Organ-confined Tumors Research Articles

CtDNA predicts clinical T1a to pathological T3a upstaging after partial nephrectomy.

Most patients diagnosed with clear cell renal cell carcinoma (ccRCC) are also detected with small and organ-confined tumors, and the majority of these are classified as clinical tumor stage 1a (cT1a). A considerable proportion of patients with cT1 RCC shows tumor upstaging to pathological stage 3a (pT3a), and these patients have worse oncological outcomes. The role of circulating tumor DNA (ctDNA) in RCC has been limited to monitoring treatment response and resistance. Therefore, the present study aimed to evaluate the potential of ctDNA in predicting pT3a upstaging in cT1a ccRCC. We sequenced plasma samples preoperatively collected from 48 patients who had undergone partial nephrectomy for cT1a ccRCC using data from a prospective cohort RCC. The ctDNA were profiled and compared with clinicopathological ccRCC features to predict pT3a upstaging. Associations between ctDNA, tumor complexity, and pT3a upstaging were evaluated. Tumor complexity was assessed using the anatomical classification system. Univariate analysis used chi-squared and Student's t-tests; multivariate analysis considered significant factors from univariate analyses. Of the 48 patients with cT1a ccRCC, 12 (25%) were upstaged to pT3a, with ctDNA detected in 10 (20.8%), predominantly in patients with renal sinus fat invasion (SFI; n = 8). Among the pT3a group, ctDNA was detected in 75%, contrasting with only 2.8% in patients with pT1a (1/36). Detection of ctDNA was the only significant preoperative predictor of pT3a upstaging, especially in SFI. This study is the first to suggest ctDNA as a preoperative predictor of pT3a RCC upstaging from cT1a based on preoperative radiological images.

Induction therapy with ipilimumab and nivolumab followed by consolidative chemoradiation as organ-sparing treatment in urothelial bladder cancer: study protocol of the INDIBLADE trial.

Studies that assessed the efficacy of pre-operative immune checkpoint blockade (ICB) in locally advanced urothelial cancer of the bladder showed encouraging pathological complete response rates, suggesting that a bladder-sparing approach may be a viable option in a subset of patients. Chemoradiation is an alternative for radical cystectomy with similar oncological outcomes, but is still mainly used in selected patients with organ-confined tumors or patients ineligible to undergo radical cystectomy. We propose to sequentially administer ICB and chemoradiation to patients with (locally advanced) muscle-invasive bladder cancer. The INDIBLADE trial is an investigator-initiated, single-arm, multicenter phase 2 trial. Fifty patients with cT2-4aN0-2M0 urothelial bladder cancer will be treated with ipilimumab 3 mg/kg on day 1, ipilimumab 3 mg/kg plus nivolumab 1 mg/kg on day 22, and nivolumab 3 mg/kg on day 43 followed by chemoradiation. The primary endpoint is the bladder-intact event-free survival (BI-EFS). Events include: local or distant recurrence, salvage cystectomy, death and switch to platinum-based chemotherapy. We will also evaluate the potential of multiparametric magnetic resonance imaging of the bladder to identify non-responders, and we will assess the clearance of circulating tumor DNA as a biomarker for ICB treatment response. This is the first trial in which the efficacy of induction combination ICB followed by chemoradiation is being evaluated to provide bladder-preservation in patients with (locally advanced) urothelial bladder cancer. The INDIBLADE trial was registered on clinicaltrials.gov on January 21, 2022 (NCT05200988).

Abstract B001: Heterogeneity of cancer network biophysical phenotypes is required for tumor muscle invasion in vivo

