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Renal medullary carcinoma (RMC) is an aggressive tumour driven by bi-allelic loss of SMARCB1 and tightly associated with sickle cell trait. However, the cell-of-origin and oncogenic mechanism remain poorly understood. Using single-cell sequencing of human RMC, we defined transformation of thick ascending limb (TAL) cells into an epithelial-mesenchymal gradient of RMC cells associated with loss of renal epithelial transcription factors TFCP2L1 , HOXB9 and MITF and gain of MYC and NFE2L2 -associated oncogenic and ferroptosis resistance programs. We describe the molecular basis for this transcriptional switch that is reversed by SMARCB1 re-expression repressing the oncogenic and ferroptosis resistance programs leading to ferroptotic cell death. Ferroptosis resistance links TAL cell survival with the high extracellular medullar iron concentrations associated with sickle cell trait, an environment propitious to the mutagenic events associated with RMC development. This unique environment may explain why RMC is the only SMARCB1-deficient tumour arising from epithelial cells, differentiating RMC from rhabdoid tumours arising from neural crest cells. The molecular mechanisms involved in the development of SMARCB1-deficient renal medullary carcinomas (RMCs) remain to be characterised. Here, the authors integrated RMC omics data to show that ferroptosis resistance contributes to transformation of renal thick ascending limb cells into several RMC cell states.

To describe clinical outcomes of patients aged 75 years and above after partial nephrectomy (PN), and to assess independent factors of postoperative complications. We retrospectively reviewed information from our multi-institutional database. Every patient over 75 years old who underwent a PN between 2003 and 2016 was included. Peri-operative and follow up data were collected. Multivariate logistic regression was performed to determine independent predictive factors of postoperative complications. We reviewed 191 procedures including 69 (40%) open-surgery, and 122 (60%) laparoscopic procedures, of which 105 were robot-assisted. Median follow-up was 25 months. The mean age was 78 [75–88]. The American Society of Anesthesiologist’s score was 1, 2, 3 and 4 in 10.5%, 60%, 29% and 0.5% of patients respectively. The mean tumor size was 4.6 cm. Indication of PN was elective in 122 (65%) patients and imperative in 52 patients (28%). The median length of surgery was 150(± 60) minutes, and the median estimated blood loss 200 ml. The mean glomerular filtration rate was 71.5 ml/minute preoperatively, and 62 ml/min three months after surgery. The severe complications (Clavien III-V) rate was 6.2%. On multivariate analysis, the robotic-assisted procedure was an independent protective factor of medical postoperative complications (Odds Ration (OR) = 0.31 [0.12–0.80], p = 0.01). It was adjusted for age and RENAL score, robotic-assisted surgery (OR = 0.22 [0.06–0.79], p = 0.02), and tumor size (OR = 1.13 [1.02–1.26], p = 0.01), but the patients age did not forecast surgical complications. Partial nephrectomy can be performed safely in elderly patients with an acceptable morbidity, and should be considered as a viable treatment option. Robotic assistance is an independent protective factor of postoperative complications.

The upregulation of PPARγ/RXRα transcriptional activity has emerged as a key event in luminal bladder tumors. It renders tumor cell growth PPARγ-dependent and modulates the tumor microenvironment to favor escape from immuno-surveillance. The activation of the pathway has been linked to PPARG gains/amplifications resulting in PPARγ overexpression and to recurrent activating point mutations of RXRα. Here, we report recurrent mutations of PPARγ that also activate the PPARγ/RXRα pathway, conferring PPARγ-dependency and supporting a crucial role of PPARγ in luminal bladder cancer. These mutations are found throughout the protein—including N-terminal, DNA-binding and ligand-binding domains—and most of them enhance protein activity. Structure-function studies of PPARγ variants with mutations in the ligand-binding domain allow identifying structural elements that underpin their gain-of-function. Our study reveals genomic alterations of PPARG that lead to pro-tumorigenic PPARγ/RXRα pathway activation in luminal bladder tumors and may open the way towards alternative options for treatment. Activation of the PPARγ/RXRα pathway in luminal bladder cancers has mainly been linked to PPARG gene amplifications and activating point mutations in RXRα. Here, the authors identify recurrent PPARγ mutations with similar effects and elucidate the structural basis for this mutational PPARγ activation.

