Urologic Oncology: Seminars and Original Investigations - Articles in Press

Prostate cancer screening and mortality: Comparison of recent randomized controlled clinical trials - Corrected Proof

Badar M. Mian — 2010-01-25

Screening and early detection of prostate cancer through the use of prostate specific antigen (PSA) is probably one of the most controversial subjects in urology, if not in all of medicine. Despite 20 years of PSA testing for prostate cancer detection, the true benefits and/or risks of early detection and active treatment have not been fully understood. Prostate cancer is associated with a heterogeneous biological behavior and often has a long preclinical phase. PSA screening introduces a relatively long lead time and length time bias, which confounds the attempts to measure its true impact on prostate cancer related mortality. In the absence of level I evidence, much of the data used to support (and oppose) prostate cancer screening comes from observational studies. The results of 2 randomized controlled trials, which were initiated nearly 15 years ago, had been awaited with great anticipation. The effects of screening on mortality in both trials were published recently and, surprisingly, the results of these 2 trials were contradictory. The trials differ from each other in many respects, including study design, follow-up, and patient population. Here, we discuss the extent to which the differences amongst these trials may be responsible for the contradictory results of screening for prostate cancer.

Squamous cell carcinoma of the penis: Predicting nodal metastases by histologic grade, pattern of invasion and clinical examination - Corrected Proof

2010-01-08

Abstract: With a diagnosis of squamous cell carcinoma of the penis, there is still a significant need to define the tumor criteria that allow the disease to be stratified according to the risk of developing lymph node metastases.The histopathology of the primary tumor in 72 consecutive patients with resected squamous cell carcinoma of the penis was reviewed for this study. Tumor tissue was reviewed for (1) histologic grade, (2) invasion pattern, (3) tumor stage, (4) proportion of poorly differentiated tumor cells, (5) invasion depth, (6) proportion of tumor necrosis, (7) angioinvasion, (8) histologic classification, (9) number of lesions, (10) growth pattern, (11) number of mitoses, (12) degree of keratinization, and (13) clinical groin status.It was found that the presence of inguinal lymph node metastases correlated in descending order of frequency with grade G2/G3, clinically positive groin status, reticular invasion, stage pT2/T3, >50% poorly differentiated tumor cells, depth of invasion, and comedolike tumor necrosis. These results revealed that the risk of inguinal lymph node metastasis in penile carcinoma can be predicted on the basis of 3 major factors: histologic grade, pattern of invasion, and clinical groin status.

Prostate-specific antigen: An evolving role in diagnosis, monitoring, and treatment evaluation in prostate cancer - Corrected Proof

Heather Payne, Philip Cornford — 2010-01-08

Abstract: Prostate specific antigen (PSA) was introduced as a prostate cancer screening tool more than 20 years ago. However, there is continuing debate regarding its utility in screening for prostate cancer. Mass screening is costly, may result in the diagnosis and treatment of prostate cancers that never become clinically significant, and the evidence of a subsequent reduction in mortality is inconclusive. In addition to its role in screening, PSA is also used to monitor the progression of the disease, both localized and metastatic. Although the evidence is contradictory, PSA is still an important tool for monitoring patient progression following treatment of definitive localized prostate cancer. However, its use in monitoring castrate-resistant prostate cancer (CRPC) is more controversial, particularly in the context of novel targeted treatments, which may have little impact on PSA levels. These issues highlight the urgent need to identify prostate cancer biomarkers that will improve early disease detection, increase accuracy of diagnosis, determine the aggressiveness of disease, and monitor treatment efficacy, particularly in late-stage disease. This review discusses the key issues associated with the use of PSA as an early screening tool for prostate cancer, as a prognostic marker to measure disease progression in both early- and late-stage prostate cancer, and as a surrogate endpoint in clinical trials with new agents.

Patterns of enlarged lymph nodes in patients with metastatic renal cell carcinoma - Corrected Proof

2010-01-07

Abstract: Objective: We reviewed the imaging studies of patients with known metastatic renal cell carcinoma (RCC) in order to more accurately assess where retroperitoneal lymphadenopathy occurs.Methods: The database of patients with metastatic RCC was reviewed and 101 patients were found from 2002 to 2006. Each patient's CT scans were then reviewed. Twenty-seven retroperitoneal sections were defined for each patient, with 3 positions in each of the x-, y-, and z-axis. Lymph nodes greater than 1 cm were then counted for each section.Results: Of the 101 patients, 31, of whom 28 qualified, were found to have retroperitoneal lymphadenopathy of a least 1 cm or greater. Two-thirds of nodes (87 out of 124) exhibited a suprahilar, intra-aortocaval, and retro-aortocaval trend of lymph node enlargement. Three patients (11%) had isolated infrahilar nodes, while 8 patients (29%) exhibited a skip lesion pattern by imaging criteria. Only 4 patients (14%) were noted to have lymph nodes that were confined to the ipsilateral (paraaortic or paracaval) nodes in the perihilar and infrahilar region, which would be readily accessible during renal surgery.Conclusions: Lymphatic drainage in RCC is ill-defined, likely due to multiple lymphatic outflow channels. However, after a review of retroperitoneal lymphadenopathy imaging in patients with known metastatic RCC, there does seem to be a cephalad, posterior, and medial drainage pattern.

Biopsy accuracy in identifying unilateral prostate cancer depends on prostate weight - Corrected Proof

2010-01-07

Abstract: Objective: To evaluate the association between prostate weight and the diagnostic performance of routine biopsy schemes in detecting unilateral prostate cancer (PCa) that may be amenable to focal therapy.Methods and Materials: Retrospective analysis of patients undergoing radical prostatectomy at Duke University Medical Center from 1990 to 2007. The cohort was dichotomized according to prostate weight (≤40 and >40 g) and further divided by biopsy scheme: 6–9 (sextant) and 10–20 cores (extended). Diagnostic accuracy, sensitivity, specificity, and positive and negative predictive values were calculated within each prostate weight group and compared between biopsy schemes.Results: A total of 859 patients were included in the study. Patients with prostates >40 g were generally older and had higher PSA levels (P < 0.0001 and P = 0.036, respectively). Unilateral disease was more common in prostates >40 g both on biopsy (69% vs. 60%, P = 0.009) and on final pathology (21% vs. 14%, P = 0.017) despite larger total tumor volume (6.1 vs. 4.8 cc, P < 0.001). Low grade PCa was also more common in larger glands (P = 0.003). Overall, extended biopsy schemes performed better than sextant but the benefit was statistically significant only in prostates >40 g.Conclusions: Despite having higher tumor volumes, men with prostate weight >40 g were more likely to have unilateral PCa than those with smaller prostates. In prostates >40 g, increasing the number of cores harvested at biopsy increased the diagnostic performance for detecting cancer laterality. Therefore, our results suggest that the benefit of more extensive tissue sampling may be higher in larger prostates compared with smaller ones when selecting candidates for prostate hemiablation.

CA125 for following up carcinoma of the bladder - Corrected Proof

Viroj Wiwanitkit — 2010-01-07

I read the recent publication on CA 125 by Kouba et al. with great interest . Kouba et al. reached the conclusion that “Serum CA-125 levels may serve as a useful predictor of pathologic outcomes in patients undergoing cystectomy for urothelial carcinoma of the bladder .” Indeed, the use of CA125 as a tumor marker for following up carcinoma of the bladder is still controversial. Chang et al. mentioned that “increased CA 125 was seen in approximately 11% of patients with high grade or invasive transitional cell carcinoma preoperatively ” but “recurrence-free survival was not associated with CA 125 .” Combing with other biomarkers, Margel et al. proposed for a fair predicting value for nomogram-confined bladder disease before cystectomy . In another immunohistochemistry study by Sangoi et al., the CA125 present poor specificity in differentiation of bladder cancer at different stages . In the small series by Kouba et al., the result might show a favorable prediction by using CA125, however, there are many factors to be concerned. First, the difference in CA125 that resulted from different analyzers using different techniques should be aware in following up of the patients. Second, comorbidity of the patients such as congestive heart failure or gynecologic tumor might alter the CA-125 levels.

Orthotopic bladder substitution following radical cystectomy in women: Comparative study between sigmoid and ileal neobladders - Corrected Proof

2010-01-07

Abstract: The objective of this study was to retrospectively compare the clinical outcomes of sigmoid and ileal neobladders (NBs) created in women. This study included 18 and 14 women who underwent orthotopic NB reconstruction using sigmoid and ileal segment, respectively, after radical cystectomy, and postoperative clinical outcomes between the sigmoid and ileal NB groups (SNBG and INBG) were compared. Eighteen early and 7 late complications occurred in 12 and 6 women, respectively; however, there was no significant difference in the incidence of complications between SNBG and INBG. The proportion of patients who could void spontaneously in SNBG (94.4%) was significantly greater than that in INBG (64.3%), while there was no significant difference in continent status between these 2 groups. Despite the lack of significant differences in maximal flow rate and voided volume, post-void residual in SNBG (15.7 ml) was significantly smaller than that in INBG (62.0 ml). SF-36 survey for postoperative quality of life (QOL) did not show any significant differences in 7 of the 8 scores between the 32 women with NB and an age-matched control population; however, 3 of the 8 scores in SNBG were significantly superior to those in INBG. During the observation period of this study, urethral recurrence did not occur in any woman, and there was no significant difference in cancer-specific survival between the 2 groups. These findings suggest that it might be preferable to create sigmoid rather than ileal NB in women following radical cystectomy considering the favorable voiding function and QOL in SNBG.

