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.

Effects of a Personalized Diet on Nutritional Status and Renal Function Outcome in Nephrectomized Patients with Renal Cancer.

Nutritional therapy (NT) based on a controlled protein intake represents a cornerstone in managing chronic kidney disease (CKD). However, if a CKD patient is at the same time affected by cancer, oncologists and nutritionists tend to suggest a dietary regimen based on high protein intake to avoid catabolism and malnutrition. International guidelines are not clear when we consider onco-nephrological patients and, as a consequence, no clinical shared strategy is currently applied in clinical practice. In particular, no precise nutritional management is established in nephrectomized patients for renal cell carcinoma (RCC), a specific oncological cohort of patients whose sudden kidney removal forces the remnant one to start a compensatory mechanism of adaptive hyperfiltration. Our study aimed to investigate the efficacy of a low-normal-protein high-calorie (LNPHC) diet based on a Mediterranean model in a consecutive cohort of nephrectomized RCC patients using an integrated nephrologist and nutritionist approach. A consecutive cohort of 40 nephrectomized RCC adult (age > 18) patients who were screened for malnutrition (malnutrition screening tool, MST < 2) were enrolled in a tertiary institution between 2020 and 2022 after signing a specific informed consent form. Each patient underwent an initial nephrological and nutritional evaluation and was subsequently subjected to a conventional CKD LNPHC diet integrated with aproteic foods (0.8 g/Kg/die: calories: 30-35 kcal per kg body weight/die) for a period of 6 months (±2 months). The diet was structured after considering eGFR (CKD-EPI 2021 creatinine formula), comorbidities, and nutritional status. MST, body mass index (BMI), phase angle (PA), fat mass percentage (FM%), fat-free mass index (FFMI), body cell mass index (BCMI), extracellular/intracellular water ratio (ECW/ICW), extracellular matrix/body cell mass ratio (ECM/BCM), waist/hip circumference ratio (WHC), lab test exams, and clinical variables were examined at baseline and after the study period. Our results clearly highlighted that the LNPHC diet was able to significantly improve several nutritional parameters, avoiding malnutrition and catabolism. In particular, the LNPHC diet preserved the BCM index (delta on median, ΔM + 0.3 kg/m2) and reduced the ECM/BCM ratio (ΔM - 0.03 *), with a significant reduction in the ECW/ICW ratio (ΔM - 0.02 *), all while increasing TBW (ΔM + 2.3% *). The LNPHC diet was able to preserve FFM while simultaneously depleting FM and, moreover, it led to a significant reduction in urea (ΔM - 11 mg/dL **). In conclusion, the LNPHC diet represents a new important therapeutic strategy that should be considered when treating onco-nephrological patients with solitary kidney due to renal cancer.

Prognostic nutritional index and prognosis in renal cell carcinoma: A systematic review and meta-analysis.

PURPOSE: To perform a systematic review and meta-analysis of the Prognostic Nutritional Index (PNI) as a prognostic factor for renal cell carcinoma (RCC). MATERIALS AND METHODS: Eligible studies that evaluated the prognostic impact of pretreatment PNI in RCC patients were identified by comprehensive searching the electronic databases PubMed, Cochrane Central Search library, and EMBASE. The end points were overall/cancer-specific survival (OS/CSS) and recurrence-free/disease-free survival (RFS/DFS). Meta-analysis using random-effects models was performed to calculate hazard ratios (HRs) with 95 % confidence intervals (CIs). RESULTS: In total, 9 retrospective, observational, case-control studies involving 5,976 patients were included for final analysis. Eight studies evaluated OS/CSS, and 5 evaluated RFS/DFS. Our results showed that lower PNI was significantly associated with unfavorable OS/CSS (HR = 1.68, 95% CI 1.44-1.96, P < 0.001, I2 = 9.2%, P = 0.359) and RFS/DFS (HR = 1.98, 95% CI 1.57-2.50, P < 0.001, I2 = 18.2%, P = 0.299) in patients with RCC. Subgroup and meta-regression analysis based on ethnicity, study sample size, presence of metastasis, PNI cut-off value, Newcastle-Ottawa quality assessment scale (NOS) score, and gender ratio all showed that lower PNI was associated with poorer OS/CSS and RFS/DFS. Funnel plots and Egger's tests indicated significant publication bias in OS/CSS (P = 0.001), but not in RFS/DFS (P = 0.757). CONCLUSION: This meta-analysis indicated that lower PNI was a negative prognostic factor and associated with tumor progression and poorer survival of patients with RCC. Therefore, PNI could be a potential prognostic predictor of treatment outcomes for patients with RCC.

