Detection of tetraploidization in chromophobe renal cell carcinoma: Insights and pitfalls.

Chromosomal losses resulting in a marked hypodiploidy are a specificity of chromophobe renal cell carcinoma (ChRCC), the third most frequent type of kidney cancer. Its detection is useful in challenging cases. However some ChRCC, especially the eosinophilic variant, do not exhibit hypodiploidy and deserve to be better explored. Using comparative genomic hybridization (array-CGH) we observed chromosomal gains in five cases of nonmetastatic ChRCC. Our objective was to determine whether these apparent chromosomal gains were instead losses within a near-polyploid genome. We performed a retrospective and prospective molecular study of 26 cases of ChRCC retrieved among 643 renal tumors (2012-2019). All tumors were analyzed using array-CGH (Agilent) and array-CGH (Affymetrix) coupled to single nucleotide polymorphism analysis (array-SNP). In silico manual centralization of the fluorescence ratio, fluorescence in situ hybridization (FISH) and next generation sequencing were made in the five cases suspected of polyploidy. Tetraploidization was observed in 19% of our series of ChRCC. None of the methods used individually could identify both chromosomal losses and tetraploidy. Only the combination of manual recentring of array-CGH and FISH provided relevant results. B-allele frequency results indicated that tetraploidization occurred secondarily to chromosomal losses in four cases while it preceded losses in one case. Tetraploidization is a frequent but underestimated phenomenon in ChRCC that may be overlooked using the individual standard genomic methods. Its potential clinical consequences are not identified yet. Whether the mechanisms that induce chromosomal losses in ChRCC are the same that generate tetraploidization is not known.

Left ventricular overloading identified by critical care echocardiography is key in weaning-induced pulmonary edema.

PURPOSE: To assess the role of left ventricular overload and cumulated fluid balance in the development weaning-induced pulmonary edema (WIPO). METHODS: Ventilated patients in sinus rhythm with COPD and/or heart failure (ejection fraction ≤ 40%) were studied. Echocardiography was performed immediately before and during a 30-min spontaneous breathing trial (SBT) using a T-tube. Patients who failed were treated according to echocardiography results before undergoing a second SBT. RESULTS: Twelve of 59 patients failed SBT, all of them developing WIPO. Patients who succeeded SBT had lower body weight (- 2.5 kg [- 4.8; - 1] vs. + 0.75 kg [- 2.95; + 5.57]: p = 0.02) and cumulative fluid balance (- 2326 ml [- 3715; + 863] vs. + 143 ml [- 2654; + 4434]: p = 0.007) than those who developed WIPO. SBT-induced central hemodynamic changes were more pronounced in patients who developed WIPO, with higher E wave velocity (122 cm/s [92; 159] vs. 93 cm/s [74; 109]: p = 0.017) and E/A ratio (2.1 [1.2; 3.6] vs. 0.9 [0.8; 1.4]: p = 0.001), and shorter E wave deceleration time (85 ms [72; 125] vs. 147 ms [103; 175]: p = 0.004). After echocardiography-guided treatment, all patients who failed the first SBT were successfully extubated. Fluid balance was then negative (- 2224 ml [- 7056; + 100] vs. + 146 ml [- 2654; + 4434]: p = 0.005). Left ventricular filling pressures were lower (E/E': 7.3 [5; 10.4] vs. 8.9 [5.9; 13.1]: p = 0.028); SBT-induced increase in E wave velocity (+ 10.6% [- 2.7/ + 18] vs. + 25.6% [+ 12.7/ + 49]: p = 0.037) and of mitral regurgitation area were significantly smaller. CONCLUSION: In high-risk patients, WIPO appears related to overloaded left ventricle associated with excessive fluid balance. SBT-induced central hemodynamic changes monitored by CCE help in guiding therapy for successful weaning.

Safety of dual kidney transplantation compared to single kidney transplantation from expanded criteria donors: a single center cohort study of 39 recipients.

