MRI accuracy for recurrence after partial gland ablation with HIFU for localized prostate cancer. A systematic review and meta-analysis.

BACKGROUND: Prostate cancer remains the most frequently diagnosed cancer among men. High-Intensity Focused Ultrasound (HIFU) has emerged as a thermal ablative technique for partial-gland-ablation (PGA), aiming to minimize collateral damage while maximizing tumor control. Monitoring after HIFU PGA relies on serial PSA testing, multiparametric-MRI, and biopsies. The diagnostic accuracy of MRI for clinically-significant cancer(csPCa) recurrence is challenging. OBJECTIVE: This systematic review and meta-analysis aim to evaluate the accuracy of MRI in detecting early recurrence of localized prostate cancer following HIFU PGA. METHODS: Adhering to PRISMA guidelines, a comprehensive literature search was conducted until May 8th 2024 using MEDLINE and Scopus. The inclusion criteria encompassed randomized controlled trials and cohort studies involving men diagnosed with localized prostate cancer who had as primary treatment HIFU PGA. The primary outcome measures included the sensitivity, specificity, positive-predictive value (PPV), and negative-predictive value (NPV) of MRI for csPCa(ISUP ≥ 2) based on biopsy results. We pooled data from studies with sufficient csPCa and csPCa-free patients (≥5) post HIFU for statistical analysis. RESULTS: Fifteen studies meet the inclusion criteria, encompassing 1093 patients and 12 studies were eligible for meta-analysis. MRI sensitivity in detecting clinically-significant prostate cancer (csPCa) recurrence post HIFU PGA varied widely (0-89%), with a pooled sensitivity of 0.52 (95% CI:0.36-0.68). Specificity ranged from 44% to 100%, with a pooled specificity of 0.81 (95% CI:0.68-0.91). The pooled NPV was 0.82 (95% CI:0.72-0.90), and the pooled PPV was 0.50 (95% CI:0.35-0.65). Three studies reported in-field diagnostic performance with sensitivities ranging from 0.42 to 0.80 and specificities from 0.45 to 0.97. CONCLUSION: MRI accuracy for clinically-significant recurrence after partial gland ablation with HIFU for localized prostate cancer shows low diagnostic performance in the treated lobe with pooled sensitivity of 0.52 (95% CI:0.36-0.68) and specificity of 0.81 (95% CI:0.68-0.91). Limits of this review include the low number of studies reporting about site of recurrence in or out of the treated lobe.

Incidence, initial management and survival of high-risk non-muscle invasive bladder cancer in Northern France.

OBJECTIVE: Information on bladder cancer (BC) according to the risk scoring for recurrence or progression in a general population is scarce despite its clinical relevance. The objective was to describe the characteristics of incident BC in a general population, with a focus on the initial management of high-risk non-muscle invasive BC (HR-NMIBC). MATERIALS: BC incident in 2011-2012 recorded in a population-based cancer registry were studied. Data was extracted from medical files. NMIBC were classified according to potential risk for recurrence/progression. Individual and tumor characteristics of incident BC were described. Incidence, initial management and survival (12/31/2021) of HR-NMIBC were assessed. RESULTS: Among 538 BC cases, 380 were NMIBC [119 low (22.1%), 163 intermediate (30.3%), 98 high (18.2%) risk] and 147 (27.3%) were MIBC. HR-NMIBC diagnostic and therapeutic management [imaging, re-TUR, multidisciplinary team meetings (MDT) assessment, specific treatment] revealed discrepancies with guidelines recommendations. Seventy-two out of 98 cases were assessed in an MDT with a median time from diagnosis of 18days [first quartile: 12-third quartile: 32]. Globally, treatment agreed with MDT decisions. Intravesical instillation was the most common treatment (n=56) but 27 HR-NMIBC did not receive specific treatment after TUR. Five and 10years overall survival was 52% [42-63] and 41% [31-51], respectively. Five years net survival was 63% [47-75]. CONCLUSIONS: Despite National cancer plans aiming to improve care giving and despite the severity of HR-NMIBC, guideline-recommended patterns of care were underused in this region. This may deserve attention to identify obstacles to guideline adoption to try to improve BC patient care and survival.

Practice patterns and survival outcomes for muscle-invasive bladder cancer: real-life experience in a general population setting.

