Emmanuel Oger

Cytoplasmic PAR-3 protein expression is associated with adverse prognostic factors in clear cell renal cell carcinoma and independently impacts survival.

Clear cell renal cell carcinomas (ccRCCs) represent 70% of renal cancers, and several clinical and histolopathological factors are implicated in their prognosis. We recently demonstrated that the overexpression of PAR-3 protein encoded by the PARD3 gene could be implicated in renal oncogenesis. The object of this work was to study the association of intratumoral PAR-3 expression with known prognostic parameters and clinical outcome. In this aim, PAR-3 expression was assessed by immunohistochemistry in ccRCC tumors of 101 patients from 2003 to 2005. The immunostaining of PAR-3 was scored either as membranous (mPAR-3) or as both membranous and cytoplasmic (cPAR-3). Cytoplasmic PAR-3 was significantly associated with worse histopathological and clinical prognostic factors: Fuhrman grades 3 and 4, tumor necrosis, sarcomatoid component, adrenal invasion, renal and hilar fat invasion, eosinophilic component, a noninactivated VHL gene, higher tumor grade, lymph node involvement, metastasis, and worse clinical Eastern Cooperative Oncology Group and S classification scores. After multivariate analysis, 2 parameters were independently associated with cPAR-3: necrosis and eosinophilic components. In addition, cPAR-3 patients had shorter overall and progression-free survivals independently from strong prognostic validated factors like metastases. A cytoplasmic expression of PAR-3 is therefore implicated in worse clinical and pathological cancer features in ccRCC and could be useful to identify patients with high-risk tumors.

Histologic prognostic factors associated with chromosomal imbalances in a contemporary series of 89 clear cell renal cell carcinomas.

Clear cell renal cell carcinoma (ccRCC) is the most common type of renal cancer. The aim of this study was to define specific chromosomal imbalances in ccRCC that could be related to clinical or histologic prognostic factors. Tumors and karyotypes of 89 patients who underwent nephrectomy for ccRCC were analyzed from April 2009 to July 2012. The mean number of chromosomal aberrations was significantly higher (7.8; P < .05) in Fuhrman grade 4 (F4) than in F3 (4) and F2 (3.4) cases. The results were similar, considering separately the mean number of chromosomal losses and gains. The F4 cases had a distinct pattern with more frequent losses of chromosomes 9, 13, 14, 18, 21, 22, and Y and gains of chromosome 20. Necrosis was associated with losses of chromosomes 7, 9, 18, and 22; sarcomatoid component, losses of chromosomes 7, 9, and 14 and gains of 20; and T stage, losses of chromosomes 18 and Y. After multivariate analysis, renal fat invasion, renal vein emboli, and microscopic vascular invasion were, respectively, associated with losses of chromosomes 13 and Y, loss of chromosome 13, and loss of chromosome 14 and gains of chromosomes 7 and 20. F4 was independently associated with losses of chromosomes 9 and Y; sarcomatoid component, loss of chromosome 9 and gain of 20; necrosis, loss of chromosome 18; and T stage, loss of chromosome Y. These chromosomal imbalances can be detected routinely by karyotype or fluorescence in situ hybridization analyses to stratify patients for risk of progression.

Emergency admissions for major haemorrhage associated with direct oral anticoagulants

INTRODUCTION To describe the population admitted in an emergency department of a teaching hospital for severe bleeding associated with direct oral anticoagulants (DOAC). METHOD During a three-year period (2012-2014) patients older than 16 years were prospectively identified by haemorrhagic symptoms from computerised requests. At least one of the following criteria defined major haemorrhage: haemorrhagic shock, unstable haemodynamic, need for transfusion or haemostatic procedure, or a life threatening location. RESULTS Fifty four patients, 23 receiving dabigatran, 30 rivaroxaban and one apixaban were included, 2 in 2012, 35 in 2013 and 17 in 2014. Median age was 84 years (range 63-99) with a sex ratio of 1.16. Haemorrhagic complications were gastrointestinal (n=27), intracranial (n=12) or miscellaneous (n=15). Indication of DOAC was stroke prevention in atrial fibrillation in 49 cases and deep vein thrombosis in 5 cases. Hospitalization was required for 45 patients (83%) with a mean length of stay of 8.5 days. Sixteen patients needed intensive care. Reversal therapy was prescribed in 11 patients. At 1 month, overall mortality was 24%, reaching 41.7% for intracranial haemorrhage. Among surviving patients, DOAC was stopped in 10 cases, continued in 17 patients and switched for other antithrombotic in 17 patients. CONCLUSION Our study contributes to the post marketing surveillance of major haemorrhagic complications associated with DOAC. It takes part to the knowledge about the course of this severe event in emergencies. Careful awareness in risk benefit assessment, especially in elderly, is needed.

Combination of Temsirolimus and tyrosine kinase inhibitors in renal carcinoma and endothelial cell lines.