Our objective was to compare the outcomes of dual kidney transplanataion (DKT) to single kidney transplantation (SKT) performed with grafts from expanded criteria donors (ECD) in recipients ≥65 years, focusing on surgical complications. All kidney transplantations (KT) performed between 2006 and 2014 in our institution were analysed. DKT was indicated according to the criteria of the French national Agence de la Biomedecine. Thirty-nine DKT and 155 SKT were included, with a median follow-up of 36 and 26.5 months, respectively. The rate of early surgical revisions was not significantly higher after DKT (23.1% vs 15.5% (P = 0.2593)) but more venous graft thromboses (12.8% vs 3.2% (P = 0.02)) were reported. The glomerular filtration rate (GFR) 24 months after KT was significantly higher after DKT (45.0 ± 16.3 vs 39.8 ± 13.8 ml/min/1.73m2 ; P = 0.04) and allowed shorter waiting time without a significant increased risk of surgical revision, excepted for venous graft thrombosis, more frequent after DKT. Graft survivals were not significantly different and GFR was higher after DKT. DKT seems to remain an appropriate strategy to address the growing graft shortage in elderly patients.

ALK-TPM3 rearrangement in adult renal cell carcinoma: Report of a new case showing loss of chromosome 3 and literature review.

Seven cases of translocation-associated renal cell carcinoma involving ALK (ALK-tRCC) were referenced in the last World Health Organization's classification (2016), in a group of emerging/provisional RCC. The first three cases were pediatric, medullary-based, associated with sickle-cell trait and showed a fusion of ALK with VCL. Thirteen cases have been further described. They displayed clinical, morphological and genomic heterogeneity. Most of them occurred in adults. None of the patients was affected by sickle-cell disease. We report a new case of ALK-tRCC in a 55-year-old woman. Genomic profile showed losses of chromosomes 3, 9 and 14, anomalies often observed in clear cell RCC. VHL mutation or morphological features suggesting a clear cell RCC were not detected. We identified an unbalanced rearrangement of ALK and TPM3. Review of the literature identified similar features in our case and previously published cases: heterogeneous solid architecture, eosinophilic cells, mucinous cytoplasmic elements, rhabdoid cells and intracytoplasmic lumina. These elements may constitute the basis of a pathological definition of ALK-tRCC. Their observation in a RCC should lead to perform molecular detection of ALK rearrangement. This may have a crucial importance for metastatic patients treatment since ALK rearrangements confer sensitivity to tyrosine kinases inhibitors such as crizotinib.

The two glycolytic markers GLUT1 and MCT1 correlate with tumor grade and survival in clear-cell renal cell carcinoma.

BACKGROUND: Clear-cell renal cell carcinoma (ccRCC) is the most common type of kidney cancer. Although ccRCC is characterized by common recurrent genetic abnormalities, including inactivation of the von Hippel-Lindau (vhl) tumor suppressor gene resulting in stabilization of hypoxia-inducible factors (HIFs), the tumor aggressiveness and outcome of ccRCC is variable. New biomarkers are thus required to improve ccRCC diagnosis, prognosis and therapeutic options. This work aims to investigate the expression of HIF and proteins involved in metabolism and pH regulation. Their correlation to histoprognostic parameters and survival was analyzed. METHODS: ccRCC of 45 patients were analyzed. HIF-1α, HIF-2α, HAF, GLUT1, MCT1, MCT4, CAIX and CAXII expression was assessed by immunohistochemistry in a semi-quantitative and qualitative manner. The GLUT1, MCT1, MCT4, CAIX and CAXII mRNA levels were analyzed in an independent cohort of 43 patients. RESULTS: A significant correlation was observed between increased GLUT1, MCT1, CAXII protein expression and a high Fuhrman grade in ccRCC patients. Moreover, while HIF-1α, HIF-2α and HAF expression was heterogenous within tumors, we observed and confirmed that HIF-2α co-localized with HAF. We confirmed, in an independent cohort, that GLUT1, MCT1 and CAXII mRNA levels correlated with the Fuhrman grade. Moreover, we demonstrated that the high mRNA level of both MCT1 and GLUT1 correlated with poor prognosis. CONCLUSIONS: This study demonstrates for the first time a link between the aggressiveness of high- Fuhrman grade ccRCC and metabolic reprogramming. It also confirms the role of HIF-2α and HAF in tumor invasiveness. Finally, these results demonstrate that MCT1 and GLUT1 are strong prognostic markers and promising therapeutic targets.

