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.

Multi-ancestry genome-wide association study of kidney cancer identifies 63 susceptibility regions.

Here, in a multi-ancestry genome-wide association study meta-analysis of kidney cancer (29,020 cases and 835,670 controls), we identified 63 susceptibility regions (50 novel) containing 108 independent risk loci. In analyses stratified by subtype, 52 regions (78 loci) were associated with clear cell renal cell carcinoma (RCC) and 6 regions (7 loci) with papillary RCC. Notably, we report a variant common in African ancestry individuals ( rs7629500 ) in the 3' untranslated region of VHL, nearly tripling clear cell RCC risk (odds ratio 2.72, 95% confidence interval 2.23-3.30). In cis-expression quantitative trait locus analyses, 48 variants from 34 regions point toward 83 candidate genes. Enrichment of hypoxia-inducible factor-binding sites underscores the importance of hypoxia-related mechanisms in kidney cancer. Our results advance understanding of the genetic architecture of kidney cancer, provide clues for functional investigation and enable generation of a validated polygenic risk score with an estimated area under the curve of 0.65 (0.74 including risk factors) among European ancestry individuals.

Prospective Comparison of Thulium and Holmium Laser Lithotripsy for the Treatment of Upper Urinary Tract Lithiasis.

Background: Lithotripsy with holmium:yttrium-aluminum-garnet (Ho:YAG) laser is the current gold standard for treating stones of the upper urinary tract (UUT). The recently introduced thulium fiber laser (TFL) has the potential to be more efficient and as safe as Ho:YAG. Objective: To compare the performance and complications between Ho:YAG and TFL for UUT lithotripsy. Design setting and participants: This was a prospective single-center study of 182 patients treated between February 2021 and February 2022. In a consecutive approach, laser lithotripsy was performed via ureteroscopy with Ho:YAG for 5 mo, and then with TFL for 5 mo. Outcome measurements and statistical analysis: Our primary outcome was stone-free (SF) status at 3 mo after ureteroscopy with Ho:YAG versus TFL lithotripsy. Secondary outcomes were complication rates and results regarding the cumulative stone size. Patients were followed at 3 mo with abdominal imaging (ultrasound or computed tomography). Results and limitations: The study cohort comprised 76 patients treated with Ho:YAG laser and 100 patients treated with TFL. Cumulative stone size was significantly higher in the TFL than in the Ho:YAG group (20.4 vs 14.8 mm; p = 0.01). SF status was similar in both groups (68.4% vs 72%; p = 0.06). Complication rates were comparable. In subgroup analysis, the SF rate was significantly higher (81.6% vs 62.5%; p = 0.04) and the operative time was shorter for stones measuring 1-2 cm, whereas the results were similar for stones <1 cm and >2 cm. The lack of randomization and single-center design are the main limitations of the study. Conclusions: TFL and Ho:YAG lithotripsy are comparable in terms of the SF rate and safety for the treatment of UUT lithiasis. According to our study, for a cumulative stone size of 1-2 cm, TFL is more effective than Ho:YAG. Patient summary: We compared the efficiency and safety of two laser types for the treatment of stones in the upper urinary tract. We found that stone-free status at 3 months did not significantly differ between the holmium and thulium lasers.

Effects of Large Extracellular Vesicles from Kidney Cancer Patients on the Growth and Environment of Renal Cell Carcinoma Xenografts in a Mouse Model.

Plasma membrane-derived vesicles, also referred to as large extracellular vesicles (lEVs), are implicated in several pathophysiological situations, including cancer. However, to date, no studies have evaluated the effects of lEVs isolated from patients with renal cancer on the development of their tumors. In this study, we investigated the effects of three types of lEVs on the growth and peritumoral environment of xenograft clear cell renal cell carcinoma in a mouse model. Xenograft cancer cells were derived from patients' nephrectomy specimens. Three types of lEVs were obtained from pre-nephrectomy patient blood (cEV), the supernatant of primary cancer cell culture (sEV) and from blood from individuals with no medical history of cancer (iEV). Xenograft volume was measured after nine weeks of growth. Xenografts were then removed, and the expression of CD31 and Ki67 were evaluated. We also measured the expression of MMP2 and Ca9 in the native mouse kidney. lEVs from kidney cancer patients (cEV and sEV) tend to increase the size of xenografts, a factor that is related to an increase in vascularization and tumor cell proliferation. cEV also altered organs that were distant from the xenograft. These results suggest that lEVs in cancer patients are involved in both tumor growth and cancer progression.