PurposeMultitargeted tyrosine kinase inhibitors (TKIs) (such as Sunitinib and Sorafenib) and mTOR inhibitors (such as Temsirolimus) are effective in treating metastatic clear-cell renal cell carcinoma (CCRCC), by acting on different pathways in both tumour and endothelial cells. A study of their combined effect could be of major interest.MethodsWe studied endothelial and CCRCC cell lines treated with Sunitinib, Sorafenib, Temsirolimus and 2 drug combinations: Sunitinib–Temsirolimus and Sorafenib–Temsirolimus. We studied inhibition of proliferation with an MTT assay under normoxia and hypoxia, VEGF expression by quantitative RT–PCR and ELISA, and angiogenesis with a Matrigel assay.ResultsTKIs and Temsirolimus inhibited proliferation of endothelial and tumour cell lines and inhibited angiogenesis. Anti-proliferative effects were more significant on cell lines with VHL gene inactivation and under hypoxic conditions. VEGF expression was induced by TKIs, but inhibited by Temsirolimus. The Sunitinib/Temsirolimus combination had synergistic or additive effects on the proliferation of tumour and endothelial cell lines. The Sorafenib–Temsirolimus combination had additive effects on the proliferation of most tumour cell lines, but not endothelial cell lines. Both combinations had additive effects on the inhibition of angiogenesis.ConclusionIn our model, Sunitinib, Sorafenib and Temsirolimus had anti-tumour and anti-angiogenic effects. The combinations of Sunitinib or Sorafenib with Temsirolimus had additive or synergistic effects on the inhibition of tumour and endothelial cell proliferation, and on the inhibition of angiogenesis. This work could lead to new trials with lower-dose combinations to prevent side effects and enhance efficacy.

Letter to the Editor: “Transdermal vs Oral Estrogen Therapy and Venous Thromboembolism: Upgrade the Level of Evidence” by

Scarabin PY, et meta-analysis by Mohammed et al (1) confirms the safety advantage of transdermal vs oral estrogens with respect to the risk of venous thromboembolism (VTE). Surprisingly, the quality of evidence is described as very low (see Table 4 in the report). We believe that this quality rating based on “the observational nature of the studies and inconsistency of results” is not appropriate...

Predicting morbidity after robotic partial nephrectomy: The effect of tumor, environment, and patient-related factors

PURPOSE To investigate the effect of tumor and nontumor related parameters on perioperative outcomes of robotic partial nephrectomy (RPN). PATIENTS AND METHODS Patients who underwent RPN for a localized renal tumor at 2 institutions between June 2010 and November 2016 were reviewed. RENAL and Mayo adhesive probability (MAP) scores were calculated and information on comorbid conditions including ASA score, performance status, Charlsons comorbidity index (CCI), and history of cardiovascular disease was collected. Correlations between each variable and warm ischemia time, estimated blood loss (EBL), operative time, change in estimated glomerular filtration rate, and length of hospital stay were assessed. Logistic regression analyses were performed to identify the best predictors of overall complications, major complications, risk of conversion, and Trifecta achievement. RESULTS A total of 500 patients were included. RENAL score was found to have a statistically significant (P<0.05) correlation with warm ischemia time, EBL, and change in estimated glomerular filtration rate. MAP score showed significant association (P<0.05) with operative time and EBL. CCI had a significant correlation (P<0.05) with length of hospital stay and postoperative complications. In multivariable analyses, MAP score as a continuous variable (OR = 7.66; P<0.001) and MAP risk group stratification (OR = 3.29; P = 0.005) were independent predictors of the risk of conversion. Major complications were significantly associated with the cardiovascular disease in both univariable (OR = 2.35; P = 0.01) and multivariable analysis (OR = 4.52, P = 0.01). Finally, the MAP score as a continuous variable was an independent factor of Trifecta achievement (OR = 0.56; P = 0.04). CONCLUSION Patients related factors were the most important determinants of postoperative complications after RPN. RENAL and MAP scores had some influence on intraoperative parameters.

Safety of Oral Propranolol for Infantile Hemangioma

In this study on a large nationwide database based on health reimbursements, we confirm the overall good safety profile of oral propranolol in children with IH. OBJECTIVES: The safety of oral propranolol for infantile hemangioma has not yet been studied at population level since the pediatric use marketing authorization was obtained in Europe. METHODS: A survey of a nationwide, claim-based observational cohort of children <3 years old, with at least 1 delivery of oral propranolol between July 2014 and June 2016, was performed by using the database of the French National Health Insurance system. Standardized morbidity ratios (SMRs) were calculated by using, from the same database, a representative random sample of nonexposed subjects. The main outcomes were hospitalizations for cardiovascular (conduction disorders, bradycardia, and hypotension), respiratory (bronchial hyperactivity and bronchospasm), or metabolic events (hypoglycemia and hyperkalaemia), identified through the hospitalization diagnostic codes of the International Classification of Diseases, 10th Revision. The main analysis was conducted separately on “healthy” children (N = 1484), that is, free from of any prespecified underlying disease and on children with 1 of these underlying diseases (N = 269). RESULTS: In all, 1753 patients <3 years of age had at least 2 deliveries of oral propranolol. In the healthy population, we observed 2 cardiovascular events (SMR = 2.8 [0–6.7]), 51 respiratory events (SMR = 1.7 [1.2–2.1]), and 3 metabolic events (SMR = 5.1 [0–10.9]). In the population with an underlying disease (mainly congenital heart disease), we observed 11 cardiovascular events leading to an SMR of 6.0 (2.5–9.6). SMRs were not significantly raised for respiratory or metabolic events in this “nonhealthy” population. CONCLUSIONS: In this study on a large continuous nationwide claims database, we confirm the safety profile of oral propranolol in healthy children to be good.

Use of 5α-reductase inhibitors for benign prostate hypertrophy and risk of high grade prostate cancer: a French population-based study

To assess the association between 5α‐reductase inhibitor (5‐ARI) use and high grade (Gleason score 8–10) prostate cancer.