Bladder cancer (BC) is a common malignancy in Europe and North America. Among BCs, muscle-invasive BCs (MIBCs) are distinguished, as they require aggressive treatment due to their spreading potential and poor prognosis. Despite its clinical relevance, little information on MIBC in a general population setting is available. This study aims to report practice patterns and survival outcomes for MIBC patients in a general population setting. MIBCs among BC incidence in 2011 and 2012 recorded in a French population-based cancer registry (810 000 inhabitants) were included in the study. Data were extracted from the medical files. Individual, tumour-related characteristics and initial management including diagnostic tools, multidisciplinary team meeting (MDT) assessment, and treatment delivered were described. Cystectomy, chemoradiation, radiotherapy, and chemotherapy were considered as specific treatments. Matching between MDT decision and the treatment provided was detailed. Management practices were discussed according to the guideline's recommendations. Overall survival (using the Kaplan-Meier method) and net survival (using the Pohar-Perme estimator) were calculated. Among 538 incident BC cases, 147 (27.3%) were MIBCs. Diagnostic practices displayed a relevant locoregional assessment of BC. Almost all cases (n = 136, 92.5%) were assessed during an uro-oncological MDT with a median time from diagnosis of 18 days (first quartile:12-third quartile:32). Discrepancies appeared between MDT decisions and treatments delivered: 71 out of 86 subjects received the recommended cystectomy or chemoradiation (with or without neoadjuvant chemotherapy); 6 out of 11 had the recommended radio- or chemotherapy; and 9 patients did not undergo any specific treatment despite the MDT decision. Cystectomy was the most common treatment performed; the time to surgery appeared consistent with the guideline's recommendations. Forty people only received supportive care. Still, the 5-year overall and net survival was poor, with 19% (13-26) and 22% (14-31), respectively. The 5-year net survival was 35% (23-48) for people who underwent curative-intent treatments. MIBC management remains challenging even for cases assessed during an MDT. Many people did not undergo any specific treatment. Prognosis was poor even when curative-intent therapies were delivered. Efforts to reduce exposure to risk factors such as tobacco smoking and occupational exposures must be maintained.

Definitions of major bleeding for predicting mortality in critically ill adult patients who survived 24 hours while supported with peripheral veno-arterial extracorporeal membrane oxygenation for cardiogenic shock: a comparative historical cohort study.

PURPOSE: The severity of bleeding events is heterogeneously defined during peripheral veno-arterial extracorporeal membrane oxygenation (pVA-ECMO). We studied three bleeding definitions in pVA-ECMO: the Extracorporeal Life Support Organization (ELSO)-serious bleeding, the Bleeding Academic Research Consortium (BARC), and the universal definition of postoperative bleeding (UPDB) classifications. METHODS: We included consecutive adult patients supported by pVA-ECMO for refractory cardiogenic shock admitted to Lille academic hospitals between January 2013 and December 2019. We assessed the association of bleeding definitions with the primary endpoint of 28-day all-cause mortality with the use of multivariate models accounting for time-dependent and competing variables. We compared models' performances using the Harrell's C-Index and the Akaike information criteria. RESULTS: Twenty-eight-day mortality occurred in 128/308 (42%) 308 patients. The ELSO-serious bleeding (hazard ratio [HR], 1.67; 95% confidence interval [CI], 1.09 to 2.56) and BARC ≥ type 2 (HR, 1.55; 95% CI, 1.01 to 2.37) were associated with 28-day mortality (Harrell's C-index, 0.69; 95% CI, 0.63 to 0.74 for both). Predictors of ELSO-serious bleeding were postcardiotomy, body mass index, baseline platelets count, fibrinogen, and hemoglobin levels. CONCLUSION: Extracorporeal Life Support Organization-serious bleeding and BARC ≥ type 2 are relevant definitions of major bleeding regarding their association with mortality in critically ill patients who survived the first 24 hr while supported with pVA-ECMO for cardiogenic shock. STUDY REGISTRATION: CERAR (IRB 00010254-2022-050, Paris, France); first submitted on 18 April 2022.