Does preoperative symptom classification impact prognosis in patients with clinically localized upper-tract urothelial carcinoma managed by radical nephroureterectomy? - Corrected Proof

2010-01-07

Abstract: Objectives: To evaluate if preoperative symptom classification could refine prediction of outcomes for patients with clinically localized upper-tract urothelial carcinoma (UTUC) managed by radical nephroureterectomy (RNU).Methods: Data on 654 patients with localized UTUC who underwent RNU were reviewed. Preoperative symptoms were classified as incidental (S1), local (S2), and systemic (S3). Clinical and pathologic data were compared between the cohorts. Kaplan-Meier analyses and Cox proportional hazard modeling were used to determine recurrence-free and cancer-specific survival amongst the symptom cohorts.Results: Symptom classification was S1 in 213 (33%) patients, S2 in 402 (61%), and S3 in 39 (6%). S3 symptoms were associated with advanced pathology, including higher stage, grade, and lymph node (LN) positivity. Five and 10-year recurrence-free and cancer-specific survival estimates were similar for patients with S1 and S2 symptoms (P = 0.75 and 0.58, respectively), but was worse for patients with S3 symptoms (P < 0.001 for both). On multivariate analysis adjusting for final pathologic stage, grade, and LN status, S3 symptoms were not an independent predictor of recurrence (HR 1.44, P = 0.19) or death due to disease (HR 1.66, P = 0.07). Addition of symptom classification, however, increased the accuracy of a model consisting of stage, grade, and LNs for prediction of recurrence-free and cancer-specific survival by 1.4% and 1.3%, respectively (P < 0.001 for both).Conclusions: Local symptoms do not confer worse prognosis compared with patients with incidentally detected UTUC. However, systemic symptoms are associated with worse outcomes despite apparently effective RNU. Patients with systemic symptoms may harbor micrometastatic disease and could potentially benefit from a more rigorous metastatic evaluation or perioperative chemotherapy regimens.

Neoadjuvant docetaxel/estramustine prior to radical prostatectomy or external beam radiotherapy in high risk localized prostate cancer: A phase II trial - Corrected Proof

2009-12-21

Abstract: Background: Patients with locally advanced or organ confined, high risk, prostate cancer are at significant risk of having disease recurrence despite definitive local therapy. We evaluated the 2-year progression-free survival of subjects treated with chemotherapy administered prior to definitive therapy with surgery or radiation.Patients and methods: Patients (n = 24) with locally advanced and high risk localized prostate cancer were treated with neoadjuvant docetaxel 36 mg/m2 i.v. weekly for 3 weeks and estramustine 140 mg orally 3 times daily for 3 consecutive days every 28 days prior to definitive treatment with prostatectomy or radiation.Results: All evaluable patients, except 1, completed the proposed cycles of neoadjuvant chemotherapy with minimal dose reductions or delays. Of the 22 evaluable patients, 12 underwent radical prostatectomy and 10 underwent external beam radiation therapy. Twenty-one of 22 patients achieved a prostate-specific antigen (PSA) reduction > 25%. There were no pathologic complete responses. With a median follow-up of 24 months, the 2-year progression-free survival was 45%.Conclusions: Our findings support the safety, tolerability, and efficacy of neoadjuvant chemotherapy in patients with men with high risk, locally advanced prostate adenocarcinoma, although the relative contributions of androgen deprivation therapy and docetaxel cannot be determined. The effectiveness of neoadjuvant chemotherapy in preventing prostate cancer relapses should be studied in a randomized trial.

Osteopontin overexpression predicts poor prognosis of upper urinary tract urothelial carcinoma - Corrected Proof

2009-12-21

Abstract: Objectives: Studies indicate overexpression of osteopontin (OPN) promotes carcinogenesis, progression and metastasis of multiple human malignancies. However, the function of OPN in urothelial carcinoma (UC) of the upper urinary tract has not been investigated. This study evaluates the clinical significance of OPN expression in upper urinary tract UC.Materials and methods: One hundred and ten cases (median age = 64, range = 24–84 years) of renal pelvic or ureter UC were retrospectively reviewed in this study. OPN expression were evaluated by immunohistochemistry staining on paraffin-embedded section of the tumor and scored by two qualified pathologists.Results: High OPN expression was found in 54 (49.1%) of the cancer specimens. OPN expression was not significantly correlated with tumor T stage (P = 0.761), N stage (P = 0.339) or grade (P = 0.349). However, OPN expression was differently expressed by gender (P = 0.012) and cancer location (P = 0.026). OPN expression did not correlate with bladder recurrence-free (P = 0.661) or extra-bladder recurrence-free (P = 0.787) survival, but high OPN expression was a significant predictor for cancer-specific survival (P = 0.014).Conclusion: Our findings indicated that higher OPN expression is a potential biomarker to predict patient survival. Further study is necessary to investigate the role of OPN in the carcinogenesis of upper urinary tract UC.

Detection of inguinal lymph node involvement in penile squamous cell carcinoma by 18F-fluorodeoxyglucose PET/CT: A prospective single-center study - Corrected Proof

2009-12-21

Abstract: Background: The extent of lymph node involvement is the most relevant prognostic factor in patients with penile cancer.Objective: To prospectively analyze the diagnostic accuracy of 18F-FDG-PET/CT-scan in the assessment of inguinal lymph node involvement in patients with invasive penile carcinoma.Patients and methods: Thirty-five patients with invasive penile carcinoma were staged prospectively by 18F-FDG-PET/CT-scan, and blindly evaluated by 2 nuclear medicine physicians. In total, lymph node involvement was assessed in 70 inguinal groins. Reference standard was either histology or clinical follow-up with a minimum of 31 months (mean: 48.4 months; range: 31–68 months).Results: 18-FDG-PET/CT showed a sensitivity of 88.2% and a specificity of 98.1%. Positive predictive value (PPV) was 93.8%, while negative predictive value (NPV) was 96.3%. In two groins, metastasis of 5 and 7 mm were missed by PET/CT scan.Conclusion: 18F-FDG-PET/CT is a promising staging tool in assessing the inguinal lymph node involvement of patients with penile carcinoma. Integration of PET/CT scanning into preoperative staging algorithms may avoid surgical staging in selected patients.

Acute toxicity of image-guided hypofractionated radiotherapy for prostate cancer: Nonrandomized comparison with conventional fractionation - Corrected Proof

2009-12-14

Abstract: Objectives: To compare acute toxicity of prostate cancer image-guided hypofractionated radiotherapy (hypo-IGRT) with conventional fractionation without image-guidance (non-IGRT). To test the hypothesis that the potentially injurious effect of hypofractionation can be counterbalanced by the reduced irradiated normal tissue volume using IGRT approach.Materials and methods: One hundred seventy-nine cT1-T2N0M0 prostate cancer patients were treated within the prospective study with 70.2 Gy/26 fractions (equivalent to 84 Gy/42 fractions, α/β 1.5 Gy) using IGRT (transabdominal ultrasound, ExacTrac X-Ray system, or cone-beam computer tomography). Their prospectively collected data were compared with data of 174 patients treated to 80 Gy/40 fractions with non-IGRT. The difference between hypo-IGRT and non-IGRT cohorts included fractionation (hypofractionation vs. conventional fractionation), margins (hypo-IGRT margins: 7 mm and 3 mm, for all but posterior margins; respectively; non-IGRT margins: 10 and 5 mm, for all but posterior margins, respectively), and use of image-guidance or not. Multivariate analysis was performed to define the tumor-, patient-, and treatment-related predictors for acute toxicity.Results: All patients completed the prescribed radiotherapy course. Acute toxicity in the hypo-IGRT cohort included rectal (G1: 29.1%; G2: 11.2%; G3: 1.1%) and urinary events (G1: 33.5%; G2: 39.1%; G3: 5%). Acute toxicity in the non-IGRT patients included rectal (G1: 16.1%; G2: 6.3%) and urinary events (G1: 36.2%; G2: 20.7%; G3: 0.6%). In 1 hypo-IGRT and 2 non-IGRT patients, radiotherapy was temporarily interrupted due to acute toxicity. The incidence of mild (G1-2) rectal and bladder complications was significantly higher for hypo-IGRT (P = 0.0014 and P < 0.0001, respectively). Multivariate analysis showed that hypo-IGRT (P = 0.001) and higher PSA (P = 0.046) are correlated with higher acute urinary toxicity. No independent factor was identified for acute rectal toxicity. No significant impact of IGRT system on acute toxicity was observed.Conclusions: The acute toxicity rates were low and similar in both study groups with some increase in mild acute urinary injury in the hypo-IGRT patients (most probably due to the under-reporting in the retrospectively analyzed non-IGRT cohort). The higher incidence of acute bowel reactions observed in hypo-IGRT group was not significant in the multivariate analysis. Further investigation is warranted in order to exclude the bias due to the nonrandomized character of the study.

The presence of circulating tumor cells does not predict extravesical disease in bladder cancer patients prior to radical cystectomy - Corrected Proof

2009-12-14

Abstract: Objective: Due to imprecise clinical staging, the finding of extravesical and node-positive disease at the time of radical cystectomy (RC) for patients with clinically localized bladder cancer is not uncommon. Circulating tumor cells (CTCs) have been shown to be present in the peripheral blood of patients with metastatic urothelial carcinoma. The object of this study was to evaluate the ability of CTCs to predict extravesical disease in bladder cancer patients prior to RC.Materials and methods: Peripheral blood samples from 43 patients with bladder cancer were evaluated using the CellSearch (Veridex, LLC, Raritan, NJ) CTC assay prior to RC. The sensitivity, specificity, and positive predictive value (PPV) of CTC status in predicting extravesical disease was calculated. Receiver operating characteristic (ROC) curves were generated to quantify the ability of CTCs to predict extravesical and node-positive disease.Results: CTCs were detected in 9 (21%) patients prior to RC. The sensitivity, specificity, and PPV of CTC status in predicting extravesical disease were 27%, 88% and 78%, respectively. The accuracy of CTC status in predicting extravesical (≥pT3 or node-positive) disease for the entire cohort was 0.576. In a model incorporating preoperative hydronephrosis, CTC status did not improve the predictive accuracy for extravesical disease (0.576 vs. 0.585, P = 0.915).Conclusion: CTCs were detected in low numbers in a small percentage (21%) of patients prior to undergoing RC at our institution. CTC status was not a robust predictor of extravesical or node-positive disease in this cohort. CTC status is not likely to be a clinically useful parameter for directing therapeutic decisions in patients with ≤cT2 bladder cancer.

