) the avoidance of neoadjuvant hormonal therapy or adjuvant hormonal and/or adjuvant radiotherapy; (iii) the availability of complete follow‐up data; (iv) no pathological T0 disease; (v) complete data regarding the clinical stage and Gleason score (Gs), the preoperative prostate‐specific antigen (PSA) level and the pathological stage.
• ? The patients were stratified as having low risk (cT1a‐T2a and cGs ≤6 and PSA level < 10 ng/mL), intermediate risk (cT2b‐T2c or cGs = 7 or PSA level = 10–19.9) or high risk of LNI (cT3 or cGs = 8–10 or PSA level ≥ 20).
• ? The 872 patients were divided into two LN groups according to the number of LNs retrieved: group 1 had no LN or one to nine LNs removed; group 2 had 10 or more LNs.
• ? The variables analysed were LN group, age, PSA level, clinical and pathological stage and Gs, surgical margin status, LN status and number of LN metastases; the primary endpoint was the BCR‐free survival.

RESULTS

• ? The mean follow‐up was 55.8 months.
• ? Of all the patients, 305 (35%) were pNx and 567 (65.0%) were pN0/1.
• ? Of the 567 patients submitted to PLND, the mean number of LNs obtained was 10.9, and 49 (8.6%) were pN1.
• ? In the 402 patients at low risk of LNI, LN group was not a significant predictor of BCR at univariate analysis, while in the 470 patients at intermediate and high risk of LNI, patients with ≥10 LNs removed had a significantly lower BCR‐free survival at univariate and multivariate analysis.

CONCLUSION

• ? In our study population, a more extensive PLND positively affects the BCR‐free survival regardless of the nodal status in intermediate‐ and high‐risk prostate cancer.

     

Lymph node mapping in patients with bladder cancer undergoing radical cystectomy and lymph node dissection to the level of the inferior mesenteric artery

Study Type – Therapy (case series)
Level of Evidence 4

OBJECTIVE

To evaluate extended lymph node dissection (LND) as a nodal staging tool in the treatment of invasive carcinoma of the urinary bladder and to suggest a reasonable proximal limit of the dissection.

PATIENTS AND METHODS

In all, 170 patients underwent radical cystectomy with extended LND up to the level of the inferior mesenteric artery. Specimens were evaluated as 13 separate packages from pre‐designated anatomical locations. The number of LNs and presence of positive LNs (LN+) at each location was prospectively registered.

RESULTS

The median (range) number of LNs removed was 24 (6–62). In all, 25.3% of the patients had LN+. The median (range) number of LN+ was 2 (1–20). Advanced T‐stage was correlated with a higher risk of LN+ but not to the specific location of the LN+. Two patients had LN+ above the common iliac bifurcation with no LN+ more distally located within the pelvic region. All other patients with LN+ above the common iliac bifurcation had more distally located LN+. There were no skip lesions to LNs above the aortic bifurcation.

CONCLUSIONS

Extended LND above the common iliac bifurcation including the presacral area provides a more accurate LN staging compared with a standard pelvic LND. Extending the limits above the aortic bifurcation is not necessary from a staging perspective.     

Cancer‐specific survival after radical cystectomy and standardized extended lymphadenectomy for node‐positive bladder cancer: prediction by lymph node positivity and density

OBJECTIVE

To investigate the associations between different overall or topographically restricted lymph node (LN) variables and cancer‐specific survival (CSS) after radical cystectomy (RC) and extended LN dissection (LND) with curative intent in patients with LN‐positive bladder cancer.

PATIENTS AND METHODS

Between 2001 and 2006, 152 patients had RC with standardized extended LND for bladder cancer with curative intent. Patients with positive LNs were stratified according to the median of the LN variables (LNs removed, number of positive LNs, LN density). CSS was related to overall and topographically restricted LN variables, e.g. different levels of LND, and relationships were tested by univariate and multivariate analyses. Level 1 LND comprised the regions of the external and internal iliac LNs and of the obturator LNs, level 2 the templates of common iliac and presacral LNs, and level 3 the para‐aortic and paracaval LNs up to the inferior mesenteric artery. The mean (range) follow‐up was 22 (1–84) months.

