Two-Staged Sacral Neuromodulation for the Treatment of Nonobstructive Urinary Retention: A Multicenter Study Assessing Predictors of Success.

OBJECTIVES: The aims of this study were to 1) determine the success rate of the tined lead test phase in patients with nonobstructive urinary retention (NOUR), 2) determine predictive factors of a successful test phase in patients with NOUR, and 3) determine long-term treatment efficacy and satisfaction in patients with NOUR. MATERIALS AND METHODS: The first part was a multicenter retrospective study at two centers in The Netherlands. Patients with NOUR received a four-week tined lead test phase. Success was defined as a ≥50% reduction of clean intermittent catheterization frequency or postvoid residual. We analyzed possible predictors of success with multivariable logistic regression. Second, all patients received a questionnaire to assess efficacy, perceived health (Patient Global Impression of Improvement), and treatment satisfaction. RESULTS: This study included 215 consecutive patients (82 men and 133 women) who underwent a tined lead test phase for the treatment of NOUR. The success rate in women was significantly higher than in men, respectively 62% (83/133) and 22% (18/82, p < 0.001). In women, age per ten years (odds ratio [OR] 0.74, 95% CI: 0.59-0.93) and a history of psychiatric illness (OR 3.92, 95% CI: 1.51-10.2), including posttraumatic stress disorder (PTSD), significantly predicted first stage sacral neuromodulation (SNM) success. In men, age per ten years (OR 0.43, 95% CI: 0.25-0.72) and previous transurethral resection of the prostate and/or bladder neck incision (OR 7.71, 95% CI: 1.43-41.5) were significant predictors of success. Conversely, inability to void during a urodynamic study (for women, OR 0.79, 95% CI: 0.35-1.78; for men, OR 3.06, 95% CI: 0.83-11.3) was not predictive of success. Of the patients with a successful first stage, 75% (76/101) responded to the questionnaire at a median follow-up of three years. Of these patients, 87% (66/76) continued to use their SNM system, and 92% (70/76) would recommend SNM to other patients. CONCLUSIONS: A history of psychiatric illness, including PTSD, in women with NOUR increased the odds of first stage SNM success 3.92 times. A previous transurethral resection of the prostate and/or bladder neck incision in men increased the odds of success 7.71 times. In addition, a ten-year age increase was associated with an OR of 0.43 in men and 0.74 in women, indicating a 2.3- and 1.3-times decreased odds of success, respectively.

[A chancre instead of cancer]. / Geen kanker, maar een sjanker.

BACKGROUND: Syphilis (lues) is a sexually transmitted infection caused by the spirochete Treponema pallidum. In adolescents, the diagnosis of primary syphilis can be made promptly by taking a sexual medical history and inspecting the glans penis. CASE DESCRIPTION: A 17-year-old male was referred to the paediatric oncology centre for additional diagnostics due to inguinal lymphadenopathy, with a strong suspicion of a malignant lymphoma. None of the physicians took a sexual medical history or investigated the glans penis, as a result of which essential information was lacking. The combination of inguinal lymphadenopathy and the ultrasound findings for the inguinal region made the physicians only consider a malignancy. However, it actually concerned a reactive lymphadenopathy associated with primary syphilis. CONCLUSION: This case demonstrates that a full medical history and thorough physical examination can prevent the need for costly and invasive diagnostics.

Phase 2 Study of Lutetium 177-Labeled Anti-Carbonic Anhydrase IX Monoclonal Antibody Girentuximab in Patients with Advanced Renal Cell Carcinoma.