Interest in conflicts anyone? - Corrected Proof

William Donald Steers — 2009-12-14

If there is no conflict in what we do as urologists, there probably is no interest in it either. Well, we're doing a lot of interesting things judging by the headlines in the New York Times and the Washington Post . One of the more disturbing blog sites is run by Gary Switzer, a professor at the University of Minnesota School of Journalism and Mass Communication, who teaches health care journalism. Frequent postings expose some urologic travesty: “Low T and CME!” “Half a million dollars to prevent one case of prostate cancer!”, “Urologists call for baseline PSAs in 40 year olds puzzles ACS chief.” These articles imply a financial self interest or industry conflict in much of what we do. Urology oriented companies aggressively market their drugs, imaging devices, automated lab testing, and therapeutic devices to urologists. In most instances, the purchase of instrumentation is accompanied by financials demonstrating a lucrative return on investment. There is nothing wrong with capitalism. Yet the temptation to over-prescribe and over-utilize is great and the topic of the much ballyhooed article by Gwande in the New Yorker on practice patterns in McAllen, Texas . The end of fee for service is near proclaim editorials .

Conditionally replicating adenovirus therapy utilizing bone sialoprotein promoter (Ad-BSP-E1a) in an in vivo study of treating androgen-independent intraosseous prostate cancer - Corrected Proof

2009-12-07

Abstract: Background: Adenoviral based gene therapy has been used in clinical trials in control of advanced prostate cancer. In this study, a promising conditionally replicating adenovirus (CRAd) driven by a tissue specific bone sialoprotein promoter in controlling prostate cancer both in vitro and in vivo is demonstrated.Methods: C4-2B, an androgen-independent prostate cancer cell line, was treated with PBS, Ad-BSP-TK, or the Ad-BSP-E1a in vitro, and in subcutaneous and intraosseous xenographs. Cell proliferation, PSA level in condition medium, tumor volume, and/or serum PSA were followed.Results: The growth of C4-2B and the PSA production was dramatically suppressed by Ad-BSP-E1a at very low dosage (0.3 MOI) compared with PBS and Ad-BSP-TK treatment in vitro. In the subcutaneous model, the tumor volume was significantly lower statistically in the Ad-BSP-E1a treated group than the Ad-BSP-TK control group (P = 0.02). In the intraosseous model, the mice treated in the Ad-BSP-E1a treatment group demonstrated a significant lower PSA compared to that in the control group (P < 0.01) at week 8 and week 16 post-treatment.Conclusions: The CRAd Ad-BSP-E1a revealed potential in treating prostate cancer in this model system. Using viral or none-viral mediated gene therapy to treat prostate carcinoma continues to be a potential avenue to treat afflicted men with prostate cancer.

Renal cell carcinoma with caval involvement: Contemporary strategies of surgical treatment - Corrected Proof

2009-12-07

Abstract: Objectives: We retrospectively evaluated the outcome of the surgical treatment of patients with renal cell carcinoma (RCC) and extensive inferior vena cava (IVC) involvement. Our aim was to investigate if a particular surgical technique could reduce morbidity and complications associated with this condition.Materials and methods: From 1996 to 2007, 22 patients with RCC and extensive IVC involvement underwent radical surgical treatment with the intention to avoid, whenever possible, sternotomy and cardiopulmonary bypass. The level of the tumor thrombus was I (<2 cm above the renal vein) in 2 patients, II (below the intrahepatic vena cava) in 9 patients, III (intrahepatic vena cava below the diaphragm) in 7 patients, and IV (atrial) in 4 patients. Extracorporeal vascular bypass was used for 4 patients with level IV and for 2 patients with level III tumor thrombi, with hypothermic circulatory arrest in 2 patients. Extensive liver mobilization techniques were adopted in 16 patients. Overall and cancer-specific survival (CSS) were analyzed based on tumor extent (N0M0, N+M+), pathologic stage (pT3b, pT3c, pT4), thrombus level, and caval wall infiltration.Results: Two patients died within 1 month of surgery and the remaining 20 patients have a mean follow-up of 32.2 months (range 6–90): 8 are alive (overall survival 40%), but 2 with disease (CSS 30%). A total of 10 severe complications developed in 8 patients (36%). Both overall and CSS were significantly associated with tumor stage (Log-rank P = 0.0237 and 0.0465), presence of nodal or systemic metastases (Log-rank P = 0.0835 and 0.0669; Wilcoxon's test P = 0.0407 and 0.0411), and caval wall infiltration (Log-rank P = 0.0200 and 0.0418).Conclusions: Despite the low overall survival, related to the high percentage of nodal and systemic metastases, aggressive surgical management with resection of synchronous metastatic disease for symptom palliation and cytoreduction, followed by immunotherapy is justified in this setting. A transabdominal approach to RCC and IVC involvement, even in patients with level III thrombus, can provide the surgeon with an exposure similar to thoracoabdominal incisions without the complications associated with thoracotomy.

Phase I trial with a combination of docetaxel and 153Sm-lexidronam in patients with castration-resistant metastatic prostate cancer - Corrected Proof

2009-12-07

Abstract: Background: This study was designed to evaluate toxicity and preliminary efficacy of 2 cycles of concomitant standard dose/schedule of 153Sm-lexidronam plus Q 3 weeks schedule escalating doses of docetaxel in metastatic castration-resistant prostate cancer (mCRPC).Methods: mCRPC patients with progressive bone metastases were treated in 4 cohorts. Docetaxel doses were escalated from 50, 50, 0 mg/m2 (on days 1, 22, 43, per 12-week cycle) to 75, 75, 75 mg/m2. 153Sm-lexidronam was administered on days 2 (Q 12 weeks) at dose of 1 mCi/kg/cycle (maximum of 2 cycles).Results: Thirteen patients received an average of 3.6 doses of docetaxel (range, 2–6 doses, median 4) and 1.5 doses of 153Sm-lexidronam (range, 1–2, median 2). Toxicity was primarily hematologic. There were total 35 episodes grade 3/4 neutropenia with a median 7 (range 7–14) days to recovery to ≤grade 1. One dose limiting grade 3 thrombocytopenia occurred on cohorts 3 and 4. Eight of 13 (62%) patients had PSA > 50% decrease as best response during the treatment. Median time to bone disease progression was 5.2 months (range 91 days–10 months+); 6/13 (46%) patients had stable/improved bone scans at 6 months and 6/6 (100%) symptomatic patients had improvement in pain.Conclusions: Concurrent 6-month administration of 4 doses (75 mg/m2) of standard Q 3 weeks schedule of docetaxel with 2 Q 3 months infusions of 1 mCi/Kg 153Sm-lexidronam is feasible with reversible bone marrow suppression, and deserves further testing in mCRPC patients with extensive bone metastasis.

Testing for urinary hyaluronate improves detection and grading of transitional cell carcinoma - Corrected Proof

2009-12-07

Abstract: Objective: The purpose of this study is to establish a method for the diagnosis and grading of transitional cell carcinoma (TCC), which is responsible for 90% of bladder tumors, using a recently developed ultrasensitive assay for the measurement of hyaluronan (HA).Materials and methods: Urine samples were collected prior to surgery (cystoscopy, transurethral resection for bladder cancer (TURBT), and cystectomy) in 350 patients. After the procedure, pathologic examination revealed that 160 patients had TCC. HA was measured directly in the urine by a noncompetitive enzyme-linked immunosorbent assay (ELISA)-like fluorometric assay. Using the receiver operator characteristic curve (ROC), t-test, Dunn test, Kruskal-Wallis test, and Mann-Whitney test, we evaluated the differences between groups (those with TCC vs. those without TCC).Results: By analyzing the ROC curve, we chose a urinary HA cutoff value of 13.0 μg/l for indicating risk of TCC. Using the value this of 13.0 μg/l, we found that this test had an overall sensitivity of 82.3% and an overall specificity of 81.2%. The positive predictive value of this assay was 78.9%, the negative predictive negative value was 84.2%, and the predictive accuracy was 81.7%. Logistic regression analysis revealed that every 1 μg/l increase in HA increased a patient's likelihood of having TCC by 3.9%. The sensitivity of this test to detect superficial tumors was 76.6%, whereas its sensitivity for detecting invasive tumors was 94.6%. The urinary HA excretion of patients with TCC, classified according to the TNM staging system and the World Health Organization (WHO) grading system, were compared, and a significant difference was observed between the HA levels of patients with superficial tumors compared with invasive tumors (P = 0.005) as well as between patients with low- vs. high-grade carcinomas (P < 0.001). Patients with urinary HA levels >35 μg/l had a 4.63 times increased risk of having an aggressive, invasive, high grade tumor (P = 0.005).Conclusions: Our results support the postulate that urinary HA may be used as a tumor marker to aid in the diagnosis and grading of TCC. Additionally, more invasive tumors produce and release more HA in urine than superficial tumors, thus higher HA levels indicate more aggressive disease.