Comprehensive study of three novel cases of TFEB-amplified renal cell carcinoma and review of the literature: Evidence for a specific entity with poor outcome.

The first case of TFEB-amplified renal cell carcinoma was published in 2014. Since then, 29 additional cases have been described. The prognostic and therapeutic implications of this rare entity remain to be determined. We describe here the clinical, histological, and genetic features of three novel cases, and the first complete literature review. Four tumors were examined from three patients selected from the large collection of genetically characterized renal tumors in our institution. The pathological and immunohistochemical features were centrally reviewed by a uropathologist. Quantitative and structural genomic abnormalities were analyzed using comparative genomic hybridization, fluorescence in situ hybridization, and next generation sequencing. The three cases showed high-level amplification but no translocation of TFEB. Histologically, two tumors showed a papillary or pseudopapillary architecture. They did not show similarities with renal cell carcinoma harboring translocation of TFEB. The tumors were locally advanced high-grade lesions. They exhibited a metastatic course, which was rapidly leading to death in one patient. A second patient developed metastatic disease that did not respond to four lines of targeted treatments. The third patient had a protracted history of pulmonary and cardiac metastases. Complete clinical and biological data were examined and compared to those of the reported cases. Within the classification of renal tumors, TFEB-amplified renal cell carcinoma may constitute a novel entity characterized histologically by high-grade, papillary or pseudopapillary architecture, and necrotic remodeling and clinically by a poor outcome. Its pathogenesis has to be further characterized to develop appropriate targeted therapy.

Outcome of Transurethral Resection of Bladder Tumor: Does Antiplatelet Therapy Really Matter? Analysis of a Retrospective Series.

INTRODUCTION: Transurethral resection of bladder tumor (TURBT) is considered to be at a moderate or high risk of bleeding during surgical procedure. The number of patients on antiplatelet (AP) drugs has been increasing; we wanted to assess their impact on the outcome of patients undergoing scheduled TURBT. MATERIALS AND METHODS: A retrospective assessment of noninferiority of 450 consecutive procedures performed between April 2013 and June 2015 was conducted. Patients were divided in two groups: naive or AP drug users. The primary endpoint was the average length of stay (ALOS). Noninferiority was set at 1 day. A subgroup analysis comparing the acetylsalicylic acid (ASA) group and clopidogrel group to the naive group was performed. Multivariate analysis was performed to find the determinants of a longer ALOS. Chi-square or Fisher tests were used to analyze categorical variables, and Student's or Mann-Whitney tests were used to analyze quantitative variables. RESULTS: We included 325 patients who underwent TURBT: 117 received AP drugs (ASA, 85; clopidogrel, 32) and 208 were naive to AP drugs (of whom 117 were consecutively analyzed). The ALOSs were 2.5 days (naive group) and 2.9 days (AP group). The subgroup analysis showed ALOSs of 2.6 days (ASA group) and 3.7 days (clopidogrel group). Clopidogrel therapy (odds ratio = 4.1 [1.7-9.6]) and the duration and depth of resection emerged as determinants of a longer ALOS in multivariate analysis. Perioperative management of AP therapies was achieved according to recommended practices. CONCLUSIONS: The ALOS of patients receiving AP drugs was not clinically different from naive patients. This result was identical for patients receiving ASA. However, clopidogrel increased the length of stay, making us question its use in perioperative management.

Salvage prostate re-irradiation using high-dose-rate brachytherapy or focal stereotactic body radiotherapy for local recurrence after definitive radiation therapy.

