Marc Olivier Timsit

A 16-gene assay to predict recurrence after surgery in localised renal cell carcinoma: development and validation studies

BACKGROUNDnThe likelihood of tumour recurrence after nephrectomy in localised clear cell renal cell carcinoma is well characterised by clinical and pathological parameters. However, these assessments can be improved and personalised by the addition of molecular characteristics of each patients tumour. We aimed to develop and validate a prognostic multigene signature to improve prediction of recurrence risk in clear cell renal cell carcinoma.nnnMETHODSnIn the development stage, we investigated the association between expression of 732 genes, measured by reverse-transcription PCR, and clinical outcome in 942 patients with stage I-III clear cell renal cell carcinoma who had undergone a nephrectomy at the Cleveland Clinic (OH, USA). 516 genes were associated with recurrence-free interval. 11 of these genes were selected by further statistical analyses, and were combined with five reference genes (ie, 16 genes in total), from which a recurrence score algorithm was developed. The recurrence score was then validated in an independent cohort of 626 patients from France with stage I-III clear cell renal cell carcinoma who had also undergone nephrectomy. The association between the recurrence score and the risk of recurrence and cancer-specific survival in the first 5 years after surgery was assessed using Cox proportional hazard regression, stratified by tumour stage (stage I vs stage II vs III).nnnFINDINGSnIn our primary univariate analysis, the continuous recurrence score (median 37, IQR 31-45) was significantly associated with recurrence-free interval (hazard ratio 3·91 [95% CI 2·63-5·79] for a 25-unit increase in score, p<0·0001). In multivariable analyses, the recurrence score was significantly associated with the risk of tumour recurrence (hazard ratio per 25-unit increase in the score 3·37 [95% CI 2·23-5·08], p<0·0001) after stratification by stage and adjustment for tumour size, grade, or Leibovich score. The recurrence score was able to identify a clinically significant number of both high-risk stage I and low-risk stage II-III patients. A heterogeneity study on separate samples showed little to no intratumoural variability among the 16 genes.nnnINTERPRETATIONnOur findings validate the recurrence score as a predictor of clinical outcome in patients with stage I-III clear cell renal cell carcinoma, providing a more accurate and individualised risk assessment beyond existing clinical and pathological parameters.nnnFUNDINGnGenomic Health Inc and Pfizer Inc.

Urinary C-X-C Motif Chemokine 10 Independently Improves the Noninvasive Diagnosis of Antibody–Mediated Kidney Allograft Rejection

Urinary levels of C-X-C motif chemokine 9 (CXCL9) and CXCL10 can noninvasively diagnose T cell-mediated rejection (TCMR) of renal allografts. However, performance of these molecules as diagnostic/prognostic markers of antibody-mediated rejection (ABMR) is unknown. We investigated urinary CXCL9 and CXCL10 levels in a highly sensitized cohort of 244 renal allograft recipients (67 with preformed donor-specific antibodies [DSAs]) with 281 indication biopsy samples. We assessed the benefit of adding these biomarkers to conventional models for diagnosing/prognosing ABMR. Urinary CXCL9 and CXCL10 levels, normalized to urine creatinine (Cr) levels (CXCL9:Cr and CXCL10:Cr) or not, correlated with the extent of tubulointerstitial (i+t score; all P<0.001) and microvascular (g+ptc score; all P<0.001) inflammation. CXCL10:Cr diagnosed TCMR (area under the curve [AUC]=0.80; 95% confidence interval [95% CI], 0.68 to 0.92; P<0.001) and ABMR (AUC=0.76; 95% CI, 0.69 to 0.82; P<0.001) with high accuracy, even in the absence of tubulointerstitial inflammation (AUC=0.70; 95% CI, 0.61 to 0.79; P<0.001). Although mean fluorescence intensity of the immunodominant DSA diagnosed ABMR (AUC=0.75; 95% CI, 0.68 to 0.82; P<0.001), combining urinary CXCL10:Cr with immunodominant DSA levels improved the diagnosis of ABMR (AUC=0.83; 95% CI, 0.77 to 0.89; P<0.001). At the time of ABMR, urinary CXCL10:Cr ratio was independently associated with an increased risk of graft loss. In conclusion, urinary CXCL10:Cr ratio associates with tubulointerstitial and microvascular inflammation of the renal allograft. Combining the urinary CXCL10:Cr ratio with DSA monitoring significantly improves the noninvasive diagnosis of ABMR and the stratification of patients at high risk for graft loss.