An adult Xp11.2 translocation renal carcinoma showing response to treatment with sunitinib - Corrected Proof

2009-12-07

Abstract: A rare variant of renal cell carcinoma (RCC) with a translocation involving Xp11.2 has become increasingly recognized as a separate entity in the 2004 World Health Organization (WHO) kidney carcinoma classification. These tumors predominantly affect children and young adults and tend to present with advanced stage disease. Although reported to be indolent in children, adult cases run a more aggressive course. Little is known about their natural history, prognosis and response to therapy.We report a case of Xp11 translocation renal cancer in a 33-year-old male patient who presented with widespread rapidly progressive metastatic disease involving extensive intra-thoracic lymph nodes, supra-clavicular, retroperitoneal lymph nodes, lung nodules, and peritoneal mass.He had failed to respond to treatment with high dose interleukin 2, but showed a significant clinical response to treatment with the multikinase inhibitor sunitinib. CT scan performed after 3 cycles (18 weeks) of therapy revealed more than 65% reduction of measurable disease by response evaluation criteria in solid tumors (RECIST) criteria, resolution of other assessable lesions, and a clinical benefit that lasted for over 13 months. But unfortunately, this was subsequently followed by a rapidly progressive course.The well-recognized clinical efficacy of multikinase inhibitors such as sunitinib and sorafenib is based on the outcomes in patients with clear cell histology. There is limited data on efficacy in non-clear cell RCC, but activity in translocation RCC has not been reported. To our knowledge, this is the first documented case of Xp11 translocation carcinoma to have demonstrated an objective durable response to sunitinib. It remains unclear how resistance to sunitinib develops, but the results to date support further evaluation of sunitinib in cases of translocation RCC.

Postoperative nomogram for invasive bladder cancer: Does it really work? A multicenter cohort study - Corrected Proof

2009-12-04

Abstract: Objectives: Nomograms are statistical models designed to maximize predictive accuracy. We have tested the statistical correlation between the predictions of International Bladder Cancer Nomogram Consortium and the clinical outcomes in a multicenter Italian cohort of patients treated with radical cystectomy (RC) and pelvic lymph-nodes dissection.Methods and materials: Two hundred four patients who underwent RC were selected for multiple variable and then enrolled in the study. Patients were tested by the “online tool” based on the nomogram, then stratified and risk grouped for 5-year predicted disease-free survival (pDFS): low risk (67%–100%), intermediate risk (34%–66%), and high risk group (0%–33%). Receiving operating characteristic curve (ROC) quantified the area under curve (AUC) as predictive accuracy. Actual overall survival (aOS) and actual disease-free survival (aDFS) were calculated with Kaplan-Meyer analysis. Median of pDFS was compared with 5-year aDFS.Results: AUC was 0.69 (P < 0.001). The aOS is 50% (95% confidence interval (95% CI, −7.68/+8.23) at 5-years after RC, the aDFS is 65.5% (95% CI, −7.56/+8.98).The 5-year aDFS is 75.3% (−8.82/+12.53) in low risk group; 67.3% (−12/+16.4) in intermediate risk group; 28.3% (−20/+17.2) in high risk group. The 5-year aDFS was well calculated by the nomogram but in all groups the nomogram slightly underestimated the prediction. In intermediate risk group, 5-year aDFS overscored both the nomogram pDFS and the pDFS range of this group (34%–66%). In all patients investigated, the pDFS was 65%, a value close to the 5-year aDFS found (65.6%).Conclusion: Statistical correlation between postoperative nomogram prediction and the clinical reality was observed.

Azacitidine favorably modulates PSA kinetics correlating with plasma DNA LINE-1 hypomethylation in men with chemonaïve castration-resistant prostate cancer - Corrected Proof

2009-12-04

Abstract: Background: Azacitidine is a hypomethylating agent that activates genes repressed by promoter methylation. Preclinically, demethylating agents reverse resistance of prostate cancer to androgen ablation. A phase II trial evaluated azacitidine for men with castration-resistant prostate cancer (CRPC) progressing on combined androgen blockade (CAB).Methods: Chemonaïve patients with CRPC on CAB and PSA-doubling time (DT) < 3 months were eligible. The primary endpoint was prolongation of PSA-DT to ≥3 months. Correlation of biologic activity (fetal hemoglobin, plasma DNA LINE-1 methylation) with prolongation of PSA-DT was tested. CAB was continued and azacitidine 75 mg/m2 was administered subcutaneously on days 1–5 of each 28-day cycle up to 12 cycles or until clinical progression/intolerable toxicities.Results: Thirty-six patients were enrolled, 80.6% had metastatic disease, and 34 were evaluable. A PSA-DT ≥ 3 months was attained in 19 patients (55.8%). Overall median PSA-DT was significantly prolonged compared to baseline (2.8 vs. 1.5 months, P < 0.01). Fourteen patients had some PSA decline during therapy and 1 patient had a ≥30% decline compared with baseline. The median clinical progression-free survival was 12.4 weeks. Grade 3 toxicities included fatigue (12%), and neutropenia (6%), with 4 patients discontinuing due to toxicities. A trend in decreasing plasma DNA LINE-1 methylation was seen with longer treatment duration (P = 0.06), which significantly correlated with prolongation of PSA-DT (P = 0.02).Conclusions: Azacitidine favorably modulates PSA kinetics in chemonaïve CRPC that correlates with decreasing plasma DNA LINE-1 methylation. Given the excellent tolerability, further development of azacitidine for CRPC may be warranted, with exploration of combination regimens.

A gene signature of primary tumor identifies metastasized seminoma - Corrected Proof

2009-11-30

Abstract: Background: The aim of this study was the prediction of metastatic status in seminoma based on examination of the primary tumor.Methods: Total RNA was isolated from metastasized seminoma (n = 10, T1N1-2M0), non-metastasized seminoma (n = 21, T1-3N0M0), and corresponding normal tissues. Pooled RNA from 10 biopsies of each tissue type was hybridized on whole genome microarrays for screening purposes. Ninety-two selected gene candidates were quantitatively examined using real-time quantitative polymerase chain reaction (RTQ-PCR).Results: Agreement in gene expression was 88% between the whole genome microarrays and RTQ-PCR. Metastasized seminoma showed 1,912 up-regulated and 2,179 down-regulated genes with ≥2-fold differences in gene expression compared non-metastasized seminoma. RTQ-PCR of selected genes showed that mean gene expression values were significantly reduced in metastasized compared with non-metastasized seminoma. The presence of metastases could be predicted based on an 85-gene expression signature by using logistic regression. Sensitivity and accuracy of the 10-fold cross-validation model were 77.8% and 84.2%, respectively.Conclusion: A logistic regression model using an 85 gene expression signature allowed identification of metastasized seminoma from the primary tumor with a sensitivity of 77.8%.

Intermediate-differentiated invasive (pT1 G2) penile cancer—oncological outcome and follow-up - Corrected Proof

2009-11-30

Abstract: Objectives and aims: Due to the low prevalence of penile cancer, little evidence exists on the metastatic potential and the ideal treatment strategies in intermediate-differentiated invasive (pT1 G2) penile cancer. The current study aimed to analyze the oncologic outcome of patients with penile carcinoma with long-term follow-up in a single-center study.Patients and methods: In this retrospective study, 38 patients with histologically proven T1 G2 squamous cell carcinoma of the penis were included. Only the ‘classic’ subtype was analyzed. Treatment of the primary tumor was Nd:YAG laser-therapy, excision, or partial amputation. Follow-up was performed according to EAU guidelines (2004).Results: Mean follow-up was 78.1 months (range: 9–285 months). Local recurrence was seen in 12 patients (31.6%), but was not correlated with disease related death (P = 0.7944). Rate of local recurrence was not dependent on treatment modality (P = 0.3481); 13 patients died, accounting for a disease related survival rate of 81.6% during observation period. Positive lymph nodes were seen in 28.9% of patients and were significantly correlated with disease related death (P = 0.00004). Clinically enlarged inguinal lymph nodes were not correlated with histologically confirmed positive lymph nodes (P = 0.5785).Conclusions: For patients with T1 G2 penile cancer, organ preserving therapy appears to be a suitable treatment option. In our series, nearly one third of patients developed inguinal lymph node metastases, which highlights the potential benefit of surgical staging. Larger prospective multicenter studies are needed to define the best treatment strategy for intermediate-differentiated invasive penile cancer.

A MicroRNA expression profile defining the invasive bladder tumor phenotype - Corrected Proof

2009-11-30

Abstract: Objective: The purpose of this study was to identify microRNA (miRNA) involved in the transition between the noninvasive and invasive urothelial carcinoma of the bladder (UCB) phenotype.Methods: Differential expression of miRNA was identified in a microarray format between noninvasive and invasive UCB cell lines and confirmed using quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) within this cell panel. Normalization of qRT-PCR with miR-222 was established from the microarray data and validated within a panel of 57 UCB tumors (26 noninvasive lesions (Ta/G1) and 31 invasive lesions (T2-T4). Pre-miR constructs were transfected into appropriate UCB cell lines to establish a change in invasive potential.Results: Differential expression of miRNAs was identified from microarray analysis and included reduced expression associated with miR-30b, miR-31, miR-141, miR-200a, miR-200b, miR-200c, miR-205, miR-21 in invasive lesions and elevated miR-99a in noninvasive UCB lesions. Reduced invasion potential was recorded in UM-UC-3, following pre-miR transfection, in all UCB cell lines with the exception of UM-UC-3/miR-30b transfectants. Our results identify a panel of miRNA modulated and expressed in invasive UCB tumors and demonstrates a role for them in the invasive phenotype.Conclusions: The diagnostic test, based on the three most discriminatory miRNAs in our panel (miR-200c, miR-141, and miR-30b), showed a sensitivity of 100% and a specificity of 96.2%. Such a panel of miRNAs has the potential to identify invasive bladder tumors misclassified in pathologic assessment of bladder biopsy specimens.