BACKGROUND: Optimal management of locally recurrent prostate cancer after definitive radiation therapy is still challenging. With the development of highly accurate radiotherapy devices, prostate salvage re-irradiation might generate lower toxicity rates than classical salvage therapies. We retrospectively evaluated the toxicity and the feasibility of a prostate re-irradiation after definitive radiation therapy failure. Two modalities were investigated: high-dose-rate brachytherapy (HDRB) on whole prostate gland and focal stereotactic radiotherapy (SBRT) using CyberKnife® linac. METHODS: Between 2011 and 2015, 28 patients with imaged and/or biopsy-proven intra-prostatic recurrence of cancer after definitive radiation therapy underwent a salvage re-irradiation using HDRB (n = 10) or focal SBRT (n = 18). The schedule of re-irradiation was 35 Gy in 5 fractions. Biological response (defined as post-salvage radiation PSA variation) and biochemical no-evidence of disease (bNED) were evaluated in the whole cohort. For patients who had a positive biological response after salvage radiation, biochemical recurrence (BCR) and survival after salvage radiotherapy were evaluated. Post-salvage toxicities were assessed according to the Common Terminology Criteria for Adverse Events (CTCAE) v4.03 and were compared to baseline status. RESULTS: Within a median follow-up of 22.5 months (IQR = 8-42), 9 (90%) patients experienced a positive biological response after salvage HDRB and 5 (50%) remained bNED at the end of the follow-up. Among patients who initially responded to salvage HDRB, the BCR rate was 44.4% after a median interval of 19.5 months (IQR = 11.5-26). Only one patient experienced a transient grade 3 urinary complication. In the SBRT group, the median follow-up was 14.5 months (IQR = 7-23) and 10 (55.6%) out of the 18 patients remained bNED. Among the 15 patients who initially responded to salvage SBRT, 5 (33.3%) experienced a BCR. One patient experienced a transient grade 4 urinary complication. At the end of the follow-up, all evaluated patients had a urinary status grade variation ≤ +1 grade. No grade 3-4 digestive toxicity was observed. CONCLUSIONS: Salvage prostate re-irradiation for locally recurrent cancer is feasible and generate low toxicities rates when using with HDRB or focal SBRT. However, further investigations are necessary to confirm these findings and to determine predictive features for patients who might benefit from such an approach.

Magnetic resonance microscopy may enable distinction between normal histomorphological features and prostate cancer in the resected prostate gland.

OBJECTIVES: To determine imaging protocol parameters for characterization of prostate tissue at histological length scales. MATERIAL AND METHODS: Rapid acquisition with relaxation enhancement, spin echo and gradient echo fast low angle shot data were acquired using ex vivo 3-Tesla or 7-Tesla magnetic field strengths from fresh prostatectomy specimens (n = 15) obtained from either organ donor or patients with prostate cancer (PCa). To achieve the closest correspondence between histopathological components and magnetic resonance imaging (MRI) results, in terms of resolution and sectioning planes, multiple high-resolution imaging protocols (ranging from a few minutes to overnight) were tested. Ductograms were generated as part of image post-processing. Specimens were subsequently submitted for histopathological evaluation. RESULTS: A total of seven imaging protocols were tested. Ex vivo 7-Tesla MRI identified normal components of prostate glands, including ducts, blood vessels, concretions and stroma at a spatial resolution of 60 × 60 × 60 µm3 to 107 × 107 × 500 µm3 . Malignant glands and nests of tumour cells identified at 60 × 60 × 90 µm3 were highly similar to low-magnification (×2) histopathology. Ductograms enhanced the differentiation between benign and malignant glands. The results of the present study were encouraging, and further work is warranted with a larger sample size. CONCLUSION: We showed that critical histopathological features of the prostate gland can be identified with high-resolution ex vivo MRI examination and this offers promise that MRI microscopy of PCa will ultimately be possible in vivo.

Dismantling papillary renal cell carcinoma classification: The heterogeneity of genetic profiles suggests several independent diseases.