Tim-3 Expression on Tumor-Infiltrating PD-1+CD8+ T Cells Correlates with Poor Clinical Outcome in Renal Cell Carcinoma

Inhibitory receptors expressed by T cells mediate tolerance to tumor antigens, with coexpression of these receptors exacerbating this dysfunctional state. Using the VectraR automated multiparametric immunofluorescence technique, we quantified intratumoral CD8+ T cells coexpressing the inhibitory receptors PD-1 and Tim-3 from patients with renal cell carcinoma (RCC). A second validation cohort measured the same parameters by cytometry. The percentage of tumor-infiltrating CD8+ T cells coexpressing PD-1 and Tim-3 correlated with an aggressive phenotype and a larger tumor size at diagnosis. Coexpression of PD-1 and Tim-3 above the median conferred a higher risk of relapse and a poorer 36-month overall survival. Notably, other CD8+T-cell subsets did not exert a similar effect on overall survival. Moreover, only the PD-1+Tim-3+ subset of CD8+ T cells exhibited impaired function after stimulation. Our findings establish intratumoral Tim-3+PD1+CD8+ T cells as critical mediators of an aggressive phenotype in RCC. Use of the Vectra tool may be useful to identify similarly critical prognostic and predictive biomarkers in other tumor types and their response to immunotherapy. Cancer Res; 77(5); 1075-82. ©2016 AACR.

Impact of surgical procedures and complications on outcomes of third and subsequent kidney transplants.

Background. Surgical procedures and complications have rarely been described in patients receiving a third or subsequent renal transplant. Methods. Data from 61 consecutive third (n=56), fourth (n=4), and fifth (n=1) renal transplants performed during 1974 to 2005 were analyzed retrospectively. Results. Actuarial graft survival was 91%, 74%, and 57% at one, five, and 10 years, respectively. Technical failure accounted for the loss of three grafts (5%). A transperitoneal approach was necessary in 41% of patients. Technical difficulties occurred in half of the procedures, mainly due to atheroma or vascular calcifications. Overall, there were 45 surgical complications in 30 patients, of urological (n=11), vascular (n=6), infectious (n=9), hemorrhagic (n=12), digestive (n=3), or wound origin (n=4). The rate of surgical revision was 16%. Univariate analysis showed that among surgical complications, only vascular complications were associated with a poor graft outcome (P=0.02). Urological complications did not influence long-term graft outcome. Multivariate analysis of all surgical procedures and complications that might have influenced graft survival showed that only vascular complications were associated with a poorer graft outcome (relative risk=6.13, P=0.015). Conclusions. Despite a high rate of surgical complications and revisions, third and subsequent kidney transplantations may be performed safely by experienced surgeons without surgical complications influencing long-term graft outcome.

Suture or Hemostatic Agent During Laparoscopic Partial Nephrectomy? A Randomized Study Using a Hypertensive Porcine Model