Ketogenic diet and ketone bodies enhance the anticancer effects of PD-1 blockade.

Limited experimental evidence bridges nutrition and cancer immunosurveillance. Here, we show that ketogenic diet (KD) - or its principal ketone body, 3-hydroxybutyrate (3HB), most specifically in intermittent scheduling - induced T cell-dependent tumor growth retardation of aggressive tumor models. In conditions in which anti-PD-1 alone or in combination with anti-CTLA-4 failed to reduce tumor growth in mice receiving a standard diet, KD, or oral supplementation of 3HB reestablished therapeutic responses. Supplementation of KD with sucrose (which breaks ketogenesis, abolishing 3HB production) or with a pharmacological antagonist of the 3HB receptor GPR109A abolished the antitumor effects. Mechanistically, 3HB prevented the immune checkpoint blockade-linked upregulation of PD-L1 on myeloid cells, while favoring the expansion of CXCR3+ T cells. KD induced compositional changes of the gut microbiota, with distinct species such as Eisenbergiella massiliensis commonly emerging in mice and humans subjected to carbohydrate-low diet interventions and highly correlating with serum concentrations of 3HB. Altogether, these results demonstrate that KD induces a 3HB-mediated antineoplastic effect that relies on T cell-mediated cancer immunosurveillance.

Preclinical renal chemo-protective potential of Prunus amygdalus Batsch seed coat via alteration of multiple molecular pathways.

Prunus amygdalus Batsch (almond) is a classical nutritive traditional Indian medicine. Along with nutritive with anti-oxidant properties, it is, clinically, used in the treatment of various diseases with underlying anti-oxidant mechanism. This study is an effort to scrutinise the renal protective effect of P. amygdalus Batsch or green almond (GA) seed coat extract and its underlying mechanism in animal model of Ferric nitrilotriacetate (Fe-NTA) induced renal cell carcinoma (RCC). RCC was induced in Swiss Albino Wistar rats by intraperitoneal injection of Fe-NTA. The rats were then treated with ethanolic extract of GA (25, 50 and 100 mg/kg per oral) for 22 weeks. Efficacy of GA administration was evaluated by change in biochemical, renal, macroscopical and histopathological parameters and alterations. Additionally, interleukin-6 (IL-6), tumour necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß) and inflammatory mediator including prostaglandin E2 (PGE2), nuclear factor-kappa B (NF-κB) were also observed to explore the possible mechanisms. The oral administration of GA significantly (p < .001) altered the Fe-NTA induced RCC in rats by inhibition of renal nodules, decolourisation of tissues, tumour promoter marker including thymidine 3[H] incorporation, ornithine decarboxylase, renal parameters and anti-oxidant parameters in serum. Additionally, GA treatment significantly (p < .001) down-regulated the IL-6, IL-1ß, TNF-α, inflammatory mediators PGE2 and NF-κB in a dose-dependent manner. Histopathology observation supported the renal protective effect of GA by alteration in necrosis, size of Bowman capsules and inflammatory cells. Hence, it can be concluded that GA possesses observable chemo-protective action and effect on Fe-NTA induced RCC via dual inhibition mechanism one by inhibiting free radical generation and second by inhibiting inflammation.

Prevention of kidney cancer incidence and recurrence: lifestyle, medication and nutrition.