Abstract Bladder, colon, gastric, prostate, and uterine cancers originate from the organ’s epithelium, and each organ is surrounded by smooth muscle. In prostate cancer, organ-confined tumors, without extracapsular extension (ECE) through muscle, have a 5-year survival rate of 99% compared to 31% for metastatic disease. Previously, we modeled tumor cluster ECE and reported that a CRISPR-Cas9 integrin mutation (α6AA) blocked ECE by switching from a cell-ECM to a cell-cell biophysical phenotype. Since tumors are mosaics and migrate as heterogeneous drug-resistant populations, we tested the functional heterogeneity of the two biophysical cell phenotypes in ECE. Experimental procedures included the in vivo mouse xenograft model of ECE as a functional endpoint of muscle invasion, the MTT assay for cell survival, and using electric cell impedance sensing (ECIS) measurements to directly compare the biophysical properties of tumor cells expressing the invasion permissive α6WT integrin, cells expressing only the α6AA mutation, or a mixed population expressing both integrin types. The α6AA integrin mutation or α6KO knockout produced cells unable to invade into and through the smooth muscle of the mouse as compared to the α6WT integrin cells, as previously reported by us. The new unpublished results are that cell adhesion mediated drug resistance was detected in the α6AA population since their LD50 to Bortezomib, Gemcitabine, and Taxotere was shifted to 33.71nM, 64.66nM, and 5.77nM respectively from 16.29nM, 31.74nM, and 3.52nM in the α6WT cells as measured by MTT assay at 72 hours of incubation. In contrast, the α6AA cells were sensitized to the NAMPT inhibitor, FK866, with LD50 shifting from 27.46nM in α6WT to 7.354nM in the α6AA cells. A mixture of α6AA and α6WT cells allowed invasion into and through the muscle in the mouse of the mutant α6AA integrin cells that could not invade on their own. Examining the live cellular biophysical parameters revealed that the integrin mutation produced a 4-fold increase in cell-cell resistance (400Hz measurement) and a 12-fold recovery time delay in re-establishing a cell-cell resistance monolayer after wounding, with response complexity decreased two-fold. Cell-ECM resistance (40,000Hz measurement) in α6AA versus α6WT population was 1.5-fold decreased with a 6-fold recovery time delay in the cell-ECM resistance monolayer and response complexity decreased 2-fold. A heterogenous population containing up to a 4:1 proportion of α6AA to α6WT cells synergistically delayed cell-cell recovery time of the wounded monolayer up to 6-fold compared to the α6WT cells. Conversely, recovery of the wounded cell-ECM resistance monolayer with 1:1 or 4:1 mixture of α6AA cell only delayed recovery time by 1.5–1.7-fold. Taken together, these data suggest that a heterogenous tumor population provides functional advantages for drug-resistant tumor cells to invade and traverse the muscle barrier. Current work is ongoing to optimize the drug combinations to eliminate both phenotypes in the invasive tumor network and prevent ECE. Citation Format: Kendra D. Marr, Jaime M.C. Gard, William L. Harryman, Elijah J. Keeswood, Allan I. Paxson, Charles Wolgemuth, Lori A. Hazlehurst, Raymond B. Nagle, Anne E. Cress. Heterogeneity of cancer network biophysical phenotypes is required for tumor muscle invasion in vivo [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr B001.

TRPM8 protein expression in hormone naïve local and lymph node metastatic prostate cancer.

SummaryObjectiveProstate cancer (PCa) is the second most common malignancy in men. Radiotherapy and surgery successfully control organ-confined tumors, although, locally advanced/high-risk PCa frequently progress to the metastatic stage of the disease, which is uncurable. Identification of novel strategies to improve the efficacy of standard clinical protocols is a primary need. Among the molecular targets of potential clinical interest recently highlighted by accurate preclinical studies, the TRPM8 cation channel is particularly promising. In this study, we aim at establishing a standardized immunohistochemistry protocol to evaluate TRPM8 expression in normal and pathological prostate tissues.MethodsThe specificity and sensitivity of TRPM8 antibody ACC-049 was validated in different human prostate cell lines by western blot and immunocytochemistry analyses. Expression of the TRPM8 channel in normal and pathological prostate tissue was evaluated by immunohistochemistry using a tissue microarray containing 58 cases of prostate adenocarcinomas and in primary and lymph nodes metastatic human PCa matched specimens.ResultsTRPM8 expression marks luminal epithelial cells in benign prostate tissue. In malignant lesions of the prostate, TRPM8 expression is frequently more abundant in advanced stages of the disease (PCa stage III/IV). Finally, lymph node metastases and matched primary tumors show similar amounts of the channel.ConclusionsCollectively, our results reinforce the importance of TRPM8 as prostate biomarker and emphasize the value of the channel as promising novel molecular target for the treatment of prostate adenocarcinoma.

Does the Distance of the Tumor from the Surgical Margin Affect Biochemical Recurrence in Patients with Pathological Organ-Confined Prostate Cancer?