RéSUMé: OBJECTIF: La gravité des événements hémorragiques est définie de manière hétérogène pendant une oxygénation par membrane extracorporelle veino-artérielle périphérique (ECMO-VA périphérique). Nous avons étudié trois définitions du saignement sous ECMO-VA périphérique : les classifications des saignements graves selon l'Extracorporeal Life Support Organization (ELSO), celles du Bleeding Academic Research Consortium (BARC) et la définition universelle du saignement postopératoire (UPDB). MéTHODE: Nous avons inclus des patient·es adultes pris·es en charge de manière consécutive par ECMO-VA périphérique à la suite d'un choc cardiogénique réfractaire et admis·es dans les centres hospitaliers universitaires de Lille entre janvier 2013 et décembre 2019. Nous avons évalué l'association des définitions du saignement avec le critère d'évaluation principal de mortalité toutes causes confondues à 28 jours à l'aide de modèles multivariés tenant compte des variables dépendantes du temps et concurrentes. Nous avons comparé les performances des modèles à l'aide de l'indice C de Harrell et du critère d'information d'Akaike. RéSULTATS: La mortalité à 28 jours est survenue chez 128/308 (42 %) patient·es. Le saignement grave selon l'ELSO (rapport de risque [RR], 1,67; intervalle de confiance [IC] à 95 %, 1,09 à 2,56) et une classification BARC ≥ type 2 (RR, 1,55; IC 95 %, 1,01 à 2,37) étaient associés à une mortalité à 28 jours (indice C de Harrell, 0,69; IC 95 %, 0,63 à 0,74 pour les deux). Les prédicteurs d'hémorragie grave selon l'ELSO étaient la postcardiotomie, l'indice de masse corporelle, la numération plaquettaire initiale, le taux de fibrinogène et les taux d'hémoglobine. CONCLUSION: Les définitions du saignement grave de l'Extracorporeal Life Support Organization et une classification BARC ≥ type 2 sont des définitions pertinentes des saignements majeurs en ce qui touche à leur association avec la mortalité chez les personnes gravement malades qui ont survécu aux premières 24 heures alors qu'elles étaient prises en charge par ECMO-VA périphérique à la suite d'un choc cardiogénique. ENREGISTREMENT DE L'éTUDE: CERAR (IRB 00010254-2022-050, Paris, France); soumis pour la première fois le 18 avril 2022.

EGFR signaling and pharmacology in oncology revealed with innovative BRET-based biosensors.

Mutations of receptor tyrosine kinases (RTKs) are associated with the development of many cancers by modifying receptor signaling and contributing to drug resistance in clinical settings. We present enhanced bystander bioluminescence resonance energy transfer-based biosensors providing new insights into RTK biology and pharmacology critical for the development of more effective RTK-targeting drugs. Distinct SH2-specific effector biosensors allow for real-time and spatiotemporal monitoring of signal transduction pathways engaged upon RTK activation. Using EGFR as a model, we demonstrate the capacity of these biosensors to differentiate unique signaling signatures, with EGF and Epiregulin ligands displaying differences in efficacy, potency, and responses within different cellular compartments. We further demonstrate that EGFR single point mutations found in Glioblastoma or non-small cell lung cancer, impact the constitutive activity of EGFR and response to tyrosine kinase inhibitor. The BRET-based biosensors are compatible with microscopy, and more importantly characterize the next generation of therapeutics directed against RTKs.

Fascin-1 expression is associated with neuroendocrine prostate cancer and directly suppressed by androgen receptor.

BACKGROUND: Neuroendocrine prostate cancer (NEPC) is an aggressive form of prostate cancer, arising from resistance to androgen-deprivation therapies. However, the molecular mechanisms associated with NEPC development and invasiveness are still poorly understood. Here we investigated the expression and functional significance of Fascin-1 (FSCN1), a pro-metastasis actin-bundling protein associated with poor prognosis of several cancers, in neuroendocrine differentiation of prostate cancer. METHODS: Differential expression analyses using Genome Expression Omnibus (GEO) database, clinical samples and cell lines were performed. Androgen or antagonist's cellular treatments and knockdown experiments were used to detect changes in cell morphology, molecular markers, migration properties and in vivo tumour growth. Chromatin immunoprecipitation-sequencing (ChIP-Seq) data and ChIP assays were analysed to decipher androgen receptor (AR) binding. RESULTS: We demonstrated that FSCN1 is upregulated during neuroendocrine differentiation of prostate cancer in vitro, leading to phenotypic changes and NEPC marker expression. In human prostate cancer samples, FSCN1 expression is restricted to NEPC tumours. We showed that the androgen-activated AR downregulates FSCN1 expression and works as a transcriptional repressor to directly suppress FSCN1 expression. AR antagonists alleviate this repression. In addition, FSCN1 silencing further impairs in vivo tumour growth. CONCLUSION: Collectively, our findings identify FSCN1 as an AR-repressed gene. Particularly, it is involved in NEPC aggressiveness. Our results provide the rationale for the future clinical development of FSCN1 inhibitors in NEPC patients.

Robot Partial Prostatectomy for Anterior Cancer: Long-term Functional and Oncological Outcomes at 7 Years.