Papillary renal cell carcinoma (pRCC) is the second most frequent renal cell carcinoma (RCC) after clear cell RCC. In contrast to clear cell RCC, there is no consensual protocol using targeted therapy for metastatic pRCC. Moreover, diagnosis of some pRCC, especially pRCC of type 2 (pRCC2) may be challenging. Our aim was to identify molecular biomarkers that could be helpful for the diagnosis and treatment of pRCC. We studied the clinical, histological, immunohistological, and comprehensive genetic features of a series of 31 pRCC including 15 pRCC1 and 16 pRCC2. We aimed to determine whether pRCC represents a unique entity or several diseases. In addition, we compared the genetic features of pRCC2 to those of eight RCC showing various degrees of tubulo-papillary architecture, including three TFE-translocation RCC and five unclassified RCC. We demonstrate that pRCC is a heterogeneous group of tumors with distinct evolution. While most pRCC2 had genetic profiles similar to pRCC1, some shared genomic features, such as loss of 3p and loss of chromosome 14, with clear cell RCC, TFE-translocation RCC, and unclassified RCC. We identified variants of the MET gene in three pRCC1. A mutation in the BRAF gene was also identified in one pRCC1. In addition, using next-generation sequencing (NGS), we identified several variant genes. Genomic profiling completed by NGS allowed us to classify pRCC2 in several groups and to identify novel mutations. Our findings provide novel information on the pathogenesis of pRCC that allow insights for personalized treatment.

Real-time in vivo periprostatic nerve tracking using multiphoton microscopy in a rat survival surgery model: a promising pre-clinical study for enhanced nerve-sparing surgery.

OBJECTIVES: To assess the ability of multiphoton microscopy (MPM) to visualise, differentiate and track periprostatic nerves in an in vivo rat model, mimicking real-time imaging in humans during RP and to investigate the tissue toxicity and reproducibility of in vivo MPM on prostatic glands in the rat after imaging and final histological correlation study. MATERIALS AND METHODS: In vivo prostatic rat imaging was carried out using a custom-built bench-top MPM system generating real-time three-dimensional histological images, after performing survival surgery consisting of mini-laparotomies under xylazine/ketamine anaesthesia exteriorising the right prostatic lobe. The acquisition time and the depth of anaesthesia were adjusted for collecting multiple images in order to track the periprostatic nerves in real-time. The rats were then monitored for 15 days before undergoing a new set of imaging under similar settings. After humanely killing the rats, their prostates were submitted for routine histology and correlation studies. RESULTS: In vivo MPM images distinguished periprostatic nerves within the capsule and the prostatic glands from fresh unprocessed prostatic tissue without the use of exogenous contrast agents or biopsy sample. Real-time nerve tracking outlining the prostate was feasible and acquisition was not disturbed by motion artefacts. No serious adverse event was reported during rat monitoring; no tissue damage due to laser was seen on the imaged lobe compared with the contralateral lobe (control) allowing comparison of their corresponding histology. CONCLUSIONS: For the first time, we have shown that in vivo tracking of periprostatic nerves using MPM is feasible in a rat model. Development of a multiphoton endoscope for intraoperative use in humans is currently in progress and must be assessed.

High-dose rate brachytherapy in localized penile cancer: short-term clinical outcome analysis.

PURPOSE: To assess clinical outcomes of high-dose rate interstitial brachytherapy (HIB) in localized penile carcinoma. MATERIAL AND METHODS: From 03/2006 to 08/2013, patients with biopsy-proven T1-T2 (<4 cm) non-metastatic localized penile squamous cell carcinoma underwent HIB. Under general anaesthesia, after Foley catheter placement, needles were placed in the target volume using a dedicated template. Planification was carried out with a post-implant CT-scan to deliver a total dose of 36 Gy in 9 fractions over 5 days (in adjuvant setting) or 39 Gy in 9 fractions over 5 days (as monotherapy). Dose-volume adaptation was manually achieved using graphical optimization. Dosimetric data and clinical outcomes were retrospectively analyzed. Toxicities were graded using the CTC v4.0. RESULTS: With a median follow-up of 27 months [5.1-83], 12 patients including 8 T1a, 3 T1b and 1 T2 N0 underwent HIB (sole therapy: 11 pts; adjuvant: 1 pt). The actuarial 5-year relapse-free, cause-specific and overall survival rates were 83%, 100% and 78% respectively. Comparing pre and post treatment evaluation, no IPSS or IIEF-5 changes were reported. Dermatitis was reported systematically 1 month after HIB including 6 G1, 5 G2 and 1 G3. Only 1 experienced long-term G3 successfully treated with hyperbaric oxygen therapy. One urethral meatus stenosis G3 required meatotomy. CONCLUSION: In selected patients with T1-T2 localized penile cancer, HIB may be considered as an optional conservative therapy. Longer follow-up is needed to confirm these encouraging preliminary results.