To investigate the effect of the distance between tumor and surgical margin on biochemical recurrence in patients with organ-confined prostate cancer. The data of 208 patients, who underwent radical prostatectomy between 2012-2018, were retrospectively analyzed. The surgical margin status of 147 pathologically organ-confined patients was categorized as positive, close ( < 1mm) and negative. Surgical margin status and parameters affecting biochemical recurrence were examined. Furthermore, multivariate analysis was done to determine the parameters associated with biochemical recurrence. Biochemical recurrence was detected in 21 (14.2%) of 147 patients. 38 (27.9%) men had negative surgical margins, 68 (46.2%) had close surgical margins and 41 (25.9%) had positive surgical margins. Tumor volume and ISUP grade were found to be statistically significant for positive surgical margin and close surgical margin patients compared to negative surgical margin patients. Close surgical margin was not statistically associated with biochemical recurrence. Preoperative high PSA (p < 0.001) and positive surgical margin (p=0.021) were independent risk factors for biochemical recurrence. According to our results, it is not necessary to include the presence of a close surgical margin in the pathology reports in patients with pathological organ-confined tumors and negative surgical margins.

Prognostic significance of architectural subtypes of Gleason grade 4 prostate cancer in radical prostatectomy: A semiquantitative method of evaluation

Studies have shown that Gleason grade 4 extent as well as architectural subtypes provide prognostic information. We aimed to evaluate the influence on biochemical recurrence following radical prostatectomy of patients with organ-confined tumor, Gleason score 7, and negative surgical margins. Total tumor extent, Gleason grade 4 total extent and the extent of each architectural subtype (fused glands, poorly defined glands, cribriform glands, and glomeruloid glands) were evaluated by a semiquantitative point-count method using different colors to identify each subtype. Microscopic morphology of glomeruloid glands was considered regardless of morphology: size (small or large), attachment (narrow or extensive), and cribriform or solid intraluminal protrusion. Gleason grade 4 total extent significantly predicted shorter time to biochemical recurrence in univariate and multivariate analysis. Stratifying extent, Gleason grade 4 with >30% of the total grade 4 extent was significantly predictive for time of recurrence. Considering architectural subtypes, cribriform and glomeruloid glands but not fused and poorly formed glands extent, significantly predicted shorter time to recurrence in univariate analysis. An important issue related to the studies on prognostic significance of Gleason grade 4 subtypes is the lack of uniformity in the definition of microscopic morphology of the subtypes particularly of the glomeruloid architecture.

The Prognostic Value of Indoleamine-2,3-Dioxygenase Gene Expression in Urine of Prostate Cancer Patients Undergoing Radical Prostatectomy as First Treatment of Choice.

Prostate cancer (PCa) is a slow-growing tumor representing one of the major causes of all new cancer cases and cancer mortality in men worldwide. Although screening methods for PCa have substantially improved, the outcome for patients with advanced PCa remains poor. The elucidation of the molecular mechanism that drives the progression from a slow-growing, organ-confined tumor to a highly invasive and castration-resistant PCa (CRPC) is therefore important. We have already proved the diagnostic potential of indoleamine-2,3-dioxygenase (IDO) when detected in urine of individuals at risk of developing PCa. The aim of this study was to implement IDO as a prognostic marker for PCa patients undergoing surgical treatment. We have thus conducted an observational study by collecting 100 urine samples from patients undergoing radical prostatectomy as first treatment of choice. To test the integrity of our investigation, scale dilution cells of an established PC3 cell line were added to urine of healthy donors and used for gene expression analysis by a TaqMan assay on the catalytic part of IDO mRNA. Our data show that the quantification of IDO mRNA in urine of patients has a very promising ability to identify patients at high risk of cancer advancement, as defined by Gleason score. Our goal is to lay the groundwork to develop a superior test for PCa. The data generated are thus necessary (i) to strengthen the IDO-based diagnostic/prognostic test and (ii) to provide patients and clinicians with an affordable and easy screening test.