Partial prostatectomy has been described as an alternative to focal ablation therapy for the management of localized low- to intermediate-risk prostate cancer. This report aims to describe the long-term outcomes in a series of 28 men (2000-2022) who underwent robotic-assisted anterior partial prostatectomy (APP) for anteriorly located tumors entirely or partially within the anterior fibromuscular stroma. The median follow-up is 7 yr (interquartile range [IQR]: 4.2-8). The median prostate-specific antigen (PSA) before APP was 9.6 (6-11). Continence remained uninterrupted in 92% of patients. Erectile function without drug remained uninterrupted in 69%. The median nadir PSA after APP was 0.36 ng/ml (IQR: 0.25-0.60). Cancer recurrence at biopsies at the margins of the primary cancer resected area in case of a PSA elevation was observed in eight patients and led to salvage completion robotic radical prostatectomy at a median time of 3.25 yr (IQR: 2.4-6). Freedom from post-APP cancer recurrence at 7 yr was 62.7% (35.0-81.3%). Pre-APP tumor volume at magnetic resonance imaging (MRI) and volume of grade 4/5 were predictive of recurrence. Freedom from biochemical recurrence after completion radical prostatectomy at 7 yr was 94.7% (68.1-99.3%). All 28 patients are alive. No one had systemic treatment or metastases. These results confirm our initial report of robotic APP with good functional results and acceptable oncological results. The use of the inclusion criteria of pre-APP tumor volume at MRI <3 cc may decrease the risk of recurrence. Patient summary: In this report, we looked at outcomes for infrequent cases of anterior prostate cancer treated with anterior partial prostatectomy, an uncommon surgical procedure as an alternative to in situ focal ablation therapy, to better preserve functional outcomes as compared with whole gland therapy. We found that functional outcomes of uninterrupted continence and erectile function were good. Out of 28 patients, eight had recurrence in the remaining prostate and were treated with a second surgical procedure, radical prostatectomy, which was feasible. We conclude that this new technique is feasible with good functional results and acceptable oncological results, which can be shared with the patients.

Risk Estimation of Metastatic Recurrence After Prostatectomy: A Model Using Preoperative Magnetic Resonance Imaging and Targeted Biopsy.

Background: The risk of prostate cancer metastatic is correlated with its volume and grade. These parameters are now best estimated preoperatively with magnetic resonance imaging (MRI) and MRI-guided biopsy. Objective: To estimate the risk of metastatic recurrence after radical prostatectomy (RP) in our model versus conventional clinical European Association of Urology (EAU) classification. The secondary objective is biochemical recurrence (BCR). Design setting and participants: A retrospective study was conducted of a cohort of 713 patients having undergone MRI-guided biopsies and RP between 2009 and 2018. The preoperative variables included prostate-specific antigen, cT stage, tumor volume (TV) based on the lesion's largest diameter at MRI, percentage of Gleason pattern 4/5 (%GP4/5) at MRI-guided biopsy, and volume of GP4/5 (VolGP4/5) calculated as TV × %GP4/5. Outcome measurements and statistical analysis: The variables' ability to predict recurrence was determined in univariable and multivariable Fine-and-Gray models, according to the Akaike information criterion (AIC) and Harrell's C-index. Results and limitations: Overall, 176 (25%), 430 (60%), and 107 (15%) patients had low, intermediate, and high-risk disease, respectively, according to the EAU classification. During a median follow-up period of 57 mo, metastatic recurrence was observed in 48 patients with a 5-yr probability of 5.6% (95% confidence interval [CI] 3.9-7.7). VolGP4/5 (categories: <0.5, 0.5-1.0, 1.01-3.2, and >3.2 ml) was the parameter with the lowest AIC and the highest C-index for metastatic recurrence of 0.82 (95% CI 0.76-0.88), and for BCR it was 0.73 (95% CI 0.68-0.78). In a multivariable model that included %GP4/5 and TV, C-index values were 0.86 (95% CI 0.79-0.91) for metastatic recurrence and 0.77 (0.72-0.82) for BCR. The same results for EAU classification were 0.74 (0.67-0.80) and 0.67 (0.63-0.72), respectively. Limitations are related to short follow-up and expertise of radiologists and urologists. Conclusions: We developed a preoperative risk tool integrating the VolGP4/5 based on MRI and MRI-guided biopsies to predict metastatic recurrence after RP. Our model showed higher accuracy than conventional clinical risk models. These findings might enable physicians to provide more personalized patient care. Patient summary: Aggressiveness of prostate cancer evaluated before treatment by incorporating magnetic resonance imaging (MRI) and MRI-guided biopsy results gives a better estimate of the risk of metastatic recurrence than previous parameters not based on MRI.