RESULTS

LN metastases were diagnosed in 46 of the 152 patients (30%) with extended LND. In these 46 patients, the median number of removed LNs was 33 (level 1, 15.5; level 2, 9.0; level 3, 7.0), the median number of positive LNs was 3 (1.5, 0.5 and 0.0, respectively) and the median LN density was 0.11 (0.10, 0.02 and 0.0, respectively). The CSS was 76% at 1 year and 23% at 3 years. There were significant correlations between the 3‐year CSS and the overall LN density (≤0.11 vs >0.11; 34% vs 8%, P = 0.008), and the total number of positive LNs (≤3 vs >3; 33% vs 8%; P = 0.05). Overall LN density (hazard ratio 0.33, 95% confidence interval 0.15–0.72; P = 0.006) was an independent predictor for CSS in multivariate analysis.

CONCLUSIONS

Overall LN density is an independent predictor of survival after RC and extended LND with curative intent. Evaluation of topographically restricted LN positivity and density for different regions and levels of LND does not improve the prediction of CSS compared with overall LN positivity and density. A low incidence of level 3 LN positivity questions the clinical relevance of removing para‐aortic and paracaval LNs. However, our data need to be confirmed by a prospective randomized trial.     

Early oncological outcomes for bladder urothelial carcinoma patients treated with robotic-assisted radical cystectomy

Study Type – Therapy (case series) Level of Evidence 4

OBJECTIVE

• ? To determine oncological outcomes including early survival rates among unselected bladder urothelial carcinoma (BUC) patients treated with robotic‐assisted radical cystectomy (RRC).

PATIENTS AND METHODS

• ? Clinicopathologic and survival data were prospectively gathered for 85 consecutive BUC patients treated with RRC.
• ? The decision to undergo a robotic rather than open approach was made without regard to tumor volume or surgical candidacy.
• ? Kaplan–Meier survival rates were determined and stratified by tumor stage and LN positivity, and multivariate analysis was performed to identify independent predictors of survival.

RESULTS

• ? Patients were relatively old (25% >80 years; median 73.5 years), with frequent comorbidities (46% with ASA class ≥3). Of these patients 28% had undergone previous pelvic radiation or pelvic surgery, and 20% had received neoadjuvant chemotherapy.
• ? Extended pelvic lymphadenectomy was performed in 98% of patients, with on average 19.1 LN retrieved.
• ? On final pathology, extravesical disease was common (36.5%).
• ? Positive surgicalmargins were detected in five (6%) patients, all of whom had extravesical tumors with perineural and/or lymphovascular invasion, and most of whom were >80 years old.
• ? At a mean postoperative interval of 18 months, 20 (24%) patients had developed recurrent disease, but only three (4%) patients had recurrence locally. Disease‐free, cancer‐specific and overall survival rates at 2 years were 74%, 85% and 79%, respectively. Patients with low‐stage/LN(?) cancers had significantly better survival than extravesical/LN(?) or any‐stage/LN(+) patients, with stage being the most important predictor on multivariate analysis.

CONCLUSION

• ? RRC can achieve adequately high LN yields with a low positive margin rate among unselected BUC patients.
• ? Early survival outcomes are similar to those reported in contemporary open series, with an encouragingly low incidence of local recurrence, however long‐term follow‐up and head‐to‐head comparison with the open approach are still needed.

     

[18F]‐fluorocholine positron‐emission/computed tomography for lymph node staging of patients with prostate cancer: preliminary results of a prospective study

Study Type – Diagnostic (case series)
Level of Evidence 4

OBJECTIVES

To evaluate prospectively [¹⁸F]‐fluorocholine positron‐emission/computed tomography (FCH PET/CT) for lymph node staging of prostate cancer before intended curative therapy, and to determine whether imaging 15 or 60 min after radiotracer injection is preferable.

PATIENTS AND METHODS

In all, 25 consecutive patients with newly diagnosed prostate cancer (Gleason score >6, and/or a prostate‐specific antigen level of >10 ng/mL, and/or T3 cancer) were scanned before lymphadenectomy. Each patient was assessed twice with imaging, at 15 and 60 min after the injection with FCH. Images were compared with the results of histopathological examination of the surgically removed lymph nodes. Maximum standardized uptake values (SUV_max) at 15 and 60 min were also compared.

RESULTS

Histopathologically, metastases were present in removed lymph nodes from three patients. FCH PET/CT showed a high radiotracer uptake in four patients, the former three and a fourth. The sensitivity, specificity, positive and negative predictive value of FCH PET/CT for patient based lymph node staging of prostate cancer were 100%, 95%, 75% and 100%, respectively; the corresponding 95% confidence intervals were 29.2–100%, 77.2–99.9%, 19.4–99.4% and 83.9–100%, respectively. Values of SUV_max at early and late imaging were not significantly different.