PURPOSE OF REVIEW: The incidence of kidney cancer rises globally with the highest rates in developed countries. This demonstrates the impact of advanced diagnostic imaging but also rising prevalence of modifiable risk factors such as smoking, obesity and hypertension. A literature search was performed with focus on recent studies on risk factors related to lifestyle, medication and nutrition. Further we searched for the effect of cancer prevention strategies. RECENT FINDINGS: Overall, we included 76 studies of the past 5 years. Based on current evidence smoking tobacco, obesity and hypertension remain established risk factors for kidney cancer. Certain analgesics and consumption of processed meat have been linked to increase development of renal cell carcinoma, although data are limited. Fruits, fiber-rich vegetables, coffee and physical activity may have a protective effect against kidney cancer but causal conclusions are not yet supported. Significantly, there is an increasing evidence of inverse association between moderate alcohol consumption. SUMMARY: Overall evidence confirms an effective way to prevent the risk of kidney cancer is maintaining a healthy weight and avoid smoking. State policies should further ensure strategies to raise public awareness and support to adopt healthy lifestyles.

Multidetector CT imaging features of invasive renal parenchyma urothelial carcinoma.

OBJECTIVE: To characterize the multidetector CT imaging features of invasive renal parenchyma urothelial carcinoma (IRPUC). METHODS: 29 patients with IRPUC were retrospectively evaluated. Tumour location, density, cystic or solid appearance, calcification, capsule sign, enhancement pattern and metastases were assessed. RESULTS: IRPUC involved the right kidney in 82.7% of patients. Medullary involvement was observed in 93.1% of patients. In 89.6% of patients, the reniform contour of the kidney was preserved. Tumours showed an infiltrative appearance (100%) with a poorly defined margin (100%), but an expansile component was also present (20.7%). Linear calcification was present (20.7%). Evidence of intra-abdominal metastatic disease (in 37.9% of cases) and regional lymphadenopathy (in 27.5% of cases) was present. Tumour attenuation was less or equal compared with the renal cortex or medulla on unenhanced CT (p-value> 0.05), after i.v. contrast administration; 100% were of homogeneous low attenuation compared with the normal renal cortex and medulla (p-value< 0.05). CONCLUSION: IRPUC tends to be more prevalent in the right kidney, poorly defined margin, medullary involvement, with homogeneous enhancement less than the cortex and medulla in all phases. ADVANCES IN KNOWLEDGE: IRPUC was more prevalent in the right kidney. IRPUC enhancement was less than that of the cortex and medulla on all phases. IRPUC showed poorly defined margin with medullary involvement and preserved reniform contour.

Polymorphisms in genes of the renin-angiotensin-aldosterone system and renal cell cancer risk: interplay with hypertension and intakes of sodium, potassium and fluid.

Hypertension is an established risk factor for renal cell cancer (RCC). The renin-angiotensin-aldosterone system (RAAS) regulates blood pressure and is closely linked to hypertension. RAAS additionally influences homeostasis of electrolytes (e.g. sodium and potassium) and fluid. We investigated single nucleotide polymorphisms (SNPs) in RAAS and their interactions with hypertension and intakes of sodium, potassium and fluid regarding RCC risk in the Netherlands Cohort Study (NLCS), which was initiated in 1986 and included 120,852 participants aged 55 to 69 years. Diet and lifestyle were assessed by questionnaires and toenail clippings were collected. Genotyping of toenail DNA was performed using the SEQUENOM® MassARRAY® platform for a literature-based selection of 13 candidate SNPs in seven key RAAS genes. After 20.3 years of follow-up, Cox regression analyses were conducted using a case-cohort approach including 3,583 subcohort members and 503 RCC cases. Two SNPs in AGTR1 were associated with RCC risk. AGTR1_rs1492078 (AA vs. GG) decreased RCC risk [hazard ratio (HR) (95% confidence interval (CI)): 0.70(0.49-1.00)], whereas AGTR1_rs5186 (CC vs. AA) increased RCC risk [HR(95%CI): 1.49(1.08-2.05)]. Associations were stronger in participants with hypertension. The RCC risk for AGT_rs3889728 (AG + AA vs. GG) was modified by hypertension (p interaction = 0.039). SNP-diet interactions were not significant, although HRs suggested interaction between SNPs in ACE and sodium intake. SNPs in AGTR1 and AGT influenced RCC susceptibility, and their effects were modified by hypertension. Sodium intake was differentially associated with RCC risk across genotypes of several SNPs, yet some analyses had probably inadequate power to show significant interaction. Results suggest that RAAS may be a candidate pathway in RCC etiology.