Comprehensive study of nine novel cases of TFEB-amplified renal cell carcinoma: an aggressive tumour with frequent PDL1 expression.

AIMS: First described in 2014, renal cell carcinoma (RCC) with TFEB amplification (6p21) is a rare molecular subgroup whose diagnosis is challenging. The prognosis and therapeutic implications remain unclear. METHODS: We report here the clinical, histological, immunohistochemical, and genetic features of nine novel cases. The pathological and immunohistochemical features were centrally reviewed by expert uropathologists. Fluorescence in situ hybridisation (FISH) confirmed the diagnosis and comparative genomic hybridisation (CGH) was performed to determine quantitative genomic alterations. We also performed an exhaustive review of the literature and compiled our data. RESULTS: TFEB-amplified RCC were locally advanced, with initial lymph node involvement in one case and liver metastasis in another case. They were high-grade eosinophilic tumours with papillary/pseudopapillary architecture, frequent positivity for melanocytic markers, and frequent PDL1 expression. FISH demonstrated high-level TFEB amplification in six cases. One case showed concomitant TFEB translocation. CGH analysis identified complex alterations with frequent losses of 1p, 2q, 3p, 6p, and frequent 6p and 8q gains. VEGFA coamplification was identified in all cases with a lower level than TFEB. The prognosis was poor, with five patients having lymph node or distant metastases. CONCLUSION: TFEB-amplified RCC is a rare molecular subgroup with variable morphology whose diagnosis is confirmed by FISH analysis. The complex alterations identified by CGH are consistent with an aggressive clinical behaviour. The coamplification of VEGFA and the expression of PDL1 could suggest a potential benefit from antiangiogenics and targeted immunotherapy in combination for these aggressive tumours.

Effector membrane translocation biosensors reveal G protein and ßarrestin coupling profiles of 100 therapeutically relevant GPCRs.

The recognition that individual GPCRs can activate multiple signaling pathways has raised the possibility of developing drugs selectively targeting therapeutically relevant ones. This requires tools to determine which G proteins and ßarrestins are activated by a given receptor. Here, we present a set of BRET sensors monitoring the activation of the 12 G protein subtypes based on the translocation of their effectors to the plasma membrane (EMTA). Unlike most of the existing detection systems, EMTA does not require modification of receptors or G proteins (except for Gs). EMTA was found to be suitable for the detection of constitutive activity, inverse agonism, biased signaling and polypharmacology. Profiling of 100 therapeutically relevant human GPCRs resulted in 1500 pathway-specific concentration-response curves and revealed a great diversity of coupling profiles ranging from exquisite selectivity to broad promiscuity. Overall, this work describes unique resources for studying the complexities underlying GPCR signaling and pharmacology.

Expanding the clinicopathological spectrum of succinate dehydrogenase-deficient renal cell carcinoma with a focus on variant morphologies: a study of 62 new tumors in 59 patients.

Most succinate dehydrogenase (SDH)-deficient renal cell carcinomas (RCCs) demonstrate stereotypical morphology characterized by bland eosinophilic cells with frequent intracytoplasmic inclusions. However, variant morphologic features have been increasingly recognized. We therefore sought to investigate the incidence and characteristics of SDH-deficient RCC with variant morphologies. We studied a multi-institutional cohort of 62 new SDH-deficient RCCs from 59 patients. The median age at presentation was 39 years (range 19-80), with a slight male predominance (M:F = 1.6:1). A relevant family history was reported in 9 patients (15%). Multifocal or bilateral tumors were identified radiologically in 5 patients (8%). Typical morphology was present at least focally in 59 tumors (95%). Variant morphologies were seen in 13 (21%) and included high-grade nuclear features and various combinations of papillary, solid, and tubular architecture. Necrosis was present in 13 tumors, 7 of which showed variant morphology. All 62 tumors demonstrated loss of SDHB expression by immunohistochemistry. None showed loss of SDHA expression. Germline SDH mutations were reported in all 18 patients for whom the results of testing were known. Among patients for whom follow-up data was available, metastatic disease was reported in 9 cases, 8 of whom had necrosis and/or variant morphology in their primary tumor. Three patients died of disease. In conclusion, variant morphologies and high-grade nuclear features occur in a subset of SDH-deficient RCCs and are associated with more aggressive behavior. We therefore recommend grading all SDH-deficient RCCs and emphasize the need for a low threshold for performing SDHB immunohistochemistry in any difficult to classify renal tumor, particularly if occurring at a younger age.

