Rubin H. Flocks and colloidal gold treatments for prostate cancer.

In the early 1950s, Rubin H. Flocks of the University of Iowa began to treat prostate cancer patients with colloidal gold (Au(198)) therapy, evolving his technique over nearly 25 years in 1515 patients. We reviewed the long-term outcomes of Flocks' prostate cancer patients as compared to those patients treated by other methods at the University of Iowa before Flocks' chairmanship. We reviewed archived patient records, Flocks' published data, and long-term survival data from the Iowa Tumor Registry to determine short- and long-term outcomes of Flocks' work with colloidal gold. We also reviewed the literature of Flocks' time to compare his outcomes against those of his contemporaries. The use of colloidal gold, either as primary or adjunctive therapy, provided short- and long-term survival benefit for the majority of Flocks' patients as compared to historical treatment options (p < 0.001). Flocks' use of colloidal gold for the treatment of locally advanced prostate cancer offered short- and long-term survival benefits compared to other contemporary treatments.

TP53 gene mutations in prostate cancer progression.

BACKGROUND: We assessed the predictive value of TP53 mutations and prostate-specific antigen (PSA) for tumor progression in prostate cancer (PCa) patients. MATERIALS AND METHODS: Ninety tumor tissue samples of patients with PCa from radical prostatectomy were used. Tumor progression was estimated biochemically by the PSA level (> 0.2 microg/l) or by detection of metastases. Screening for TP53 mutations was performed by temperature gradient gel electrophoresis (TGGE) in exon-specific manner. Follow-up data were collected from medical protocols. Statistical analysis was performed by uni- and multivariate techniques. RESULTS: In 32 out of 90 patients (35.6%), TP53 mutations were detected. Thirteen out of 32 patients (40.6%) with TP53 mutations and nine out of 58 patients (15.5%) with TP53 wild-type showed tumor progression after 25 and 45 months, respectively. CONCLUSION: TP53 mutations in exon 7 and exon 8 are factors of tumor progression in PCa. Their contribution to tumor recurrence is more significant than tumor stage and pretherapeutic PSA level.

The role of surgery in clinical management of patients with metastatic papillary renal cell carcinoma.

OBJECTIVES: Patients with metastatic papillary renal cell carcinoma (RCC) show special clinical behavior compared to patients with other histologic subtypes of RCC. This study aimed to assess the relevance of surgical and systemic options used in treatment of these patients prior to the recent era of targeted therapies. METHODS: Retrospectively, we assessed clinical data of 61 patients with metastatic papillary RCC who were treated at eight centers in Germany. RESULTS: Median follow-up was 20 (range 1-114) months and median age at time of diagnosis was 62 (range 24-85) years. Men were affected predominantly (50/61; 82%). Twenty-one patients (34%) showed metastases at time of diagnosis. In the remaining 40 patients, median time to development of metastases was 30.4 (range 3-143; mean 16.5) months. Sites of metastases were lung (37; 61%), bone (24; 38%), liver (20; 33%), lymph nodes (24; 38%), and local recurrence (17; 28%). Others sites of disease were brain metastases (6 patients/10%), peritoneal carcinosis (5 patients/8%), and others. A surgical approach with potentially curative intention was performed primarily in 11 patients (18%). 31 patients received an immuno- (interferon-alpha +/- interleukin-2) or immunochemotherapy as first line treatment for metastatic disease. Overall, 42/61 patients (69%) received systemic therapy. Supportive care only was performed in 12 patients (20%) because of poor performance status. Median overall survival after diagnosis of metastatic disease was longer than 48 months in patients with tumor resection (n = 11) compared to 13.0 +/- 4.3 months 95% CI 4.5-21.5 (n = 42) months in patients without surgical approach. CONCLUSIONS: Complete resection of metastases represents a valid option in management of patients with relapsing or metastatic papillary RCC.

Acute partial segmental thrombosis of the corpus cavernosum: imaging findings on ultrasound, computed tomography, and magnetic resonance imaging.

Partial segmental thrombosis of the corpus cavernosum is a rare disease of unknown etiology; the thrombosis is always located in the proximal part of the corpus cavernosum, usually unilaterally. Typical clinical presentation with perineal pain and swelling in combination with cross-sectional imaging allows one to confidentially establish this diagnosis.

