P. Rischmann

Sphingosine Kinase-1 as a Chemotherapy Sensor in Prostate Adenocarcinoma Cell and Mouse Models

Systemic chemotherapy was considered of modest efficacy in prostate cancer until the recent introduction of taxanes. We took advantage of the known differential effect of camptothecin and docetaxel on human PC-3 and LNCaP prostate cancer cells to determine their effect on sphingosine kinase-1 (SphK1) activity and subsequent ceramide/sphingosine 1-phosphate (S1P) balance in relation with cell survival. In vitro, docetaxel and camptothecin induced strong inhibition of SphK1 and elevation of the ceramide/S1P ratio only in cell lines sensitive to these drugs. SphK1 overexpression in both cell lines impaired the efficacy of chemotherapy by decreasing the ceramide/S1P ratio. Alternatively, silencing SphK1 by RNA interference or pharmacologic inhibition induced apoptosis coupled with ceramide elevation and loss of S1P. The differential effect of both chemotherapeutics was confirmed in an orthotopic PC-3/green fluorescent protein model established in nude mice. Docetaxel induced a stronger SphK1 inhibition and ceramide/S1P ratio elevation than camptothecin. This was accompanied by a smaller tumor volume and the reduced occurrence and number of metastases. SphK1-overexpressing PC-3 cells implanted in animals developed remarkably larger tumors and resistance to docetaxel treatment. These results provide the first in vivo demonstration of SphK1 as a sensor of chemotherapy.

Positive Surgical Margin Appears to Have Negligible Impact on Survival of Renal Cell Carcinomas Treated by Nephron-Sparing Surgery

BACKGROUND The occurrence of positive surgical margins (PSMs) after partial nephrectomy (PN) is rare, and little is known about their natural history. OBJECTIVE To identify predictive factors of cancer recurrence and related death in patients having a PSM following PN. DESIGN, SETTING, AND PARTICIPANTS Some 111 patients with a PSM were identified from a multicentre retrospective survey and were compared with 664 negative surgical margin (NSM) patients. A second cohort of NSM patients was created by matching NSM to PSM for indication, tumour size, and tumour grade. MEASUREMENTS PSM and NSM patients were compared using student t tests and chi-square tests on independent samples. A Cox proportional hazards regression model was used to test the independent effects of clinical and pathologic variables on survival. RESULTS AND LIMITATIONS Mean age at diagnosis was 61+/-12.5 yr. Mean tumour size was 3.5+/-2 cm. Imperative indications accounted for 39% (43 of 111) of the cases. Some 18 patients (16%) underwent a second surgery (partial or total nephrectomy). With a mean follow-up of 37 mo, 11 patients (10%) had recurrences and 12 patients (11%) died, including 6 patients (5.4%) who died of cancer progression. Some 91% (10 of 11) of the patients who had recurrences and 83% of the patients (10 of 12) who died belonged to the group with imperative surgical indications. Rates of recurrence-free survival, of cancer-specific survival, and of overall survival were the same among NSM patients and PSM patients. The multivariable Cox model showed that the two variables that could predict recurrence were the indication (p=0.017) and tumour location (p=0.02). No other variable, including PSM status, had any effect on recurrence. None of the studied parameters had any effect on the rate of cancer-specific survival. CONCLUSIONS PSM status occurs more frequently in cases in which surgery is imperative and is associated with an increased risk of recurrence, but PSM status does not appear to influence cancer-specific survival. Additional follow-up is needed.

Sphingosine kinase-1 activity and expression in human prostate cancer resection specimens

PURPOSE Sphingosine kinase-1 (SphK1) was shown in preclinical models and non-genitourinary cancers to be instrumental in cancer progression, adaptation to hypoxia and in tumour angiogenesis. No data were available in human prostate cancer. The present study was designed to assess SphK1 expression and activity in radical prostatectomy specimens and to research correlations with clinical features. MATERIALS AND METHODS Transverse section of fresh tissue was obtained from 30 consecutive patients undergoing laparoscopic prostatectomy. SphK1 enzymatic activities of tumour and normal counterpart were determined. Relationships with PSA, Gleason sum, pathological stage, resection margin status and treatment failure were researched. SphK1 pattern of expression was then assessed on tissue microarray. RESULTS A significant 2-fold increase in SphK1 enzymatic activity(11.1 ± 8.4 versus 5.9 ± 3.2 (P<0.04)) was observed in cancer. The upper quartile of SphK1 activity was associated with higher PSA (16.7 versus 6.4 ng/ml, P = 0.04), higher tumor volumes (20.7 versus 9.8, P = 0.002), higher rates of positive margins (85.7% versus 28.6%, P = 0.01) and surgical failure (71.4% versus 9.5%, P = 0.003) than the lower three quartiles. Odds ratios (OR) for treatment failure showed a strong relationship with SphK1 activity (OR: 23.7, P = 0.001), positive resection margins (OR: 15.0, P = 0.007) and Gleason sum (≥4+3, OR: 8.0, P = 0.003). Tissue microarrays showed discrete epithelial expression that varied with Gleason sum with significant relationship between SphK1 expression and higher Gleason sum. CONCLUSION In complement to preclinical literature, the demonstrated relationships between SphK1-increased activity in cancer and relevant clinical features confirm a central role for SphK1 in prostate cancer that herald promising avenues in risk-assessment and treatment.

