The mutational landscape of melanoma brain metastases presenting as the first visceral site of recurrence

Brain metastases are a major cause of melanoma-related mortality and morbidity. We undertook whole-exome sequencing of 50 tumours from patients undergoing surgical resection of brain metastases presenting as the first site of visceral disease spread and validated our findings in an independent dataset of 18 patients. Brain metastases had a similar driver mutational landscape to cutaneous melanomas in TCGA. However, KRAS was the most significantly enriched driver gene, with 4/50 (8%) of brain metastases harbouring non-synonymous mutations. Hotspot KRAS mutations were mutually exclusive from BRAF^V600, NRAS and HRAS mutations and were associated with a reduced overall survival from the resection of brain metastases (HR 10.01, p = 0.001). Mutations in KRAS were clonal and concordant with extracranial disease, suggesting that these mutations are likely present within the primary. Our analyses suggest that KRAS mutations could help identify patients with primary melanoma at higher risk of brain metastases who may benefit from more intensive, protracted surveillance.Subject terms: CNS cancer, Metastasis, Melanoma, Tumour biomarkers, Cancer     

Postprocedural Antiplatelet Treatment after Emergent Carotid Stenting in Tandem Lesions Stroke: Impact on Stent Patency beyond Day 1

BACKGROUND AND PURPOSE:Postprocedural dual-antiplatelet therapy is frequently withheld after emergent carotid stent placement during stroke thrombectomy. We aimed to assess whether antiplatelet regimen variations increase the risk of stent thrombosis beyond postprocedural day 1.MATERIALS AND METHODS:Retrospective review was undertaken of all consecutive thrombectomies for acute stroke with tandem lesions in the anterior circulation performed in a single comprehensive stroke center between January 9, 2011 and March 30, 2020. Patients were included if carotid stent patency was confirmed at day 1 postprocedure. The group of patients with continuous dual-antiplatelet therapy from day 1 was compared with the group of patients with absent/discontinued dual-antiplatelet therapy.RESULTS:Of a total of 109 tandem lesion thrombectomies, 96 patients had patent carotid stents at the end of the procedure. The early postprocedural stent thrombosis rate during the first 24 hours was 14/96 (14.5%). Of 82 patients with patent stents at day 1, in 28 (34.1%), dual-antiplatelet therapy was either not initiated at day 1 or was discontinued thereafter. After exclusion of cases without further controls of stent patency, there was no significant difference in the rate of subacute/late stent thrombosis between the 2 groups: 1/50 (2%) in patients with continuous dual-antiplatelet therapy versus 0/22 (0%) in patients with absent/discontinued dual-antiplatelet therapy (P = 1.000). In total, we observed 88 patient days without any antiplatelet treatment and 471 patient days with single antiplatelet treatment.CONCLUSIONS:Discontinuation of dual-antiplatelet therapy was not associated with an increased risk of stent thrombosis beyond postprocedural day 1. Further studies are warranted to better assess the additional benefit and optimal duration of dual-antiplatelet therapy after tandem lesion stroke thrombectomy.

In around 15% of endovascular procedures for anterior circulation stroke,¹ there is a tight stenosis or occlusion of the cervical carotid artery in addition to the intracranial artery occlusion. The optimal endovascular management of tandem lesions has yet to be defined; however, there is mounting evidence^2,3 that emergent stent placement in the carotid artery associated with at least 1 antiplatelet agent could lead to better recanalization rates and improved clinical outcomes. A more definitive answer should be provided by the Thrombectomy In TANdem lesions (TITAN) randomized multicenter trial,⁴ designed to assess the safety and efficacy of emergent internal carotid artery stent placement in tandem lesion thrombectomy. This study recently enrolled the first patient in early 2020.In patients undergoing emergent carotid stent placement, there is no consensus regarding the optimal periprocedural antiplatelet therapy. Many groups^5,6 chose to avoid dual-antiplatelet therapy (DAPT) during the first 24 hours in an attempt to reduce the risk of hemorrhagic transformation. Conversely, less aggressive antiplatelet regimens might increase the risk of carotid stent thrombosis.Stent thrombosis was recently identified as a predictor of unfavorable clinical outcome.^7,8 To date, available data regarding stent patency rates remain scarce. Most case series of endovascular management for tandem lesions^5,9-11 do not report postprocedural stent patency, while some publications^12-15 offer partial data for a subgroup of patients for whom carotid imaging controls were available. Reported rates of stent thrombosis ranged between 1.2% and 22.0%.^{6-8,12-14,16,17}To date, no study has attempted to differentiate between early (first 24 hours) and subacute/late postprocedural stent thrombosis. During the first 24 hours, protection against stent thrombosis is conferred by antiplatelet agents administered during the procedure (periprocedural antiplatelets). Beyond 24 hours, the recommended antiplatelet regimen is DAPT for 4–12 weeks,^9,17 but in reality, antiplatelets are often tailored in view of neurological and extra-neurological hemorrhagic events. It is currently unknown whether discontinuation of DAPT is associated with an increased risk of late stent thrombosis.Thus, we aimed to describe the variations in the postprocedural antiplatelet regimen in a large consecutive cohort of tandem lesion thrombectomies with emergent carotid artery stent placement and to assess whether discontinuation of DAPT was associated with an increased risk of carotid stent thrombosis.     