Very Early Continence After Radical Prostatectomy and Its Influencing Factors

Introduction and Objectives: Surgical techniques such as preservation of the full functional-length of the urethral sphincter (FFLU) have a positive impact on postoperative continence rates. Thereby, data on very early continence rates after radical prostatectomy (RP) are scarce. The aim of the present study was to analyze very early continence rates in patients undergoing FFLU during RP.Materials and Methods: Very early-continence was assessed by using the PAD-test within 24 h after removal of the transurethral catheter. The PAD-test is a validated test that measures the amount of involuntary urine loss while performing predefined physical activities within 1 h (e.g., coughing, walking, climbing stairs). Full continence was defined as a urine loss below 1 g. Mild, moderate, and severe incontinence was defined as urine loss of 1–10 g, 11–50 g, and >50 g, respectively.Results: 90 patients were prospectively analyzed. Removal of the catheter was performed on the 6th postoperative day. Proportions for no, mild, moderate and severe incontinence were 18.9, 45.5, 20.0, and 15.6%, respectively. In logistic regression younger age was associated with significant better continence (HR 2.52, p = 0.04), while bilateral nerve-sparing (HR 2.56, p = 0.057) and organ-confined tumor (HR 2.22, p = 0.078) showed lower urine loss, although the effect was statistically not significant. In MVA, similar results were recorded.Conclusion: Overall, 64.4% of patients were continent or suffered only from mild incontinence at 24 h after catheter removal. In general, reduced urine loss was recorded in younger patients, patients with organ-confined tumor and in patients with bilateral nerve sparing. Severe incontinence rates were remarkably low with 15.6%.

Clonal evaluation of early onset prostate cancer by expression profiling of ERG, SPINK1, ETV1, and ETV4 on whole-mount radical prostatectomy tissue.

Expression profiles of erythroblast transformation-specific (ETS)-related gene fusions and serine protease inhibitor Kazal-type 1 (SPINK1) in early onset prostate cancer have not been thoroughly explored. We retrieved 151 radical prostatectomy specimens from young men with prostate cancer (<55 years) and characterized the expression of ETS-related gene (ERG), SPINK1, ETS Variant 1 (ETV1), and ETV4 by dual immunohistochemistry and dual RNA in situ hybridization. Age, race, family history, preoperative prostate-specific antigen, biochemical recurrence, and pathological variables using whole-mount radical prostatectomy tissue were collected. A total of 313 tumor nodules from 151 men including 68 (45%) Caucasians and 61 (40%) African Americans were included in the analysis. Positive family history of prostate cancer was seen in 65 (43%) patients. Preoperative prostate-specific antigen ranged from 0.3 to 52.7 ng/mL (mean = 7.04). The follow-up period ranged from 1 to 123.7 months (mean = 30.3). Biochemical recurrence was encountered in 8 of 151 (5%). ERG overexpression was observed in 85 of 151 (56%) cases, followed by SPINK1 in 61 of 151 (40%), ETV1 in 9 of 149 (6%), and ETV4 in 4 of 141 (3%). There were 25 of 151 (17%) cases showing both ERG and SPINK1 overexpression within different regions of either the same tumor focus or different foci. Higher frequency of ERG overexpression was seen in younger patients (≤45 years old; 76% vs 49%, P = .002), Caucasian men (71% vs 41% P = .0007), organ-confined tumors (64% vs 33%, P = .0008), and tumors of Gleason Grade groups 1 and 2 (62% vs 26%, P = .009). SPINK1 overexpression was more in African American men (68% vs 26%, P = .00008), in tumors with high tumor volume (>20%) and with anterior located tumors. ETV1 and ETV4 demonstrated rare overexpression in these tumors, particularly in the higher-grade tumors. This study expands the knowledge of the clonal evolution of multifocal cancer in young patients and support differences in relation to racial background and genetics of prostate cancer.

Renal cell carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up†.

Renal cell carcinoma (RCC) accounts for 2%–3% of all adultmalignancies, representing the seventh most common cancer inmen and the ninth most common cancer in women [1].Worldwide, there are ∼209000 new cases and 102000 deathsper year. The incidence of all stages of RCC has increased overthe past several years, contributing to a steadily increasing mor-tality rate per unit population. Active and passive cigarettesmoking is an established risk factor for RCC as well as hyper-tension. However, anti-hypertensive medications such as diure-tics are not independently associated with RCC development.RCC also appears to be more common in patients with obesity,end-stage renal failure, acquired renal cystic disease and tuber-ous sclerosis.Approximately 2%–3% of RCC are hereditary and severalautosomal dominant syndromes are described, each with a dis-tinct genetic basis and phenotype, the most common one beingVon Hippel Lindau disease.In recent years, many new genes associated with RCC havebeen reported (such as PBRM1, SETD2, BAP1). Their roles inpathogenesis and as prognostic biomarkers are currently underinvestigation.