Objectives To retrospectively evaluate diagnostic accuracy and complications of magnetic resonance imaging (MRI)-guided biopsy of radiologically indeterminate solid renal masses (RM). Methods Electronic records of all consecutive patients undergoing MRI-guided biopsy of solid RM (using free-breathing T2-BLADE and BEAT-IRTTT sequences) between April 2014 and October 2018 were reviewed; 101 patients (69 men, 32 women; median age 68 years; range 32–76) were included. Patient and RM characteristics, procedural details/complications, pathologic diagnosis, and clinical management were recorded. Diagnostic accuracy was calculated on an intention-to-diagnose basis. Diagnostic yield was also evaluated. Multi-variable analysis was performed for variables with p  < .20, including patient age/sex; RM size/location/contact with vascular pedicle, RENAL score, number and total length of biopsy samples, and biopsy tract embolization, to determine factors associated with diagnostic samples, diagnostic accuracy, and complications. Results Median RM size was 2.4 cm (range 1–8.4 cm). There were 86 (85%; 95%CI 77–91%) diagnostic and 15 (15%; 95%CI 9–23%) non-diagnostic samples; 6/15 (40%) non-diagnostic biopsies were repeated with 50% malignancy rate. Sensitivity, specificity, positive predictive value, negative predictive value, and diagnostic accuracy were 96% (95%CI 89–99%), 100% (95%CI 77–100%), 100% (95%CI 95–100%), 82% (95%CI 57–96%), and 97% (95%CI 90–99%), respectively. Primary and secondary diagnostic yields were 85% (95%CI 77–91%) and 91% (95%CI 84–96%), respectively. Seven (7%; 95%CI 1–10%) complications were observed. No tested variables were associated with diagnostic samples, diagnostic accuracy, or complications. Conclusions MRI-guided biopsy of solid RM is associated with high diagnostic accuracy and low complication rate. The technique might be helpful for inaccessible tumors. Key Points • MRI-guided biopsy of radiologically indeterminate solid renal masses (RM) appears safe, with a low rate of minor self-limiting hemorrhagic complications. • Diagnostic accuracy and primary/secondary diagnostic yield are high and appear similar to reported estimates for US- and CT-guided RM biopsy. • MRI guidance may be particularly useful for RM with poor conspicuity on US and CT, for relatively inaccessible tumors (e.g., tumors requiring double-oblique steep-angled approaches), and for young patients or those with renal failure.

Metastatic clear cell renal cell carcinoma (CCC) remains incurable despite advances in the development of anti-angiogenic targeted therapies and the emergence of immune checkpoint inhibitors. We have previously shown that the sonic hedgehog-Gli signaling pathway is oncogenic in CCC allowing us to identify the developmental Lim1 transcription factor as a Gli target and as a new oncogene in CCC regulating cell proliferation and apoptosis, and promoting tumor growth. In this previous study, preliminary in vitro results also suggested that Lim1 may be implicated in metastatic spread. Here we investigated the potential pro-metastatic role of Lim1 in advanced CCC (1) in vitro using a panel of CCC cell lines expressing or not the von Hippel-Lindau (VHL) tumor suppressor gene either naturally or by gene transfer and (2) ex vivo in 30 CCC metastatic tissues, including lymph nodes, lung, skin, bone, and adrenal metastases, and (3) in vivo, using a metastatic model by intravenous injection of siRNA-transfected cells into Balb/c nude. Our in vitro results reveal that Lim1 knockdown time-dependently decreased CCC cell motility, migration, invasion, and clonogenicity by up to 50% regardless of their VHL status. Investigating the molecular machinery involved in these processes, we identified a large panel of Lim1 targets known to be involved in cell adhesion (paxillin and fibronectin), epithelial-mesenchymal transition (Twist1/2 and snail), invasion (MMP1/2/3/8/9), and metastatic progression (CXCR4, SDF-1, and ANG-1). Importantly, Lim1 was found constitutively expressed in all metastatic tissues. The H -score in metastatic tissues being significantly superior to the score in the corresponding primary tumor tissues ( P value = 0.009). Furthermore, we showed that Lim1 silencing decreases pulmonary metastasis development in terms of number and size in the in vivo metastatic model of human CCC. Taken together, these experiments strengthen the potential therapeutic value of Lim1 targeting as a promising novel approach for treating metastatic human CCC.

