DICER1-sarcomas of GYN tract: Expanding on an emerging entity.

Tumors with pathogenic DICER1 mutation are rare and encompass sporadic or hereditary benign, intermediate and malignant tumors. DICER1-associated sarcomas are heterogeneous; however, the prototypical ones in the GYN-tract include embryonal rhabdomyosarcoma, adenosarcoma and moderately to poorly differentiated Sertoli-Leydig tumor. In this report, we present three unique uterine sarcomas with DICER1 mutation and remarkable diffuse round/spindle cell morphology. The tumors occurred in cervix (n = 1), and uterine corpus (n = 2). The patient ages were 30, 37 and 59 years with tumor size of 8.8, 10 and 8.6 cm, respectively. Morphologically all three tumors were characterized by distinct spindle/round cell morphology and various amounts of neuroectodermal differentiation (yolk sac-like tubules, blastomatous areas and rosette formation). Other morphologic features of DICER1-sarcoma reported in the literature including cambium layer, focal or diffuse anaplasia, solid and cystic architecture, and chondroid/osteoid areas were absent. All three sarcomas were positive for SALL4 and had variable neuroendocrine marker expression. Whole genome methylation analysis was performed on one of the uterine sarcomas, which clustered the tumor with embryonal tumor with multilayered rosettes. Follow up information was available on all three cases. Two patients were alive with no evidence of disease 13 and 14 months post operation, while one patient had imaging evidence of local recurrence 4 months post operation. In summary, we describe three unique DICER1-sarcomas and expand the phenotypic spectrum of this emerging entity, particularly with GYN-tract origin.

Aberrant activation of AXL may drive progression of squamous cell carcinoma in CLL patients: a mechanistic study with clinical implications.

BACKGROUND: Occurrence of squamous cell carcinoma (SCC) even in early-stage, untreated chronic lymphocytic leukemia (CLL) patients can be a significant morbidity issue with occasional transformation into metastatic skin lesions. METHODS: CLL cells and extracellular vesicles (EVs) from CLL patients' blood/plasma were purified and used. Expression/activation of AXL and its functions in normal keratinocytes (HEKa) were assessed in vitro co-culture system and in SCC tissues. RESULTS: We detected aberrant activation of AXL, AKT and ERK-1/2 in SCC cell lines compared to HEKa. We also detected increased expression of AXL in primary SCC tissues obtained from CLL patients. Increased activation of AXL, AKT, ERK-1/2 and Src was discernible in HEKa upon co-culturing with CLL cells. Further analysis suggests that Gas6, a ligand of AXL, regulates AXL activation in co-cultured HEKa. Interestingly, exposure of HEKa cells to CLL plasma-derived EVs induced expression of AXL, P-AKT, and EMT-associated markers leading to migration of the cells. Finally, pharmacologic inhibition of AXL induced cell death in SCC lines in a dose dependent manner. CONCLUSIONS: Our findings that CLL cells likely are involved in driving SCC progression, at least in part, via activation of the AXL signaling axis, indicating that AXL inhibition may be beneficial for our CLL patients with SCC.

Adamantinoma-Like Ewing Sarcoma of the Mandible Evaluated on 18F-FDG PET/CT.

ABSTRACT: Ewing sarcoma is the second most common primary bone tumor in children. Typical Ewing sarcoma most frequently occurs in long bones and within the pelvis. ALES (adamantinoma-like Ewing sarcoma) is a rare subtype of Ewing sarcoma that is characterized by epithelial differentiation in addition to small round blue cells. Unlike typical Ewing sarcoma, ALES has been described in several cases in the head and neck. Herein, we describe a case of a 9-year-old boy with ALES of the mandible evaluated on 18F-FDG PET/CT with correlative MRI scans.

Consensus Approaches to Identify Incident Dementia in Cohort Studies: Systematic Review and Approach in the Successful Aging after Elective Surgery Study.