CD146 protein in prostate cancer: revisited with two different antibodies.

AIMS: CD146 is a potentially metastasis promoting cell adhesion molecule and its expression has been described in various solid tumours. We aimed to evaluate the expression of CD146 in prostate cancer by immunohistochemistry in a clinically characterised study cohort to evaluate its prognostic properties. METHODS: We evaluated the CD146 protein expression using a polyclonal and a monoclonal antibody on 169 clinico-pathologically characterised cases. Statistical analyses were applied to test for correlations and diagnostic and prognostic associations. RESULTS: CD146 detection with the polyclonal antibody revealed marked differential expression between tumour and normal tissue and was also a significant marker for shortened PSA relapse free survival. The monoclonal CD146 antibody demonstrated a weaker epithelial signal, which was significantly correlated with that of the polyclonal antibody, but revealed no prognostic value. However, the Western blot of the polyclonal antibody displayed a clearly reduced specificity. CONCLUSIONS: Evaluation of protein expression can be highly dependent on the primary antibody employed. A credible evaluation of antibody specificity is crucial to prove the validity of protein expression studies. The immunoreactivity of the polyclonal CD146 antibody (Abcam, ab28360) is prognostic of PSA-relapse in prostate cancer patients, although its immunoreactivity is possibly not restricted to CD146 associated epitopes.

High expression of KLK14 in prostatic adenocarcinoma is associated with elevated risk of prostate-specific antigen relapse.

OBJECTIVE: Reliable prognostic tools for prostate cancer are still needed and KLK14, a young member of the growing family of human kallikrein-related peptidases, has been estimated to become a new significant marker. It is the aim of this study to analyze the clinical value of immunohistochemical expression of KLK14 in prostate cancer tissue samples. METHODS: Protein expression of KLK14 was assessed immunohistochemically in 186 tissue samples from radical prostatectomies. Areas of normal prostatic tissue, of prostatic epithelial neoplasia and of prostatic adenocarcinoma were checked in relation to clinicopathological parameters of the patients. Expression of KLK14 mRNA was quantified in 25 matches of normal and cancerous prostatic tissue, collected by laser capture microdissection. Real-time reverse transcriptase polymerase chain reaction analysis was used to supplement the immunohistochemical data. RESULTS: Expression of the KLK14 protein correlated with the pathological tumor status in prostate cancer and was associated with disease progression defined by prostate-specific antigen relapse in univariate Kaplan-Meier analysis. The multivariate Cox proportional hazards regression model proved KLK14 to be an independent prognostic factor in prostate cancer. CONCLUSION: In conclusion, we consider KLK14 to be a suitable prognostic marker for the detection of cases at risk of disease progression after radical prostatectomy.

Serum amyloid A as indicator of distant metastases but not as early tumor marker in patients with renal cell carcinoma.

The aim of the present study was to evaluate the clinical significance of the concentration of serum amyloid A (SAA) in patients with renal cell carcinoma (RCC). SAA protein was determined with enzyme-linked immunosorbent assay in serum samples of 55 healthy controls and 98 RCC patients subdivided into groups with localized tumor (N0M0, n=40), with lymph node metastases (N1M0, n=13), and distant metastases (M1, n=45). SAA concentrations in controls and N0M0 group of RCC were not different while SAA concentrations were significantly elevated in M1 patients compared to the N1M0 and N0M0 patients. In this respect, SAA provided an accurate detection of distant metastases with the area under the ROC curve of 0.86. SAA was identified as a significant independent factor of survival in RCC patients using the multivariate Cox proportional hazards regression model. SAA could be a useful analyte in predicting the survival outcome of RCC patients.

TP53 gene mutations as an independent marker for urinary bladder cancer progression.