Impact of positive vascular margins status after surgical resection of non-metastatic renal cell carcinoma with caval tumour thrombus: a propensity score multicentre study.

BACKGROUND: Data evaluating the impact of positive vascular margins (PVMs) following surgical resection of non-metastatic renal cell carcinoma (RCC) with inferior vena cava (IVC) tumor thrombus are lacking. OBJECTIVE: To analyze the oncological impact of positive vascular margins following surgical resection of RCC with IVC tumor thrombus. METHODS: Patients who underwent radical nephrectomy with the removal of IVC tumour thrombus for RCC between 2000 and 2019 were included. PVMs were identified from pathology reports defined as microscopically identified tumour present in the IVC wall at the site of resection or in case of thrombus was not completely removed. To achieve balance in baseline characteristics between patients with PVMs versus negative vascular margins, we used inverse probability of treatment weighting (IPTW) based on the propensity score. Local recurrence, distant metastasis and overall mortality were evaluated between groups using Cox proportional hazards regression models. RESULTS: 209 patients were analyzed. Among them, 49 (23%) patients with PVMs were identified. Median follow-up was 55 months. After adjustment, excellent balance was achieved for most propensity score variables. In IPTW analysis, PVMs was associated with a higher risk of local recurrence (HR = 3.66; p < 0.001) without any impact on systemic recurrence (HR = 1.15; p = 0.47) or overall mortality (HR = 1.23; p = 0.48). Limitations include the sample size and unmeasured confounding. CONCLUSION: Our results suggest that a PVMs in patients with RCC after nephrectomy with thrombectomy is associated with a higher risk of local recurrence, however, it did not appear to influence the risk of distant metastasis or death.

Asymmetric Synthesis and Biological Screening of Quinoxaline-Containing Synthetic Lipoxin A4 Mimetics (QNX-sLXms).

Failure to resolve inflammation underlies many prevalent pathologies. Recent insights have identified lipid mediators, typified by lipoxins (LXs), as drivers of inflammation resolution, suggesting potential therapeutic benefit. We report the asymmetric preparation of novel quinoxaline-containing synthetic-LXA4-mimetics (QNX-sLXms). Eight novel compounds were screened for their impact on inflammatory responses. Structure-activity relationship (SAR) studies showed that (R)-6 (also referred to as AT-02-CT) was the most efficacious and potent anti-inflammatory compound of those tested. (R)-6 significantly attenuated lipopolysaccharide (LPS)- and tumor-necrosis-factor-α (TNF-α)-induced NF-κB activity in monocytes and vascular smooth muscle cells. The molecular target of (R)-6 was investigated. (R)-6 activated the endogenous LX receptor formyl peptide receptor 2 (ALX/FPR2). The anti-inflammatory properties of (R)-6 were further investigated in vivo in murine models of acute inflammation. Consistent with in vitro observations, (R)-6 attenuated inflammatory responses. These results support the therapeutic potential of the lead QNX-sLXm (R)-6 in the context of novel inflammatory regulators.

Downregulation of the FTO m6A RNA demethylase promotes EMT-mediated progression of epithelial tumors and sensitivity to Wnt inhibitors.

Post-transcriptional modifications of RNA constitute an emerging regulatory layer of gene expression. The demethylase fat mass- and obesity-associated protein (FTO), an eraser of N6-methyladenosine (m6A), has been shown to play a role in cancer, but its contribution to tumor progression and the underlying mechanisms remain unclear. Here, we report widespread FTO downregulation in epithelial cancers associated with increased invasion, metastasis and worse clinical outcome. Both in vitro and in vivo, FTO silencing promotes cancer growth, cell motility and invasion. In human-derived tumor xenografts (PDXs), FTO pharmacological inhibition favors tumorigenesis. Mechanistically, we demonstrate that FTO depletion elicits an epithelial-to-mesenchymal transition (EMT) program through increased m6A and altered 3'-end processing of key mRNAs along the Wnt signaling cascade. Accordingly, FTO knockdown acts via EMT to sensitize mouse xenografts to Wnt inhibition. We thus identify FTO as a key regulator, across epithelial cancers, of Wnt-triggered EMT and tumor progression and reveal a therapeutically exploitable vulnerability of FTO-low tumors.