Metastatic risk stratification of clear cell renal cell carcinoma patients based on genomic aberrations.

Prognostic markers for the definition of the individual metastatic risk in renal cell carcinoma are still missing. The aim of our study was to establish a total number of specific aberrations (TNSA) genetic score as a new prognostic test for metastatic risk evaluation. Fluorescence in situ hybridization (FISH) was performed on isolated cell nuclei of 100 ccRCCs (50 M1/50 M0) and 100 FFPE sections (second cohort, 32 M1/68 M0). For each chromosomal region (1q21.3, 7q36.3, 9p21.3p24.1, 20q11.21q13.32) cut-off values were determined by receiver-operator curve (ROC)-curve analysis. TNSA was calculated based on the dichotomized specific CNVs. The prognostic significance of CNVs was proven by Cox and logistic regression. TNSA was the best predictor of metastasis and recurrence free survival in both cohorts. We derived an algorithm for risk stratification by combining TNSA and T-category, which increased the prognostic accuracy to 87% (specificity = 86%, sensitivity = 88%). This model divides patients into two risk groups with significantly different RFS, CSS, and OS (P = 3.8×10-5 , P = 5×10-6 and P = 3.57×10-8 respectively). The genetic risk model was superior to Leibovich score and was able to identify patients with metachronous metastatic spread which were incorrectly classified as "low" or "intermediate risk." We present a new tool for individual risk stratification by combining genetic alterations with clinico-pathologic parameters. Interphase FISH proves to be a dependable method for prognostic evaluation in primary tumor tissue on isolated cell nuclei as well as on FFPE sections. Especially in organ-confined tumors the genetic score seems to be an important tool to identify patients at high risk for metastatic disease.

Radiological Wheeler staging system: a retrospective cohort analysis to improve the local staging of prostate cancer with multiparametric MRI.

The knowledge of tumor location and extension can allow a modulated radical prostatectomy in order to minimize positive surgical margins and reduce functional morbidity after surgery in patients with prostate cancer (PCa). Multiparametric (mp) magnetic resonance imaging (MRI) could allow the assessment of tumor extension and of its relationship with external structures. Aim of this study is to propose a new radiological Wheeler (rW) staging system applied to mp-MRI, based on the pathologic staging system (pW) for the local assessment of PCa. This retrospective single-center multi-reader study included consecutive patients with PCa and preoperative mp-MRI, who underwent non-nerve sparing radical prostatectomy. Three radiologists reported on all examinations and classified each selected lesion according to imaging criteria following rW. Whole-mount histological sections were used as the reference standard. An experienced pathologist classified the extent of prostatic capsular invasion of each PCa according to the pW. Each histological section was scanned for comparison with mp-MRI findings. The rate of PCa correctly classified by radiologists using the pW was assessed. To evaluate the accuracy of mp-MRI in the discrimination between T2 and T3 PCa, the AUC was computed. One-hundred and five patients with a total of 195 PCa foci were included in the study. 130/195 tumors with a clear overlap between mp-MRI and surgical specimens were selected. The sensitivity of the most experienced reader was lower than that of the other two readers (48.6% vs. 68.6% and 62.9%, P>0.09) while specificity and PPV were higher (95.8% vs. 79.0% and 57.9%, P<0.001; 81.0% vs. 54.6% and 35.5%, P<0.041; respectively). The AUC values for the most and the intermediate experienced readers in the detection of extracapsular extension were in the range 0.72-0.74. The rW staging system has low accuracy in predicting each single pW class, while accuracy was over 80% for experienced readers in the identification of organ-confined (T2 stage class) tumors and non-organ confined cases (T3 stage class).

