Clinical and pathological nodal staging score for urothelial carcinoma of the bladder: an external validation.

PURPOSE: Radical cystectomy (RC) and pelvic lymph node dissection (LND) are standard treatments for muscle-invasive urothelial carcinoma of the bladder. Lymph node staging is a prerequisite for clinical decision-making regarding adjuvant chemotherapy and follow-up regimens. Recently, the clinical and pathological nodal staging scores (cNSS and pNSS) were developed. Prior to RC, cNSS determines the minimum number of lymph nodes required to be dissected; pNSS quantifies the accuracy of negative nodal staging based on pT stage and dissected LNs. cNSS and pNSS have not been externally validated, and their relevance for prediction of cancer-specific mortality (CSM) has not been assessed. METHODS: In this retrospective study of 2,483 RC patients from eight German centers, we externally validated cNSS and pNSS and determined their prediction of CSM. All patients underwent RC and LND. Median follow-up was 44 months. cNSS and pNSS sensitivities were evaluated using the original beta-binominal models. Adjusted proportional hazards models were calculated for pN0 patients to assess the predictive value of cNSS and pNSS for CSM. RESULTS: cNSS and pNSS both pass external validation. Adjusted for other clinical parameters, cNSS can predict outcome after RC. pNSS has no independent impact on prediction of CSM. The retrospective design is the major limitation of the study. CONCLUSIONS: In the present external validation, we confirm the validity of both cNSS and pNSS. cNSS is an independent predictor of CSM, thus rendering it useful as a tool for planning the extent of LND.

DEPROMP Trial: the additive value of PSMA-PET/CT-guided biopsy for prostate cancer management in biopsy naïve men-study protocol for a randomized trial.

BACKGROUND: The primary objective is to determine the proportion of men with suspected prostate cancer (PCA) in whom the management plans are changed by additive gallium-68 prostate-specific membrane antigen positron emission tomography/computed tomography (PSMA-PET/CT) guided prostate biopsy (PET-TB) in combination with standard of care (SOC) using systematic (SB) and multiparametric magnetic resonance imaging-guided biopsy (MR-TB) compared with SOC alone. The major secondary objectives are to determine the additive value of the combined approach of SB + MR-TB + PET-TB (PET/MR-TB) for detecting clinically significant PCA (csPCA) compared to SOC; to determine sensitivity, specificity, positive and negative predictive value and diagnostic accuracy of imaging techniques, respective imaging classification systems, and each biopsy method; and to compare preoperatively defined tumor burden and biomarker expression and pathological tumor extent in prostate specimens. METHODS: The DEPROMP study is a prospective, open-label, interventional investigator-initiated trial. Risk stratification and management plans after PET/MR-TB are conducted randomized and blinded by different evaluation teams of experienced urologists based on histopathological analysis and imaging information: one including all results of the PET/MR-TB and one excluding the additional information gained by PSMA-PET/CT guided biopsy. The power calculation was centered on pilot data, and we will recruit up to 230 biopsy-naïve men who will undergo PET/MR-TB for suspected PCA. Conduct and reporting of MRI and PSMA-PET/CT will be performed in a blinded fashion. DISCUSSION: The DEPROMP Trial will be the first to evaluate the clinically relevant effects of the use of PSMA-PET/CT in patients with suspected PCA compared to current SOC. The study will provide prospective data to determine the diagnostic yields of additional PET-TB in men with suspected PCA and the impact on treatment plans in terms of intra- and intermodal changes. The results will allow a comparative analysis of risk stratification by each biopsy method, including a performance analysis of the corresponding rating systems. This will reveal potential intermethod and pre- and postoperative discordances of tumor stage and grading, providing the opportunity to critically assess the need for multiple biopsies. TRIAL REGISTRATION: German Clinical Study Register DRKS 00024134. Registered on 26 January 2021.

Prostate cancer treatment costs increase more rapidly than for any other cancer-how to reverse the trend?