CONCLUSIONS

This small series supports the use of FCH PET/CT as a tool for lymph node staging of patients with prostate cancer. Values of SUV_max at early and late imaging did not differ. However, larger prospective studies are needed to validate these findings.     

Lymph node dissection during robotic‐assisted laparoscopic prostatectomy: comparison of lymph node yield and clinical outcomes when including common iliac nodes with standard template dissection

Study Type – Therapy (case series)
Level of Evidence 4

OBJECTIVE

To compare the perioperative outcomes of standard pelvic to full‐template lymph node (LN) dissection (LND) during robotic‐assisted laparoscopic prostatectomy (RALP).

PATIENTS AND METHODS

The study included 94 patients undergoing RALP with LND between January 2007 and August 2008, by one surgeon. In February 2008 the LND template was modified to include common iliac and medial hypogastric LNs. Clinical and pathological patient characteristics were analysed, including total number of retrieved and positive LNs in each area of dissection, operative duration and complications.

RESULTS

Of the 94 patients, 62 underwent standard LND (group 1) and 32 underwent full‐template pelvic LND (group 2). The median (mean) number of LNs retrieved in groups 1 and 2 were 12 (13.3) and 17.5 (21.4), respectively. Of the five patients with positive LNs (5%), four were in group 2 (13%); two of these patients had positive LNs in the common iliac dissection, and for one of these patients it was the sole site of involvement. Deep venous thrombosis, pulmonary embolism or transient neuropraxia occurred in six patients (five in group 1 and one in group 2). The median additional operative time for resection of common and internal LNs was 25 min.

CONCLUSIONS

LN yield increased and additional sites of LN metastases were identified during full‐template pelvic LND during RALP. This modification was not associated with an increased rate of complications. Derived benefits of including additional nodal dissection and the effect on staging accuracy remain to be determined.     

Altered bladder function in elastin-deficient mice at baseline and in response to partial bladder outlet obstruction

Study Type – Aetiology (case control) Level of Evidence 3b What's known on the subject? and What does the study add? As one of the major components of the extracellular matrix, elastic fibres are believed to enhance tissue compliance. However, the role of elastic fibres in normal bladder function and dysfunction remains speculative. Although transgenic mice overexpressing elastin showed increased bladder compliance, the findings in patients with non‐compliant bladders are inconsistent. Using transgenic elastin‐deficient mouse models, this study provides the first direct evidence that sufficient elastin content is critical for healthy bladder function, and elastin is involved in the detrusor response to partial bladder outlet obstruction.

OBJECTIVE

• ? To examine functional and molecular changes of the bladders from elastin‐haploinsufficient mice (Eln^+/?) at baseline as well as in response to partial bladder outlet obstruction (pBOO).

MATERIALS AND METHODS

• ? Female Eln^+/? and wild type (Wt) mice (3–4 months old) were studied.
• ? The bladder elastin content was quantified by measuring desmosine.
• ? Mice were divided into two groups to undergo surgery to create pBOO or to undergo sham surgery. Three days after surgery, bladder function was evaluated by in vivo cystometry, and the contractile response of bladder strips exposed to electrical field stimulation (EFS) and carbachol was examined by ex vivo myography.

RESULTS

• ? The Eln^+/?‐sham mice had a 33.6% decrease in bladder elastin compared with Wt‐sham mice.
• ? Cystometry showed significantly decreased bladder compliance and capacity in Eln^+/?‐sham vs Wt‐sham mice; pBOO increased bladder compliance and capacity to a greater extent in Eln^+/? mice compared with Wt mice.
• ? Bladder strips from Eln^+/?‐sham mice showed a significantly heightened contractile response to both EFS and carbachol compared with Wt‐sham mice.
• ? A significantly increased contractile response to carbachol was detected in Wt‐pBOO vs Wt‐sham but not between Eln^+/?‐pBOO and Eln^+/?‐sham mice.

CONCLUSION

• ? The results that elastin‐deficient mice had decreased bladder compliance and capacity and increased bladder contractility; and that Wt‐pBOO mice showed an enhanced contractile response to carbachol, but Eln^+/?‐pBOO mice did not, suggest that elastin is critical for normal bladder function and is involved in bladder response to pBOO.

     

How can we predict lymphorrhoea and clinically significant lymphocoeles after radical prostatectomy and pelvic lymphadenectomy? Clinical implications

Study Type – Therapy (case series)
Level of Evidence 4

OBJECTIVE

• ? To identify clinical and pathological variables that may help clinicians in predicting, preventing and managing lymphorrhoea and clinically significant lymphocoeles (CSL), which are reported complications after pelvic lymphadenectomy (PLND) and retropubic radical prostatectomy (RRP).