UNLABELLED: Despite advances in the treatment of metastatic clear cell renal cell carcinoma (ccRCC), there is still an unmet need in the treatment of this disease. A phase 2 radioimmunotherapy (RIT) trial with lutetium 177 ((177)Lu)-girentuximab was initiated to evaluate the efficacy of this approach. In this nonrandomized single-arm trial, patients with progressive metastatic ccRCC who met the inclusion criteria received 2405 MBq/m(2) of (177)Lu-girentuximab intravenously. In the absence of persistent toxicity and progressive disease, patients were eligible for retreatment after 3 mo with 75% of the previous activity dose. A total of 14 patients were included. After the first therapeutic infusion, eight patients (57%) had stable disease (SD) and one (7%) had a partial regression. The treatment was generally well tolerated but resulted in grade 3-4 myelotoxicity in most patients. After the second cycle, continued SD was observed in five of six patients, but none were eligible for retreatment due to prolonged thrombocytopenia. In conclusion, RIT with (177)Lu-girentuximab resulted in disease stabilization in 9 of 14 patients with progressive metastatic ccRCC, but myelotoxicity prevented retreatment in some patients. PATIENT SUMMARY: We investigated the efficacy of lutetium 177-girentuximab radioimmunotherapy in patients with metastatic kidney cancer. The treatment resulted in disease stabilization in 9 of 14 patients. The main toxicity was prolonged low blood cell counts. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02002312 (https://clinicaltrials.gov/ct2/show/NCT02002312).

Optical Imaging of Renal Cell Carcinoma with Anti-Carbonic Anhydrase IX Monoclonal Antibody Girentuximab.

UNLABELLED: Near-infrared dye-tagged antibodies can be used for the sensitive detection of tumor tissue in vivo. Surgery for clear-cell renal cell carcinoma (ccRCC) might benefit from the use of optical imaging to facilitate the intraoperative detection of carbonic anhydrase IX (CAIX)-expressing tumor lesions with chimeric monoclonal antibody (mAb) girentuximab, which has been shown to have excellent imaging capabilities for ccRCC. Here we studied the potential of fluorescence imaging to detect ccRCC tumors in nude mice with RCC xenografts by using mAb girentuximab conjugated with IRDye800CW; SPECT imaging was used as a reference. METHODS: Groups of athymic BALB/c mice with subcutaneous CAIX-positive SK-RC-52 ccRCC tumors were injected intravenously with (125)I-labeled girentuximab-IRDye800CW or (125)I-labeled girentuximab. For determination of the specificity of the accumulation of the anti-CAIX antibody conjugate in ccRCC, separate groups of mice bearing a CAIX-positive tumor (SK-RC-52) and a CAIX-negative tumor (SK-RC-59) received (125)I-girentuximab-IRDye800CW or (125)I-labeled MOPC21-IRDye800CW (control mAb). Optical images and micro-SPECT images were acquired until 3 d after injection. Mice were euthanized after the last imaging session, and the biodistribution of the radiolabeled antibody preparations was determined. RESULTS: Optical imaging and micro-SPECT imaging at 1 d after the injection of (125)I-girentuximab-IRDye800CW showed clear delineation of the CAIX-expressing ccRCC xenografts, and image contrast improved with time. Fluorescence imaging and biodistribution studies showed high and specific uptake of (125)I-girentuximab-IRDye800CW in CAIX-positive ccRCC xenografts (SK-RC-52, 31.5 ± 9.6 percentage injected dose per gram [%ID/g] at 72 h after injection). Tumor uptake was specific, as very low uptake of (125)I-girentuximab-IRDye800CW was noted in the CAIX-negative SK-RC-59 tumor (4.1 ± 1.5 %ID/g), and no uptake of (125)I-MOPC21-IRDye800CW (control mAb) was noted in the CAIX-positive SK-RC-52 tumor (1.2 ± 0.1 %ID/g). CONCLUSION: Subcutaneous CAIX-expressing ccRCC xenografts were visualized by optical imaging with (125)I-girentuximab-IRDye800CW. Optical images showed good concordance with micro-SPECT images. The accumulation of (125)I-girentuximab-IRDye800CW in ccRCC tumors was high and specific. Girentuximab-IRDye800CW potentially could be used for the intraoperative detection of CAIX-expressing tumors and the assessment of residual tumor in resection margins or metastatic lesions in patients with ccRCC.

Tyrosine kinase inhibitor sorafenib decreases 111In-girentuximab uptake in patients with clear cell renal cell carcinoma.