This study evaluates the influence of the TP53 genetic status on tumour recurrence and progression with a highly effective electrophoretic technique. DNA from tissue of 75 non-invasive urinary bladder cancers was PCR amplified in the TP53 exons 5-8 and run on horizontal polyacrylamide gels under defined temperature conditions to yield specific gel shifts. Kaplan-Meier and Cox-Regression analysis were performed with tumour progression. The overall tumour recurrence in our patient population was 76.0% (57/75). Tumour recurrence frequency was 69.4% (34/49) in patients with TP53 wild-type, and 88.5% (23/26) in patients with TP53 mutation. There was no statistically significant difference with regard to recurrence frequency and time to recurrence. The progression-free survival was significantly shorter in patients with TP53 mutations, and the frequency of tumour progression was significantly higher in mutated as compared to wild-type tumours. Cox-Regression analysis showed a significant and independent influence of TP53 mutation on tumour progression in comparison with tumour grade, stage and history of prior bladder cancer. If segregated by exons, mutations in the DNA binding region of exon 8 seem to have a particular high influence on tumour progression. We conclude that genetic analysis of TP53 can select patients at high risk of bladder tumour progression that should be followed closely and may benefit from early radical surgical procedures.

Body mass index (BMI) and mutations of tumor suppressor gene p53 (TP53) in patients with urinary bladder cancer.

OBJECTIVE: Obesity is estimated to account for up to 20% of all cancer deaths. Mutations of TP53 are frequently correlated with tumor development and progression. We evaluated the effect of body mass index (BMI) and mutation status of tumor suppressor gene p53 (TP53) on patients with urinary bladder cancer. MATERIALS AND METHODS: Clinical samples were used from 75 patients with tumors of the urinary bladder. Mutation status in TP53 exons 5, 6, 7, and 8 was analyzed by temperature gradient gel electrophoresis of exon-specific PCR products and by sequence analysis. Statistical analysis included Pearson's correlation. RESULTS: For noninvasive bladder cancer, the mutation frequency in TP53 was 44.6%, while for invasive bladder cancer the mutation frequency in TP53 was 84.2%. Normal weight, overweight, and patients with obesity had a TP53 mutation frequency of 68.4%, 44.8%, and 25%, respectively (P < 0.05). CONCLUSIONS: TP53 mutation frequently occurs in higher stages of bladder tumors. Body mass index is not associated with a higher TP53 mutation frequency in our study, but BMI should be included for collecting data of bladder cancer risk profile.

Attitude to nephrolithiasis in the potential living kidney donor: a survey of the German kidney transplant centers and review of the literature.

Living donor kidney transplantation (LD-KTX) is increasing worldwide. With the prevalence of urolithiasis ranging between 4% and 15%, the number of donors with current nephrolithiasis or a history of the disease will increase as well. A questionnaire was sent to all German centers with LD-KTX programs (urologists and general surgeons). Answers were compared for differences between urological and surgical kidney transplant centers. Response rate was 74%. Nephrolithiasis at the time of KTX is an exclusion criterion at 36% of the German centers (58% urological/19% surgical, chi(2) = 4.65, p = 0.03, Fishers exact p = 0.05), 96% of the centers accept kidney donors with a history of nephrolithiasis. The length of the stone-free episode is regarded as relevant by 42% of all centers (58% urological vs. 32% surgical centers, p = ns). Stone composition is a criterion for 54% of centers (66% vs. 44%, p = ns). More than half of the centers accept a history of cystine stones, almost all centers of struvite and urate stones. Donors with current nephrolithiasis were less commonly accepted by urologists than by general surgeons. For almost all centers history of nephrolithiasis does not preclude living kidney donation. Stone composition proved to be of little relevance for decision making.

Cross-over kidney transplantation with simultaneous laparoscopic living donor nephrectomy: initial experience.

With cross-over living donor kidney transplantation, immunologic incompatibilities within the original donor/recipient pair can be overcome. As minimal invasive techniques for organ recovery are increasingly applied, this should also be performed in a cross-over kidney transplantation. We present the first report of a successful simultaneous laparoscopic kidney recovery for cross-over kidney transplantation as well as a review of the international practice of cross-over kidney transplantation in the context of national laws. Cross-over kidney transplantation should be encouraged. A databank on pairs willing to participate in organ exchange programs should be created.

[Thermal therapy of prostate cancer using magnetic nanoparticles]. / Termoterapia en cáncer de próstata mediante el uso de nanopartículas magnéticas.