PATIENTS AND METHODS

• ? We prospectively analysed 552 consecutive men with prostate cancer who underwent RRP and PLND (2006–2008).
• ? All patients had detailed clinical and pathological data prospectively recorded in an electronic database. Drains were removed when the amount of lymph was <20 mL in the previous 24 h. A CSL was defined as the presence of a symptomatic lymphocoele requiring treatment. Lymphorrhoea was defined as the total amount of lymph drained by the drains until their removal.
• ? Univariable and multivariable logistic regression models were used to test the association between all the predictors (age, body mass index, American Society of Anesthesiologists score, prostate volume, clinical stage, number of LNs removed, surgeon, pathological T and N stage) and the presence of CSL.
• ? Univariable and multivariable linear regression models were also used to test the association between the available predictors and lymphorrhoea.

RESULTS

• ? The median (range) number of LNs removed was 20 (1–63). Both linear and logistic multivariable regression analysis showed that the number of removed LNs and age were the only two statistically significant predictors of total amount of lymphorrhoea and CSL after RRP and PLND (both P < 0.01).
• ? Specifically, the risk of developing a CSL increased by 5% for every LN removed. Similarly, every year of age increased the risk of having CSL by 5%.
• ? The most informative thresholds for predicting CSL were 65 years of age and 20 LNs removed.
• ? External iliac lymphadenectomy resulted in a higher associated risk of lymphorrhoea and CLS relative to obturator LN removal (P= 0.001 vs P= 0.1, respectively).

CONCLUSIONS

• ? There was a positive association between the number of LNs removed and age at RRP with the amount of lymphorrhoea and the risk of developing a CSL.
• ? The most informative thresholds in predicting CSL were 65 years of age and 20 LNs removed. External iliac lymphadenectomy resulted in a higher risk of lymphorrhoea and CLS relative to obturator LN removal.

     

GreenLight laser prostatectomy: a safe and effective treatment for bladder outlet obstruction by prostate cancer

Study Type – Therapy (case series) Level of Evidence 4 What’s known on the subject? and What does the study add? Although looked on as standard of care there is little published data on the use of “channel TURP” . Those case series that have been published show significant morbidity (in particular stress incontinence) and relatively long hospitalization compared to standard TURP. The use of vaprorising lasers in this patient group has not been addressed. GreenLight laser is a safe and efficacious treatment for bladder outflow obstruction in men with prostate cancer. Hospitalization is minimal (most were day cases) which we feel is important in men who are often in their last few months. We had no serious complications apart from a few patients with stress incontinence. The stress incontinence rate was dramatically lower than that reported in previous reported series of channel TURP – we are not however able to offer any obvious explanation for that finding.

OBJECTIVE

• ? To present our experience on photoselective vaporization of the prostate (PVP) in a cohort of men with bladder outlet obstruction (BOO) by prostate cancer.

PATIENTS AND METHODS

• ? From 2003 to 2008 we identified 43 patients with prostate cancer treated with PVP.
• ? The patients’ hospital records were comprehensively reviewed to obtain preoperative, intra‐operative and postoperative data.
• ? Inclusion criteria were patients with BOO or urinary retention with a diagnosis of prostate cancer.

RESULTS

• ? Mean operating time was 42 min, mean post‐operative hospital stay was 9.6 h. 32 out of 43 patients were discharged home within 24 h. Twelve patients (28%) did not need post‐operative catheter. Mean and median catheter times were 22 and 21.5 h respectively.
• ? Complications were mild: 1 patient needed bladder irrigation, 3 failed initial TWOC, 1 had early stress incontinence. Three had clot retention.
• ? At 3 months post‐operatively, 41 of 42 evaluable patients were voiding without a catheter. The mean peak flow rate had increased by 80% and a mean residual volume decreased of 49%.
• ? Four patients underwent a second laser treatment. Three had developed further retention between 7 and 23 months post‐operatively and did not want further surgery. The local failure rate at a mean follow up of 22 months was 7 of 39 patients (18%).

CONCLUSION

• ? The present study is the first on PVP applied to patients with prostate cancer.
• ? It is shown that, for patients with CaP bothered by LUTS or retention, GreenLight laser prostatectomy is very safe and gives excellent relief from symptoms, with a good improvement in peak flow rate.