OBJECTIVES: To survey the current methods used to ascertain dementia and mild cognitive impairment (MCI) in longitudinal cohort studies, to categorize differences in approaches and to identify key components of expert panel methodology in current use. METHODS: We searched PubMed for the past 10 years, from March 6, 2007 to March 6, 2017 using a combination of controlled vocabulary and keyword terms to identify expert panel consensus methods used to diagnose MCI or dementia in large cohort studies written in English. From these results, we identified a framework for reporting standards and describe as an exemplar the clinical consensus procedure used in an ongoing study of elective surgery patients (the Successful Aging after Elective Surgery study). RESULTS: Thirty-one articles representing unique cohorts were included. Among published methods, membership of experts panel varied significantly. There was more similarity in what types of information was use to ascertain disease status. However, information describing the diagnostic decision process and resolution of disagreements was often lacking. CONCLUSIONS: Methods used for expert panel diagnosis of MCI and dementia in large cohort studies are widely variable, and there is a need for more standardized reporting of these approaches. By describing the procedure in which our expert panel achieved consensus diagnoses, we hope to encourage the development and publication of well-founded and reproducible methods for diagnosis of MCI and dementia in longitudinal studies.

Postoperative atrial fibrillation is not pulmonary vein dependent: results from a randomized trial.

BACKGROUND: Although often short-lived and self-limiting, postoperative atrial fibrillation (POAF) is a well-recognized postoperative complication of cardiac surgery and is associated with a 2-fold increase in cardiovascular mortality and morbidity. OBJECTIVE: Our aim was to determine whether intraoperative bilateral pulmonary vein radiofrequency ablation decreases the incidence of POAF in patients undergoing coronary artery bypass grafting (CABG). METHODS: A total of 175 patients undergoing CABG was prospectively randomized to undergo adjuvant bilateral radiofrequency pulmonary vein ablation in addition to CABG (group A; n = 89) or CABG alone (group B; n = 86). Intraoperative pulmonary vein isolation was confirmed by the inability to pace the heart via the pulmonary veins after ablation. All patients received postoperative ß-blocker. RESULTS: There was no difference in the incidence of POAF in the treatment group who underwent adjuvant pulmonary vein ablation (group A; 37.1%) compared with the control group who did not (group B; 36.1%) (P = .887). There were no differences in postoperative inotropic support, antiarrhythmic drug use, need for oral anticoagulation, and complication rates. The mean length of postoperative hospital stay was 8.2 ± 6.5 days in the ablation group and 6.7 ± 4.6 days in the control group (P < .001). CONCLUSION: Adjuvant pulmonary vein isolation does not decrease the incidence of POAF or its clinical impact but increases the mean length of stay in the hospital. The mechanism of POAF does not appear to depend on the pulmonary veins.

Beyond low tidal volumes: ventilating the patient with acute respiratory distress syndrome.

The cornerstone of lung protective ventilation in patients with acute respiratory distress syndrome (ARDS) is a pressure- and volume-limited strategy. Other interventions have also been investigated. Although no method for positive end-expiratory pressure (PEEP) titration has proven most advantageous, experimental and clinical data support the use of higher PEEP in patients with moderate/severe ARDS. There is no benefit to the early use of high-frequency oscillatory ventilation (HFOV) in patients with moderate/severe ARDS, although it may be considered as rescue therapy. Further investigations of novel methods of bedside monitoring of mechanical ventilation may help identify the optimal ventilatory strategy.

Clinical outcomes of minimally invasive endoscopic and conventional sternotomy approaches for atrial septal defect repair.