The relevance of testing the efficacy of anti-angiogenesis treatments on cells derived from primary tumors: a new method for the personalized treatment of renal cell carcinoma.

Despite the numerous available drugs, the most appropriate treatments for patients affected by common or rare renal cell carcinomas (RCC), like those associated with the Xp11.2 translocation/transcription factor for immunoglobulin heavy-chain enhancer 3 (TFE3) gene fusion (TFE3 RCC), are not clearly defined. We aimed to make a parallel between the sensitivity to targeted therapies on living patients and on cells derived from the initial tumor. Three patients diagnosed with a metastatic RCC (one clear cell RCC [ccRCC], two TFE3 RCC) were treated with anti-angiogenesis drugs. The concentrations of the different drugs giving 50% inhibition of cell proliferation (IC50) were determined with the Thiazolyl Blue Tetrazolium Bromide (MTT) assay on cells from the primary tumors and a reference sensitive RCC cell line (786-O). We considered the cells to be sensitive if the IC50 was lower or equal to that in 786-O cells, and insensitive if the IC50 was higher to that in 786-O cells (IC 50 of 6 ± 1 µM for sunitinib, 10 ± 1 µM for everolimus and 6 ± 1 µM for sorafenib). Based on this standard, the response in patients and in cells was equivalent. The efficacy of anti-angiogenesis therapies was also tested in cells obtained from five patients with non-metastatic ccRCC, and untreated as recommended by clinical practice in order to determine the best treatment in case of progression toward a metastatic grade. In vitro experiments may represent a method for evaluating the best first-line treatment for personalized management of ccRCC during the period following surgery.

A rare case of histopathological bladder necrosis associated with Actinobaculum schaalii: the incremental value of an accurate microbiological diagnosis using 16S rDNA sequencing.

We describe here a rare case of bladder wall necrosis associated with Actinobaculum schaalii in a 72-year-old patient with non-muscle-invasive bladder cancer (NMIBC). A. schaalii microbiological diagnosis requires high index of suspicion and accurate identification methods such as 16S rDNA sequencing or MALDI-TOF Mass spectrometry.

Focal cryoablation: a treatment option for unilateral low-risk prostate cancer.

OBJECTIVES: To assess oncological (biochemical and histological recurrence) and functional (urinary and potency) outcomes in patients with unilateral low-risk organ-confined prostate cancer (PCa) treated with focal cryoablation (FC). PATIENTS AND METHODS: From January 2009 to March 2012, patients with localized PCa who refused active surveillance were assigned to a FC protocol. This was a prospective, single-arm cohort study. Inclusion criteria were: unilateral disease, clinical stage T1c to T2a, prostate-specific antigen (PSA) concentration <10 ng/mL, low volume index lesion and Gleason score ≤6 (3+3). Hemi-ablation was carried out using the Precise(TM) cryoablation system (Galil Medical, Inc., Arden Hills, MN, USA). Oncological (PSA values) and functional (International Prostate Symptom Score and International Index of Erectile Function (IIEF)-5 score) outcomes were analysed at 3-, 6- and 12-month follow-up. The primary endpoint for oncological efficacy, no cancer in ipsilateral side, was based on the 12-month mandatory biopsy. RESULTS: A total of 48 consecutive patients with a mean age of 67 years were included. The median (interquartile range) follow-up was 13.2 (7.4-26.5) months. Follow-up prostate biopsies were negative for the treated lobe in 86% of patients. The mean PSA concentration dropped significantly at 3 months (by 55%) but did not correlate well with positive biopsy results. Urinary symptoms were unchanged. A slight decrease in the IIEF-5 score was present at 3 months, but did not differ significantly from baseline at 6-month follow-up. There were 15% grade 1 and 4% grade 2 complications (Clavien classification). CONCLUSIONS: Focal cryoablation is a low-morbidity option in selected patients with low-risk PCa. We showed PSA concentration to be an unreliable marker for monitoring FC and recommend a protocol of mandatory biopsies for follow-up. A multicentre randomized controlled trial is necessary to confirm the low-morbidity and the biopsy-proven PCa cure rates.

