Stephanie G.C. Kroeze

Examining the 'gold standard': a comparative critical analysis of three consecutive decades of monopolar transurethral resection of the prostate (TURP) outcomes.

Whats known on the subject? and What does the study add?

Expression of nuclear FIH independently predicts overall survival of clear cell renal cell carcinoma patients.

AIM The hypoxia inducible factor (HIF) pathway plays an important role in sporadic clear cell renal cell carcinoma (ccRCC) by stimulating processes of angiogenesis, cell proliferation, cell survival and metastases formation. Herein, we evaluate the significance of upstream proteins directly regulating the HIF pathway; the prolyl hydroxylases domain proteins (PHD)1, 2 and 3 and factor-inhibiting HIF (FIH), as prognostic markers for ccRCC. METHODS Immunohistochemical marker expression was examined on a tissue microarray containing tumour tissue derived from 100 patients who underwent nephrectomy for ccRCC. Expression levels of HIF, FIH and PHD1, 2 and 3 were correlated with overall survival (OS) and clinicopathological prognostic factors. RESULTS HIF-1α was positively correlated with HIF-2α (p<0.0001), PHD1 (p = 0.024), PHD2 (p<0.0001), PHD3 (p = 0.004), FIH (p<0.0001) and VHL (p = 0.031). HIF-2α levels were significantly associated with FIH (p<0.0001) and PHD2 (p = 0.0155). Mutations in the VHL gene, expression variations of HIF-1α, HIF-2α and PHD1, 2, 3 did not show a correlation to OS or clinicopathological prognostic factors. Tumour stage, grade, diameter, metastastic disease and intensity of nuclear FIH were significantly correlated to OS in univariable analysis (p = 0.023). Low nuclear FIH levels remained a strong independent prognostic factor in multivariable analysis (p = 0.009). CONCLUSION These results show that low nuclear expression of FIH is a strong independent prognostic factor for a poor overall survival in ccRCC.

Incomplete thermal ablation stimulates proliferation of residual renal carcinoma cells in a translational murine model

Whats known on the subject? and What does the study add?

Impact of comorbidity on complications after nephrectomy: use of the Clavien Classification of Surgical Complications

Study Type – Retrospective (cohort)

Intratumoral administration of Holmium-166 Acetylacetonate Microspheres: antitumor efficacy and feasibility of multimodality imaging in renal cancer

Purpose The increasing incidence of small renal tumors in an aging population with comorbidities has stimulated the development of minimally invasive treatments. This study aimed to assess the efficacy and demonstrate feasibility of multimodality imaging of intratumoral administration of holmium-166 microspheres (166HoAcAcMS). This new technique locally ablates renal tumors through high-energy beta particles, while the gamma rays allow for nuclear imaging and the paramagnetism of holmium allows for MRI. Methods 166HoAcAcMS were administered intratumorally in orthotopic renal tumors (Balb/C mice). Post administration CT, SPECT and MRI was performed. At several time points (2 h, 1, 2, 3, 7 and 14 days) after MS administration, tumors were measured and histologically analyzed. Holmium accumulation in organs was measured using inductively coupled plasma mass spectrometry. Results 166HoAcAcMS were successfully administered to tumor bearing mice. A striking near-complete tumor-control was observed in 166HoAcAcMS treated mice (0.10±0.01 cm3 vs. 4.15±0.3 cm3 for control tumors). Focal necrosis and inflammation was present from 24 h following treatment. Renal parenchyma outside the radiated region showed no histological alterations. Post administration CT, MRI and SPECT imaging revealed clear deposits of 166HoAcAcMS in the kidney. Conclusions Intratumorally administered 166HoAcAcMS has great potential as a new local treatment of renal tumors for surgically unfit patients. In addition to strong cancer control, it provides powerful multimodality imaging opportunities.

Radio Frequency Ablation Combined with Interleukin-2 Induces an Antitumor Immune Response to Renal Cell Carcinoma in a Murine Model

PURPOSE Immune based therapy has gained renewed interest in the search for treatment strategies for metastasized renal cell carcinoma. We determined whether radio frequency ablation combined with interleukin-2 would induce a tumor specific immune response and serve as an in situ vaccine against renal cell carcinoma. MATERIALS AND METHODS Mice with orthotopic renal tumors were treated with radio frequency ablation combined with interleukin-2, radio frequency ablation only, interleukin-2 only or no treatment as the control. Immunohistochemistry was done to determine which cells were present in the tumor after treatment. In vitro tumor specific cytotoxicity assays were performed with CD8+ T and natural killer cells derived from the spleen of treated mice. To study whether treatment could prevent metastasis or affect the growth of established metastases we induced lung metastasis intravenously before or after treatment and subsequently quantified it. RESULTS The number of natural killer, CD4+ and CD8+ T cells was significantly increased in the tumor tissue of radio frequency ablation/interleukin-2 treated mice (p <0.0001). Natural killer and CD8+ T cells showed strong antitumor activity in vitro after combination treatment. Lung metastatic formation was significantly prevented in mice that received combination therapy (p <0.0001). Lung metastases were significantly smaller after combination treatment (vs interleukin-2 p = 0.025). CONCLUSIONS Radio frequency ablation of the primary tumor combined with interleukin-2 induces a systemic antitumor immune response to renal cell carcinoma, which is much stronger than that of interleukin-2 monotherapy. This effect appears to be mediated by natural killer and CD8+ T cells. It may have an important role in the development of new immunotherapy strategies for renal cell carcinoma.

