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.

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.

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.

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.

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.

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.

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.

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.

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.

Evaluating the prognostic potential of the Ki67 proliferation index and tumour-infiltrating lymphocytes in olfactory neuroblastoma.

AIMS: Olfactory neuroblastomas (ONBs) are rare malignant tumours that arise in the nasal vault. To date, the Hyams grade remains the only widely used histological grading system. However, it is based only on morphological criteria, and has not been updated since 1988. The objective of this study was to explore the prognostic potential of the Ki67 proliferation index (PI) and tumour-infiltrating lymphocytes (TILs) in ONB. METHODS AND RESULTS: A retrospective study was conducted on a bicentric series of 45 cases. The Ki67 PI was determined by counting at least 1000 nuclei on whole slides. TILs were evaluated with CD20, CD4 and CD8 immunohistochemical markers on whole slides. In this series, Hyams grades I, II, III and IV accounted for 13.4%, 44.4%, 20% and 22.2% of all cases, respectively. The Ki67 PI ranged from 1 to 93; the Ki67 PI was significantly higher in Hyams grade III-IV ONBs than in Hyams grade I-II ONBs (P < 0.0001). A Ki67 PI of ≥25 was associated with poorer survival (P = 0.02). TILs were present in both stromal and intratumoral compartments, but were located predominantly in the stromal component of the tumour. The numbers of intratumoral CD8+ cells/mm2 and CD4+ cells/mm2 were greater in high-grade ONBs than in low-grade ONBs (P = 0.0015 and P = 0.043, respectively). The numbers of T cells/mm2 and B cells/mm2 were not associated with survival, but a CD4/CD8 ratio of >2 was significantly associated with shorter survival (P = 0.04). CONCLUSION: Our findings suggest that the Ki67 PI and TILs could be used as prognostic markers, as a potential alternative to the Hyams grade.

Low-risk prostate cancer selected for active surveillance with negative MRI at entry: can repeat biopsies at 1 year be avoided? A pilot study.

PURPOSE: In patients considered for active surveillance (AS), the use of MRI and targeted biopsies (TB) at entry challenges the approach of routine "per protocol" repeat systematic biopsies (SB) at 1 year. This pilot study aimed to assess whether an approach of performing repeat biopsies only if PSA kinetics are abnormal would be safe and sufficient to detect progression. METHODS: Prospective single-centre study of 149 patients on AS with low-risk PCa, a negative MRI at entry, followed for a minimum of 12 months between 01/2007 and 12/2015. Group 1 (n = 78) patients had per-protocol 12-month repeat SB; group 2 (n = 71) patients did not. Surveillance tests for tumour progression were for both groups: for cause SB and MRI-TB biopsies if PSA velocity (PSA-V) > 0.75 ng/ml/year, or PSA doubling time (PSADT) < 3 years. The main objectives are to compare the 2-year rates of tumour progression and AS discontinuation between groups. The secondary objectives are to estimate the diagnostic power of PSA-V and PSA-DT, to predict the risk of tumour progression. RESULTS: Overall, 21 out of 149 patients (14.1%) showed tumour progression, 17.1% for group 1 and 12.3% for group 2, and 31 (21.2%) discontinued AS at 2 years. There was no difference between the 2 groups (p = 0.56). The area under the PSA-V and PSADT curves to predict tumour progression was 0.92 and 0.83, respectively. CONCLUSIONS: We did not find any significant difference for progression and AS discontinuation rate between the 2 groups. The PSA kinetic seems accurate as a marker of tumour progression. These results support the conduct of a multi-centre prospective trial to confirm these findings.

Biphasic papillary renal cell carcinoma is a rare morphological variant with frequent multifocality: a study of 28 cases.

AIMS: To further characterise biphasic squamoid renal cell carcinoma (RCC), a recently proposed variant of papillary RCC. METHODS AND RESULTS: We identified 28 tumours from multiple institutions. They typically showed two cell populations-larger cells with eosinophilic cytoplasm and higher-grade nuclei, surrounded by smaller, amphophilic cells with scanty cytoplasm. The dual morphology was variable (median 72.5% of tumour, range 5-100%); emperipolesis was found in all cases. The male/female ratio was 2:1, and the median age was 55 years (range 39-86 years). The median tumour size was 20 mm (range 9-65 mm). Pathological stage pT1a was found in 21 cases, pT1b in three, and pT3a and pT3b in one each (two not available). Multifocality was found in 32%: multifocal biphasic RCC in one case, biphasic + papillary RCC in two cases, biphasic + clear cell RCC in three cases, biphasic + low-grade urothelial carcinoma of the renal pelvis in one case, and biphasic + Birt-Hogg-Dubé syndrome in one case. Positive immunostains included: PAX8, cytokeratin (CK) 7, α-methylacyl-CoA racemase, epithelial membrane antigen, and vimentin. Cyclin D1 was expressed only in the larger cells. The Ki67 index was higher in the larger cells (median 5% versus ≤1%). Negative stains included: carbonic anhydrase 9, CD117, GATA-3, WT1, CK5/6, and CK20; CD10 and 34ßE12 were variably expressed. Gains of chromosomes 7 and 17 were found in two evaluated cases. Follow-up was available for 23 patients (median 24 months, range 1-244 months): 19 were alive without disease, one was alive with recurrence, and one had died of disease (two had died of other causes). CONCLUSIONS: Biphasic papillary RCC is a rare variant of papillary RCC, and is often multifocal.