UNLABELLED: Tyrosine kinase inhibitors (TKIs) have revolutionized the treatment of metastatic clear cell renal cell carcinoma (RCC). Although TKIs have demonstrated good clinical efficacy, the lack of complete responses, the chronic nature of the treatment, and the side effects are clear disadvantages. An interesting new approach in the treatment of clear cell RCC is antibody-mediated therapy with the chimeric anti-carbonic anhydrase IX (CAIX) antibody girentuximab (cG250). As the results of several girentuximab trials become available, the question arises of whether TKI treatment can be combined with girentuximab-based therapy. In this study, we assessed the effect of the widely used TKI sorafenib on the tumor-targeting potential of (111)In-labeled girentuximab. METHODS: (111)In-girentuximab imaging was performed on 15 patients suspected of having a renal malignancy, with surgery being part of their treatment plan. Of these, 10 patients were treated in a neoadjuvant setting with sorafenib (400 mg orally twice daily). Five patients received treatment during 1 wk, and 5 patients received treatment during 4 wk. In both sorafenib-treated groups, baseline and posttreatment tumor targeting of (111)In-girentuximab were compared. Surgery was performed 3 d after the last image acquisition. Five additional patients were included as a control group and had only a single (111)In-girentuximab injection and scintigraphy without any treatment. Distribution of (111)In-girentuximab was determined scintigraphically ex vivo in a 1-cm lamella of the resected tumorous kidney. Expression of CAIX and of the vascular marker CD31 was determined immunohistochemically on specimens of both tumor and normal kidney tissue. RESULTS: Treatment with sorafenib resulted in a marked decrease of (111)In-girentuximab uptake in the tumor in clear cell RCC patients, especially in the group treated for 4 wk (mean change in both sorafenib-treated groups, -38.4%; range, +9.1% to -79.4%). Immunohistochemical analysis showed markedly reduced CD31 expression and vessel density in the sorafenib-treated groups but no differences in CAIX expression between the sorafenib-treated groups and the nontreated patients. CONCLUSION: Treatment with sorafenib resulted in a treatment duration-dependent significantly decreased uptake of (111)In-girentumab in clear cell RCC lesions. These results indicate that the efficacy of antibody-mediated treatment or diagnosis modalities is hampered by TKI treatment.

ImmunoPET imaging of renal cell carcinoma with (124)I- and (89)Zr-labeled anti-CAIX monoclonal antibody cG250 in mice.

INTRODUCTION: Monoclonal antibody (mAb) cG250 recognizes carbonic anhydrase IX (CAIX), overexpressed on clear cell renal cell carcinoma (ccRCC). (124)I-cG250 is currently under clinical investigation for the detection of ccRCC. However, the (124)I label is rapidly excreted from the tumor cells after internalization of the radiolabeled mAb. We hypothesized that labeling cG250 with the residualizing positron emitter (89)Zr would lead to higher tumor uptake and more sensitive detection of ccRCC lesions. MATERIALS AND METHODS: Nude mice with CAIX-expressing ccRCC xenografts (SK-RC-52 or NU-12) were i.v. injected with (89)Zr-cG250 or (124)I-cG250. To determine specificity of (89)Zr-cG250 uptake in ccRCC, one control group was i.v. injected with (89)Zr-MOPC21 (irrelevant mAb). PET images were acquired using a small animal PET camera and the biodistribution of the radiolabeled mAb was determined. RESULTS: The ccRCC xenografts were clearly visualized after injection of (89)Zr-cG250 and (124)I-cG250. Tumor uptake of (89)Zr-cG250 was significantly higher compared with (124)I-cG250 in the NU-12 tumor model (114.7% ± 25.2% injected dose per gram (%ID/g) vs. 38.2 ± 18.3%ID/g, p=0.029), but in the SK-RC-52 the difference in tumor uptake was not significant (48.7 ± 15.2%ID/g vs. 32.0 ± 22.9%ID/g, p=0.26). SK-RC-52 tumors were not visualized with (89)Zr-MOPC21 (tumor uptake 3.0%ID/g). Intraperitoneal SK-RC-52 lesions as small as 7 mm(3) were visualized with (89)Zr-cG250 PET. CONCLUSION: ImmunoPET imaging with cG250 visualized s.c. and i.p. ccRCC lesions in murine models. This confirms the potential of cG250 immunoPET in the diagnosis and (re)staging of ccRCC. PET imaging of ccRCC tumors with (89)Zr-cG250 could be more sensitive than (124)I-cG250-PET.

Phase 1 radioimmunotherapy study with lutetium 177-labeled anti-carbonic anhydrase IX monoclonal antibody girentuximab in patients with advanced renal cell carcinoma.