Obesity does not correlate with adverse pathologic findings on transperineal template-guided mapping biopsy of the prostate - Corrected Proof

2009-11-30

Abstract: Background: Obesity has correlated with adverse pathologic features on prostate biopsy and may predispose to a higher rate of prostate cancer-related death after radical prostatectomy. In this study, we examine the potential relationship between body mass index (BMI) and histopathologic findings on transperineal template-guided mapping biopsy of the prostate (TTMB).Methods: From January 2005 to January 2008, 244 consecutive patients underwent TTMB using an anatomic-based technique. The criteria for TTMB included previously negative transrectal ultrasound (TRUS) biopsy with persistently elevated PSA and/or diagnosis of ASAP, or HG-PIN. The study population was divided into 4 different BMI cohorts (BMI < 25, BMI 25–29.9, BMI 30–34.9, and BMI ≥ 35 kg/m2). Biopsy findings were compared between the various BMI cohorts using one-way analysis of variance (ANOVA) and the χ2 test.Results: Pre-TTMB clinical parameters, including PSA and prostate volume, were not significantly different between the various BMI cohorts. On average, the study population had undergone 1.7 TRUS biopsies before TTMB. Of the 244 study patients, 112 (45.9%), were diagnosed with prostate adenocarcinoma on TTMB. There was no difference in the rate of cancer detection between the different BMI cohorts. Among patients diagnosed with prostate cancer, BMI did not correlate with Gleason score or percent of positive biopsy cores. When the geography of biopsy-positive cores was analyzed, there were no statistically significant differences in cancer location among the different BMI groups.Conclusions: In this study, obesity did not predispose toward higher Gleason score, larger cancer volume, or geographic cancer distribution on repeat biopsy with TTMB.

Significance of P-glycoprotein, P53, and survivin expression in renal cell carcinoma - Corrected Proof

Firat Baytekin, Burcin Tuna, Ugur Mungan, Guven Aslan, Kutsal Yorukoglu — 2009-11-30

Abstract: Objectives: This study addresses the relationship between cell cycle control protein p53, apoptosis inhibitor gene survivin, and chemotherapy resistance protein P-glycoprotein (P-gp) expression, and their prognostic impact in renal cell carcinoma (RCC).Methods: A group consisting of 104 patients with RCC was included from a predefined period of time. The median follow-up was 46 months. Tumor stage was defined according to the 2002 Tumor-Node-Metastasis staging system, and Fuhrman nuclear grading was used. Expression of p53, survivin, and P-gp was assessed on immunohistochemically stained slides of the representative blocks of the tumors.Results: A significant relationship was found between survival and histologic subtype (P = 0.001), tumor stage (P = 0.011), and tumor grade (P < 0.001). Although there was inverse correlation between p53 expression and stage (P = 0.014) and grade (P = 0.04), no correlation was observed with the histopathologic type or survival. There was no correlation between survivin expression and histologic subtype, stage, or survival, but there was a significant inverse correlation between survivin expression and tumor grade (P = 0.018). No significant correlation was found between any parameters tested, and P-gp expression.Conclusions: Survivin, P-gp, and p53 expression do not play a role in prognosis of RCC. Our results suggest that survivin expression may be positively regulated by mutant p53 in RCC, and this expression may have an impact on resistance to chemotherapy in RCC.

The multi-disciplinary management of high-risk prostate cancer - Corrected Proof

2009-11-30

Abstract: Prostate cancer is the most frequently diagnosed cancer and the second most common cause of cancer death in men in the United States. Such men can experience a continuum of disease presentations from indolent to highly aggressive. For physicians who care for these men, a significant challenge has been and continues to be identifying and treating those men with localized cancer who are at a higher risk of dying from their disease. We discuss the risk stratification of patients in order to better identify those patients at higher risk of progression. A comprehensive review of the literature was then performed reviewing the roles of surgery, radiotherapy, hormone therapy, and chemotherapy, as well as combinations of these modalities, in treating these challenging patients. An integrated approach combining local and systemic therapies can be beneficial in the management of high-risk localized prostate cancer. The choice of therapy or combination of therapies is dependant upon many considerations, including patient preference and quality of life aspects. It is becoming clearer that the addition of hormonal therapies or chemotherapies to established therapies, such as radiotherapy or surgery, will have significant benefits. As evidence accumulates regarding the efficacy of these new regimens, our hope is that the challenge of optimizing the management of high-risk prostate cancer will be delivered. However, many important questions remain unresolved regarding the optimal type, combination, timing of therapy, and duration of therapy. Such questions will only be answered with large, well-designed prospective clinical trials.

Improving the efficacy of targeted trials by multiple-marker analysis in castration-resistant prostate cancer - Corrected Proof

2009-11-30

Abstract: Objectives: In order to improve the efficacy of targeted therapy trials, the expression profiles of several molecular markers that are potential candidates for targeted therapy were analyzed in patients with progressive castration-resistant prostate cancer.Methods and materials: Paraffin-embedded samples of tumor tissue from 51 patients obtained from biopsies of metastases or remaining prostates were analyzed immunohistochemically for the expression of EGFR, PDGFRβ, Her-2/neu, c-Kit, and VEGF. Staining was analyzed according to the percentage of positively stained tumor cells and the intensity of staining.Results: According to the different cut-off values of 10%, 30%, 50%, or 70% for the percentage of positively stained cells, different rates of expression were found. Expression rates ranged from 30.6% to 61.2% for EGFR, from 34.7% to 57.1% for PDGFRβ, from 9.6% to 28.8% for Her-2/neu, from 12.5% to 22.4% for c-Kit, and from 51.1% to 74.5% for VEGF. Defining positive expression as ≥30% positively stained tumor cells, with an intensity of staining of ≥2+, resulted in positive expression of EGFR in 38.8%, PDGFRβ in 24.5%, Her-2/neu in 13.5%, c-Kit in 6.4%, and VEGF in 44.7% of the patients.Conclusions: Our results demonstrate simultaneous expression of several markers in castration-resistant prostate cancer tissue. Translation of the results into modern, multi-arm clinical trial designs will improve the efficacy of recruiting and obtaining results, compared with multiple double-arm trials.

GREB1 tissue expression is associated with organ-confined prostate cancer - Corrected Proof

2009-11-30

Abstract: Objective: By reason of its heterogeneous behavior, it is difficult to determine the prognosis of many prostate cancer cases. Patients with the same clinicopathologic conditions may present varying clinical findings and rates of progression. We determined the role of new genes as potential molecular markers for prostate cancer prognosis.Materials and methods: We performed a microarray analysis of two pools of patients with prostate cancer divided according to their clinicopathologic characteristics. After that, we validated these results by testing the genes with most different expressions between the two pools using the quantitative real time polymerase chain reaction method. We analyzed gene expression in 33 patients with localized prostate cancer according to prostate specific antigen (PSA), pathologic stage, Gleason score, and biochemical recurrence. For statistical analysis we used the Mann-Whitney Test.Results: The microarray analysis revealed that 4,147 genes presented a different expression between the two pools. Among them, 3 genes, TMEFF2, GREB1, and TH1L, were at least 13-times overexpressed, and 1 gene, IGH3, which was at least 5times under-expressed in pool 1 (good prognosis) compared with pool 2 (bad prognosis), were selected for analysis. After the validation tests, GREB1 was significantly more overexpressed among patients with stage T2 compared with T3 (P = 0.020). The expressions of other 3 genes did not present significant differences according to the clinicopathological variables.Conclusions: Tissue expression of GREB1 is associated with organ-confined prostate cancer and may constitute a gene associated with a favorable prognosis.

Urothelial dysplasia and inflammation induced by Schistosoma haematobium total antigen instillation in mice normal urothelium - Corrected Proof

2009-11-30

Abstract: Objectives: Squamous cell carcinoma of the urinary bladder has been associated with Schistosoma haematobium infection in many parts of Africa. The epidemiologic association is based on case control studies and on the close correlation of urinary bladder cancer incidence with prevalence of S. haematobium infection within different geographic areas. A parasite-tumor linkage is further suggested by the predominance of squamous cell (as opposed to transitional cell) morphology of bladder carcinomas seen in S. haematobium-endemic areas. The cellular mechanisms linking S. haematobium infection with cancer formation are not yet defined. In the present study, we hypothesized that the parasite antigens might induce alterations in urothelium.Materials and methods: We investigated the effects of S. haematobium total antigen in CD-1 mice normal bladders after intravesical administration of the parasite antigens. The bladders were analyzed histopathologically 20 and 40 weeks after treatment.Results: Intravesical instillation of S. haematobium total antigens induces the development of urothelial dysplasia and inflammation.Conclusions: In our work, we demonstrate for the first time that S. haematobium antigens are the direct cause of alterations in urothelium.

Fluorescence-guided laser therapy for penile carcinoma and precancerous lesions: Long-term follow-up - Corrected Proof

2009-11-30

Abstract: Objectives and aims: Laser therapy for penile carcinoma is commonly used despite high recurrence rates of up to 48%. The aim of our study was to investigate the long-term recurrence rate of patients treated by fluorescence-guided laser therapy for penile carcinoma and its impact on oncologic outcome.Patients and methods: Between 1999 and 2005, a total of 26 patients with premalignant carcinoma in situ (Tis) (n = 11) or invasive penile carcinoma (n = 15) were treated by fluorescence-guided laser therapy in our center. The mean follow-up was 71.1 months (range 41–104 months). Recurrence rate, time to recurrence, and impact on survival was investigated for Tis patients and penile carcinoma patients separately.Results: No patient died tumor-associated recurrence during follow-up. No local progression of T stage was observed in patients with Tis tumor. In the group with invasive penile cancer, there were 4 (15.4%) local recurrences. However, 3 of them occurred after more than 3 years and, therefore, are more likely to be considered as “de novo” carcinoma. No intra- or perioperative side effects of photodynamic diagnosis (PDD) were observed.Conclusions: Local recurrence rate of laser therapy can be reduced by fluorescence guidance without impairing cosmetic or functional results. The necessary equipment is available in many centers that perform PDD for urothelial bladder cancer. PDD, therefore, can be considered to be cost-effective and easy to perform. Prospective multi-center studies to directly compare recurrence rates between white light and fluorescence-guided laser therapy for penile carcinoma are required.