     

Diagnostic efficacy of [11C]choline positron emission tomography/computed tomography compared with conventional computed tomography in lymph node staging of patients with bladder cancer prior to radical cystectomy

Background

Current imaging techniques are of limited value for lymph node (LN) staging in bladder cancer (BCa) patients scheduled for radical cystectomy (RC).

Objective

Evaluate the diagnostic efficacy of [11C]choline positron emission tomography in combination with computed tomography (PET/CT) for LN staging of patients with BCa scheduled for RC and compare that efficacy with the diagnostic efficacy of CT and the gold standard of histopathologic evaluation.

Design, setting, and participants

From June 2004 to May 2007, 44 patients with localized BCa were staged with [11C]choline PET with low-dose CT for attenuation correction and simultaneous intravenous and rectal contrast-enhanced diagnostic CT before RC and pelvic lymph node dissection (PLND). LNs were dissected from the internal and external iliac arteries up to the origin of the inferior mesentery artery according to a template with 14 predefined anatomic fields.

Intervention

Diagnostic [11C]choline PET/CT before RC and regional LN dissection.

Measurements

Histopathologic findings of resected LN were correlated with the results of [11C]choline PET/CT and CT alone in a patient- and field-based manner. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy of [11C]choline PET/CT and CT were assessed.

Results and limitations

LN metastases were found in 12 of 44 patients (27%). On patient-based analysis, sensitivity, specificity, PPV, NPV, and accuracy for [11C]choline PET/CT were calculated as 58%, 66%, 39%, 81%, and 64%, respectively; and for CT the calculated percentages were 75%, 56%, 39%, 86%, and 61%, respectively. Twenty-five of 471 dissected LN fields (5%) showed metastases. On field-based analysis, sensitivity, specificity, PPV, NPV, and accuracy for [11C]choline PET/CT were 28%, 95%, 21%, 96%, and 91%, respectively; for CT, the calculated percentages were 39%, 92%, 20%, 96%, and 90%, respectively. Limitations of this study are small patient number and the fact that not all patients underwent extensive PLND.

Conclusions

In patients with BCa who were scheduled for RC, preoperative LN staging with [11C]choline PET/CT was not able to improve diagnostic efficacy compared with conventional CT alone.     

Automatic evaluation of ultrasonography-estimated bladder weight and bladder wall thickness in community-dwelling men with presumably normal bladder function

Study Type – Diagnostic (exploratory cohort) Level of Evidence 2b What's known on the subject? and What does the study add? The diagnostic potential of ultrasound derived measurements of bladder wall thickness and bladder weight in men with LUTS and varying degrees of BOO have been explored. However, there is a paucity of such measurements in the asymptomatic population with which to compare such patients. This study investigates these measurements in community‐dwelling men with presumably normal bladder function.

OBJECTIVE

• ? To identify measurements of ultrasonography (US)‐derived bladder wall thickness (BWT) and bladder weight in community‐dwelling men with presumably normal bladder function.

SUBJECTS AND METHODS

• ? A total of 100 male volunteers underwent transabdominal US measurements of BWT and bladder weight, using the BVM 9500 bladder scanner (Verathon Medical, Bothell, WA, USA), at a variety of bladder filling volumes.
• ? The data were explored for any correlation between measurements of BWT and US‐estimated bladder weight (UEBW) with subject age, height, weight, body mass index (BMI), International Consultation on Incontinence Questionnaire – Male Lower Urinary Tract Symptoms (ICIQ M‐LUTS) score, International Prostate Symptom Score (IPSS) and IPSS Quality of Life index (IPSS QoL).

RESULTS

• ? Several statistically significant but weak correlations were observed: BWT and weight (r= 0.216, P= 0.032); BWT and BMI (r= 0.246, P= 0.014); UEBW and weight (r= 0.304, P= 0.002); and UEBW and BMI (r= 0.260, P= 0.009).
• ? Bladder filling volume appeared to have a greater effect on BWT than on UEBW, although this could not be determined accurately.
• ? There was a substantial difference in measurements of BWT and UEBW in the assessment of inter‐ and intra‐observer reliability testing.

CONCLUSION

• ? Further studies are required to validate automated measurements of BWT and UEBW and to investigate such measurements in the symptomatic and asymptomatic male population.