Photodynamic Therapy as Novel Nephron Sparing Treatment Option for Small Renal Masses

PURPOSE Photodynamic therapy has great potential as nephron sparing therapy for small renal masses. Using mTHPC [meso-tetra(hydroxyphenyl)chlorin] (BioLitec Pharma, Dublin, Ireland), a photosensitizer that targets vasculature and tissue, we determined whether renal tumors could be ablated using mTHPC mediated photodynamic therapy in a translational renal carcinoma mouse model. MATERIALS AND METHODS We administered mTHPC intravenously in kidney tumor bearing mice. Tumor diameter was about 7 mm. At several drug-light intervals a cylindrical laser fiber was placed intratumorally for interstitial illumination using a wavelength of 652 nm. We determined mTHPC biodistribution up to 48 hours after administration and tumor destruction after mTHPC mediated photodynamic therapy. In vitro mTHPC uptake and photodynamic therapy induced cytotoxicity were studied in human endothelial, renal and renal cell carcinoma cell lines. RESULTS Ablated regions with a maximum diameter of 9.3 mm and complete loss of cell viability were observed at a drug-light interval of 4 hours, when mTHPC was increased in blood and tissue. Viable renal tissue remained detectable outside the illuminated area. In endothelial cells mTHPC uptake and sensitivity to photodynamic therapy were increased compared to those in renal cell carcinoma and renal cells. CONCLUSIONS mTHPC mediated photodynamic therapy is a nephron sparing therapy. The extent of renal tumor destruction is adequate for clinical translation. Localization of mTHPC in tumor vasculature and tissue produces a strong combined effect. Our findings justify further preclinical studies of the applicability of photodynamic therapy for renal cell carcinoma before photodynamic therapy can become a valuable addition to current minimally invasive treatments of small renal masses.

Incomplete cryo- of radiofrequente ablatie van een niertumor stimuleert de groei van achterblijvende tumorcellen: studie in een muismodel

SamenvattingIntroductie:De studie is opgezet om het effect van onvolledige behandeling met radiofrequente ablatie (RFA) te vergelijken met dat van cryoablatie (CA) en partiële nefrectomie (PN) op de aanwezigheid van celgroei, apoptose en groeistimulerende factoren.Methoden:Renca-niertumoren werden getransplanteerd onder het nierkapsel in Balb/C-muizen (4-6 muizen/groep) en onvolledig behandeld met RFA, CA of PN, of niet behandeld (controle). Na 2 uur en na 1, 3, 7 en 14 dagen werd de aanwezigheid van celproliferatie (Ki67), apoptose (Casp3), hypoxie, inflammatie (CD45, F4/80) en heat shock proteins (HSP70 en HSP90) geëvalueerd door middel van immunohistochemie.Resultaten:Er was een toegenomen groei en afgenomen apoptose van achterblijvende tumorcellen na RFA en CA. Proliferatie was hoger (p < 0,05) en apoptose lager (p < 0,05) na RFA dan na CA. Er was sprake van meer hypoxie en meer HSP’s vanaf 2 uur tot 7 dagen na ablatie (p < 0,0001). Inflammatoire cellen waren later aanwezig (piek na 1 week). Al deze factoren waren niet of nauwelijks verhoogd na PN.Conclusie:De conclusie is dat er sprake is van een toegenomen groei en verminderde apoptose van achterblijvende niertumorcellen na onvolledige behandeling met RFA en CA in dit studiemodel, waarbij vooral na onvolledige behandeling met RFA significant meer proliferatie en minder apoptose wordt geobserveerd. Dit is niet het geval na onvolledige behandeling met PN. Door ablatie geïnduceerde groeistimulerende factoren als hypoxie en HSP’s kunnen hieraan ten grondslag liggen. Deze studie onderstreept het belang van het streven naar complete ablatie, wil men een goede oncologische uitkomst bereiken.SummaryIncomplete thermal ablation stimulates proliferation of residual renal carcinoma cells in a translational murine modelAim:Aim of the study was to compare the effect of incomplete thermal ablation versus partial nephrectomy (PN) on growth stimulation and cellular survival in renal tumours.Methods:Renca tumours were transplanted under the renal capsule in Balb/C mice (4-6 mice/group) and not (control), or incompletely treated with radiofrequency ablation (RFA), cryoablation (CA) or partial nephrectomy (PN). After 2 hours and 1, 3, 7, 14 days, the presence of proliferation (Ki67), apoptosis (Casp3), hypoxia, inflammation (CD45, F4/80) and heat shock proteins (HSP70 en HSP90) was evaluated using immunohistochemistry.Results:There was an increased proliferation and decreased apoptosis of residual tumor cells after RFA and CA. Proliferation rate was higher (p < 0.05) and apoptosis lower (p < 0.05) following RFA compared to CA. Hypoxia and HSPs were increasingly present from 2 hours up to 7 days following ablation (p < 0.0001). Inflammatory cells were present at later timepoints (peak at 1 week). These factors were not or minimally present following PN.Conclusion:There is an increased proliferation and decreased apoptosis of residual cells after incomplete RFA and CA. This effect is stronger following RFA compared to CA, and not present following PN. Growth stimulatory factors, such as hypoxia and HPSs could play an important role in this phenomenon. This study underlines the importance of achieving complete tumour destruction.