FGFR3 alterations (mutations or translocation) are among the most frequent genetic events in bladder carcinoma. They lead to an aberrant activation of FGFR3 signaling, conferring an oncogenic dependence, which we studied here. We discovered a positive feedback loop, in which the activation of p38 and AKT downstream from the altered FGFR3 upregulates MYC mRNA levels and stabilizes MYC protein, respectively, leading to the accumulation of MYC, which directly upregulates FGFR3 expression by binding to active enhancers upstream from FGFR3 . Disruption of this FGFR3/MYC loop in bladder cancer cell lines by treatment with FGFR3, p38, AKT, or BET bromodomain inhibitors (JQ1) preventing MYC transcription decreased cell viability in vitro and tumor growth in vivo . A relevance of this loop to human bladder tumors was supported by the positive correlation between FGFR3 and MYC levels in tumors bearing FGFR3 mutations, and the decrease in FGFR3 and MYC levels following anti‐FGFR treatment in a PDX model bearing an FGFR3 mutation. These findings open up new possibilities for the treatment of bladder tumors displaying aberrant FGFR3 activation. Synopsis In bladder carcinoma, alterations of FGFR3 receptor are often observed and lead to constitutive activation and oncogene addiction, which can be targeted with a pan‐FGFR inhibitor. Our identification and characterization of a FGFR3/MYC positive feedback loop opens new avenues for targeted therapies. MYC is a key master regulator of proliferation activated by aberrantly activated FGFR3. FGFR3‐dependent MYC accumulation is dependent on p38, which regulates MYC mRNA levels, and AKT, which stabilizes MYC protein. FGFR3 is directly targeted by MYC. Disrupting the FGFR3/MYC loop using FGFR3, p38, AKT, or BET bromodomain inhibitors decreases cell viability and tumor growth in FGFR3‐dependent cell lines. Evidence for the relevance of the FGFR3/MYC feedback loop to human tumors is provided by the decrease in both FGFR3 and MYC levels induced by a pan‐FGFR inhibitor in a PDX model bearing an FGFR3 mutation, and by the positive correlation between MYC and FGFR3 levels in human tumors with FGFR3 mutations. Graphical Abstract In bladder carcinoma, alterations of FGFR3 receptor are often observed and lead to constitutive activation and oncogene addiction, which can be targeted with a pan‐FGFR inhibitor. Our identification and characterization of a FGFR3/MYC positive feedback loop opens new avenues for targeted therapies.

Purpose Complete lymph node dissection is the recommended treatment for clinically detectable lymph nodes in stage III melanoma. This surgery is associated with substantial morbidity. We hypothesize that combining percutaneous imaging-guided cryoablation of locoregional lymph nodes metastases with neoadjuvant in situ and systemic immunotherapy could allow disease control and evaluate the feasibility of this combination in this proof-of-concept study. Methods We enrolled 15 patients with stage IIIB/IIIC melanoma. Patients were treated as follows: a single 240 mg flat dose infusion of nivolumab on day 1, cryoablation under local anesthesia using CT on day 2, and a single intralesional injection of 10–20 mg of ipilimumab into the lymphadenopathy treated by cryotherapy on day 3. Five–eight weeks after this procedure, complete lymph node dissection was performed according to routine care. The primary outcome measure of this study was feasibility, measured as the number of failures (i.e., inability to complete the entire procedure). Results The procedure was carried out successfully in 15 out of 15 patients with an observed number of failures of 0. The Bayesian analysis showed an estimated failure rate of 4.2% [0.2–20.6]. Eight patients (53%) had adverse events secondary to either immunotherapy or cryotherapy. Grade 3/4 events occurred in three patients, but all resolved quickly and patients could proceed to surgery as scheduled. Eight patients (53%) had a pathological complete or near complete response. Conclusion Combining percutaneous cryotherapy with in situ ipilimumab and systemic nivolumab for stage III resectable melanoma is feasible with tolerable toxicity. Graphical Abstract