According to GLOBOCAN, about 1.41 million new prostate cancer (PCa) cases were registered in the year 2020 globally. The corresponding socio-economic burden is enormous. Anti-cancer mRNA-based therapy is a promising approach, the principle of which is currently applied for anti-COVID-19 vaccination, undergoing a detailed investigation in populations considering its short- and long-term effectiveness and potential side effects. Pragmatically considered, it will take years or even decades to make mRNA therapy working for any type of cancers, and if possible, for individual malignancy sub-types which are many specifically for the PCa. Actually, the costs of treating PCa are increasing more rapidly than those of any other cancer. The trend has to be reversed now, not in a couple of years. In general, two main components are making currently applied reactive (management of clinically manifested disease) PCa treatment particularly expensive. On one hand, it is rapidly increasing incidence of the disease and metastatic PCa as its subtype. To this end, rapidly increasing PCa incidence rates in young and middle-aged male sub-populations should be taken into account as a long-term contributor to the metastatic disease potentially developed later on in life. On the other hand, patient stratification to differentiate between non-metastatic PCa (no need for an extensive and costly treatment) and particularly aggressive cancer subtypes requiring personalised treatment algorithms is challenging. Considering current statistics, it becomes obvious that reactive medicine got at its limit in PCa management. Multi-professional expertise is unavoidable to create and implement anti-PCa programmes in the population. In our strategic paper, we exemplify challenging PCa management by providing detailed expert recommendations for primary (health risk assessment), secondary (prediction and prevention of metastatic disease in PCa) and tertiary (making palliative care to the management of chronic disease) care in the framework of predictive, preventive and personalised medicine.

The lncRNA Fer1L4 is an adverse prognostic parameter in clear-cell renal-cell carcinoma.

PURPOSE: Long non-coding RNAs (lncRNA) are involved in oncogenesis and tumor progression in various tumor entities. At present, little is known about the role in tumor biology of the lncRNA Fer-1 like family member 4 (Fer1L4) in clear-cell renal-cell carcinoma (ccRCC). The aim of this study is to evaluate the expression of Fer1L4 in patients with ccRCC, its association with clinicopathological parameters, and value as prognostic biomarker. MATERIAL AND METHODS: The expression of Fer1L4 was analyzed in the TCGA ccRCC cohort (n = 603; ccRCC n = 522, normal n = 81) and subsequently validated by quantitative real-time PCR in an independent cohort (n = 103, ccRCC n = 69, normal n = 34). Expression profiles were statistically correlated with clinicopathological and survival data. RESULTS: Fer1L4 lncRNA is overexpressed in ccRCC compared to adjacent normal tissues. Increased expression significantly correlates with tumor aggressiveness: high expression levels of Fer1L4 RNA were found in higher grade, higher stage, and metastatic tumors. Furthermore, Fer1L4 overexpression is an independent prognostic factor for overall, cancer-specific, and progression-free survival of patients with ccRCC. CONCLUSION: Fer1L4 expression significantly correlates with aspects of tumor aggressiveness. Based on this impact on tumor progression and its influence as an independent prognostic factor, Fer1L4 appears to exert properties as an oncogene in ccRCC. As a prognostic tissue biomarker, further functional investigations are warranted to investigate Fer1L4 as a potential therapeutic target.

[CpG island hypermethylation of the DNA. Perspectives of a molecular biomarker for prostate cancer]. / CpG-Insel-Hypermethylierung der DNA. Perspektiven eines molekularen Biomarkers für das Prostatakarzinom.

The exact classification of clinically significant versus insignificant prostate cancer displays one of major problems in current urological practice. Using novel molecular biomarkers, we are trying to decrease overdiagnosis of insignificant cancer. CpG island hypermethylation as a common epigenetic event is a well-recognized phenomenon during carcinogenesis. We have shown that hypermethylation at several gene loci distinguishes between benign and malignant forms of prostatic disorders. Furthermore using tests in cancer tissue and serum samples, one can draw prognostic conclusions and predict biochemical failure following radical prostatectomy with curative intent.

[Prostate cancer research. Biomarkers as promising options for optimized diagnosis and treatment]. / Prostatakarzinomforschung. Biomarker als Hoffnung für optimierte Diagnostik und Therapie.

A better understanding of signal transduction and gene regulation during prostate carcinogenesis will allow the development of novel diagnostic and prognostic biomarkers and a better prediction of the individual course of prostate cancer disease. It will also enhance the design and development of specific small molecular components aiming for specific therapies. The research groups in Bonn succeeded in the competition for an endowed professorship supported by the Rudolf Becker Stiftung (German Science Endowment Fund) settled in the"Centrum für integrierte Onkologie" funded by the German Cancer Aid. This should be the perfect breeding ground for future research in the field of prostate cancer.