BACKGROUND: Concerns remain that minimally invasive atrial septal defect (ASD) repair may compromise patient outcomes. We compared clinical outcomes of adult patients undergoing ASD repair via a minimally invasive endoscopic approach versus a "gold standard" sternotomy. METHODS: We retrospectively reviewed the clinical outcomes of consecutive patients who underwent ASD patch repair at our institution between 2002 and 2012. We compared in-hospital/30-day mortality, postoperative complications, length of stay in hospital and in the intensive care unit and blood product requirements between patients who underwent right mini-thoracotomy (MT) and those who underwent conventional sternotomy. RESULTS: During the study period, 73 consecutive patients underwent ASD patch repair at our institution: 51 (age 47 ± 16 yr, 66.7% women) in the MT group and 22 (age 46 ± 21 yr, 59.1% women) in the sternotomy group. In-hospital mortality was similar between the 2 groups (MT 0% v. sternotomy 4.5%, p = 0.30). There were no significant differences in any postoperative complications or blood product requirements. No patients in the MT group suffered stroke, retrograde aortic dissection or leg ischemia. Mean intensive care unit (MT 1.2 ± 1.2 d v. sternotomy 1.7 ± 2.2 d, p = 0.26) and hospital length of stays (MT 5.1 ± 2.2 d v. sternotomy 6.3 ± 3.6 d, p = 0.17) were similar between the groups; however, there was a trend toward fewer patients requiring prolonged hospital stays (> 10 d) in the MT group (3.9% v. 18.2%, p = 0.06). CONCLUSION: Repair of ostium secundum and sinus venosus ASD can be performed safely via MT endoscopic approach with similar outcomes as sternotomy. Patient preference for a more cosmetically appealing incision may be considered without concern of compromised outcomes.

CONTEXTE: Des inquiétudes persistent au sujet des résultats potentiellement négatifs chez les patients soumis à une intervention de réparation de communication interauriculaire (CIA) minimalement effractive. Nous avons comparé les résultats cliniques chez des patients adultes soumis à une réparation de CIA par approche endoscopique minimalement effractive ou par sternotomie classique ­ « l'étalon-or ¼. MÉTHODES: Nous avons passé en revue de manière rétrospective les résultats cliniques chez des patients consécutifs qui ont subi un traitement d'occlusion de leur CIA dans notre établissement, entre 2002 et 2012. Nous avons comparé la mortalité en cours d'hospitalisation et à 30 jours, les complications postopératoires, la durée des séjours à l'hôpital et aux soins intensifs et le recours aux produits sanguins chez les patients selon qu'ils avaient subi une mini-thoracotomie (MT) ou une sternotomie classique. RÉSULTATS: Durant la période de l'étude, 73 patients consécutifs ont subi un traitement d'occlusion de leur CIA dans notre établissement : 51 (âge 47 ± 16 ans, 66,7 % femmes) dans le groupe MT et 22 (âge 46 ± 21 ans, 59,1 % femmes) dans le groupe sternotomie. La mortalité perhospitalière a été similaire entre les 2 groupes (MT 0 % c. sternotomie 4,5 %, p = 0,30). On n'a noté aucune différence significative quant aux complications postopératoires et aux besoins en produits sanguins. Aucun patient du groupe MT n'a subi d'AVC, de dissection aortique rétrograde ou d'ischémie à la jambe. La durée moyenne des séjours aux soins intensifs (MT 1,2 ± 1,2 j c. sternotomie 1,7 ± 2,2 j, p = 0,26) et à l'hôpital (MT 5,1 ± 2.2 j c. sternotomie 6,3 ± 3,6 j, p = 0,17) a été similaire entre les groupes; toutefois, on a noté une tendance à un nombre moindre de patients nécessitant une hospitalisation prolongée (> 10 j) dans le groupe MT (3,9 % c. 18,2 %, p = 0,06). CONCLUSION: La réparation de la CIA au niveau de l'ostium secundum et du sinus veineux peut se faire de manière sécuritaire par approche endoscopique MT, avec des résultats similaires à ceux de la sternotomie. On peut tenir compte de la préférence des patients pour une incision plus acceptable au plan esthétique sans crainte de compromettre les résultats.

VMA21 deficiency prevents vacuolar ATPase assembly and causes autophagic vacuolar myopathy.

X-linked Myopathy with Excessive Autophagy (XMEA) is a childhood onset disease characterized by progressive vacuolation and atrophy of skeletal muscle. We show that XMEA is caused by hypomorphic alleles of the VMA21 gene, that VMA21 is the diverged human ortholog of the yeast Vma21p protein, and that like Vma21p, VMA21 is an essential assembly chaperone of the vacuolar ATPase (V-ATPase), the principal mammalian proton pump complex. Decreased VMA21 raises lysosomal pH which reduces lysosomal degradative ability and blocks autophagy. This reduces cellular free amino acids which leads to downregulation of the mTORC1 pathway, and consequent increased macroautophagy resulting in proliferation of large and ineffective autolysosomes that engulf sections of cytoplasm, merge, and vacuolate the cell. Our results uncover a novel mechanism of disease, namely macroautophagic overcompensation leading to cell vacuolation and tissue atrophy.