Sarcomatoid features in renal cell carcinoma (RCC) have long been associated with dismal prognosis and poor response to therapy, while biological mechanisms underpinning sarcomatoid dedifferentiation remained obscure. Several efforts have been conducted to break down the molecular profile of sarcomatoid RCC and investigate different targeted therapeutic approaches. Mutations enriched for in sarcomatoid RCC involve, notably, TP53, BAP1, cell cycle, and chromatin-remodeling genes. The immunological landscape of these tumors is also gradually being uncovered, showing frequent expression of programmed cell death ligand-1 (PD-L1) and high levels of tumor-infiltrating lymphocytes. These features may be major determinants for the activity of immune checkpoint inhibitors in this population, which has been confirmed by retrospective studies and subgroup analyses of large randomized phase 3 trials. Combinations based on PD-1/PD-L1 inhibition have demonstrated response rates and complete responses in >50% and >10% of patients in the first-line metastatic setting, respectively, with median overall survival exceeding two years. This remarkable improvement in outcomes effectively establishes immune checkpoint inhibitor combinations as a new standard of care in patients with sarcomatoid RCC. New research fields, including epigenetic regulations and tumor–microenvironment interactions, may further sharpen understanding of sarcomatoid RCC and advance therapeutic developments.

The oncological impact of positive surgical margins (PSM) after robot-assisted partial nephrectomy (RAPN) is still under debate. We compared PSM and Negative Surgical Margins (NSM) in terms of recurrence-free survival (RFS), metastasis-free survival (MFS) and overall survival (OS) after RAPN, and we identified predictive factors of PSM. Multi-institutional study using the UroCCR database, which prospectively included 2166 RAPN between April 2010 and February 2021 (CNIL DR 2013-206; NCT03293563). Two groups were retrospectively compared: PSM versus NSM. Prognostic factors were assessed using Kaplan–Meyer curves with log-Rank test, cox hazard proportional risk model and logistic regression after univariate comparison. 136 patients had PSM (6.3%) and 2030 (93.7%) had NSM. During a median follow-up of 19 (9–36) months after RAPN, 160 (7.4%) recurrences were reported. Kaplan–Meier curves and analysis suggested that RFS, MFS and OS were not affected by a PSM ( p  = 0.68; 0.71; 0.88, respectively). In multivariate analysis predictors of PSM were a lower RENAL score ( p  = 0.001), longer warm ischemia time (WIT) ( p  = 0.003) and Chromophobe Renal Cell Carcinoma (chrRCC) ( p  = 0.043). This study found no impact of PSM on RFS, MFS or OS, and predictors of PSM were the RENAL score, WIT and chrRCC.

Purpose New follow-up models of care are needed to ensure long-term comprehensive care for cancer survivors. We investigated the impact of a general practitioner (GP)–led follow-up program for prostate cancer (PCa) and renal cell cancer (RCC) survivors. Methods This retrospective monocentric study compared standard urologist-led follow-up to experimental GP-led follow-up within a nurse-led network for PCa and RCC survivors. To assess the safe continuity of follow-up, the number of patients lost to follow-up (LFU) was collected. A microcosting analysis from the French national health system perspective was conducted to describe incremental costs associated with experimental follow-up. A satisfaction survey was conducted to determine participating patient’s and GP’s satisfaction scores, ranging from 0 to 4 and 0 to 5, respectively. Results Among the 1274 patients included, 92/753 (12.2%) were LFU during standard follow-up vs 0/521 (0%) during experimental follow-up ( p  < 0.001). In the latter, the median management delay of suspected recurrence for PCa and RCC survivors was 20 [12–27] and 16 [10.5–31.25] days, and the mean incremental cost on a per-patient basis was 34.68 ± 105.87€ and 64.24 ± 93.55€, respectively. Patient and GP mean satisfaction scores were 3.6/4 and 3.9/5, respectively. Conclusion The GP-led follow-up of PCa and RCC survivors within a nurse-led network seems to provide safe continuity of follow-up and seems not to be associated with major incremental costs. The surveys indicated high level of patient’s satisfaction and encouraging results regarding GP’s satisfaction. Randomized clinical trials are needed to confirm these findings and promote larger implementation of this type of follow-up care.