[Pediatric renal cell carcinoma. A rare differential diagnosis of Wilms' tumor]. / Das Nierenzellkarzinom beim Kind. Eine seltene Differenzialdiagnose zum Wilms-Tumor.

Renal cell carcinoma (RCC) is a very rare pediatric disease and should be treated as an entity of its own because of differences in symptoms, therapy, and prognosis from the adult form of the disease. Our objective is to discuss the difficulties in clinical diagnosis, prognosis, and therapy of this very rare disease in children and to provide a review of the current literature.

Prostate cancer tissue is masked by bicalutamide: a case report.

Prostate cancer is the most common malignant tumor in men. Recently, a slightly decreased frequency of margin positivity following neoadjuvant bicalutamide treatment due to tumor shrinkage was reported. Trials investigating other anti-androgens in the past also reported lower frequencies of surgical margin positivity, but patients outcome has not improved. In this case, local recurrence was confirmed by needle biopsy in a patient five years following radical prostatectomy for prostate adenocarcinoma. After therapy with 50 mg bicalutamide for a month, the tumour was resected. Despite of detailed histological work-up and immunohistochemistry cancer suspicious lesions were not found. We think that bicalutamide may be capable of masking prostate cancer cells.

[Aggressive course of a malignant alveolar soft tissue sarcoma]. / Aggressive Verlaufsform eines malignen alveolären Weichteilsarkoms.

Alveolar soft part sarcoma is a rare soft tissue tumor. Most patients who are affected by this sarcoma are between 15 and 35 years old. The tumor is characterized by its uncommon location of metastasis. Publications concerning this sarcoma subform are rare and the best therapeutic procedure is not yet clear. Surgical excision, radiation and chemotherapy are performed, whereas complete surgical excision achieves the best results in long-term follow-up. We report a patient's history who rapidly died of his sickness despite the low initial tumor stage.

[Ureterocystoplasty in the treatment of "low-compliance" bladder in children]. / Ureteraugmentation der Blase bei Kindern mit "Low-compliance-Blase".

In cases of inadequate or insufficient conservative treatment of non-compliant bladders the function of the upper urinary tract is jeopardized. We present our experience with ureterocystoplasty as one possible treatment option.A total of eight children underwent ureterocystoplasty. The etiology of bladder non-compliance and the need for augmentation was neurogenic in five children, posterior urethral valves in two children, and in one child after repeated antireflux surgery. In all patients the kidney of the used ureter was functionless. Surgery was done through a transperitoneal approach. Following nephrectomy, the renal pelvis and the ureter were spatulated and sutured into the bladder incision. An additional MACE procedure was performed in three patients, antireflux surgery for the contralateral kidney in two patients, and one patient underwent stone removal in the remaining kidney. In one patient the ureter was used as a free transplant and was covered by an omental flap. In addition a simultaneous living donor kidney transplant was performed. The storage function could be improved in all patients. The function of the ureter which was used as a free transplant showed good clinical results. The longest follow-up is 8 years. Ureterocystoplasty is a useful and metabolically neutral alternative to bowel segments. In patients with only one functioning kidney and a contralateral megaureter, ureterocystoplasty is the treatment of choice in our institution.

[Molecular biomarkers and prognostic factors for prostate cancer]. / Genetische Marker und Prognosefaktoren beim Prostatakarzinom.

In the era of personalized medicine and precision oncology, innovative genetic biomarkers are of emerging interest to close the diagnostic and prognostic gap that is left by current clinicopathologic risk classifiers. The current review article summarizes evidence regarding prognostic and predictive genetic biomarkers that are currently in widespread clinical use at initial diagnosis as well as following definitive treatment of prostate cancer. We give a brief summary about basic principles of biomarker research studies and present current data for the Progensa PC3 test, TMPRSS2:ERG gene fusion, ConfirmMDx, Prolaris gene panel, OncotypeDX Genomic Prostate score, and Decipher classifier. Evidence regarding those genetic biomarkers has heavily increased recently. However, there is still a lack of large, multicentric and prospective clinical validation studies. Furthermore, comparative studies that investigate the prognostic value of various genetic biomarkers are needed.

[When is surgical resection of the primary tumor indicated in metastatic urothelial carcinoma of the bladder and what is the scientific rationale?] / Wann ist bei eingetretener Metastasierung des Harnblasenkarzinoms die operative Entfernung des Primärtumors angezeigt und gibt es eine wissenschaftliche Grundlage dafür?