Combining Bulk Temperature and Nanoheating Enables Advanced Magnetic Fluid Hyperthermia Efficacy on Pancreatic Tumor Cells

Many efforts are made worldwide to establish magnetic fluid hyperthermia (MFH) as a treatment for organ-confined tumors. However, translation to clinical application hardly succeeds as it still lacks of understanding the mechanisms determining MFH cytotoxic effects. Here, we investigate the intracellular MFH efficacy with respect to different parameters and assess the intracellular cytotoxic effects in detail. For this, MiaPaCa-2 human pancreatic tumor cells and L929 murine fibroblasts were loaded with iron-oxide magnetic nanoparticles (MNP) and exposed to MFH for either 30 min or 90 min. The resulting cytotoxic effects were assessed via clonogenic assay. Our results demonstrate that cell damage depends not only on the obvious parameters bulk temperature and duration of treatment, but most importantly on cell type and thermal energy deposited per cell during MFH treatment. Tumor cell death of 95% was achieved by depositing an intracellular total thermal energy with about 50% margin to damage of healthy cells. This is attributed to combined intracellular nanoheating and extracellular bulk heating. Tumor cell damage of up to 86% was observed for MFH treatment without perceptible bulk temperature rise. Effective heating decreased by up to 65% after MNP were internalized inside cells.

Targeting a solute carrier to metabolically reprogram tumour-promoting stromal cells in pancreatic cancer

Patients with metastatic prostate cancer (PCa) have a poorer prognosis than patients with organ-confined tumors. We strove to uncover the proteome signature of primary PCa and associated lymph node metastases (LNMs) in order to identify proteins that may indicate or potentially promote metastases formation. We performed a proteomic comparative profiling of PCa tissue from radical prostatectomy (RPE) of patients without nodal metastases or relapse at the time of surgical resection (n = 5) to PCa tissue from RPE of patients who suffered from nodal relapse (n = 5). For the latter group, we also included patient-matched tissue of the nodal metastases. All samples were formalin fixed and paraffin embedded. We identified and quantified more than 1200 proteins by liquid chromatography tandem mass spectrometry with subsequent label-free quantification. An increase of ribosomal or proteasomal proteins in LNM (compared to corresponding PCa) became apparent, while extracellular matrix components rather decreased. Immunohistochemistry (IHC) corroborated accumulation of poly-(ADP-ribose)-polymerase 1 and N-myc-downstream-regulated-gene 3, alpha/beta hydrolase domain-containing protein 11, and protein phosphatase slingshot homolog 3 in LNM. These findings strengthen the present interest in examining PARP inhibitors for the treatment of aggressive PCa. IHC also corroborated increased abundance of retinol dehydrogenase 11 in metastasized primary PCa compared to organ-confined PCa. Generally, metastasizing primary tumors were characterized by an enrichment of proteins involved in cellular lipid metabolic processes with concomitant decrease of cell adhesion proteins. This study highlights the usefulness of a combined proteomic-IHC approach to explore novel aspects in tumor biology. Our initial results open novel opportunities for follow-up studies.