     

IL-23 gene therapy for mouse bladder tumour cell lines

OBJECTIVES

• ? To evaluate the antitumour effects of IL‐23 gene transfer into mouse bladder carcinoma (MBT2) cells.
• ? To investigate the mechanisms underlying the subsequent constitutive secrection of IL‐23 by the MBT2 cells

MATERIALS AND METHODS

• ? An expression vector containing IL‐23 gene was introduced into MBT2 cells by liposome‐mediated gene transfer, and secretion of IL‐23 was confirmed by ELISA.
• ? The in vivo antitumour effect of IL‐23‐secreting MBT2 cells (MBT2/IL‐23) was examined by injecting the cells into syngeneic C3H mice.
• ? A tumour vaccination study using mitomycin C (MMC)‐treated IL‐23‐secreting MBT2 cells was carried out, and the usefulness of in vivo CD25 depletion for an additional vaccine effect was also investigated.
• ? The mechanisms underlying the antitumour effects were investigated by antibody depletion of CD8 or CD4 T cells, or natural killer cells, and cells infiltrating the tumour sites in vivo were assessed using immunohistochemistry.

RESULTS

• ? Stable transformants transduced with MBT2/IL‐23 secreted IL‐23 into the culture supernatant.
• ? Genetically engineered IL‐23‐secreting MBT2 cells were rejected in syngeneic mice.
• ? MBT2/IL‐23‐vaccinated mice inhibited the tumour growth of parental MBT2 cells injected at a distant site and this vaccine effect was enhanced by combination with in vivo CD25 depletion by an antibody.
• ? The main effector cells for the direct antitumour effect of MBT2/IL‐23 were CD8 T cells, which was shown by in vivo depletion and immunohistochemical study.

CONCLUSIONS

• ? IL‐23‐secreting MBT2 cells were rejected in syngeneic mice by the activation of CD8 T cells.
• ? MMC‐treated MBT2/IL‐23 can have a tumour vaccine effect for parental MBT2 cells, and this effect was enhanced by combination with in vivo CD25 depletion.

     

Evans blue as a selective dye marker for white-light diagnosis of non-muscle-invasive bladder cancer: an in vitro study

What's known on the subject? and What does the study add? We found that Evans blue preferentially accumulate in spheroids prepared from urothelial cell carcinoma (UCC) cells as compared to spheroids composed of normal human urothelial (NHU) cells. The present findings could be important for future developments in clinical diagnostics for early bladder cancer detection staging and grading involving white light cystocopy.

OBJECTIVE

• ? To develop a diagnostic method relying on the preferential accumulation of a dye in non‐muscle‐invasive bladder cancer (NMIBC) that is visible in conjunction with white‐light cystoscopy (WLC).

MATERIALS AND METHODS

• ? We investigated in detail the permeation of Evans blue in urothelial cell carcinoma (UCC) spheroids prepared from T24, J82 and RT‐112 human cell lines and spheroids composed of normal human urothelial (NHU) cells.
• ? To gain more insight into the differential accumulation, all spheroids were investigated ultrastructurally using transmission electron microscopy (TEM).

RESULTS

• ? We found that, after exposure to Evans blue for 2 h, UCC spheroids accumulated dramatically more dye than spheroids composed of NHU cells.
• ? Using TEM it was found that the malignant spheroids contain similar ultrastructural characteristics, i.e. a wide intercellular space and a decreased number of desmosome‐like cell attachments, to those from clinical samples of non‐papillary carcinoma in situ of the bladder.

CONCLUSION

• ? We believe the present findings could be important for future developments in clinical diagnostics for early bladder cancer detection, staging and grading involving WLC.

     

How accurate is 68Gallium-prostate specific membrane antigen positron emission tomography / computed tomography (68Ga-PSMA PET/CT) on primary lymph node staging before radical prostatectomy in intermediate and high risk prostate cancer? A study of patient- and lymph node- based analyses