Mind the gap: Teachers’ conceptions of student-staff partnership and its potential to enhance educational quality

Abstract

Introduction: Student-staff partnerships as a concept to improve medical education have received a growing amount of attention. Such partnerships are collaborations in which students and teachers seek to improve education by each adding their unique contribution to decision-making and implementation processes. Although previous research has demonstrated that students are favourable to this concept, teachers remain hesitant. The present study investigated teachers’ conceptions of student-staff partnerships and of the prerequisites that are necessary to render such partnerships successful and enhance educational quality.

Method: We conducted semi-structured interviews with 14 course coordinators who lead course design teams and also teach in 4 bachelor health programmes, using Bovill and Bulley’s levels of student participation as sensitising concepts during data analysis.

Results: The results pointed to three different conceptions of student-staff partnerships existing among teachers: Teachers teach and students study; teachers teach and value students’ feedback; and teachers and students co-create. The prerequisites for effective co-creation teachers identified were: Teachers must be open to involve students and create dialogues; students must be motivated and have good communication skills; the organisation must be supportive; and teachers should have the final say.

Conclusion: We conclude that teachers’ conceptions are consistent with Bovill and Bulley’s levels of student participation. Under certain conditions, teachers are willing to co-create and reach the highest levels of student participation.     

Prolonged mechanical ventilation after cardiac surgery: substudy of the Transfusion Requirements in Cardiac Surgery III trial

Purpose

Prolonged mechanical ventilation (MV) is a major complication following cardiac surgery. We conducted a secondary analysis of the Transfusion Requirements in Cardiac Surgery (TRICTS) III trial to describe MV duration, identify factors associated with prolonged MV, and examine associations of prolonged MV with mortality and complications.

Methods

Four thousand, eight hundred and nine participants undergoing cardiac surgery at 71 hospitals worldwide were included. Prolonged MV was defined based on the Society of Thoracic Surgeons definition as MV lasting 24 hr or longer. Adjusted associations of patient and surgical factors with prolonged MV were examined using multivariable logistic regression. Associations of prolonged MV with complications were assessed using odds ratios, and adjusted associations between prolonged MV and mortality were evaluated using multinomial regression. Associations of shorter durations of MV with survival and complications were explored.

Results

Prolonged MV occurred in 15% (725/4,809) of participants. Prolonged MV was associated with surgical factors indicative of complexity, such as previous cardiac surgery, cardiopulmonary bypass duration, and separation attempts; and patient factors such as critical preoperative state, left ventricular impairment, renal failure, and pulmonary hypertension. Prolonged MV was associated with perioperative but not long-term complications. After risk adjustment, prolonged MV was associated with perioperative mortality; its association with long-term mortality among survivors was weaker. Shorter durations of MV were not associated with increased risk of mortality or complications.

Conclusion

In this substudy of the TRICS III trial, prolonged MV was common after cardiac surgery and was associated with patient and surgical risk factors. Although prolonged MV showed strong associations with perioperative complications and mortality, it was not associated with long-term complications and had weaker association with long-term mortality among survivors.