A prospective comparison of surgical and pathological outcomes obtained after robot‐assisted or pure laparoscopic partial nephrectomy in moderate to complex renal tumours: results from a French multicentre collaborative study

Nephron‐sparing surgery has become the standard of care for small renal masses because it allows for the same oncological control as radical nephrectomy and achieves better overall survival, while lowering the risk of subsequent chronic renal failure. Mini‐invasive surgical approaches have also been developed, e.g. laparoscopic partial nephrectomy (LPN) and robot‐assisted laparoscopic PN (RAPN), which result in less bleeding, reduced postoperative pain, shorter length of stay (LOS) and shorter recovery time. LPN requires advanced surgical skill, has a longer learning curve and requires perseverance, which limits its large diffusion. From this prospective comparative study, we can now claim that RAPN is not inferior to pure LPN in terms of perioperative outcomes (i.e. blood loss, operative duration, warm ischaemia time, LOS).

Development of a standardised training curriculum for robotic surgery: a consensus statement from an international multidisciplinary group of experts

To explore the views of experts about the development and validation of a robotic surgery training curriculum, and how this should be implemented.

Sphingosine Kinase-1 Is Central to Androgen-Regulated Prostate Cancer Growth and Survival

Background Sphingosine kinase-1 (SphK1) is an oncogenic lipid kinase notably involved in response to anticancer therapies in prostate cancer. Androgens regulate prostate cancer cell proliferation, and androgen deprivation therapy is the standard of care in the management of patients with advanced disease. Here, we explored the role of SphK1 in the regulation of androgen-dependent prostate cancer cell growth and survival. Methodology/Principal Findings Short-term androgen removal induced a rapid and transient SphK1 inhibition associated with a reduced cell growth in vitro and in vivo, an event that was not observed in the hormono-insensitive PC-3 cells. Supporting the critical role of SphK1 inhibition in the rapid effect of androgen depletion, its overexpression could impair the cell growth decrease. Similarly, the addition of dihydrotestosterone (DHT) to androgen-deprived LNCaP cells re-established cell proliferation, through an androgen receptor/PI3K/Akt dependent stimulation of SphK1, and inhibition of SphK1 could markedly impede the effects of DHT. Conversely, long-term removal of androgen support in LNCaP and C4-2B cells resulted in a progressive increase in SphK1 expression and activity throughout the progression to androgen-independence state, which was characterized by the acquisition of a neuroendocrine (NE)-like cell phenotype. Importantly, inhibition of the PI3K/Akt pathway—by negatively impacting SphK1 activity—could prevent NE differentiation in both cell models, an event that could be mimicked by SphK1 inhibitors. Fascinatingly, the reversability of the NE phenotype by exposure to normal medium was linked with a pronounced inhibition of SphK1 activity. Conclusions/Significance We report the first evidence that androgen deprivation induces a differential effect on SphK1 activity in hormone-sensitive prostate cancer cell models. These results also suggest that SphK1 activation upon chronic androgen deprivation may serve as a compensatory mechanism allowing prostate cancer cells to survive in androgen-depleted environment, giving support to its inhibition as a potential therapeutic strategy to delay/prevent the transition to androgen-independent prostate cancer.