Incidence, clinicopathological features and fusion transcript landscape of translocation renal cell carcinomas.

AIMS: Translocation renal cell carcinoma (tRCC) is a rare subtype of kidney tumour characterized by translocations involving the transcription factor TFE3 or TFEB. tRCC was introduced into the World Health Organization classification in 2004, but much is still unknown about the natural history, clinicopathological features and outcomes of the disease. The aim of this study was to describe the landscape of fusion transcript in a large single-institution series of fluorescence in-situ hybridization (FISH)-confirmed tRCCs and then to compare it to morphological and clinical data. METHODS AND RESULTS: Paired-end RNA sequencing was performed within a prospective database of the Department of Pathology, Centre Hospitalier Régional Universitaire (Lille, France). The diagnosis of tRCC was confirmed by FISH. Among a total of 1130 identified renal cell carcinomas, 21 cases (1.9%) showed rearrangement of the TFE3 (n = 20) or (TFEB) (n = 1) gene. Median patient age was 31 years (range = 15-47), and the female-to-male ratio was 6:1. Five different TFE3 fusion transcripts were identified; the most frequent TFE3 partners were PRCC (n = 4) and SFPQ (n = 4). The other partners involved were ASPCR1 (n = 1) and MED15 (n = 1) genes as well as a novel TFE3 partner, GRIPAP1. CONCLUSIONS: We identified a new fusion partner, GRIPAP1. The prognostic role of transcript type could not be determined because our number of cases was too small. Four patients (19%) died of the disease, all of which presented with a lymph node involvement at diagnosis. We confirm that tRCC can be an aggressive tumour, especially those of advanced clinical stage.

Targeting miR-21 decreases expression of multi-drug resistant genes and promotes chemosensitivity of renal carcinoma.

Renal cell carcinoma, the most common neoplasm of adult kidney, accounts for about 3% of adult malignancies and is usually highly resistant to conventional therapy. MicroRNAs are a class of small non-coding RNAs, which have been previously shown to promote malignant initiation and progression. In this study, we focused our attention on miR-21, a well described oncomiR commonly upregulated in cancer. Using a cohort of 99 primary renal cell carcinoma samples, we showed that miR-21 expression in cancer tissues was higher than in adjacent non-tumor tissues whereas no significant difference was observed with stages, grades, and metastatic outcome. In vitro, miR-21 was also overexpressed in renal carcinoma cell lines compared to HK-2 human proximal tubule epithelial cell line. Moreover, using Boyden chambers and western blot techniques, we also showed that miR-21 overexpression increased migratory, invasive, proliferative, and anti-apoptotic signaling pathways whereas opposite results were observed using an anti-miR-21-based silencing strategy. Finally, we assessed the role of miR-21 in mediating renal cell carcinoma chemoresistance and further showed that miR-21 silencing significantly (1) increased chemosensitivity of paclitaxel, 5-fluorouracil, oxaliplatin, and dovitinib; (2) decreased expression of multi-drug resistance genes; and (4) increased SLC22A1/OCT1, SLC22A2/OCT2, and SLC31A1/CTR1 platinum influx transporter expression. In conclusion, our results showed that miR-21 is a key actor of renal cancer progression and plays an important role in the resistance to chemotherapeutic drugs. In renal cell carcinoma, targeting miR-21 is a potential new therapeutic strategy to improve chemotherapy efficacy and consequently patient outcome.

Quantified analysis of histological components and architectural patterns of gleason grades in apparent diffusion coefficient restricted areas upon diffusion weighted MRI for peripheral or transition zone cancer locations.