Study registration

www.ClinicalTrials.gov (NCT02042898); registered 23 January 2014. This is a substudy of the Transfusion Requirements in Cardiac Surgery (TRICS) III trial.

     

Does ablation of atrial fibrillation at the time of septal myectomy improve survival of patients with obstructive hypertrophic cardiomyopathy?

ObjectiveTo evaluate the outcomes after septal myectomy in patients with obstructive hypertrophic cardiomyopathy according to atrial fibrillation and surgical ablation of atrial fibrillation.MethodsWe reviewed patients with obstructive hypertrophic cardiomyopathy who underwent septal myectomy at the Mayo Clinic from 2001 to 2016. History of atrial fibrillation was obtained from patient histories and electrocardiograms. All-cause mortality was the primary end point.ResultsA total of 2023 patients underwent septal myectomy, of whom 394 (19.5%) had at least 1 episode of atrial fibrillation preoperatively. Among patients with atrial fibrillation, 76 (19.3%) had only 1 known episode, 278 (70.6%) had recurrent paroxysmal atrial fibrillation, and 40 (10.2%) had persistent atrial fibrillation. Surgical ablation was performed in 190 patients at the time of septal myectomy, including 148 with pulmonary vein isolation and 42 with the classic maze procedure. Among all patients, operative mortality was 0.4%, and there were no early deaths in patients undergoing surgical ablation. Over a median follow-up of 5.6 years, patients with preoperative atrial fibrillation had increased mortality (hazard ratio, 1.36; 95% confidence interval, 0.97-1.91; P = .070) after multivariable adjustment for comorbidities. When considering the impact of atrial fibrillation with or without surgical treatment, the adjusted hazard ratio for mortality in patients undergoing ablation compared with no ablation was 0.93 (95% confidence interval, 0.52-1.69; P = .824).ConclusionsAtrial fibrillation is present preoperatively in one-fifth of patients with obstructive hypertrophic cardiomyopathy undergoing myectomy and showed a trend toward higher all-cause mortality. Survival of patients undergoing septal myectomy with preoperative atrial fibrillation was similar between those who did and did not receive concomitant surgical ablation.     

Novel Risk Factors for Progression of Diabetic and Nondiabetic CKD: Findings From the Chronic Renal Insufficiency Cohort (CRIC) Study

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A Diagnostic Algorithm for Posterior Fossa Tumors in Children: A Validation Study

BACKGROUND AND PURPOSE:Primary posterior fossa tumors comprise a large group of neoplasias with variable aggressiveness and short and long-term outcomes. This study aimed to validate the clinical usefulness of a radiologic decision flow chart based on previously published neuroradiologic knowledge for the diagnosis of posterior fossa tumors in children.MATERIALS AND METHODS:A retrospective study was conducted (from January 2013 to October 2019) at 2 pediatric referral centers, Children''s Hospital of Philadelphia, United States, and Great Ormond Street Hospital, United Kingdom. Inclusion criteria were younger than 18 years of age and histologically and molecularly confirmed posterior fossa tumors. Subjects with no available preoperative MR imaging and tumors located primarily in the brain stem were excluded. Imaging characteristics of the tumors were evaluated following a predesigned, step-by-step flow chart. Agreement between readers was tested with the Cohen κ, and each diagnosis was analyzed for accuracy.RESULTS:A total of 148 cases were included, with a median age of 3.4 years (interquartile range, 2.1–6.1 years), and a male/female ratio of 1.24. The predesigned flow chart facilitated identification of pilocytic astrocytoma, ependymoma, and medulloblastoma sonic hedgehog tumors with high sensitivity and specificity. On the basis of the results, the flow chart was adjusted so that it would also be able to better discriminate atypical teratoid/rhabdoid tumors and medulloblastoma groups 3 or 4 (sensitivity = 75%–79%; specificity = 92%–99%). Moreover, our adjusted flow chart was useful in ruling out ependymoma, pilocytic astrocytomas, and medulloblastoma sonic hedgehog tumors.CONCLUSIONS:The modified flow chart offers a structured tool to aid in the adjunct diagnosis of pediatric posterior fossa tumors. Our results also establish a useful starting point for prospective clinical studies and for the development of automated algorithms, which may provide precise and adequate diagnostic tools for these tumors in clinical practice.