MP28-06 METASTATIC RISK STRATIFICATION OF CLEAR CELL RENAL CELL CARCINOMA PATIENTS BASED ON A GENOMIC SCORE

You have accessJournal of UrologyKidney Cancer: Epidemiology & Evaluation/Staging I1 Apr 2018MP28-06 METASTATIC RISK STRATIFICATION OF CLEAR CELL RENAL CELL CARCINOMA PATIENTS BASED ON A GENOMIC SCORE Julia Grimm, MArtin Janssen, Stefan Wagenpfeil, Arndt Hartmann, Christine Stöhr, Bastian Keck, Andreas Kahlmeyer, Michael Stöckle, and Kerstin Junker Julia GrimmJulia Grimm More articles by this author , MArtin JanssenMArtin Janssen More articles by this author , Stefan WagenpfeilStefan Wagenpfeil More articles by this author , Arndt HartmannArndt Hartmann More articles by this author , Christine StöhrChristine Stöhr More articles by this author , Bastian KeckBastian Keck More articles by this author , Andreas KahlmeyerAndreas Kahlmeyer More articles by this author , Michael StöckleMichael Stöckle More articles by this author , and Kerstin JunkerKerstin Junker More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2018.02.906AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Prognostic markers for the definition of the individual metastatic risk are still missing. Chromosomal copy number variations have the potential to be prognostic markers. Aim of this study was to establish a total number of specific aberrations score as a new prognostic test. METHODS FISH was performed on isolated cell nuclei of 100 ccRCCs (50 M1/50 M0) and 100 FFPE sections on TMAs from a 2nd cohort (32 M1/68 M0). For each chromosomal region (1q21.3, 7q36.3, 9p21.3p24.1 and 20q11.21q13.32) cut-off values were determined by ROC-curve analysis. TNSA was calculated based on the dichotomized specific CNVs. The prognostic significance of CNVs was proven by Cox and logistic regression. RESULTS TNSA was the best predictor of metastasis in both cohorts. We derived an algorithm for risk stratification by combining TNSA and T-category, which increased the prognostic accuracy to 87% (Specificity= 86%, Sensitivity= 88%) and 84% (Specificity=93%, Sensitivity= 66%) respectively. Both TNSA and T-category are independent prognostic factors of progression in cohort 1 and metastatic risk increases with each additional CNV by 3.7-fold. TNSA was an independent predictor of PFS in both cohorts. In organ confined tumors TNSA was the only significant indicator of progression. CONCLUSIONS We present a new, powerful tool for individual as well as whole cohort risk stratification by combining genetic alterations with clinico-pathologic parameters. TNSA was validated as an independent prognostic factor for ccRCC. Interphase FISH proves to be a dependable method for prognostic evaluation in primary tumor tissue on isolated cell nuclei as well as on FFPE sections. Especially in organ-confined tumors the genetic score seems to be an important tool to identify patients at high risk for metastatic disease. © 2018FiguresReferencesRelatedDetails Volume 199Issue 4SApril 2018Page: e358 Advertisement Copyright & Permissions© 2018MetricsAuthor Information Julia Grimm More articles by this author MArtin Janssen More articles by this author Stefan Wagenpfeil More articles by this author Arndt Hartmann More articles by this author Christine Stöhr More articles by this author Bastian Keck More articles by this author Andreas Kahlmeyer More articles by this author Michael Stöckle More articles by this author Kerstin Junker More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Combined robot assisted right partial nephrectomy and cholecystectomy with single docking

ΑBSTRACT: We report the first case of robot-assisted partial nephrectomy (RARN) and Robot assisted cholecystectomy in a 66years old female overweight patient with organ-confined right kidney tumor identified on the investigation of gastrointestinal symptoms with a single docking. A modified position of the patient and a slight altered placement of the trocars made feasible the concomitant performance of the two operations. Total blood loss was 80ml, operation time was 253min and console time 187min. The drain was removed on second post-operative day and the patient was discharged at the 3rd post-operative day. Using a single docking of the da Vinci S system, intraoperative time and cost are minimized in patients with both organ-confined kidney tumors and gall bladder stones.

Robotic surgery in urology: facts and reality. What are the real advantages of robotic approaches for prostate cancer patients?

Despite the worldwile increasing use of robotic assistance for oncology surgery, no level 1 evidence-based benefit favoring robot-assisted radical prostatectomy (RARP) versus pure laparoscopic or open approaches has been demonstrated. We aimed to perform an update of the available evidence by evaluating most recent 2016-2017 data. Population-based and prospective nonrandomized studies and one phase III randomised trial have been recently published. Early results from the phase III trial suggested that RARP led to similar early functional and oncologic outcomes compared with open radical prostatectomy. Shorter operative time, hospital stay, and lower complications rate and blood loss were reported in RARP group compared with open radical prostatectomy group. Population-based data did not demonstrate any benefit from one approach over another in terms of functional and oncologic outcomes. Robot assistance is predictive for improved potency recovery in organ-confined tumor in one large prospective trial. Main limitations, different among studies, were lack of randomization or single operator cohorts, short-term follow-up, and absence of confounding factors analysis. Robotic assistance seems to confer better results than open radical prostatectomy procedures in terms of intra- and immediate postoperative parameters (operative time, blood loss and hospital stay). Clear advantages of one technique over another on robust functional or oncologic endpoints remain unproven.