Negative Prebiopsy Magnetic Resonance Imaging and Risk of Significant Prostate Cancer: Baseline and Long-Term Followup Results.

PURPOSE: Prostate biopsy should be discussed with the patient in cases of negative magnetic resonance imaging and low clinical suspicion of prostate cancer.Our primary objective was to describe the risk of clinically significant prostate cancer in a negative magnetic resonance imaging biopsy naïve population at baseline and during long-term followup. The secondary objective was to evaluate clinical factors and prostate specific antigen as predictors of clinically significant prostate cancer at baseline. MATERIALS AND METHODS: All 503 consecutive patients who were biopsy naïve referred from 2007 to 2017 for biopsy with negative magnetic resonance imaging (PI-RADS™ 1-2) who had systematic 12-core biopsies at baseline were included. Clinical factors were digital rectal examination, prostate cancer family history and prostate specific antigen. In case of suspicious digital rectal examination or prostate specific antigen kinetics during followup, magnetic resonance imaging and biopsy were performed. Clinically significant prostate cancer was defined as either Gleason Grade 1 with cancer core length greater than 5 mm or 3 or more positive systematic 12-core biopsies in addition to Gleason Grade 2 or greater (clinically significant prostate cancer-1) or any Gleason Grade 2 or greater (clinically significant prostate cancer-2). Nonclinically significant prostate cancer was defined as either Gleason Grade 1 with cancer core length 5 mm or less and fewer than 3 positive systematic 12-core biopsies (nonclinically significant prostate cancer-1) or any Gleason Grade 1 (nonclinically significant prostate cancer-2). Definition of high risk clinically significant prostate cancer was Gleason Grade 3 or greater. Univariate and multivariate models were fitted to identify predictors of clinically significant prostate cancer risk. RESULTS: At baseline, biopsy showed clinically significant prostate cancer-1 in 9% (45), clinically significant prostate cancer-2 in 6% (29) and nonclinically significant prostate cancer in 22% (111). At median followup of 4 years (IQR 1.6-7.1), 31% (95% CI 27-36) of 415 untreated patients had a second magnetic resonance imaging and 24% (95% CI 20-28) a second biopsy that showed clinically significant prostate cancer-1 in 5% (21/415, 95% CI 3-7), clinically significant prostate cancer-2 in 2% (7/415, 95% CI 1-3) and nonclinically significant prostate cancer in 8%. Overall incidence was 13% (66/503, 95% CI 7-21) for clinically significant prostate cancer-1, 7% (36/503, 95% CI 5-9%) for clinically significant prostate cancer-2 and 2% (12/503, 95% CI 1.1-3.7) for high risk prostate cancer. Predictors of clinically significant prostate cancer risk were prostate specific antigen density 0.15 ng/ml/ml or greater (OR 2.43, 1.19-4.21), clinical stage T2a or greater (OR 3.32, 1.69-6.53) and prostate cancer family history (OR 2.38, 1.10-6.16). Performing biopsy in patients with negative magnetic resonance imaging and prostate specific antigen density 0.15 ng/ml/ml or greater or abnormal digital rectal examination or prostate cancer family history would have decreased from 9% to 2.4% the risk of missing clinically significant prostate cancer-1 at baseline while avoiding biopsy in 56% of cases. CONCLUSIONS: The risk of clinically significant prostate cancer in a negative magnetic resonance imaging biopsy naïve population was 6% to 9% at baseline and 7% to 13% at long-term followup depending on clinically significant prostate cancer definitions.

A Spontaneously Necrotic Wilms' Tumor Mimicking Renal Abscess: A Tricky Diagnosis not to Miss.

Wilms' tumor (WT) is the most common renal malignancy in children. Its clinical and radiologic presentation may mimic other pediatric renal diseases, including pyonephrosis or renal abscess. The authors report a case of a 3-year-old girl presenting with pyelonephritis and right renal mass suggestive of a renal abscess, not responding to antibiotics. Further investigations were conducted, including a percutaneous renal needle core biopsy. A stage I fully necrotic WT was finally diagnosed. This amazing case of a fully necrotic WT at diagnosis demonstrates the importance of anatomopathologic analyses in pediatric renal masses, even when the infection is suspected.

HIC1 (Hypermethylated in Cancer 1) modulates the contractile activity of prostate stromal fibroblasts and directly regulates CXCL12 expression.