[Nutritional prevention of urological tumours]. / Alimentäre Prävention urologischer Tumoren.

Through the last decade considerations on the role of vitamins and antioxidants in the primary prevention of genitourinary tumors have changed dramatically. In spite of all efforts, the efficacy of a specific compound has not been proven so far. In consequence, recommendations to use vitamins or other supplements for the primary prevention of urological tumors should be avoided. However, there is some evidence that moderate food consumption, reduction of dairy products and an Asian or Mediterranean diet may not only prevent prostate cancer (PCA) but also harbour additional beneficial effects on general health. Although quantification of these findings may be difficult, it becomes evident that these measures will have additional synergistic effects on cardiovascular diseases. Considering the large number of PCA patients dying not cancer-related but from concomitant diseases, primary prevention in particular of PCA should always also consider the general health of the target population. More recent studies suggest a potential effect of nutritional compounds on biochemical tumour recurrence in PCA patients after definite therapy. These observations may serve as a starting point for validation within controlled clinical trials.

Long-term dietary sodium, potassium and fluid intake; exploring potential novel risk factors for renal cell cancer in the Netherlands Cohort Study on diet and cancer.

BACKGROUND: As sodium, potassium and fluid intake are related to hypertension, an established risk factor for renal cell cancer (RCC), they may be independent risk factors for RCC. METHODS: The Netherlands Cohort Study (NLCS) with case-cohort design included 120,852 participants aged 55-69 years. At baseline, diet and lifestyle were assessed with questionnaires. After 17.3 years of follow-up, 485 RCC cases and 4438 subcohort members were available for analyses. RESULTS: Sodium intake increased RCC risk (P-trend=0.03), whereas fluid and potassium intake did not. For high sodium and low fluid intake, the RCC risk additionally increased (P-interaction=0.02). CONCLUSION: Sodium intake is a potential risk factor for RCC, particularly if fluid consumption is low.

Dietary selenium supplementation modifies breast tumor growth and metastasis.

The survival rate for breast cancer drops dramatically once the disease progresses to the metastatic stage. Selenium (Se) is an essential micronutrient credited with having high anticancer and chemopreventive properties. In our study, we investigated if dietary Se supplementation modified breast cancer development in vivo. Three diets supplemented with sodium selenite, methylseleninic acid (MSA) or selenomethionine (SeMet), as well as a Se-deficient and a Se-adequate diet were fed to mice before mammary gland inoculation of 4T1.2 cells. The primary tumor growth, the numbers of cancer cells present in lungs, hearts, livers, kidneys and femurs and several proinflammatory cytokines were measured. We found that inorganic selenite supplementation provided only short-term delay of tumor growth, whereas the two organic SeMet and MSA supplements provided more potent growth inhibition. These diets also affected cancer metastasis differently. Mice fed selenite developed the most extensive metastasis and had an increased incidence of kidney and bone metastasis. On the other hand, mice fed the SeMet diet showed the least amount of cancer growth at metastatic sites. The MSA diet also provided some protection against breast cancer metastasis although the effects were less significant than those of SeMet. The cytokine profiles indicated that serum levels of interlukin-2, interleukin-6, interferon γ and vascular endothelial growth factor were elevated in SeMet-supplemented mice. There was no significant difference in tumor growth and the patterns of metastasis between the Se-deficient and Se-adequate groups. Our data suggest that organic Se supplementation may reduce/delay breast cancer metastasis, while selenite may exacerbate it.

Constitutional genetic variants as predictors of antiangiogenic therapy outcome in renal cell carcinoma.