BACKGROUND: Patients with metastatic clear cell renal cell carcinoma (ccRCC) have a dismal prognosis. Therefore, new and less toxic treatments are needed. OBJECTIVE: We determined the maximum tolerated dose (MTD) and potential therapeutic efficacy of multiple infusions of lutetium 177 ((177)Lu)-girentuximab (cG250) on various dose levels in a phase 1 trial in patients with progressive metastasized ccRCC. DESIGN, SETTING, AND PARTICIPANTS: In this uncontrolled case series in 23 patients with progressive ccRCC metastases, cG250 accumulation was verified by diagnostic indium 111-cG250 imaging. Patients then received a high-activity dose of (177)Lu-cG250. INTERVENTION: Groups of three patients received (177)Lu-cG250, starting at a dose level of 1110 MBq/m(2)(177)Lu-cG250, with dose increments of 370 MBq/m(2) per group. In the absence of persistent toxicity, progressive disease, and accelerated blood clearance, patients were eligible for retreatment after 3 mo with 75% of the previous activity dose. Patients could receive a total of three treatment cycles. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Determination of the MTD was the primary and therapeutic efficacy was the secondary outcome measurement of the study. RESULTS AND LIMITATIONS: The MTD was 2405 MBq/m(2) because higher doses resulted in dose-limiting myelotoxicity. Some patients received second (13 of 23 [56%]) and third (4 of 23 [17%]) treatment cycles. Most patients (17 of 23 [74%]) demonstrated stable disease 3 mo after the first treatment, and one patient showed a partial response that lasted for 9 mo. Mean growth of target tumor lesions was reduced from 40.4% (95% confidence interval [CI], ± 17.0) during the last 3 mo before study entry to 5.5% (95% CI, ± 5.3; p<0.001) at 3 mo after the first treatment cycle. No major nonhematologic side effects were observed. CONCLUSIONS: (177)Lu-cG250 radioimmunotherapy in metastatic ccRCC patients is well tolerated at an activity dose level as high as 2405 MBq/m(2) (MTD). Radioimmunotherapy with (177)Lu-cG250 may stabilize previously progressive metastatic ccRCC.

Dosimetric analysis of 177Lu-cG250 radioimmunotherapy in renal cell carcinoma patients: correlation with myelotoxicity and pretherapeutic absorbed dose predictions based on 111In-cG250 imaging.

UNLABELLED: This study aimed to estimate the radiation absorbed doses to normal tissues and tumor lesions during radioimmunotherapy with (177)Lu-cG250. Serial planar scintigrams after injection of (111)In-cG250 or (177)Lu-cG250 in patients with metastasized renal cell carcinoma were analyzed quantitatively. The estimated radiation doses were correlated with observed hematologic toxicity. In addition, the accuracy of the predicted therapeutic absorbed doses, based on diagnostic (111)In-cG250 data, were determined. METHODS: Twenty patients received a diagnostic tracer activity of (111)In-cG250 (185 MBq), followed by radioimmunotherapy with (177)Lu-cG250. The administered activity of (177)Lu-cG250 was escalated by entering 3 patients at each activity level starting at 1,110 MBq/m(2), with increments of 370 MBq/m(2). After each diagnostic and therapeutic administration, whole-body scintigraphic images and pharmacokinetic data were acquired. Hematologic toxicity was graded using the Common Toxicity Criteria, version 3.0. Diagnostic (111)In-cG250 data were used to simulate (177)Lu and (90)Y data by correcting for the difference in physical decay. Absorbed doses were calculated for the whole body, red marrow, organs, and tumor metastases for the therapeutic (177)Lu-cG250, simulated (177)Lu-cG250, and simulated (90)Y-cG250 data. RESULTS: Observed hematologic toxicity, especially platelet toxicity, correlated significantly with the administered activity (r = 0.85), whole-body absorbed dose (r = 0.65), and red marrow dose (r = 0.62 and 0.75). An inverse relationship between the mass and absorbed dose of the tumor lesions was observed. Calculated mean absorbed doses were similar for the simulated and measured (177)Lu-cG250 data. Absorbed doses (whole body and red marrow) based on the simulated (177)Lu-cG250 data correlated with the observed platelet toxicity (r = 0.65 and 0.82). The tumor-to-red marrow dose ratio was higher for radioimmunotherapy with (177)Lu-cG250 than for radioimmunotherapy with (90)Y-cG250, indicating that (177)Lu has a wider therapeutic window for radioimmunotherapy with cG250 than (90)Y. CONCLUSION: In patients with metastasized renal cell carcinoma, hematologic toxicity after treatment with (177)Lu-cG250 can be predicted on the basis of administered activity and whole-body and red marrow-absorbed dose. Diagnostic (111)In-cG250 data can be used to accurately predict absorbed doses and myelotoxicity of radioimmunotherapy with (177)Lu-cG250. These estimations indicate that in these patients, higher radiation doses can be guided to the tumors with (177)Lu-cG250 than with (90)Y-cG250.