A novel method of interstitial heating using magnetic nanoparticles and a direct injection technique has been evaluated in human cancers in recent clinical trials. In prostate cancer, this approach was investigated in two separate phase-I-studies, employing magnetic nanoparticle thermotherapy alone and in combination with permanent seed brachytherapy. The feasibility and good tolerability was shown in both trials, using the first prototype of a magnetic field applicator. As with any other heating technique, this novel approach requires specific tools for planning, quality control and thermal monitoring, based on appropriate imaging and modelling techniques. In these first clinical trials, a newly developed method for planning and non-invasive calculations of the 3-dimensional temperature distribution based on computed tomography could be validated. Limiting factors of this approach at present are patient discomfort at high magnetic field strengths and suboptimal intratumoral distribution of nanoparticles. Until these limitations will be overcome and thermal ablation can safely be applied as a monotherapy, this treatment modality is being evaluated in combination with irradiation in patients with localized prostate cancer.

Serum (-5, -7) proPSA for distinguishing stage and grade of prostate cancer.

BACKGROUND: ProPSA has been suggested for the detection of preferentially aggressive prostate cancer (PCa). We report on the use of proPSA and free PSA to enhance preoperative staging and grading. PATIENTS AND METHODS: Serum samples from 376 PCa patients within the PSA range 1-25 microg/l who underwent radical prostatectomy were analysed for PSA, free PSA (fPSA) and (-5, -7) proPSA. RESULTS: ProPSA was only significantly different between pT2 and pT3 PCa (p = 0.02) in the subgroup of patients with % fPSA < 10%. The ratio proPSA/% fPSA differed between G2 and G3 (p = 0.004), Gleason < 7 and Gleason > or =7 (p = 0.001), and pT2 and pT3 tumors (p < 0.0001) at PSA 1-25 microg/l. However, % fPSA improved differentiation only between Gleason < 7 and Gleason > or = 7 tumors, not between pT2 and pT3 or G2 and G3 tumors. CONCLUSION: ProPSA as a single parameter did not improve the detection of non-organ confined or aggressive PCa whereas proPSA/% fPSA further improved staging and grading within all analysed PSA ranges.

S100A8, S100A9, and the S100A8/A9 complex in circulating blood are not associated with prostate cancer risk-A re-evaluation study.

BACKGROUND: To evaluate the diagnostic performance of plasma S100A8, S100A9, and the S100A8/A9 complex as novel markers to discriminate between benign and malignant prostatic diseases as recently suggested for S100A9. METHODS: The study included 90 prostate cancer (PCa) patients (pN0M0, n = 50; pN1M0, n = 27; M1, n = 13), 50 controls without PCa, and six patients within 72 hr after radical prostatectomy for repeated measurements. The S100 proteins were analyzed with specific ELISAs. Comparisons were made to the prostate-specific antigen (tPSA) and the ratio of free to tPSA (%fPSA). RESULTS: The plasma concentrations of the S100 proteins in controls had either significantly higher values (S100A8; P = 0.020) or the tendency to higher values compared with the results in PCa patients. Differences between the three PCa groups were almost negligible. No correlation could be found between S100 protein levels and PSA concentration (r(s) = -0.110 to 0.433, P = 0.317-0.433) or prostate volume (r(s) = -0.038 to 0.018, P = 0.676-0.844). Tumor stage and tumor grade had no observed effect on S100 protein concentrations. After prostatectomy, there were discordant elimination kinetics for PSA and the S100 proteins, as the S100 proteins partially increased while PSA continuously decreased. Analyses of receiver-operating curves showed that, compared with PSA, S100A8, S100A9, and S100A8/A9 did not improve the differentiation between patients with and without PCa, while the discrimination ability was significantly lower than that of %fPSA. CONCLUSIONS: Our re-evaluation study showed that S100A8, S100A9, and the complex S100A8/A9 were less indicative than %fPSA and that they are not suitable to replace PSA.