OBJECTIVESnTo compare the efficacy of 3 biologic hemostatic devices with that of conventional suture during laparoscopic partial nephrectomy (LPN) in a hypertensive porcine model. Improving hemostasis, urinary tract closure, and the warm ischemia (WI) time are important in the development of LPN.nnnMETHODSnA total of 40 pigs were randomized prospectively into 4 groups before bilateral LPN. Right LPN involved 30% of the renal parenchyma without a urinary tract opening, and left LPN involved 40% of the renal parenchyma with a urinary tract opening. The renal section was treated with fibrin/thrombin sealant, fibrin glue, thrombin/gelatin granules, and conventional suture in groups 1, 2, 3, and 4, respectively. At 10 days postoperatively, left retrograde pyelography was performed. The pigs were then killed and the kidneys sent for pathologic analysis. The main criteria were the estimated blood loss, perioperative WI time, leaking pressure during retrograde pyelography, and parenchyma necrotic-induced lesions.nnnRESULTSnThe estimated blood loss was lower in the pigs treated with either thrombin/gelatin granules or suture (P < .001). The use of thrombin/gelatin granules decreased the WI time compared with the use of suture (P < .001). However, the leaking pressure was greater in the pigs treated with suture (P < .01). The mean area of necrosis around the renal section was shorter when no suturing was performed (P < .01).nnnCONCLUSIONSnThe use of thrombin/gelatin granules alone controlled hemostasis as effectively as suture and significantly decreased the WI time. However, conventional suture of the urinary tract, when opened, should be considered. Additional evaluation in humans is required before any clinical recommendation can be made.

Sunitinib for the treatment of benign and malignant neoplasms from von Hippel-Lindau disease: A single-arm, prospective phase II clinical study from the PREDIR group

Von Hippel-Lindau (VHL) disease is an autosomal dominant hereditary cancer syndrome that predisposes affected individuals to the development of multiple benign and malignant tumors. One of the main manifestations of VHL is renal cell carcinoma (RCC). RCC is increasingly being treated with targeted therapies, which offer an alternative treatment option for patients with VHL disease. This study investigated the effectiveness of sunitinib in VHL patients with advanced tumors or tumors unsuitable for surgery. This multicenter, phase II, open-label study from the PREDIR VHL network, treated patients with genetically-confirmed advanced VHL disease with oral sunitinib (50 mg/day for 28 days then a 2-week rest period) until progression. Lesions were performed using magnetic resonance imaging (MRI) and computed tomographic (CT) scan. The primary endpoint was objective response rate; secondary endpoints included tolerability and overall survival. All five patients showed stable disease as best response at 6 months. Two patients showed impressive transitory clinical improvement during early cycles. No patient died during sunitinib treatment. Reasons for discontinuing sunitinib therapy were disease progression (n=1), unacceptable toxicity (n=3) and lack of clinical improvement after 7 cycles (10.5 months) with unacceptable toxicity (n=1). In conclusion, sunitinib was of limited benefit in patients with advanced VHL disease, but had better efficacy against metastatic RCC than other VHL-related lesions. Treatment-related toxicity is an important limiting factor in this frail patient population. New agents with different mechanisms of action are required to treat this disease.

Immunothérapie dans les cancers de la prostate

IMMUNOTHERAPY IN URO-ONCOLOGYnImmunotherapy is moving forward in prostate cancer. The autologous vaccine, Sipuleucel-T has been the first vaccine to be approved by FDA. First results with GVAX, tasquinimob or anti-PD-1 have been disappointing. Ipilimumab seen to be more active at an earlier stage of prostate disease. Identifying predictive factor or surrogate markers of activity of immunotherapy and which agents are clinically effective alone or in combination with others therapies such as hormonal or bone targeted therapies are warranted.

Prospective assessment of the adherent perinephric fat in partial nephrectomies: Predictors and impact on peri-operative outcomes.

543 Background: The surgical complexity of partial nephrectomy (PN) can be partly anticipated using renal morphometric scores that do not consider patient related issues such as obesity or perirenal fat. Our primary objective was to prospectively assess the predictive factors for adherent perinephric fat (APF) and its impact on the onset of complications. The secondary objective was to correlate the surgical appraising with the histological reality of APF. Methods: Fifty consecutive patients undergoing robotic or open PN were prospectively included from November 2014 to March 2015. The previously published Mayo adhesive probability score (MAP score) was calculated and compared to the per-operative surgical assessment of APF using a 0 to 3 scale (APF being defined by a score ≥ 2). Fat was analyzed histologically for fibrosis (HES staining and picrosirius red) and inflammatory infiltrate of macrophages (immunohistochemistry using anti-CD68 antibody). Results: APF was present in 18 patients (36%), with no im...