Prevalence and prognostic value of acute cor pulmonale and patent foramen ovale in ventilated patients with early acute respiratory distress syndrome: a multicenter study.

PURPOSE: We sought to determine the prevalence of and factors associated with acute cor pulmonale (ACP) and patent foramen ovale (PFO) at the early phase of acute respiratory distress syndrome (ARDS), and to assess their relation with mortality. METHODS: In this prospective multicenter study, 200 patients submitted to protective ventilation for early moderate to severe ARDS [PaO2/F(I)O2: 115 ± 39 with F(I)O2: 1; positive end-expiratory pressure (PEEP): 10.6 ± 3.1 cmH2O] underwent transthoracic (TTE) and transesophageal echocardiography (TEE) <48 h after admission. Echocardiograms were independently interpreted by two experts. Factors associated with ACP, PFO, and 28-day mortality were identified using multivariate regression analysis. RESULTS: TEE depicted ACP in 45/200 patients [22.5%; 95% confidence interval (CI) 16.9-28.9%], PFO in 31 patients (15.5%; 95% CI 10.8-21.3%), and both ACP and PFO in 9 patients (4.5%; 95% CI 2.1-8.4%). PFO shunting was small and intermittent in 27 patients, moderate and consistent in 4 patients, and large or extensive in no instances. PaCO2 >60 mmHg was strongly associated with ACP [odds ratio (OR) 3.70; 95% CI 1.32-10.38; p = 0.01]. No factor was independently associated with PFO, with only a trend for age (OR 2.07; 95% CI 0.91-4.72; p = 0.08). Twenty-eight-day mortality was 23%. Plateau pressure (OR 1.15; 95% CI 1.05-1.26; p < 0.01) and air leaks (OR 5.48; 95% CI 1.30-22.99; p = 0.02), but neither ACP nor PFO, were independently associated with outcome. CONCLUSIONS: TEE screening allowed identification of ACP in one-fourth of patients submitted to protective ventilation for early moderate to severe ARDS. PFO shunting was less frequent and never large or extensive. ACP and PFO were not related to outcome.

Number of supervised studies required to reach competence in advanced critical care transesophageal echocardiography.

PURPOSE: To determine the minimum number of supervised transesophageal echocardiography (TEE) that intensivists should perform to reach competence in performing and interpreting a comprehensive hemodynamic assessment in ventilated intensive care unit patients. METHODS: Prospective and multicentric study. Skills of 41 intensivists (trainees) with no (level 0) or little (level 1) experience in echocardiography was evaluated over a 6-month period, using a previously validated skills assessment score (/40 points). Trainees were evaluated at 1 (M1), 3 (M3) and 6 months (M6) by their tutor while performing 2 TEE examinations in ventilated patients. Competence was a priori defined by a skills assessment score >35/40 points. RESULTS: No difference in the score was observed between level 0 and level 1, except at M1 (22.2 ± 6.2 vs. 25.9 ± 4.4 points, p = 0.03). After 6 months, trainees performed a mean of 31 ± 9 supervised TEE. The score gradually increased from M1 to M6 (24 ± 6, 32 ± 3, and 35 ± 3 points, p < 0.001), regardless of trainees' initial level. A correlation was found between the number of supervised TEE and the skills assessment score (r (2) = 0.60; p < 0.001). The number of supervised TEE examinations which best predicted a score >35/40 points was 25, with a sensitivity of 81 % and a specificity of 93 % (area under the ROC curve: 0.91 ± 0.04). A number of 31 supervised TEE examinations predicted a score >35/40 points with a specificity close to 100 %. CONCLUSION: The performance of at least 31 supervised examinations over 6 months is required to reach competence in TEE driven hemodynamic evaluation of ventilated patient.