Cisplatin-based polychemotherapy is still the standard therapy for metastatic urothelial carcinoma, although disease progression is often noted at an early time point even in patients with response. In recent years, cytoreductive surgery has been gaining increasing interest in many tumor entities in the setting of metastatic disease to improve patients outcome, but urothelial carcinoma is not regarded as a candidate for such a multimodal therapy approach. However, several retrospective studies suggest a survival benefit of radical cystectomy and/or metastasectomy for well-selected patients with metastatic urothelial carcinoma. Prognostically relevant parameters for consolidative cystectomy/metastasectomy after chemotherapy seem to be a distinct response to inductive chemotherapy and limited metastatic spread (regional lymph node, single lung metastasis).

[Primitive neuroectodermal tumor of the kidney]. / Primitiver neuroektodermaler Tumor der Niere.

Primitive neuroectodermal Tumor (PNET) is a rare malignant tumor of young adult. Patients often present with the classical trias of renal cancer (pain, haematuria, palpable tumor). Specific radiological signs are missing, and therefore a PNET is often diagnosed postoperatively. It is characterized by the expression of MIC2, neural markers (Vimentin, S-100, Synaptophysin) and EWS/FLI1-translocation. The tumor is often diagnosed in advanced stage, and prognosis is poor despite of multimodal treatment including radical nephrectomy, polychemotherapy (vincristine, adriamycin, cyclophosphamid, etoposide, ifosfamide) and radiation in case of metastases or incomplete resection of primary tumor. We represent two cases of metastatic renal PNET in a 28- and 39-year-old patient. Due to the multimodal treatment a partial and a complete remission was achieved, respectively.

[Detection of cell-free lncRNA in serum of cancer patients]. / Nachweis von zellfreier lncRNA im Serum von Tumorpatienten.

BACKGROUND: The analysis of circulating RNA molecules is of increasing interest since tumor-specific RNA expression patterns could be a useful cancer biomarker. A new entity of RNA molecules, the so-called long non-coding RNAs (lncRNA), are of particular interest because of its high tissue- and tumor-specificity. The importance of analytical factors in the quantification of lncRNAs is largely unclear and should therefore be investigated in the present study. PATIENTS AND METHODS: Serum RNA was isolated from patients with bladder, prostate and kidney cancer as well as patients with non-malignant disease. Analytical variables like different RNA isolation procedures, cDNA synthesis and preamplification were studied with respect to quantification of MALAT1 and ACTB via real-time PCR. RESULTS: The quantification of cell-free serum RNA is feasible although the levels of ACTB and MALAT1 were often only slightly above the detection limit. RNA isolation with a combined phenol-based column purification (Ambion mirVana PARIS miRNA Isolation Kit; Qiagen miRNeasy Serum/Plasma Kit) was most effective. The elimination of DNA contamination was most successful during cDNA synthesis with (Takara-Bio PrimeScript RT Reagent Kit with gDNA Eraser). Preamplification with the Applied Biosystems TaqMan PreAmp Master Mix Kit improved sensitivity. Serum ACTB and MALAT1 levels were not significantly increased in patients with urological tumors compared to patients with non-malignant diseases. CONCLUSION: An optimized protocol for the analysis of circulating lncRNAs is described in the present study.

Arterial regeneration over polydioxanone prostheses in the rabbit.

We analyzed histologic, ultrastructural, and functional characteristics of rabbit aortic conduits regenerated over absorbable polydioxanone prostheses. Twenty-eight polydioxanone-elicited prosthesis/tissue complexes harvested two weeks to 12 months following implantation were analyzed grossly; photographed; sectioned for light, scanning, and transmission electron microscopy; and studied for compliance, bursting strength, and prostacyclin and thromboxane metabolite contents. No aortic-related deaths or hemorrhages occurred. Smooth regenerated conduits without stenoses were seen in 27 of 28 specimens, with one small aneurysm. Transprosthetic myofibroblast migration and proliferation paralleled the kinetics of macrophage-mediated prosthetic dissolution, which was consequently delayed compared with polyglycolic acid prostheses. Confluent endothelial-like luminal surfaces were present after two weeks. Progressive inner capsular thickening ended after three months at 420 micron. Ex vivo compliance curves resembled arterial elasticity. Regenerated tissue withstood 1200 mm Hg of systolic pressure, and 6-keto-prostaglandin F1 alpha to thromboxane B2 ratios did not differ from normal control specimens.