Termoterapia en cáncer de próstata mediante el uso de nanopartículas magnéticas / Therman therapy of prostate cancer using magnetic nanoparticles

En recientes ensayos clínicos, se ha evaluado en tumores malignos humanos, un nuevo método de dispensación de calor en pequeños espacios (intersticios) utilizando nanopartículas magnéticas y una técnica de inyección directa. En el cáncer de próstata, este procedimiento se ha investigado en dos estudios fase I separados empleando en uno solamente termoterapia de nanopartículas magnéticas y en otro en combinación con braquiterapia (implantes permanentes). En ambos estudios se demostró viabilidad y buena tolerancia, usando el primer prototipo de un aplicador de campo magnético. Como con cualquier otra técnica por calor, este nuevo procedimiento requiere herramientas específicas para su planificación, control de calidad y monitorización térmica, basado en una imagen apropiada y en técnicas de planificación. En estos primeros estudios, se evalúa un nuevo método que permite una planificación y distribución tridimensional no invasiva de la temperatura basado en la tomografía computerizada (TC). En la actualidad, los factores limitantes de este procedimiento son el malestar del paciente a altas intensidades de campos magnéticos y la distribución intratumoral subóptima de las nanopartículas. Hasta que estas limitaciones sean superadas y la termoablación pueda ser aplicada con seguridad como monoterapia, esta modalidad de tratamiento está siendo evaluada en combinación con la irradiación en pacientes con cáncer de próstata localizado

A novel method of interstitial heating using magnetic nanoparticles and a direct injection technique has been evaluated in human cancers in recent clinical trials. In prostate cancer, this approach was investigated in two separate phase-I-studies, employing magnetic nanoparticle thermotherapy alone and in combination with permanent seed brachytherapy. The feasibility and good tolerability was shown in both trials, using the first prototype of a magnetic field applicator. As with any other heating technique, this novel approach requires specific tools for planning, quality control and thermal monitoring, based on appropriate imaging and modelling techniques. In these first clinical trials, a newly developed method for planning and non-invasive calculations of the 3-dimensional temperature distribution based on computed tomography could be validated. Limiting factors of this approach at present are patient discomfort at high magnetic field strengths and suboptimal intratumoral distribution of nanoparticles. Until these limitations will be overcome and thermal ablation can safely be applied as a monotherapy, this treatment modality is being evaluated in combination with irradiation in patients with localized prostate cancer

Elevated plasma osteopontin as marker for distant metastases and poor survival in patients with renal cell carcinoma.

PURPOSE: To evaluate diagnostic and prognostic significance of plasma osteopontin (OPN) in patients with renal cell carcinoma (RCC). METHODS: The retrospective study included 80 patients with RCC (pN0M0, n = 32; pN1M0, n = 11; M1, and n = 37), and 52 healthy controls (27 females and 25 males). OPN, the bone marker bone-specific alkaline phosphatase (bALP) and carboxyterminal telopetide of type-I collagen (ICTP), and the enzymes alanine aminotransferase (ALAT), and gamma-glutamyltransferase (GGT) were evaluated together with Memorial Sloan-Kettering Cancer Center (MSKCC) laboratory parameters. Data were analyzed by receiver-operating characteristics (ROC), survival analysis, and Cox proportional hazards regression model. RESULTS: OPN and ICTP levels in RCC patients with distant metastases were significantly elevated (medians 115 and 4.7 microg/l, P < 0.001) compared to those without metastases (31.1 and 2.5 microg/l) and controls (28.9 and 2.1 microg/l) but did not differ between patients with bone or non-bone metastases. Both bALP and ALAT were not different between all study groups, while GGT was only increased in patients with non-bone metastases. In ROC analysis, OPN showed the best discrimination between patients with and without metastases (area under the curve: 0.888). High OPN values were associated with poor survival (Kaplan-Meier analysis, log-rank test, P = 0.002). Multivariate Cox regression with forward and backward stepwise elimination confirmed plasma OPN as independent predictive survival factor in RCC patients. CONCLUSIONS: Our results show that high plasma OPN levels are associated with distant metastases and poor survival in RCC patients. The use of OPN as potential marker to monitor new treatment strategies in patients with advanced RCC should be evaluated in prospective studies.

Different prostate-specific antigen assays give different results on the same blood sample: an obstacle to recommending uniform limits for prostate biopsies.