111In-bevacizumab imaging of renal cell cancer and evaluation of neoadjuvant treatment with the vascular endothelial growth factor receptor inhibitor sorafenib.

UNLABELLED: Clear cell renal cell cancer (ccRCC) prominently expresses vascular endothelial growth factor-A (VEGF-A), and new treatment strategies for renal cell cancer (RCC) aim at the inhibition of VEGF-VEGF receptor signaling. This study explores the ability of (111)In-bevacizumab scintigraphy to depict RCC and to evaluate response to neoadjuvant treatment with sorafenib, a VEGF receptor inhibitor. METHODS: The ability to depict RCC with (111)In-bevacizumab scintigraphy was tested in 14 patients scheduled to undergo a tumor nephrectomy; of these, 9 RCC patients were treated in a neoadjuvant setting with sorafenib (400 mg orally twice a day). In the latter group, baseline and posttreatment (111)In-bevacizumab scans were compared. The intratumoral distribution of (111)In-bevacizumab was determined scintigraphically ex vivo in a 1-cm lamella of the resected tumorous kidney. Expression of VEGF-A, glucose transporter-1, carbonic anhydrase IX, α-smooth-muscle actin, and Ki67 was determined by immunohistochemistry and compared with the local concentration of (111)In-bevacizumab. Additionally, the VEGF-A content in tumor samples was determined quantitatively by enzyme-linked immunosorbent assay. RESULTS: In all 5 non-neoadjuvant-treated patients, preferential accumulation of (111)In-bevacizumab was observed in the tumors. All ccRCC lesions with enhanced (111)In-bevacizumab targeting expressed high levels of VEGF-A. Treatment with sorafenib resulted in a significant decrease of (111)In-bevacizumab uptake in the tumor in the patients with ccRCC (mean change, -60.5%; range, +1.5% to -90.1%). The decrease in uptake was due to destruction of the tumor neovasculature, whereas the VEGF-A expression remained intact. In the patient with papillary RCC, limited uptake without change after sorafenib was observed. CONCLUSION: RCC lesions were clearly delineated with (111)In-bevacizumab scintigraphy. Neoadjuvant treatment with sorafenib resulted in a significant decrease of (111)In-bevacizumab uptake in RCC. (111)In-bevacizumab scintigraphy can be an attractive biomarker for response and needs further study.

Carbonic anhydrase IX in renal cell carcinoma: implications for prognosis, diagnosis, and therapy.

CONTEXT: The clinical management of patients with renal cell carcinoma (RCC) remains difficult, and the development of new diagnostic, prognostic, and therapeutic tools is still required. OBJECTIVE: To review the current knowledge on the RCC-associated antigen carbonic anhydrase IX (CAIX) and provide evidence for how this antigen may aid in the clinical management of RCC. EVIDENCE ACQUISITION: Clinical papers describing diagnostic, prognostic, and/or therapeutic applications of CAIX in RCC were selected from the Pubmed database. The search was manually augmented by reviewing the reference lists of articles. EVIDENCE SYNTHESIS: Expression of CAIX is regulated by the Von Hippel Lindau (VHL) protein (pVHL). Because of the invariable VHL mutational loss in clear-cell RCC (ccRCC) patients, CAIX expression is ubiquitous in ccRCC. Determination of CAIX expression in nephrectomy specimens of RCC patients improves prognostic accuracy; high CAIX expression appears to correlate with a favourable prognosis and a greater likelihood of response to systemic treatment for metastatic disease. Therefore, CAIX expression might be used to stratify metastatic ccRCC (mRCC) patients for systemic treatment. When incorporated into the RCC nomogram, CAIX expression seems to improve diagnostic accuracy for primary RCC as well as mRCC patients, but further evidence is required. Clinical studies with the CAIX-specific monoclonal antibody (mAb) cG250 have provided unequivocal evidence that ccRCC lesions can be imaged with radiolabeled cG250. Results are awaited of a large, randomised trial that aims to establish the value of cG250 imaging for primary RCC. The outcome of another large, placebo-controlled study is awaited to establish the usefulness of CAIX-targeted therapy in the adjuvant setting. Therapeutic trials with high-dose radiolabeled cG250 and CAIX-loaded dendritic cells in mRCC patients are still in phase 1 or 2. CONCLUSIONS: CAIX improves diagnostic accuracy and is an attractive target for imaging of and therapy for ccRCC.