Plasma polymerized tetrafluoroethylene/polyethylene terephthalate vascular prostheses.

Tetrafluoroethylene (TFE) was discharged onto woven polyethylene terephthalate (PET) prostheses, and the PET prostheses (50 mm long) with or without TFE were implanted into canine carotid arteries and aortas. Additional controls included polytetrafluoroethylene and Dacron. Specimens were explanted after one to 12 months, photographed, and sectioned for light and scanning and transmission electron microscopy, and thrombus-free surface areas calculated by computerized planimetry. Results showed no significant patency differences among carotid or aortic groups. However, both PET carotid groups had significantly greater thrombus-free surface areas. Histologically, both PET groups appeared identical. An endothelialized neointima covered PET carotid specimens by six months, compared with three months in the aortic position, with greater pannus ingrowth in both PET groups. Plasma polymerized TFE offered no additional advantage in these long-term experiments.

Hemodynamic effects on endothelial cell monolayer detachment from vascular prostheses.

The establishment of an early blood-contacting endothelialized surface may improve the graft-host relationship. This study evaluated the adherence of indium 111-radiolabeled endothelial cells that were cultured to confluence on fibronectin-treated polyester elastomer (Hytrel) grafts that were perfused for two hours on a pulse duplicator apparatus under high- and low-shear conditions. Perfusate samples were serially assayed for radioactivity. After perfusion, grafts were sectioned into four segments and assayed for retained radioactivity. All graft segments were hematoxylin stained and examined under light microscopy for evaluation of cell density. Excellent endothelial cell adherence (90%) was observed under both hemodynamic conditions at 120 minutes, with most losses occurring within the first 15 minutes. No differences were seen between high- and low-shear conditions or proximal vs distal graft segments.

In vivo platelet deposition on polytetrafluoroethylene coated with fibrin glue containing fibroblast growth factor 1 and heparin in a canine model.

BACKGROUND: We previously reported that the coating of expanded polytetrafluoroethylene (ePTFE) with fibrin glue containing fibroblast growth factor 1 (FGF-1) and heparin accelerates endothelial coverage of grafts implanted into animals. We report here the effect of this surface modification on early platelet deposition. MATERIALS AND METHODS: Nine dogs received 7-cm ePTFE grafts, 60-microns internodal distance, 4-mm internal diameter, as bilateral aortoiliac implants, one coated (luminal cross section and abluminal surface) with fibrin glue (fibrinogen 32.1 mg/mliters, thrombin 0.32 U/mliters) containing FGF-1 (11 ng/mliters and heparin (250 U/mliters), the other uncoated. After 5, 30, or 120 minutes of circulation with blood containing autologous platelets radiolabelled with indium 111, gamma emissions were quantitated on explants and correlated to surface areas measured by computerized planimetry. RESULTS: Both global and segmental comparisons showed significantly (P < 0.05, Student's t-test) less platelet deposition on coated than on uncoated grafts after 120 minutes of circulation, but no difference at 5 and 30 minutes. CONCLUSIONS: In this model, ePTFE coating with fibrin glue containing FGF-1 and heparin shows no adverse effect on early platelet deposition.

Biomaterial-induced macrophage activation and monokine release.

This study quantifies macrophage acid phosphatase release as a marker of cell activation when cultured with or without biomaterials. Peritoneal macrophages were harvested from six New Zealand White rabbits and cultured in minimum essential media with 10% equine serum. After cell identification by morphology, nonspecific esterase, and RAM 11 immunoperoxidase, cells were passaged twice, and second-passage macrophages were seeded in 96-well plates (5,000 cells/well) and grown to confluence. After collection of day zero media, circular disks of polyglactin 910 and two types of commercially available polyethylene terephthalate with different construction and sterilization characteristics were placed on the cell monolayer. Controls without biomaterials were also established. Media was collected and pooled for each group and time point beginning on day 2 and continuing every other day for 22 days. Conditioned media were quantitatively assayed for acid phosphatase colorimetrically at 402 nm using p-nitrophenylphosphate as the substrate. Acid phosphatase activity increased progressively at late time points for each group but no difference was noted between groups at any time point. These data show that the activation of cultured macrophages with time is not altered differentially by the presence of biomaterials. The previously demonstrated monokine release following biomaterial exposure is therefore a specific event and not simply part of the generalized activation phenomenon.