Background and aimGallium-68 (68Ga)-Prostate Membrane Specific Antigen Positron Emission Tomography/Computed Tomography (68Ga-PSMA PET/CT) is an emerging diagnostic modality which is gaining importance in individualized prostate cancer (PCa) management era. This study aimed to investigate the diagnostic accuracy of ⁶⁸Ga-PSMA PET/CT on primary LN staging before radical prostatectomy (RP) in intermediate and high risk PCa.Materials and MethodsThe retrospectively documented 49 patients with intermediate and high risk non-metastatic PCa who had ⁶⁸Ga-PSMA PET/CT before RP were enrolled into this study. The histopathology of dissected LNs was used as reference standard to evaluate the accuracy of ⁶⁸Ga-PSMA PET/CT on primary LN staging, both in per-patient (n = 49) and in per-node (n = 454) analyses. The diagnostic accuracy was investigated using sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV), and by area under the curve (AUC) provided using receiver operating curve (ROC) analysis.ResultsMedian age was 64 (48-79) years and, median and mean PSA values were 10 (1.31–138) ng/ml and 16.2 (±19.8) ng/ml, respectively. 22 (44.9%) and 27 (55.1%) of patients had intermediate and high risk PCa, respectively. A total of 5 (10.2%) patients had histopathologically proven LN metastasis and 3 (60%) of them was detected in ⁶⁸Ga-PSMA PET/CT. In per patient analysis, the sensitivity, specifity, PPV and NPV of ⁶⁸Ga-PSMA PET/CT on primary LN staging were 0.60, 0.96, 0.60 and 0.96, respectively. Among overall 454 LNs, 16 (3.5 %) of them were reported as metastatic in histopathology and, 13 (2.9%) of these metastatic LNs were detected in ⁶⁸Ga-PSMA PET/CT. In per-node analysis, the sensitivity, specificity, PPV and NPV of ⁶⁸Ga-PSMA PET/CT on primary LN staging were 0.82, 0.99, 0.87 and 0.99, respectively. The ROC analyses found AUCs for primary LN staging as 0.777 (95%CI:0.508–1.0) in per patient analysis and, as 0.904 (95%CI:0.790 – 1.0) in per node analysis, respectively.ConclusionThe use of ⁶⁸Ga-PSMA PET/CT has promising diagnostic accuracy on primary LN staging before RP in intermediate and high risk PCa. However, the efforts should be taken to increase sensitivity of ⁶⁸Ga-PSMA PET/CT in individualized treatment era.     

<Superscript>99m</Superscript>Tc-HDP bone scintigraphy and <Superscript>18</Superscript>F-sodiumfluoride PET/CT in primary staging of patients with prostate cancer

Introduction/Aim

Correct staging of patients with prostate cancer is important for treatment planning and prognosis. Although bone scintigraphy with ^99mTc-phosphonates (BS) is generally advised for staging by guidelines in high risk prostate cancer, this imaging technique is hampered by a high rate of inconclusive results and moderate accuracy. Potentially better imaging techniques for detection of bone metastases such as ¹⁸F-sodiumfluoride PET/CT (NaF PET/CT) are therefore being evaluated. In this observational cohort study we evaluate the performance and clinical impact of both BS and NaF PET/CT in primary staging of patients with prostate cancer.

Methods

The first of two cohorts consisted of patients who received a BS while the second included patients who received a NaF PET/CT for primary staging of prostate cancer. For both cohorts the number of positive, negative and equivocal findings, calculated diagnostic performance of the imaging modality in terms of sensitivity and specificity, as well as the impact on clinical management were studied. The ranges of the diagnostic performance were calculated both assuming that equivocal findings were positive and assuming that they were negative for bone metastases. For the NaF PET/CT cohort the number of patients with signs of lymph node metastases on low dose CT were also recorded, including the impact of these findings on clinical management.

Results

One-hundred-and-four patients underwent NaF PET/CT, whereas 122 patients underwent BS. Sensitivities of 97–100 and 84–95% and specificities of 98–100 and 72–100% were found on a patient basis for detection of bone metastases with NaF PET/CT and BS, respectively. Equivocal findings warranted further diagnostic procedures in 2% of the patients in the NaF cohort and in 16% in the BS cohort. In addition NaF PET/CT demonstrated lymph node metastases in 50% of the included patients, of which 25% showed evidence of lymph node metastases only.

Conclusion

Our data indicate better diagnostic performance of NaF PET/CT compared to BS for detection of bone metastases in primary staging of prostate cancer patients. Less equivocal findings are encountered with NaF PET/CT. Moreover, NaF PET/CT has additional value over BS since lymph node metastases are encountered frequently.

     

Detection of circulating tumour cells in peripheral blood of patients with advanced non‐metastatic bladder cancer

What’s known on the subject? and What does the study add? Circulating tumour cells (CTC) have prognostic relevance for patients with different metastatic carcinomas. Detection of CTC using the CellSearch system has also been reported in bladder cancer, but mainly in patients with metastatic disease. This is the largest report demonstrating that detection of CTC in non‐metastatic bladder cancer patients is feasible using the CellSearch system. Presence of CTC may be predictive for early systemic disease.