A pilot study on safety and clinical utility of a single-use 72-hour indwelling transesophageal echocardiography probe.

PURPOSE: To evaluate the hemodynamic monitoring capability and safety of a single-use miniaturized transesophageal echocardiography (TEE) probe left in place in ventilated critically ill patients. METHODS: The probe was inserted in 94 patients and designed to be left in place for up to 72 h. Three views were obtained: the superior vena caval transverse, the mid-esophageal four-chamber, and the transgastric mid-papillary short-axis views. Observational data on the feasibility of insertion, complications, image quality, and influence on management were recorded and analyzed. RESULTS: No failure of probe insertion was observed. The nasogastric tube had to be removed in 17 % of cases. Image quality was judged as adequate or optimal in 91/94 (97 %) of cases in the superior vena caval view, 89/94 (95 %) of cases in the four-chamber view, and 86/94 (91 %) of cases in the short-axis view. The duration of monitoring was 32 ± 23 h, allowing 2.8 ± 1.6 hemodynamic evaluations per patient that led to a mean of 1.4 ± 1.5 therapeutic changes per patient. Among the 263 hemodynamic assessments, 132 (50 %) had a direct therapeutic impact in 62 patients (66 %). Two patients developed lip ulceration from the probe, and two patients had self-limited gastric bleeding. CONCLUSION: The single-use miniaturized probe could be inserted in all patients. Image quality was acceptable in the majority of cases, and the information derived from the device was useful in making management decisions in patients with hemodynamic failure on ventilatory support. Further studies are needed to confirm the good tolerance and to compare the new device with other hemodynamic monitoring techniques.

Monitoring of metformin-induced lactic acidosis in a diabetic patient with acute kidney failure and effect of hemodialysis.

Metformin associated lactic acidosis (MALA) is a serious complication occurring especially in elderly patients given high doses of the drug. We report a non-fatal case of MALA with pronounced acidosis (pH 6.76, lactate 30.81 mmol/l) and high metformin concentrations (127 mg/l) in a patient who had developed acute renal failure after undergoing an operation. Multiple measurements of biological parameters and metformin blood concentrations showed the effectiveness of repeated hemodialysis sessions on metformin elimination. Cases previously reported with such a severe MALA were associated with a high mortality rate. We show that close monitoring in an intensive care unit together with prompt and repeated dialysis sessions can lead to a favorable outcome.

A renal metanephric adenoma showing both a 2p16e24 deletion and BRAF V600E mutation: a synergistic role for a tumor suppressor gene on chromosome 2p and BRAF activation?

Metanephric adenomas (MAs) are rare benign tumors that may be difficult to recognize. Specific genetic anomalies might aid in diagnosis, but genomic data are limited and conflicting. Consistent mutations of the BRAF gene have been recently reported in MAs and could become useful as a discriminative marker among renal tumors. We report here a case of MA, showing both a BRAF V600E mutation and a segmental loss within bands 2p16 and 2p24 as the sole quantitative genomic anomaly. We compared the borders and size of the deleted region in our case to those of five cases of MAs previously reported. We identified a common minimal region containing 87 genes, among which several tumor suppressor genes could be candidate actors in the pathogenesis of MA. We ruled out MSH2 and MSH6 as target gene candidates, both located in the deleted region, on the basis of preserved expression and microsatellite sequence stability. Our study confirms the recurrence of a BRAF mutation and of 2p alterations in MAs. This first case showing simultaneous presence of a BRAF mutation and a 2p deletion raises the question of a synergistic role for these two anomalies in the pathogenesis of MAs.