The orthotopic Fischer/AY-27 rat bladder urothelial cell carcinoma model to test the efficacy of different apaziquone formulations - Corrected Proof

2009-11-30

Abstract: Objectives: Apaziquone used intravesically showed significant activity in phase I and II marker lesion studies in non-muscle-invasive bladder cancer. The objective of this study was to assess antitumor activity and safety of 3 different formulations of intravesical apaziquone in an orthotopic rat bladder cancer model.Materials and methods: Female Fischer F344 rats were instilled with 1.5 × 106 AY-27 urothelial cell carcinoma cells and divided in 3 treatment groups (n = 10) and 1 placebo group (n = 6). Intravesical treatment was administered for 1 hour on days 2 and 5. Rats were treated with apaziquone in the formulation used in phase I/II clinical trials (group 1); apaziquone with an altered buffering capacity being used in phase III clinical trials (group 2), and apaziquone as in group 2, but without propylene glycol in the diluent (group 3). On days 5 and 14, the bladder wall was inspected by cystoscopy and evaluated for macroscopic tumor growth. After sacrificing the rats (day 14), cystectomy was performed and the bladders were investigated.Results: There were no signs of any toxicity due to the study drug. On histopathologic examination of the bladders 0, 1, and 2 tumors per group were found in group 1, 2, and 3, respectively. In the placebo-treated group, 60% of animals developed tumor, which is comparable to untreated animals.Conclusions: Apaziquone showed an excellent antitumor activity. The effectiveness of apaziquone in this orthotopic rat bladder tumor model corroborates the clinical observations and implies the validity of this model.

Antiproliferative and apoptosis inducing effects of indirubin-3′-monoxime in renal cell cancer cells - Corrected Proof

2009-11-30

Abstract: Objectives: Indirubin-3′-monoxime, which is a selective and potent inhibitor of cyclin-dependent kinases (CDKs) has shown preclinical activity in several human cancer cells. This study investigated if indirubin-3′-monoxime can induce apoptosis and tumor cell death in 3 human (A498, CAKI-1, CAKI-2) and 1 murine renal cell cancer (RENCA) cell line.Methods: The growth inhibitory and apoptosis induction properties were evaluated by EZ4U, a cytotoxic assay and by flow cytometry of annexin-V/PI staining during treatment with doses ranging from 5.0 to 15.0 μM indirubin-3′-monoxime over 72 hours. To further establish the underlying molecular targets of indirubin-3′-monoxime, survivin, a major anti-apoptotic protein was additionally determined by intracellular flow cytometry.Results: Our results show that indirubin-3′-monoxime induces growth arrest and apoptosis in all renal cell cancer (RCC) cell lines. All RCC lines expressed survivin. However, a clear correlation between apoptosis induction and expression of survivin was not found.Conclusions: As treatment of metastatic renal cell cancer (mRCC) remains a challenge, and the need for continuing assessment of novel agents in the treatment of this disease is mandatory. Indirubin-3′-monoxime seems to be a candidate for further evaluation.

Immunohistochemistry for the differential diagnosis of renal tumors with oncocytic features - Corrected Proof

M. Jesus Fernández-Aceñero, Alicia Cazorla, F. Manzarbeitia — 2009-11-20

Abstract: Objective: Histologic analysis of renal tumors usually enables accurate diagnosis, but some tumors may show overlapping histopathologic features, which makes classification difficult. Diagnosis can be extremely challenging in tumors showing oncocytic change, mainly for oncocytomas, chromophobe carcinoma, papillary carcinomas with eosinophilic cells (type 2), and conventional renal cell carcinomas with eosinophilic oncocytic-like cells. The purpose of the present study is to analyze whether the patterns of immunohistochemical expression can help differential diagnosis of these tumors.Material and methods: A thorough review of the files of the Department of Surgical Pathology, Fundación Jiménez Díaz, Madrid, Spain has retrieved 308 records of renal cell carcinomas in the last 12 years, with 15 renal oncocytomas (RO), 28 papillary carcinomas (PRCC), and 13 chromophobe carcinomas (CHRCC). We have performed immunohistochemistry on representative paraffin blocks from 9 oncocytomas, 11 chromophobe carcinomas, 10 papillary carcinomas, and 11 conventional cell carcinomas with oncocytic cells, from which we had suitable material. The immunohistochemical panel included CD117, α-methylacyl-coenzyme A racemase, CD10, p53, progesterone receptors, and cytokeratins 7 and 20.Results: Our results show a considerable overlap between immunohistochemical expression in these tumors. Although immunohistochemistry can be helpful in some difficult cases, no markers allow a clear-cut distinction between these tumors, and diagnosis must still rely on morphologic features and histochemical techniques, as well as on molecular techniques when available.

Expression of glutathione-S-transferases isoenzymes and P53 in exfoliated human bladder cancer cells - Corrected Proof

2009-11-20

Abstract: Objectives: This study investigates the usefulness of glutathione-S-transferases (GST) isoenzymes and p53 immunostaining as a marker of malignancy in urinary cytology, and evaluates their potential effect in increasing diagnostic accuracy in a series of urine cytologic samples. They are also correlated with cytopathology diagnosis and histopathologic diagnosis.Materials and methods: In this study, the slides from 124 bladder carcinoma patients prepared by the cytocentrifugation method were observed. The cytomorphologic properties of these cancer cells were determined. Moreover, the immunocytochemical distributions of GST alpha (GSTA), pi (GSTP), mu (GSTM4), theta (GSTT1) isoenzymes and p53 protein were studied for the patients.Results: The urothelial cancer cells had small cytoplasm and rough nuclear membrane. The chromatin granules were heterogeneously distributed in each malignant cell's nucleus. There was a pleomorphism of the malignant cells' nuclei. According to immunocytopathologic observations, the urothelial cancer cells had stronger staining intensity than the benign cells had in 48% of cases for GSTA, 46% of cases for GSTP, 38% of cases for GSTM4, and 42% of cases for GSTT1. For all papillary cases, the malignant cells were stained negative, while the benign cells were positive. For 83% of patients, the malignant cells were stained positive for p53. There was a significant difference in GSTA (P = 0.006), GSTT1 (P = 0.004), GSTP (P = 0.000) and p53 (P = 0.000) expressions for benign cells whereas, a non-statistical difference in the malignant cells for GSTA, GSTT1, GSTP, GSTM4, and p53 expressions (P > 0.05).Conclusions: GST isoenzymes and p53 immunostaining were not found to be markers of malignancy in urinary cytology.

Prevalent and incident use of androgen deprivation therapy among men with prostate cancer in the United States - Corrected Proof

Scott M. Gilbert, Yong-fang Kuo, Vahakn B. Shahinian — 2009-11-20

Abstract: Purpose: Androgen deprivation therapy (ADT) for prostate cancer increased substantially through the 1990s, but more recent national trends regarding incident and prevalent use have been incompletely characterized.Methods: Linked Surveillance, Epidemiology, and End Results (SEER)–Medicare data were used to study patterns of ADT utilization. Prevalence of ADT in the male Medicare population was estimated by examining a cohort of prostate cancer patients and a 5% noncancer control population, from 1991 to 2005. ADT use across different indications was examined for men with incident cancers from 2000 to 2002. Nested logit models were used to examine determinants of ADT use in men with lower risk prostate cancer not treated definitively by surgery or radiation.Results: Prevalent ADT use increased through the 1990s, peaked in 2000 at 3.17% of all male Medicare beneficiaries, subsequently stabilized, then dropped in 2005 to 2.92%. Between 2000 and 2002, use in incident prostate cancer was stable, with 44.8% use in all cases, 15% of cases as an adjuvant with radiation, and 14% as a primary therapy. In the nested logit model, predictors of ADT use in a lower risk setting were older age, higher stage and grade, and elevated prostate-specific antigen levels.Conclusions: Following a period of rapid expansion during the 1990s, incident and prevalent use of ADT has leveled, and may be starting to decline. Further research is needed to monitor how reductions in reimbursement for GnRH agonists will affect appropriate use of ADT as well as use in settings where its benefits may be marginal.

Oncologic control obtained after radical prostatectomy in men with a pathological Gleason score ≥ 8: A single-center experience - Corrected Proof

2009-11-20

Abstract: Objective: To assess the oncologic control afforded by radical prostatectomy (RP) in high-risk prostate cancers with a Gleason score ≥ 8.Materials and methods: We performed a retrospective review of prostate cancer patients who underwent RP between 1995 and 2005 for prostate cancer and who had a pathologic Gleason score ≥ 8. Biochemical recurrence was defined as a single rise in PSA levels over 0.2 ng/ml after surgery.Results: Overall, 64 patients were included and followed for a median time of 84.3 months. The mean age was 63 ± 5.2 years. The mean preoperative PSA was 11.9 ± 7.3 ng/ml (1.9–31), and 29 patients (46%) had a PSA > 10 ng/ml. The biopsy Gleason score was ≤7 for 49 patients (76.6%). After pathologic analysis, there were 25 (39%) stage pT2, 37 (58%) stage pT3, and 2 (3%) stage pT4 patients. Nine patients had lymph node involvement (14%). The surgical margins were positive in 25 patients (39%). In 51 patients, (80%) the Gleason score was underestimated by biopsies: 40 patients with a definitive score of Gleason 8 had a Gleason score of 6 or 7 on biopsies, while 11 patients with a Gleason score of 9 initially, had a Gleason score of 7 or 8. Twenty-seven patients underwent adjuvant treatment: external radiation therapy (n = 19), HRT (n = 3), or both (n = 5). During follow-up, 41 patients (64%) presented with a biochemical recurrence, and 11 (17%) died. The PSA-free survival rate at five year was 44%.Conclusion: RP remains a possible therapeutic option in certain cases of the high-risk cohort of patients with a Gleason score ≥ 8. However, patients should be warned that surgery might only be the first step of a multi-modal treatment approach. The modalities of adjuvant treatments and the right schedule to deliver it following RP still need to be defined.