The prostate cancer gene 3 (PCA3) urine test in men with previous negative biopsies: does free-to-total prostate-specific antigen ratio influence the performance of the PCA3 score in predicting positive biopsies?

OBJECTIVE: to determine the performance characteristics of the prostate cancer gene 3 (PCA3) score on the outcome of biopsy relative to different ranges of free-to-total prostate-specific antigen (PSA) ratio (f/tPSA) in men with a previous negative biopsy and a PSA level of 2.5-10 ng/mL, as urine tests like PCA3 are currently under investigation in order to improve prostate cancer diagnosis and to decrease the rate of unnecessary rebiopsies. PATIENTS AND METHODS: data from the previous prospective European multicentre study were reviewed. Only patients with a PSA level of 2.5-10 ng/mL were included in the present study. In all, 301 patients had complete data. The diagnostic accuracy of the PCA3 score for predicting a positive biopsy outcome was studied using sensitivity, specificity, negative and positive predictive values. The PCA3 performance was evaluated relative to three different subgroups of f/tPSA, as follows: >20% (group 1), 10-20% (group 2) and <10% (group 3). RESULTS: the prostate cancer detection rates were 18.8%, 23.9% and 34.8% in groups 1, 2 and 3, respectively. The area under the receiver operating characteristic curve of the PCA3 score, total PSA and f/tPSA was 0.688, 0.553 and 0.571, respectively. The percentage of men with positive biopsies was 30.6%, 37.0% and 44.4% in those with a PCA3 score of >30, vs 10.3%, 15.5% and 28.6% when the PCA3 score was <30, in groups 1, 2 and 3, respectively. The difference was significant only in groups 1 and 2. In men with a f/tPSA of ≤ 10% the difference in detection rates relative to the PCA3 score was not statistically significant regardless of which PCA3 threshold was used. A high PCA3 score was significantly associated with age, clinical T2 stage and positive biopsy (P < 0.001, 0.013 and <0.001, respectively). In bivariate analysis accounting for the PCA3 score and the f/tPSA, a PCA3 score of >30 was a significant independent predictor of positive biopsies (odds ratio 3.01; 95% confidence interval 1.74-5.23; P < 0.001). CONCLUSIONS: PCA3 remained a better predictor of prostate cancer than f/tPSA. In men with a f/tPSA of >10%, the use of the PCA3 score was highly correlated with the risk of having cancer on re-biopsy, and could prevent unnecessary prostate biopsies if the value is low.

Prostate cancer gene 3 (PCA3): development and internal validation of a novel biopsy nomogram.