Perceptions of emergency medicine residents and fellows regarding competence, adverse events and reporting to supervisors: a national survey.

OBJECTIVE: We sought to characterize the perceptions of emergency medicine (EM) residents and fellows of their clinical and procedural competence, as well as their attitudes, practices and perceived barriers to reporting these perceptions to their supervisors. METHODS: A Web-based survey was distributed to residents and fellows, via their residency directors, in all Canadian EM residency programs outside of Quebec. RESULTS: Of 220 residents and fellows contacted in 9 of 10 EM programs of the Royal College of Physicians and Surgeons of Canada and 12 of 13 EM programs of The College of Family Physicians of Canada, 82 (37.3%) completed all or part of the survey. Response rates varied slightly by question; 25 of 82 re-spondents (30.5% [95% confidence interval (CI) 19.9%-41.1%]) agreed with the statement, "I sometimes feel unsafe or un-qualified with undertaking unsupervised responsibilities or procedures, but I do not report this to my senior physician" and 32 of 81 (39.5% [95% CI 28.2%-50.8%]) had felt this within the past 6 months. Moreover, 34 of 82 (41.5% [95% CI 30.2%-52.7%]) reported their lack of competence to a supervisor half the time or less. Trainees reported worry about loss of trust, autonomy or respect (38/80, 47.5% [95% CI 35.9%-59.1%]) or reputation (32/80, 40.0% [95% CI 28.6%-51.4%]). Nights on-call (30/79, 38% [95% CI 26.6%-49.3%]), admission decisions (13/79, 16.5% [7.6%-25.3%]) and central line insertion (13/79, 16.5% [95% CI 7.6%-25.3%]) were reported to be frequently undertaken despite not feeling competent. Suggestions to improve reporting included encouragement to report without penalty (41/82, 50.0% [95% CI 38.6%-61.4%]) and a less judgmental environment (32/82, 39.0% [95% CI 27.9%-50.2%]). CONCLUSION: Emergency medicine trainees report that they frequently do not feel competent when undertaking responsibilities without supervision. Barriers to reporting these feelings or reporting adverse events appear to relate to social pressures and authority gradients. Modifications to the training culture are encouraged to improve patient safety.

VMA21 deficiency causes an autophagic myopathy by compromising V-ATPase activity and lysosomal acidification.

X-linked myopathy with excessive autophagy (XMEA) is a childhood-onset disease characterized by progressive vacuolation and atrophy of skeletal muscle. We show that XMEA is caused by hypomorphic alleles of the VMA21 gene, that VMA21 is the diverged human ortholog of the yeast Vma21p protein, and that like Vma21p it is an essential assembly chaperone of the V-ATPase, the principal mammalian proton pump complex. Decreased VMA21 raises lysosomal pH, which reduces lysosomal degradative ability and blocks autophagy. This reduces cellular free amino acids, which upregulates the mTOR pathway and mTOR-dependent macroautophagy, resulting in proliferation of large and ineffective autolysosomes that engulf sections of cytoplasm, merge together, and vacuolate the cell. Our results uncover macroautophagic overcompensation leading to cell vacuolation and tissue atrophy as a mechanism of disease.

Sequence variants within exon 1 of MECP2 occur in females with mental retardation.

A new splice variant of the Rett syndrome gene, MECP2, was recently identified, that includes coding sequence from exon 1, and is the predominant transcript in the central nervous system. This sequence encodes polyalanine and polyglycine stretches within the N-terminal portion of MeCP2, and may confer novel functional properties to the protein. We screened autism, mental retardation (MR), and control populations for sequence variation within this region, and identified variation in approximately 1% of MR cases screened (N = 1,410). No variants were identified in the autism sample (N = 401). Most of these variants occur within a trinucleotide repeat region and result in change in number of alanine or glycine residues within the repeat stretches. We suggest some of these variants may be a relatively frequent cause of non-specific MR or developmental delay.