Technical solutions to improve the management of non‐muscle‐invasive transitional cell carcinoma: summary of a European Association of Urology Section for Uro‐Technology (ESUT) and Section for Uro‐Oncology (ESOU) expert meeting and current and future perspectives

The aim of the present review was to compare state‐of‐the‐art care and future perspectives for the detection and treatment of non‐muscle‐invasive transitional cell carcinoma (TCC) of the bladder. We provide a summary of the third expert meeting on ‘Optimising the management of non‐muscle‐invasive bladder cancer, organized by the European Association of Urology Section for Uro‐Technology (ESUT) in collaboration with the Section for Uro‐Oncology (ESOU), including a systematic literature review. The article includes a detailed discussion on the current and future perspectives for TCC, including photodynamic diagnosis, optical coherence tomography, narrow band imaging, the Storz Professional Image Enhancement system, magnification and high definition techniques. We also provide a detailed discussion of future surgical treatment options, including en bloc resection and tumour enucleation. Intensive research has been conducted to improve tumour detection and there are promising future perspectives, that require proven clinical efficacy. En bloc resection of bladder tumours may be advantageous, but is currently considered to be experimental.

Venous thromboembolism prophylaxis in patients undergoing abdominal or pelvic surgery for cancer - A real-world, prospective, observational French study: PRéOBS☆ , ☆☆ ,★

INTRODUCTION Data on the epidemiology and prevention of venous thromboembolism in patients undergoing abdominal or pelvic cancer surgery in real practice are limited. The primary objective of this observational study was to describe the thromboprophylactic strategy implemented in routine practice. The main secondary objective was to assess the incidence of outcomes. MATERIALS AND METHODS Patients admitted to public or private hospitals for abdominal or pelvic cancer surgery were included between November 2009 and November 2010; endoscopic route for surgery was the only exclusion criterion. Study outcomes were recorded at hospital discharge and at routine follow-up (generally 9±3weeks). RESULTS 2380 patients (mean±SD age: 66.4±11.6years, women: 36.8%) admitted to hospital for abdominal (47.8%), urological (41%), or gynaecological (11.2%) cancer surgery were included in the analysis. Of these, 2179 had data available at study end. Perioperative antithrombotic prophylaxis, consisting mainly of low-molecular-weight heparin, was given to 99.5% of patients. At hospital discharge, thromboprophylaxis was continued in 91.7% of patients, 57.4% receiving a 4-6week prophylaxis. This management strategy was associated with an overall venous thromboembolic event rate of 1.9%, 34.7% of events occurring after discharge. Incidences of fatal bleeding, bleeding in a critical organ and bleeding necessitating re-intervention were 0.1%, 0.3% and 1.7%, respectively. Overall mortality was 1.5%. CONCLUSIONS Thromboprophylaxis is routinely used in French patients undergoing major cancer surgery. For more than a third of patients, however, treatment duration did not comply with best-practice recommendations, which might explain the non-negligible rate of thromboembolic complications still observed in this patient population.

Prostate cancer incidence on cystoprostatectomy specimens is directly linked to age: results from a multicentre study

To assess the incidence and age‐related histopathological characteristics of incidentally diagnosed prostate cancer from specimens obtained via radical cystoprostatectomy (RCP) for muscle‐invasive bladder cancer.

Une taille tumorale supérieure à 7 cm influence-t-elle les résultats de la néphrectomie partielle pour tumeur du rein ?

OBJECTIVE To assess the impact of a tumor size higher than 7cm on partial nephrectomy (PN) outcomes compared to a tumor size ranging between 4 and 7cm and to compare this impact to one of the RENAL score. PATIENTS AND METHODS Data from patients who underwent PN between 2006 and 2013 were retrospectively analysed. Patients with cT1b tumors and cT2 were included. Functional and oncological outcomes were compared. Analysis of the achievement of Trifecta (defined as a combination of warm ischemia time<25min, negative surgical margins and no perioperative complications) was performed according to the tumor size and the RENAL score. RESULTS Among 334 PN, 57 patients were included, (41 cT1b and 16 cT2), with a median follow-up of 23.5 months (6-88). There was no difference between the groups regarding intraoperative parameters except for the conversion rate, which was higher in the cT2 group (30% vs. 4.3%; P=0.02). The cT2 group also presented higher renal function impairment at postoperative day 4 (P=0.04) which did not persist at 6 months. There was no significant difference in oncologic outcomes between the 2 groups. The rate of achievement of the Trifecta did not differ between cT1b and cT2 groups. Conversely, Trifecta rate was higher in case of low complexity renal masses (RENAL score 4-6) compared to complex renal tumors (RENAL score 7-9 and 10-12). CONCLUSION Our results showed that a tumor size higher than 7cm had no impact on PN outcomes in selected tumors according to complexity scores such as the RENAL score. Furthermore, a lower RENAL score appeared to be significantly associated with the Trifecta achievement. LEVEL OF EVIDENCE 5.