BACKGROUND: Urinary prostate cancer gene 3 (PCA3) represents a promising novel marker of prostate cancer detection. OBJECTIVE: To test whether urinary PCA3 assay improves prostate cancer (PCa) risk assessment and to construct a decision-making aid in a multi-institutional cohort with pre-prostate biopsy data. DESIGN, SETTING, AND PARTICIPANTS: PCA3 assay cut-off threshold analyses were followed by logistic regression models which used established predictors to assess PCa-risk at biopsy in a large multi-institutional data set of 809 men at risk of harboring PCa. MEASUREMENTS: Regression coefficients were used to construct four sets of nomograms. Predictive accuracy (PA) estimates of biopsy outcome predictions were quantified using the area under the curve of the receiver operator characteristic analysis in models with and without PCA3. Bootstrap resamples were used for internal validation and to reduce overfit bias. The extent of overestimation or underestimation of the observed PCa rate at biopsy was explored graphically using nonparametric loss-calibration plots. Differences in PA were tested using the Mantel-Haenszel test. Finally, nomogram-derived probability cut-offs were tested to assess the ability to identify patients with or without PCa. RESULTS AND LIMITATIONS: PCA3 was identified as a statistically independent risk factor of PCa at biopsy. Addition of a PCA3 assay improved bootstrap-corrected multivariate PA of the base model between 2% and 5%. The highest increment in PA resulted from a PCA3 assay cut-off threshold of 17, where a 5% gain in PA (from 0.68 to 0.73, p=0.04) was recorded. Nomogram probability-derived risk cut-off analyses further corroborate the superiority of the PCA3 nomogram over the base model. CONCLUSIONS: PCA3 fulfills the criteria for a novel marker capable of increasing PA of multivariate biopsy models. This novel PCA3-based nomogram better identifies men at risk of harboring PCa and assists in deciding whether further evaluation is necessary.

Clinical utility of the PCA3 urine assay in European men scheduled for repeat biopsy.

BACKGROUND: The Prostate CAncer gene 3 (PCA3) assay has shown promise as an aid in prostate cancer (pCA) diagnosis in identifying men with a high probability of a positive (repeat) biopsy. OBJECTIVE: This study evaluated the clinical utility of the PROGENSA PCA3 assay. DESIGN, SETTING, AND PARTICIPANTS: This European prospective, multicentre study enrolled men with one or two negative biopsies scheduled for repeat biopsy. MEASUREMENTS: After digital rectal examination (DRE), first-catch urine was collected to measure PCA3 mRNA concentration and to calculate the PCA3 score. The PCA3 score was compared to biopsy outcome. The diagnostic accuracy of the PCA3 assay was compared to percent of free prostate-specific antigen (%fPSA). RESULTS AND LIMITATIONS: In 463 men, the positive repeat biopsy rate was 28%. The higher the PCA3 score, the greater the probability of a positive repeat biopsy. The PCA3 score (cut-off of 35) had a greater diagnostic accuracy than %fPSA (cut-off of 25%). The PCA3 score was independent of the number of previous biopsies, age, prostate volume, and total prostate-specific antigen (PSA) level. Moreover, the PCA3 score was significantly higher in men with high-grade prostate intraepithelial neoplasia (HGPIN) versus those without HGPIN, clinical stage T2 versus T1, Gleason score >or=7 versus <7, and "significant" versus "indolent" (clinical stage T1c, PSA density [PSAD] <0.15ng/ml, Gleason score in biopsy

Radiolabeled antibodies in renal cell carcinoma.

Renal cell carcinoma (RCC) is a radio- and chemotherapy resistant tumor, which has a very high morbidity and mortality when metastasized. The current treatment options demonstrate limited efficacy and severe side-effects. Therefore, there is a need for new therapeutic strategies for RCC. As for other malignancies, monoclonal antibodies (mAbs) targeting tumor-associated antigens have been developed for RCC. One of these, mAb G250, targets the MN/CAIX/G250 antigen, which is ubiquitously expressed in clear cell RCC (ccRCC). ccRCC is the most common form of RCC with a prevalence of 80%. Expression of G250 in normal tissue is restricted to the gastrointestinal mucosa and related structures, thereby making it a suitable candidate for targeting ccRCC. In several clinical studies the efficient accumulation of mAb G250 in ccRCC has been demonstrated, resulting in high contrast images. G250-imaging could prove to be a valuable tool in diagnosing metastases in patients with a G250-antigen positive primary tumor and/or in the differential diagnosis of suspect kidney lesions. Furthermore, the therapeutic efficacy of radiolabeled G250 has been investigated in a series of studies. Thus far, most efforts have been devoted to G250 labeled with high doses of 131I. Other radionuclides which may enhance the therapeutic index of this radiolabeled mAb are currently under investigation. In our institution, an activity dose escalation study is currently ongoing to investigate the therapeutic potential of 177Lu-labeled G250 in metastatic ccRCC patients. In this review, the current status of the diagnostic and therapeutic properties of radiolabeled antibodies in RCC is described.