Serotonin activates MAP kinase and PI3K/Akt signaling pathways in prostate cancer cell lines - Corrected Proof

2009-11-20

Abstract: Purpose: This study was conducted to examine the effects of 5-HT on extracellular signal-regulated kinase 1/2 (Erk1/2) and Akt pathways in prostate cancer (PC) cells.Methods: PC cell lines PC-3, Du145, and LNCaP stimulated with 5-HT in the presence of MEK or PI3K inhibitors and 5-HT receptor subtype 1A antagonist were analyzed by Western blotting and immunofluorescence. The proliferation assay BrdU and Boyden chamber were used to determine proliferation and migration, respectively.Results: 5-HT dose-dependently induced rapid activation of Erk1/2 in PC-3 and Du145 cells, whereas in LNCaP cells, Erk1/2 phosphorylation was slow and sustained for up to 18 h. Similarly, 5-HT induced phosphorylation of Akt within 1 hour of stimulation, however, Akt phosphorylation was more pronounced in Du145 cells compared with PC-3 or LNCaP cells. The action of 5-HT was inhibited to varying degrees by inhibitors of MAPK and PI3K as well as by a 5-HT receptor subtype 1A antagonist. In addition to proliferation, 5-HT induced migration of PC-3 and Du145 cells, which were alleviated by the aforementioned inhibitors. The effects of 5-HT on LNCaP cells appeared to be related to neuroendocrine-phenotype acquisition and chromogranin A and neuron specific enolase expression.Conclusions: This study addresses the role of 5-HT in Erk1/2 and Akt activation in PC cells. The data presented here identify 5-HT receptors as a novel target in castration-resistant PC. Furthermore, our observations are in line with previous studies, which point towards neuroendocrine factors facilitating progression and migration of prostatic cancer cells in an androgen-deficient environment. Nonetheless, additional studies are warranted to corroborate the role of 5-HTR antagonists as a potential target for anticancer therapy.

Potential use of circulating endothelial cells as a biomarker of renal cell carcinoma - Corrected Proof

Kevin V.S. Tan, Benjamin Namdarian, Anthony J. Costello, Christopher M. Hovens — 2009-11-16

Abstract: Each year, renal cell carcinoma (RCC) accounts for significant mortality in the population. Whilst the disease is now being diagnosed earlier, determining patient prognosis remains a challenge. Current prognostic indicators, such as TNM stage, Fuhrman grade, and RCC subtype, are inadequate. Unlike several other malignancies, RCC lacks a biomarker that can stratify patients into high, intermediate, or low risk for developing metastases. Additionally, antiangiogenic therapy is currently offered to patients with metastatic disease, however, a biomarker to monitor treatment efficacy is lacking. Recent attention has focused on surrogate markers of tumor vascularization as a source of prognostic biomarkers, as tumor growth is ultimately dependent on neovascularization. Two cell populations of interest, circulating endothelial cells (CECs) and circulating endothelial progenitors (CEPs), have been demonstrated across several studies to contribute to tumor vascularization. Given these findings, studies have examined their utility as biomarkers of prognosis by correlating their levels with progression-free survival and prognostic determinants such as tumor volume and weight. However, their role in predicting prognosis in RCC, as well as their potential to act as markers of treatment efficacy in metastatic RCC, remains to be established. Previous studies on CECs and CEPs in the context of cancer will be outlined in this review.

Evolution of renal function in patients treated with antiangiogenics after nephrectomy for renal cell carcinoma - Corrected Proof

2009-11-16

Abstract: Purpose: Side effects of antiangiogenic agents are moderate compared with other therapies. The most frequent adverse events are of a renovascular origin and manifest as hypertension (HTN) and thrombotic microangiopathy. To date, data are scanty on the renal tolerance of such drugs regarding renal function as itself, i.e., glomerular filtration rate (GFR). We report on the evolution of GFR in patients receiving antiangiogenic therapy after unilateral nephrectomy for kidney cancer.Patients and methods: Data from 73 patients followed in our oncology department for kidney cancer, who had undergone unilateral nephrectomy, and received any antiangiogenic therapy were reviewed. Their GFR was calculated using the aMDRD formula.Results: All patients showed a declining renal function over time (−1.23 and −2.51 mL/min/1.73 m2 using the slope of the curve or the difference between GFR at baseline and that at the end of treatment, respectively). Among them, patients who were recorded as having HTN before initiation of antiangiogenic therapy showed a higher decrease in their GFR of −13.28 and −12.06 mL/min/1.73 m2.Conclusion: We recommend that blood pressure should be measured closely in those patients before initiation of antiangiogenic therapy. When HTN is diagnosed, it should be treated and renal function should be monitored since those patients may be at risk for rapidly decreasing renal function under therapy.

Targeted therapies in non-muscle-invasive bladder cancer according to the signaling pathways - Corrected Proof

2009-11-16

Abstract: With 300,000 annually new cases worldwide, urothelial-cell carcinoma of the bladder (UCCB) is the second most common urologic neoplasm after prostate carcinoma. Non-muscle-invasive bladder cancer (NMIBC), which is not immediately life-threatening, represents 70% to 80% of these initial cases. Despite optimal treatment (transurethral resection with intravesical chemo- or immunotherapy), 70% of these NMIBC will recur, and 10% to 20% will progress, highlighting the need for a new therapeutic approach. Indeed, the identification of patients at high risk of disease recurrence and progression would be beneficial in predicting which patients with NMIBC would benefit from strict follow-up and which would benefit from a more aggressive therapy. To date, conventional treatment remains disappointing in terms of oncologic results and morbidity. The growing understanding in tumor biology has enabled the signaling pathways involved in bladder tumorigenesis and progression to be identified, but few molecular targets have been available until now. The encouraging results seen in various human carcinomas suggests that these new agents should become part of the arsenal of drugs available in the treatment of NMIBC, alone or in combination with already known agents. In this article, we have tried to highlight the main molecular signaling pathways involved in NMIBC tumorigenesis and progression, and the potential targets useful for improving the treatment of NMIBC.

Value of magnetic resonance spectroscopy (MSR) and dynamic contrast-enhanced magnetic resonance (DCEMR) imaging for the characterization of high-grade prostatic intraepithelial neoplasia (HGPIN) foci - Corrected Proof

2009-11-16

Abstract: Background: Despite an increasing interest in high-grade prostatic intraepithelial neoplasia (HGPIN), the clinical suspicious aspect of this premalignant lesion remains poorly characterized. The aim of this study was to analyze the magnetic resonance spectroscopy (MSR) and dynamic contrast-enhanced magnetic resonance (DCEMR) imaging features of isolated HGPIN lesions.Materials and methods: From January 2007 to January 2009, 330 cases were included in a protocol that involve the use of MSR and DCEMR for the diagnosis of prostate diseases. Of these, 27 patients with isolated (no associated prostate cancer diagnosis) HGPIN histologic diagnosis at the first prostate biopsy were included in the present study. All cases were previously submitted to MSR/DCEMR (1.5 T scanner) and, no later than 10 days to a random 12-core biopsy scheme. Biopsy targeting was done in zones corresponding to those analyzed with MSR and DCEMR.Results: In the 27 patients, 30 HGPIN foci with a diameter of 6 mm or greater were analyzed and compared with 27 peripheral zone areas of normal prostate tissue. With MSR, HGPIN foci were characterized by a significantly higher (P < 0.05) absolute value of choline and choline + creatine/citrate ratio compared with normal tissue. With DCEMR, HGPIN foci were characterized by lower values of all dynamic parameters but differences did not reach statistical significance (P > 0.05).Conclusions: In our experience, HGPIN lesions can be metabolically characterized by MSR through the absolute value of choline and the choline + creatine/citrate ratio.

The role of lymphovascular space invasion in renal cell carcinoma as a prognostic marker of survival after curative resection - Corrected Proof

2009-11-16

Abstract: Objectives: Lymphovascular invasion (LVI) correlates with adverse outcomes in numerous malignancies. However, its role in predicting outcomes in RCC is unclear. Herein, we evaluated what effect LVI had on metastasis free survival (MFS), disease-specific survival (DSS), and overall survival (OS) in patients with RCC treated with surgical excision.Methods: Eight hundred forty-one consecutive patients who underwent partial or radical nephrectomy from 1989 to 2004 were identified. Pathologic and gross features examined were LVI, subtype, Fuhrman grade, stage, and size. Age and gender were also analyzed. Slides were re-reviewed by a single pathologist (MS). Variables with P < 0.1 on univariate analysis were incorporated in a Cox proportional hazards multivariate model. MFS, DSS, and OS were described for patients with and without LVI using the Kaplan-Meier method, and compared with the log-rank test.Results: LVI was seen on H and E stained slides in 91 patients (11%); 120 (14%) developed metastatic disease, 91 (11%) died of RCC, and 306 (36%) died during a median follow-up of 61 months. While on univariate analysis, LVI was strongly associated with decreased MFS, DSS, and OS (P < 0.0001), on multivariate analysis, LVI was no longer statistically significant for MFS, DSS, and OS with a HR of 0.976 (95% CI: 0.583–1.63; P = 0.93), 0.96 (95% CI: 0.542–1.69; P = 0.88), and 1.24 (95% CI: 0.869–1.77; P = 0.24).Conclusions: We found LVI to be associated with worse MFS, DSS, and OS on univariate analysis, but not on multivariate analysis for patients with nonmetastatic RCC. In contrast to previously reported studies, LVI may not be an independent prognostic variable in patients with localized RCC.