De follow-up na chirurgische behandeling van het gelokaliseerde niercelcarcinoom: een vragenlijst onder Nederlandse urologen

SamenvattingInleiding:Momenteel bestaat er geen consensus over de followupstrategie na de chirurgische behandeling van een gelokaliseerd niercelcarcinoom (NCC). Het doel van deze studie is inzicht te krijgen in de klinische toepassing en de persoonlijke visie van Nederlandse urologen over de follow-upstrategieën bij NCC.Materiaal:Een anonieme enquête is verzonden naar alle Nederlandse urologen. Vragen betroffen enkele karakteristieken van de uroloog in kwestie, het huidige follow-upbeleid dat is gevolgd door deze uroloog en de persoonlijke mening over het nut en de toekomst van follow-up bij NCC. De uitkomsten zijn gekwantificeerd en vergeleken.Resultaten:Er reageerden 154 urologen (41%). 86% van de respondenten gebruikt een richtlijn, de helft volgt deze richtlijn exact. De meest gebruikte richtlijnen zijn die van de EAU (27%) en de VIKC/NVU (46%), of een combinatie van beide (14%). De voornaamste reden voor follow-up is het vroeg ontdekken en behandelen van recidieven (64%). 42% van de respondenten is van mening dat het vroeg behandelen van metastasen de overleving verbetert en 52% denkt zo over het vroeg behandelen van lokale recidieven. Een meerderheid (68%) vindt dat de follow-upstrategie gestandaardiseerd zou moeten worden in Nederland; 67% denkt dat deze strategie zou moeten worden aangepast aan het risicoprofiel van de tumor.Conclusie:De meerderheid van de urologen is van mening dat er 1 gestandaardiseerde follow-uprichtlijn in Nederland zou moeten zijn, gebaseerd op het risicoprofiel van de tumor.SummaryFollow-up strategies for surgically treated localized renal cell carcinoma (RCC): a questionnaire among Dutch urologistsBackground:There is no consensus regarding follow-up strategies for surgically treated localized renal cell carcinoma (RCC). This study aimed to get an insight in current clinical practice and attitude of urologists regarding follow-up strategies for RCC.Design:A 16-point anonymous questionnaire was sent to all urologists in the Netherlands. Questionnaire subjects were respondent characteristics, current clinical practice regarding follow-up, personal perceptions on the use of follow-up and future directions. Answers were quantified and compared.Results:The response rate was 41% (154/374). At decisive moments 86% used a guideline, approximately 50% followed these guidelines exactly. A majority (67%) agreed that the follow-up guidelines should be standardized and adapted to the risk-profile of the tumor.Conclusions:The majority of Dutch urologists use guidelines for follow-up after surgical treatment of localized RCC. However, these are often not specifically followed. The majority believes that one standardised follow-up guideline should be available, a guideline adapted to the risk profile of the tumor.

383 RADIOFREQUENCY ABLATION COMBINED WITH INTERLEUKIN-2 PREVENTS METASTASIS FORMATION IN MOUSE RENAL CELL CARCINOMA

curves showed that patients with positive Hsp27 expression had significantly shorter cancer specific survival than those with negative Hsp27 expression (log-rank: p 0.0001). Other factors shown by univariate analysis to be significantly associated with shortened cancer specific survival were advanced pathological stage (T3-4, p 0.0001), regional lymph node metastasis (N1 or greater, p 0.0044), distant metastasis (M1, p 0.0001), higher histological grade (G3, p 0.0050) and microvascular invasion (p 0.0001). A multivariate Cox proportional hazard model analysis demonstrated that positive Hsp27 expression, and distant metastasis and microvascular invasion were independent predictors of shortened cancer specific survival (p 0.0048, 0.0065, 0.0107). CONCLUSIONS: Our data suggest that increased Hsp27 expression might be an indicator of tumor aggressiveness and poor prognosis of RCC. Patients with Hsp27 positive tumors should be followed closely and carefully, and adjuvant therapy should be considered.