Proteomic Characterization of Prostate Cancer to Distinguish Nonmetastasizing and Metastasizing Primary Tumors and Lymph Node Metastases

Patients with metastatic prostate cancer (PCa) have a poorer prognosis than patients with organ-confined tumors. We strove to uncover the proteome signature of primary PCa and associated lymph node metastases (LNMs) in order to identify proteins that may indicate or potentially promote metastases formation. We performed a proteomic comparative profiling of PCa tissue from radical prostatectomy (RPE) of patients without nodal metastases or relapse at the time of surgical resection (n=5) to PCa tissue from RPE of patients who suffered from nodal relapse (n=5). For the latter group, we also included patient-matched tissue of the nodal metastases. All samples were formalin fixed and paraffin embedded. We identified and quantified more than 1200 proteins by liquid chromatography tandem mass spectrometry with subsequent label-free quantification. An increase of ribosomal or proteasomal proteins in LNM (compared to corresponding PCa) became apparent, while extracellular matrix components rather decreased. Immunohistochemistry (IHC) corroborated accumulation of poly-(ADP-ribose)-polymerase 1 and N-myc-downstream-regulated-gene 3, alpha/beta hydrolase domain-containing protein 11, and protein phosphatase slingshot homolog 3 in LNM. These findings strengthen the present interest in examining PARP inhibitors for the treatment of aggressive PCa. IHC also corroborated increased abundance of retinol dehydrogenase 11 in metastasized primary PCa compared to organ-confined PCa. Generally, metastasizing primary tumors were characterized by an enrichment of proteins involved in cellular lipid metabolic processes with concomitant decrease of cell adhesion proteins. This study highlights the usefulness of a combined proteomic-IHC approach to explore novel aspects in tumor biology. Our initial results open novel opportunities for follow-up studies.

Positive margin length and highest Gleason grade of tumor at the margin predict for biochemical recurrence after radical prostatectomy in patients with organ-confined prostate cancer.

To evaluate the pathologic features after radical prostatectomy to determine if the length of positive surgical margin (PSM) and the highest Gleason grade within the tumor at the PSM could risk stratify patients for biochemical recurrence (BCR). We performed a retrospective, matched, cohort study to identify patients with pathologically organ-confined (pT2) tumors and negative nodes (pN0/Nx), receiving no adjuvant therapy. Specimens underwent single pathologist review. BCR-free survival was estimated using the Kaplan-Meier method and compared between subgroups using two-sided log-rank test. Using Classification and Regression Tree analysis (CART), we identified an optimal cutoff for the PSM length which differentiated risk for BCR. Cox proportional hazards regression models were fit to assess the association between variables and BCR-free survival. Two-hundred PSM patients were matched to 200 patients with negative surgical margins (NSM). Median follow-up was 64 months. 5 year BCR-free survival was 90% (95% CI 84-97%) in the NSM group and 70% (95% CI 63-79%) in the PSM group. There was an increased risk of BCR with any PSM. Multivariable analysis demonstrated an association with length of PSM ( > 1 mm vs. ≤ 1 mm, HR 2.29; 95% CI 1.2-4.5) and having a highest Gleason grade of the cancer focus at the margin ≥ 4 (HR 6.8; 95% CI 1.6-29). We demonstrated that patients with pathologic T2 tumors with PSM > 1 mm or a Gleason grade of tumor focus at the margin ≥ 4 are at elevated risk for BCR. However, this study suggests that patients with pT2 tumors with positive surgical margins have a relatively low risk of biochemical recurrence and adjuvant radiation may be over treating this sub population. The subsets at greatest risk for BCR may benefit from more frequent PSA monitoring to direct salvage therapies.

Agglomeration of magnetic nanoparticles and its effects on magnetic hyperthermia

Abstract Magnetic fluid hyperthermia (MFH) is a promising approach for organ-confined tumor treatment. In MFH, magnetic nanoparticles (MNP) are magnetically targeted at the tumor site and heated in an alternating magnetic field. The heat produced by the MNP is used to cause tumor cell death. At the tumor site, MNP bind to the cell membrane and form agglomerates before they are internalized into the intracellular compartments. Intracellular immobilization and the formation of agglomerates influence heating properties of MNP making it difficult to control the local heating inside the tumor. In this study, we investigated MNP agglomerated samples for their heating efficiency. We found an increase in heating of 22 % upon agglomeration. If MNP are additionally immobilized, however, the heating decreases by 30 %. Consequently, due to the binding of bigger MNP agglomerates at cellular level, heating efficiency inside tumors is assumed to decrease.