The development of specific angiogenesis inhibitors has drastically improved renal cancer treatment in recent years. Currently, four VEGF receptor inhibitors (sorafenib, sunitinib, pazopanib and axitinib), one anti-VEGF monoclonal antibody (bevacizumab) and two inhibitors of the mTOR pathway (temsirolimus and everolimus) have been approved to treat renal cell carcinoma (RCC), and several other molecules are under investigation. However, lack of response to antiangiogenic drugs and adverse drug reactions leading to treatment suspension are critical clinical problems that need to be solved. Because antiangiogenic drugs act on nonmalignant endothelial cells, the genetic background of the patient may play a crucial role determining the efficacy of these drugs. This article focuses on the identification of polymorphisms associated with antiangiogenic drugs outcome in RCC patients. It reviews and summarizes our current knowledge on this area and discusses future strategies to identify new biomarkers that could be used to personalize RCC management.

G250: a carbonic anhydrase IX monoclonal antibody.

G250 or carbonic anhydrase IX (CA IX) is a membrane-associated carbonic anhydrase (CA) thought to play a role in the regulation of cell proliferation in response to hypoxic conditions and may be involved in oncogenesis and tumor progression. G250 refers to a monoclonal antibody (mAb) that was raised by immunization of mice with human renal cell carcinoma (RCC) homogenates. The RCC-associated transmembrane protein designated G250 has since proven to be identical to tumor-associated protein MN or CA IX. Previous studies using a mAb against CA IX have shown that CA IX is induced constitutively in certain tumor types, but is absent in most normal tissues with the exception of epithelial cells of the gastric mucosa. Furthermore, previous immunobiochemical studies of malignant and benign renal tissues revealed that CA IX was also highly expressed in RCC. Studies on tumor-bearing kidneys demonstrate selective uptake of mAb CA IX in antigen-positive cells versus antigen-negative cells. Furthermore, extraordinarily high uptake and the requirement of a low protein dose to obtain tumor saturation with respect to tumor targeting occur with mAb CA IX. These studies formed the basis of numerous clinical trials aimed at mAb-guided therapy in patients with metastatic RCC.

Interferon alfa-2b three times daily and thalidomide in the treatment of metastatic renal cell carcinoma.

PURPOSE: The antiangiogenic effect of interferon (IFN) may improve with frequent dosing and by combination with other agents with antiangiogenic activity. To evaluate this potential, we treated patients with metastatic renal cell carcinoma (RCC) with frequently dosed IFN and thalidomide. PATIENTS AND METHODS: Thirty patients were given IFN-alpha-2b 0.9 MU subcutaneously three times daily for 1 month and subsequently 1.2 MU tid unless serious toxicity was encountered. Thalidomide was first given 100 mg/d for 1 week and 300 mg/d thereafter. Sera were collected before and during treatment for serum vascular endothelial growth factor (S-VEGF) analyses performed using enzyme-linked immunosorbent assay. RESULTS: The intention-to-treat response rate was 20% (95% CI, 6% to 34%) and response rate for assessable patients (n = 27) was 22% (95% CI, 6% to 38%). All responses were partial. In addition, 17 patients (63%; 95% CI, 45% to 81%) had stable disease for 3 months or longer. The median time to treatment failure was 7.7 months, and median survival time was 14.9 months. The most common cause of thalidomide discontinuation was neuropathy. S-VEGF levels decreased more in patients who responded to therapy compared with those in patients whose condition had stabilized or who had progressive disease (P =.036). CONCLUSION: The combination of frequently dosed IFN-alpha-2b and low-dose thalidomide is feasible and active in advanced RCC, but the clinical benefit may remain small compared with that of IFN alone. Results from an ongoing phase III trial comparing IFN-alpha with or without thalidomide need to be analyzed before this combination can be recommended for use outside clinical studies.

[Acute peritonitis: a rare presentation of chylous ascites]. / Péritonite aiguë: un mode de révélation rare d'ascite chyleuse.

Chylous ascites is a rare case of peritonitis. We report here a case arising in a 21-year-old lady.