HIC1 (Hypermethylated In Cancer 1) a tumor suppressor gene located at 17p13.3, is frequently deleted or epigenetically silenced in many human tumors. HIC1 encodes a transcriptional repressor involved in various aspects of the DNA damage response and in complex regulatory loops with P53 and SIRT1. HIC1 expression in normal prostate tissues has not yet been investigated in detail. Here, we demonstrated by immunohistochemistry that detectable HIC1 expression is restricted to the stroma of both normal and tumor prostate tissues. By RT-qPCR, we showed that HIC1 is poorly expressed in all tested prostate epithelial lineage cell types: primary (PrEC), immortalized (RWPE1) or transformed androgen-dependent (LnCAP) or androgen-independent (PC3 and DU145) prostate epithelial cells. By contrast, HIC1 is strongly expressed in primary PrSMC and immortalized (WMPY-1) prostate myofibroblastic cells. HIC1 depletion in WPMY-1 cells induced decreases in α-SMA expression and contractile capability. In addition to SLUG, we identified stromal cell-derived factor 1/C-X-C motif chemokine 12 (SDF1/CXCL12) as a new HIC1 direct target-gene. Thus, our results identify HIC1 as a tumor suppressor gene which is poorly expressed in the epithelial cells targeted by the tumorigenic process. HIC1 is expressed in stromal myofibroblasts and regulates CXCL12/SDF1 expression, thereby highlighting a complex interplay mediating the tumor promoting activity of the tumor microenvironment. Our studies provide new insights into the role of HIC1 in normal prostatic epithelial-stromal interactions through direct repression of CXCL12 and new mechanistic clues on how its loss of function through promoter hypermethylation during aging could contribute to prostatic tumors.

Deficit of resolution receptor magnifies inflammatory leukocyte directed cardiorenal and endothelial dysfunction with signs of cardiomyopathy of obesity.

Chronic unresolved inflammation is the primary determinant of cardiovascular disease. Precise mechanisms that define the genesis of unresolved inflammation in heart failure with preserved ejection fraction (HFpEF) are of interest due to the obesity epidemic. To examine the obesity phenotype and its direct/indirect consequences, multiple approaches were employed using the lipoxin receptor (abbreviated as ALX) dysfunction mouse model. Indirect calorimetry analyses revealed that the deletion of ALX dysregulated energy metabolism driving toward age-related obesity. Heart function data suggest that obesity-prone ALX deficient mice had impaired myocardium strain. Comprehensive measurement of chemokines, extracellular matrix, and arrhythmogenic arrays confirmed the dysregulation of multiple ion channels gene expression with amplified inflammatory chemokines and cytokines response at the age of 4 months compared with WT counterparts. Quantitative analyses of leukocytes demonstrated an increase of proinflammatory Ly6Chi CCR2+ macrophages in the spleen and heart at a steady-state resulting in an inflamed splenocardiac axis. Signs of subtle inflammation were marked with cardiorenal, endothelial defects with decreased CD31 and eNOS and an increased iNOS and COX2 expression. Thus, ALX receptor deficiency serves as an experimental model that defines multiple cellular and molecular mechanisms in HFpEF that could be a target for the development of HFpEF therapy in cardiovascular medicine.

hPCL3S promotes proliferation and migration of androgen-independent prostate cancer cells.

Polycomb repressive complex 2 (PRC2) allows the deposition of H3K27me3. PRC2 facultative subunits modulate its activity and recruitment such as hPCL3/PHF19, a human ortholog of Drosophila Polycomb-like protein (PCL). These proteins contain a TUDOR domain binding H3K36me3, two PHD domains and a "Winged-helix" domain involved in GC-rich DNA binding. The human PCL3 locus encodes the full-length hPCL3L protein and a shorter isoform, hPCL3S containing the TUDOR and PHD1 domains only. In this study, we demonstrated by RT-qPCR analyses of 25 prostate tumors that hPCL3S is frequently up-regulated. In addition, hPCL3S is overexpressed in the androgen-independent DU145 and PC3 cells, but not in the androgen-dependent LNCaP cells. hPCL3S knockdown decreased the proliferation and migration of DU145 and PC3 whereas its forced expression into LNCaP increased these properties. A mutant hPCL3S unable to bind H3K36me3 (TUDOR-W50A) increased proliferation and migration of LNCaP similarly to wt hPCL3S whereas inactivation of its PHD1 domain decreased proliferation. These effects partially relied on the up-regulation of genes known to be important for the proliferation and/or migration of prostate cancer cells such as S100A16, PlexinA2, and Spondin1. Collectively, our results suggest hPCL3S as a new potential therapeutic target in castration resistant prostate cancers.