Expression of cell cycle-associated proteins in non-muscle-invasive bladder cancer: Correlation with intravesical recurrence following transurethral resection - Corrected Proof

2009-11-16

Abstract: The objective of this study was to evaluate the expression patterns of cell cycle-associated proteins in newly diagnosed non-muscle-invasive bladder cancer (NMIBC) to clarify the significance of these proteins as prognostic predictors in 161 consecutive patients undergoing transurethral resection (TUR). Expression levels of 7 cell cycle-associated proteins, including Aurora-A, c-erbB2, cyclin-D1, Ki-67, p21, p27, and p53, in TUR specimens were measured by immunohistochemical staining. Of the 7 proteins, weak expression of p21 was significantly associated with the incidence of intravesical recurrence (P = 0.012). Univariate analysis identified expression level of p21, tumor size, T stage, and concomitant carcinoma in situ (CIS) as significant predictors for intravesical recurrence (P = 0.0053, 0.0014, 0.024, and 0.035, respectively). Of these, p21 expression, tumor size, and concomitant CIS appeared to be independently related to intravesical recurrence (P = 0.029, 0.025, and 0.016, respectively). Furthermore, there were significant differences in intravesical recurrence-free survival according to positive patterns of these 3 independent factors; that is, intravesical recurrence occurred in 17 of 72 patients who were negative for risk factor (23.6%), 30 of 57 positive for a single risk factor (52.6%), and 24 of 32 positive for 2 or 3 risk factors (75.0%). These findings suggest that consideration of expression levels of cell cycle-associated proteins, in addition to conventional parameters, would contribute to accurate prediction of intravesical recurrence following TUR of NMIBC. Moreover, combined evaluation of p21 expression, tumor size, and concomitant CIS might be particularly useful for further refinement of the outcome in predicting intravesical recurrence following TUR of NMIBC.

Epothilones in prostate cancer - Corrected Proof

William K. Kelly — 2009-11-16

Abstract: Objectives: Treatment options for castration-resistant prostate cancer (CRPC) are limited. Although taxane-based regimens offer limited survival benefits, patients frequently relapse, and there are no standard regimens beyond progression. The epothilones represent a new class of chemotherapeutics that stabilize microtubules but have a distinct mechanism of action to the taxanes and low susceptibility to drug resistance. This article seeks to provide a review of what is currently known about the preclinical and clinical activity of this emerging class of agents.Materials and methods: A literature search was conducted using PubMed and congress abstract databases to identify clinical data relevant to the epothilones and their use in CRPC. Preference was given to recently published, well-designed preclinical reports and clinical studies.Results: Preclinical activity has been shown for several epothilones in taxane-resistant cell lines across several tumors, including CRPC. Ixabepilone, sagopilone, and patupilone have demonstrated clinical activity and tolerability in phase II CRPC trials.Conclusion: The epothilones have demonstrated efficacy in CRPC, and ongoing studies will help define their roles in this disease state, including optimal dosing, combination regimens, and clinical biomarkers of response.

Expression of hypoxia inducible factor-1α and 2α in conventional renal cell carcinoma with or without sarcomatoid differentiation - Corrected Proof

2009-11-16

Abstract: Objectives: Expressions of hypoxia inducible factor (HIF)-1α and HIF-2α in epithelial and sarcomatoid components from the same patients with clear cell renal cell carcinoma (RCC) are lacking. We performed this study to define better the correlations among these molecules in RCC tissues.Materials and methods: Immunohistochemical staining of paraffin sections for HIF-1α and HIF-2α was performed in 24 cases of RCC with sarcomatoid differentiation using a streptavidin-peroxidase procedure. Control samples were collected from 58 patients with no sarcomatoid differentiation matched to cases by age, gender, and TNM stage.Results: HIF-1α was more expressed within the epithelial component of clear cell RCC with no sarcomatoid differentiation (82.8%) than within that with sarcomatoid differentiation (66.7%). HIF-2α was expressed in most of the epithelial component, regardless of the sarcomatoid differentiation. However, HIF-1α and HIF-2α were not expressed in the sarcomatoid component in about 50.0% of clear cell RCC regardless of the sarcomatoid differentiation. Multivariate Cox proportional hazards model analysis showed that HIF-1α expression was an independent predictor of cancer-specific survival in clear cell RCC with sarcomatoid differentiation (P = 0.029).Conclusions: HIF-1α and HIF-2α are not expressed in the sarcomatoid component in about a half of clear cell RCC with sarcomatoid differentiation, while HIF-2α was consistently overexpressed in the epithelial component in a majority of the tumors. Only HIF-1α expression regardless of tumor component is an independent prognostic factor in clear cell RCC with sarcomatoid differentiation.

Abnormalities of thyroid function in Japanese patients with metastatic renal cell carcinoma treated with sorafenib: A prospective evaluation - Corrected Proof

2009-11-16

Abstract: The objective of this study was to characterize features of thyroid dysfunction in Japanese patients with metastatic renal cell carcinoma (RCC) who were treated with sorafenib. We performed a prospective observational study including 69 Japanese patients who were diagnosed as having metastatic RCC refractory to cytokine therapy and subsequently treated with sorafenib for at least 12 weeks. Thyroid function was assessed before and every 4 weeks after the initiation of sorafenib treatment. Of the 69 patients, 23 (33.3%) did not show any biochemical thyroid abnormality, while the remaining 46 (67.7%) developed hypothyroidism. However, 11 (23.9%) of these 46 hypothyroid patients initially had a suppressed thyroid-stimulating hormone (TSH) value accompanying the increase in free triiodothyronine (T3) and/or free thyroxine (T4) before developing hypothyroidism, suggesting sorafenib-induced thyroiditis. During the observation period of this study, 4 patients (5.8%) demonstrated severe clinical symptoms caused by hypothyroidism and received thyroid hormone replacement. Among several factors examined, only age was significantly associated with the risk for hypothyroidism. These findings suggest that although the incidence of clinically significant hypothyroidism requiring thyroid hormone replacement therapy was not very high, biochemical thyroid abnormality was frequently observed in Japanese RCC patients treated with sorafenib. Accordingly, regular surveillance of thyroid function by the measurement of TSH, free T3, and T4 is warranted during sorafenib treatment in Japanese RCC patients.

DNA repair gene polymorphisms and prostate cancer risk in South Australia—results of a pilot study☆ - Corrected Proof

Varinderpal S. Dhillon, Eric Yeoh, Michael Fenech — 2009-11-16

Abstract: Objective: Single nucleotide polymorphisms (SNPs) in DNA repair genes may impact on DNA damage, and cancer risk. To elucidate the role of SNPs in DNA repair genes in prostate cancer (PC) we conducted a case-control study comprising of 118 Caucasian men affected with late onset PC and 132 age-matched healthy controls from South Australia.Methods and materials: We examined the association between PC risk with nonsynonymous SNPs (nsSNPs) in 5 genes involved in 3 DNA-repair pathways: (1) base excision repair (BER): hOGG1 C1245G (Ser326Cys) and XRCC1 G28152A (Arg399Gln); (2) nucleotide excision repair (NER): XPD G23591A (Asp312Asn); (3) homologous recombination repair: RAD51 G135C (in 5′ untranslated region) and XRCC3 C18067T (Thr241Met).Results: Prostate cancer risk was significantly increased only for carriers of the G allele of the C1245G polymorphism in the hOGG1 gene (OR = 2.28; 95% CI = 1.36–3.83; P = 0.002).Conclusion: Our results suggest that this common nsSNP in a gene involved in repair of oxidative damage to DNA may contribute to PC susceptibility in South Australian men.

Diffuse lymphangiomatosis with genital involvement—evaluation with magnetic resonance lymphangiography - Corrected Proof

Christian Lohrmann, Etelka Foeldi, Mathias Langer — 2009-11-16

Abstract: Objective: To assess, for the first time, the morphology of the lymphatic system in patients with diffuse lymphangiomatosis and genital involvement by magnetic resonance lymphangiography (MRL).Materials and methods: Ten patients with diffuse lymphangiomatosis and genital involvement were examined by MRL. Three locations were examined: first, the lower leg and foot region; second, the upper leg and the knee region; and third, the pelvic with retroperitoneal region. MR imaging was performed with a 1.5-T system equipped with high-performance gradients. For MRL, a T1-weighted 3D-spoiled gradient-echo and a T2-weighted 3D-TSE sequence were used.Results: The size of the genital lymphangiomas, which were revealed in all patients, varied between 6 and 85 mm. In 60% of the patients, lymphangiomas were additionally detected at the level of the lower legs, and in 70% patients at the level of the upper leg. Furthermore, lymphangiomas were seen in the inguinal and retroperitoneal regions in 80%, and in the pelvic region and anterior abdominal wall in 90% of the patients examined. The genital lymphangiomas feeding lymphatic vessels were detected in 80% of the patients in the anterior abdominal wall and in 90% of the patients in the inguinal and pelvic regions; 90% of the patients suffered consecutively from a lymphedema of the lower extremities. All patients suffered from recurrent infections in the genital region; 80% of the patients repeatedly experienced genital lymphorrhea due to lympho-cutaneous fistulas and lymphcysts.Conclusion: MRL is a safe and accurate minimal-invasive imaging modality for the evaluation of the lymphatic circulation in patients with diffuse lymphangiomatosis and genital involvement. Because the site and extent of the lymphangiomas with their feeding lymphatic vessels are important prognostic factors, performing radiologic evaluation with a high resolution is crucial for the therapeutic planning of patients.

Ablative therapies in the treatment of small renal tumors: How far from standard of care? - Corrected Proof

2009-11-09

Abstract: Objectives: To determine the current clinical value of minimally invasive thermoablative techniques (MI thermoablative T) to ablate small renal tumors through a literature review.Methods: A literature search was conducted on the most commonly used MI thermoablative T for small renal tumors, namely cryoablation (CA) and radiofrequency ablation (RFA). Primary objective was to carry out a comparative assessment of the complication rate, recurrence rate, and cancer specific survival rates across techniques. Secondary objective was to critically review technical aspects of the procedures.Results: Five-year follow-up data were available only for laparoscopic CA, with a recurrence rate varying from 0% to 15%. Follow-up of percutaneous cryoablation (PCA) and RFA did not go beyond 2 years, and excellent recurrence free rates were obtained at the price of a significant retreatment rate. The need for retreatment was perceived as lower with PCA than with RFA. Overall complication rate did not exceed 5% in all techniques albeit laparoscopic CA carried a significant degree of invasiveness compared with other percutaneous techniques.Conclusions: MI thermoablative T for small renal tumors should still be confined to carefully selected patients. PCA seems to hold the premises for the best compromise between low invasiveness and high efficacy, while RFA appears highly advantageous in terms of procedural costs.