OBJECTIVE: To show the effect of different results for total prostate specific antigen (tPSA) and percentage free/total PSA (%fPSA) obtained with different assays for differentiating between benign and malignant prostate diseases. PATIENTS AND METHODS: Data were used for tPSA and fPSA levels from 596 patients with prostate cancer (314) or no evidence of cancer (282) within the PSA range 0.5-10 ng/mL, analysed with assays from Abbott (AxSYM), Beckman Coulter (Access), DPC (Immulite 2000), and Roche (Elecsys 2010), and with tPSA and complexed PSA (cPSA) assays from Bayer (ADVIA Centaur), as already reported. Receiver operating characteristics (ROC), specificities at assay-dependent and fixed thresholds, and the percentages of correct classification rates of patients were calculated. RESULTS: Whereas the areas under the ROC curves were no different among all tPSA assays, the assay-specific thresholds at 90% sensitivity were 2.5-3.1 ng/mL. When using fixed 2.5 or 4 ng/mL tPSA thresholds there was a wide sensitivity range, with significant differences among almost all assays, resulting in significantly different classification rates of patients. These differences were even larger when using fixed %fPSA thresholds. CONCLUSIONS: The current situation of differences among PSA values measured with different assays do not allow the recommendation of uniform PSA limits as biopsy criteria. For that purpose, better harmonization of PSA values between the different PSA test systems must be realized.

Serial markers of bone turnover in men with metastatic prostate cancer treated with zoledronic Acid for detection of bone metastases progression.

OBJECTIVES: This study assessed the usefulness of serial measurements of bone turnover markers in men with metastatic prostate cancer treated with zoledronic acid to detect disease progression. METHODS: Serum measurements of total alkaline phosphatase (tALP), bone-specific alkaline phosphatase (bALP), cross-linked N-terminal (NTx) and cross-linked C-terminal (CTx) telopeptides of type I collagen, amino-terminal procollagen propeptides of type I collagen (PINP), C-terminal telopeptides of type I collagen (ICTP), and prostate-specific antigen (PSA) were performed in 77 prostate cancer patients suffering from bone metastases and treated with zoledronic acid up to 15 mo. Fifty patients were with and 27 patients without objective evidence of metastatic bone progression during the administration of zoledronic acid. RESULTS: The baseline bone marker concentrations were not significantly different between the groups. After administration of zoledronic acid all bone markers except of ICTP decreased compared with baseline. CTx showed the greatest decrease. In patients with metastatic bone progression PINP, tALP, bALP, and ICTP were significantly higher at weeks 24, 36, 48, and 60 after starting treatment with zoledronic acid compared with patients without progression. In addition to the information of prostate-specific antigen as a monitoring parameter, the bone formation marker showed a better distinction between patients with and without disease progression. CONCLUSIONS: Selected bone turnover markers provide valuable information regarding progression of bone metastasis in men with metastatic prostate cancer under bisphosphonate therapy. The clinical impact should be confirmed in prospective randomised studies.

Electrophoretic subforms of free prostate-specific antigen in serum as promising diagnostic tool in prostate cancer diagnostics.

OBJECTIVES: To assess the diagnostic performance of the major electrophoretic subforms of free prostate-specific antigen (PSA), named F2 and F3, for differentiating between benign and malignant prostatic disease in men with total PSA (tPSA) concentrations up to 10 microg/L. METHODS: In sera from 50 patients with prostate cancer (PCa) and 44 men without evidence of malignancy (NPCa), F2 and F3 were quantified by two-dimensional electrophoresis and Western blotting. The F2/F3 ratios were compared with the conventional parameter tPSA and percentage fPSA/tPSA ratio (%fPSA) in univariate and multivariate analyses using receiver operating characteristic analysis. RESULTS: F2 was lower in the NPCa group (median 17%) than in the PCa group (55%), and F3 was greater in the NPCa group (62%) than in the PCa group (45%), resulting in a significantly lower F2/F3 ratio in the NPCa group than in the PCa group (0.32 versus 1.21). The F2/F3 ratio correlated with the %fPSA and prostate volume but not Gleason score, tumor stage, age, or tPSA. The F2/F3 ratio and F2-F3/%fPSA ratio had greater areas under the receiver operating characteristic curves than did tPSA or %fPSA, especially in the subgroup of %fPSA greater than 15%. Models of binary logistic regression confirmed the improvement of diagnostic accuracy using the F2/F3 ratio as an independent variable. CONCLUSIONS: Compared with tPSA and %fPSA, the fPSA subforms F2 and F3, assessed as F2/F3 or F2-F3/%fPSA ratios, enhanced the differentiation between men with and without PCa for tPSA levels up to 10 microg/L. Additional characterization of these forms should be performed to develop a feasible assay.