PURPOSE: To quantify and compare the histological components and architectural patterns of Gleason grades in cancerous areas with restriction on apparent diffusion coefficient (ADC) maps. MATERIALS AND METHODS: Twelve consecutive cases with 14 separate ADC restriction areas, positive for cancer in the peripheral zone (PZ) and transition zone (TZ) were included. All had 3 Tesla MRI and radical prostatectomy. Ten regions of interest (ROIs) within and outside the 14 ADC restriction areas positive for cancer were selected. For each ROI, we performed quantitative analysis of (a) prostate benign and malignant histological component surface ratios, including stroma, glands, epithelium, lumen, cellular nuclei; (b) percent of Gleason grades and measures of ADC values. Means of histological components according to ADC restriction for cancerous area were compared with analyses of variance with repeated measures. RESULTS: Independent predictors of the probability of cancer were median epithelium/ROI ratio (P = 0.001) and nuclei/ROI ratio (P = 0.03). Independent predictors of the probability of ADC restriction were malignant glands/ROI and luminal space/ROI (P < 0.0001). Effect of malignant glands/ROI area was different according to the localization of the ROI (P = 0.03). We observed an overall difference between the means for all of the histological components for the comparison of true positive and false negative (P < 0.0001), except for the percent of Gleason grade 4 (P = 0.18). In TZ cancers, a predominant grade 3 pattern was associated with low ADC values. In PZ cancers, a predominant grade 4 pattern was associated with low ADC values. CONCLUSION: Determinants of low ADC were high ratio of malignant glands/ROI area which may be seen in Gleason grades 3 or 4 cancers. LEVEL OF EVIDENCE: 3 Technical Efficacy: Stage 3 J. Magn. Reson. Imaging 2017;46:1786-1796.

Dilated Cardiomyopathy Caused by Wilms Tumor.

The authors report the case of a 7-month-old girl with unilateral Wilms tumor with dilated cardiomyopathy, leading to cardiac failure and requiring intensive care. After chemotherapy and tumor removal, cardiac function has improved. This is a rare report on the association between nephroblastoma and dilated cardiomyopathy without hypertension.

Comparison of endoscopic and external resections for sinonasal instestinal-type adenocarcinoma.

Endoscopic sinus surgery (ESS) is considered as a valid option in the management of nasal adenocarcinoma (ADC). Comparative studies with open approaches are still required. A monocentric retrospective study was carried out from May 2002 to December 2013, including 43 patients with intestinal-type adenocarcinoma of the ethmoid sinus. Non-resectable tumours or recurrences were excluded. Before 2008, open approach with lateral rhinotomy (LR) was performed as the gold standard of treatment. From 2008, ESS was systematically used as a first-line option as long as a complete resection was achievable. Adjuvant radiation therapy was delivered (RT) for all the patients. LR and ESS were performed in, respectively, 23 and 20 patients. The two groups were comparable in terms of age, occupational dust exposure, histopathological subtypes, and T stage based on the pathological assessment of the specimen (10 pT2, 26 pT3, 2 pT4a, and 5 pT4b). The tumour origin was mainly located in the olfactory cleft with the involvement of the cribriform plate in 60 % of patients. No major complication was observed in ESS group with a reduced hospital stay (5.6 vs 7.6 days). The disease-free survival was not different between LR and ESS groups over a mean follow-up period of 6.6 years. Even for local advanced stages with skull base involvement, we confirm the reliability and the advantages of ESS in terms of oncological outcomes and morbidity. We advocate complete excision of the olfactory cleft to ensure an appropriate control of the tumoral origin.

Improvement of the initial management of sarcomas after the dissemination of evidence-based guidelines depends on the primary sarcoma location: a population-based study.

BACKGROUND: Improvement of the initial management of sarcomas after the dissemination of evidence-based guidelines depends on the primary sarcoma location: a population-based study. To improve the initial management of adult sarcomas, a regional expert team in Northern France performed two actions: dissemination of evidence-based guidelines (EBG) for the management of soft tissue/visceral sarcoma and yearly educational symposia. The aim of this study was to measure the impact of the dissemination of EBG on the key-indicators of adult sarcoma management. METHODS: We conducted a before-after population-based study (before: 2005 with 63 cases, after: 2008-2009 with 86 cases) in the Lille area (Northern France urban/sub-urban area with 800,000 inhabitants). The following were the key-indicators of adult sarcoma management: pre-therapeutic biopsy, appropriate tumour and chest imaging, expert interdisciplinary discussion, expert interdisciplinary discussion before the first treatment and in operated cases, the rate of R0 resection. RESULTS: There was no statistically significant difference in patient and tumour characteristics for the two time periods in terms of gender, prior cancer, primary location, histological subtype, grade, size, metastasis and lymph node involvement. There was no statistically significant improvement in primary tumour imaging (83 versus 87%), chest imaging (67 vs 71%), pre-therapeutic biopsy (57 vs 58%). There was an improvement in expert multidisciplinary discussion (37 vs 45%) or discussion before the first treatment (26 vs 44%) but no statistically significant. However, when soft tissue and bone sarcomas were analysed separately, we observed statistically significant improvements in expert multidisciplinary discussion (50 vs 74%, p = 0.02) and R0 resection rate (58 vs 91%, p = 0.002). In contrast, in cases of visceral sarcoma, there was no improvement in expert multidisciplinary discussion (10 vs 16%, p = 0.7) or in R0 resection (88 vs 81%, p = 0.7). CONCLUSIONS: The dissemination of EBG was associated with a limited improvement in sarcoma management when measured in this before-after population-based study, and this improvement was dependent on the primary location of the tumour. Efforts to implement these guidelines by all surgical teams that could treat sarcoma, including visceral sarcoma, need to be made.