Ketogenic diet enhances the anti-cancer effects of PD-L1 blockade in renal cell carcinoma.

Introduction: Clear cell renal cell carcinoma (ccRCC) is characterized by a predominant metabolic reprogramming triggering energy production by anaerobic glycolysis at the expense of oxydative phosphorylation. Ketogenic diet (KD), which consists of high fat and low carbohydrate intake, could bring required energy substrates to healthy cells while depriving tumor cells of glucose. Our objective was to evaluate the effect of KD on renal cancer cell tumor metabolism and growth proliferation. Methods: Growth cell proliferation and mitochondrial metabolism of ACHN and Renca renal carcinoma cells were evaluated under ketone bodies (KB) exposure. In vivo studies were performed with mice (nude or Balb/c) receiving a xenograft of ACHN cells or Renca cells, respectively, and were then split into 2 feeding groups, fed either with standard diet or a 2:1 KD ad libitum. To test the effect of KD associated to immunotherapy, Balb/c mice were treated with anti-PDL1 mAb. Tumor growth was monitored. Results: In vitro, KB exposure was associated with a significant reduction of ACHN and Renca cell proliferation and viability, while increasing mitochondrial metabolism. In mice, KD was associated with tumor growth reduction and PDL-1 gene expression up-regulation. In Balb/c mice adjuvant KD was associated to a better response to anti-PDL-1 mAb treatment. Conclusion: KB reduced the renal tumor cell growth proliferation and improved mitochondrial respiration and biogenesis. KD also slowed down tumor growth of ACHN and Renca in vivo. We observed that PDL-1 was significantly overexpressed in tumor in mice under KD. Response to anti-PDL-1 mAb was improved in mice under KD. Further studies are needed to confirm the therapeutic benefit of adjuvant KD combined with immunotherapy in patients with kidney cancer.

Does the Time to Start First-Line Treatment Influence the Survival of Favorable-Risk Patients With Metastatic Renal Cell Carcinoma? Results of the MetaSurv-UroCCR 79 Study.

INTRODUCTION AND OBJECTIVES: Many patients in the favorable International Metastatic renal cell carcinoma (RCC) Data Base Consortium group (F-MRC) may have a relatively indolent disease course. Surveillance and delay of systemic therapy could be an option in this specific population. However, the question whether this delay could alter patients' outcome remains unanswered. Our objective was to determine if delaying first-line treatment influences the survival of F-MRC patients. MATERIALS AND METHODS: We performed a retrospective multicenter national study involving the French Network for Research on Kidney Cancer UroCCR (NCT03293563). We included treatment naive F-MRC patients. We compared the overall survival of patients with immediate medical treatment (IMT) (started less than 3 months after metastatic diagnosis) to those with delayed medical treatment (DMT). RESULTS: We included 90 patients treated between 2009 and 2018. The median time before occurrence of metastases from diagnosis was 28 (12-137) months. The two groups (IMT vs. DMT) were comparable for follow-up, age, sarcomatoid feature, number, and localization of metastatic sites and ECOG performance status. IMT was given in 25 (27.8 %) patients. Local treatment of metastasis (LTM) was performed in 47 (52%) patients. Patients with DMT had more LTM (63% vs. 24%, P = .001). Among patients with DMT (n = 65); 27 (41%) received a systemic treatment and median systemic treatment-free survival was 39 months (95% CI, 26.3-51.6). Median overall survival from metastasis disease diagnosis was 55 months (95% CI, 42.4-67.5) in the IMT group and 88 months (95%CI, 64-111.9) in the DMT group (P = .028). In multivariable analysis LTM was the only prognostic factor associated to survival improvement (HR: 0.33; P = .024). CONCLUSIONS: Selected Patients with F-MRC may safely undergo DMT. LTM positively impacted survival in this population and should be considered whenever possible. Prospective trial with a larger population is needed to confirm these results.

[Impact of delay before partial nephrectomy of a localized kidney tumor]. / Impact du délai avant prise en charge par néphrectomie partielle d'une tumeur du rein localisée.

INTRODUCTION: Partial nephrectomy is the treatment of choice for small localized renal tumors. In case of doubt, a biopsy can confirm the diagnosis. The aim of this study was to evaluate the impact of a delayed time to partial nephrectomy on cancer development. MATERIALS AND METHODS: Our single center study enrolled localized renal tumor patients who underwent a partial nephrectomy between 2015 and 2020; the collected data were included in the uroCCR prospective database. The histopathological stage of the tumors and the recurrence rate in patients treated with surgery >90 days after diagnosis were investigated. The impact a preoperative biopsy on was also explored. Statistical significance was tested using Student's t-test and Chi-squared test (SPSS software). RESULTS: The cohort consisted of 179 patients, among which 41 (23 %) received a preoperative biopsy. 89 patients (50 %) were treated surgically >3 months after diagnosis. The median time to nephrectomy was 86 days (13-1 037). A delayed time to surgery did not lead to significantly higher recurrence rates (P=0.66). Preoperative biopsy led to a doubling time to surgery (P<0.001) but was neither correlated to a more severe tumor stage (P=0.944) nor to a higher recurrence rate (P=0.08). Tumor growth was not significantly different with or without the presence of a biopsy (P=0.122). CONCLUSION: Our data evidence that a substantial delayed time to partial nephrectomy does not result in a negative impact on cancer prognosis in localized renal tumor patients.