OBJECTIVE

• ? To prospectively detect and evaluate the biological significance of circulating tumour cells (CTC) in patients with bladder cancer, especially in those patients with non‐metastatic, advanced bladder cancer (NMABC).

PATIENTS AND METHODS

• ? Between July 2007 and January 2009, blood samples of 50 consecutive patients with localized bladder cancer and five patients with metastatic disease scheduled for cystectomy were prospectively investigated for CTC. Peripheral blood (7.5 ml) was drawn before cystectomy.
• ? Detection of CTC was performed using the USA Food and Drug Administration‐approved CellSearch^TM system. Data were compared with the clinical and histopathological findings.

RESULTS

• ? CTC were detected in 15 of 50 patients (30%) with non‐metastatic disease and five of five patients with metastatic disease. The overall mean number of CTC was 33.7 (range: 1–372; median: 2). In non‐metastatic patients, the mean number of CTC was 3.1 (range: 1–11; median: 1). Except for a univariate association between CTC with vessel infiltration (P= 0.047), all other common clinical and histopathological parameters did not reveal a significant correlation with CTC detection.
• ? A median 1‐year follow up was available for 53 patients (96.4%). Ten out of 19 preoperatively CTC‐positive patients died as a result of cancer progression.
• ? CTC‐positive patients showed significantly worse overall (P= 0.001), progression‐free (P < 0.001) and cancer specific survival (P < 0.001) compared to preoperatively CTC‐negative patients.

CONCLUSION

• ? This is the largest study demonstrating that detection of CTC in NMABC patients is feasible using the CellSearch^TM system. Our findings suggest that the presence of CTC may be predictive for early systemic disease.

     

Prognostic value of molecular markers, sub-stage and European Organisation for the Research and Treatment of Cancer risk scores in primary T1 bladder cancer

Study Type – Prognosis (case series) Level of Evidence 4 What's known on the subject? and What does the study add? The stakes are high when making treatment decisions in T1 bladder cancer (BC). Conservative management may lead to progression and possibly death from BC. Conversely, radical cystectomy could be over‐treatment of non‐progressive disease. The problem for clinicians is that reliable prognostic indices are lacking. We performed a head‐to‐head comparison of two substaging systems, European Organisation for the Research and Treatment of Cancer (EORTC) risk scores and four molecular markers in T1 carcinomas of the bladder treated conservatively with BCG. T1 sub‐stage according to a new system (micro‐invasive [T1m] and extensive‐invasive [T1e]) was the most important clinical variable for predicting progression to carcinoma invading bladder muscle. The performance of the EORTC risk scores was disappointing for this T1 sub‐group. Molecular markers were not significant in multivariable analysis for predicting progression. Future studies may lead to the incorporation of sub‐stage (T1m/T1e) in the TNM classification system for urinary BC to guide clinical decision‐making in T1 BC.

OBJECTIVE

• ? To evaluate the prognostic significance of four molecular markers, sub‐stage and European Organisation for the Research and Treatment of Cancer (EORTC) risk scores in primary T1 bladder cancer (BC) treated with adjuvant bacille Calmette–Guérin.

PATIENTS AND METHODS

• ? The slides of 129 carcinomas of the bladder from two university hospitals were reviewed and the T1 diagnosis was confirmed.
• ? T1 sub‐staging was done in two separate rounds, using a new system that identifies micro‐invasive (T1m) and extensive‐invasive (T1e) T1BC, and then according to invasion of the muscularis mucosae (T1a/T1b/T1c).
• ? The EORTC risk scores for recurrence and progression were calculated.
• ? Uni‐ and multivariable analyses for recurrence and progression were performed using clinicopathological variables, T1 sub‐stage, EORTC risk scores and molecular markers (fibroblast growth factor receptor 3 gene mutation and Ki‐67, P53, P27 expression).

RESULTS

• ? The median follow‐up was 6.5 years. Forty‐two patients remained recurrence‐free (33%). Progression to T2 or metastasis was observed in 38 (30%) patients.
• ? In multivariable analysis for recurrence, multiplicity was significant. In multivariable analysis for progression, female gender, sub‐stage (T1m/T1e) and carcinoma in situ (CIS) were significant.
• ? Molecular markers were significant in univariable and in multivariable analyses for recurrence.
• ? EORTC risk scores were not significant.

CONCLUSIONS

• ? CIS, female gender and sub‐stage (T1m/T1e) were the most important variables for progression.
• ? The additional value of molecular markers was modest.
• ? Sub‐stage (T1m/T1e) could potentially be incorporated in future tumour‐node‐metastasis classifications.