In the past 10 years, there has been an exponential increase in knowledge of the molecular characteristics of pediatric brain tumors, which was only partially incorporated in the 2016 World Health Organization Classification of Tumors of the Central Nervous System.¹ The main update in the 2016 Classification was the introduction of the molecular profile of a tumor as an important factor for predicting different biologic behaviors of entities which, on histology, look very similar or even indistinguishable.² A typical example is the 4 main groups of medulloblastoma: wingless (WNT), sonic hedgehog (SHH) with or without the p53 mutation, group 3, and group 4. Although they may appear similar on microscopy, these categories have distinct molecular profiles, epidemiology, prognosis, and embryologic origin.³Subsequent to the publication of the 2016 World Health Organization Classification, further studies have identified even more molecular subgroups of medulloblastoma with possible prognostic implications⁴ and also at least 3 new molecular subgroups of atypical teratoid/rhabdoid tumor (AT/RT)⁵ and several subgroups of ependymoma.⁶ MR imaging shows promise as a technique for differentiating histologic tumors and their molecular subgroups. This capability relies on not only various imaging characteristics but also the location and spatial extension of the tumor, evident on MR imaging, which can be traced to the embryologic origin of the neoplastic cells.^5,7-10One approach to the challenge of identifying imaging characteristics of different tumors in children is to use artificial intelligence. Yet despite this exciting innovation, correctly identifying the location of the mass and its possible use as an element for differential diagnosis still requires the expertise of an experienced radiologist. Previously, D''Arco et al¹¹ proposed a flow chart (Fig 1) for the differential diagnosis of posterior fossa tumors in children based on epidemiologic, imaging signal, and location characteristics of the neoplasm. The aims of the current study were the following: 1) to validate, in a retrospective, large cohort of posterior fossa tumors from 2 separate pediatric tertiary centers, the diagnostic accuracy of that flow chart, which visually represents the neuroadiologist''s mental process in making a diagnosis of posterior fossa tumors in children, 2) to describe particular types of posterior fossa lesions that are not correctly diagnosed by the initial flow chart, and 3) to provide an improved, clinically accessible flow chart based on the results.Open in a separate windowFIG 1.Predesigned radiologic flow chart created according to the literature before diagnostic accuracy analysis. The asterisk indicates brain stem tumors excluded from the analysis. Double asterisks indicate relative to gray matter. Modified with permission from D''Arco et al.¹¹     

Evaluation of DISORDER: Retrospective Image Motion Correction for Volumetric Brain MRI in a Pediatric Setting

BACKGROUND AND PURPOSE:Head motion causes image degradation in brain MR imaging examinations, negatively impacting image quality, especially in pediatric populations. Here, we used a retrospective motion correction technique in children and assessed image quality improvement for 3D MR imaging acquisitions.MATERIALS AND METHODS:We prospectively acquired brain MR imaging at 3T using 3D sequences, T1-weighted MPRAGE, T2-weighted TSE, and FLAIR in 32 unsedated children, including 7 with epilepsy (age range, 2–18 years). We implemented a novel motion correction technique through a modification of k-space data acquisition: Distributed and Incoherent Sample Orders for Reconstruction Deblurring by using Encoding Redundancy (DISORDER). For each participant and technique, we obtained 3 reconstructions as acquired (Aq), after DISORDER motion correction (Di), and Di with additional outlier rejection (DiOut). We analyzed 288 images quantitatively, measuring 2 objective no-reference image quality metrics: gradient entropy (GE) and MPRAGE white matter (WM) homogeneity. As a qualitative metric, we presented blinded and randomized images to 2 expert neuroradiologists who scored them for clinical readability.RESULTS:Both image quality metrics improved after motion correction for all modalities, and improvement correlated with the amount of intrascan motion. Neuroradiologists also considered the motion corrected images as of higher quality (Wilcoxon z = −3.164 for MPRAGE; z = −2.066 for TSE; z = −2.645 for FLAIR; all P < .05).CONCLUSIONS:Retrospective image motion correction with DISORDER increased image quality both from an objective and qualitative perspective. In 75% of sessions, at least 1 sequence was improved by this approach, indicating the benefit of this technique in unsedated children for both clinical and research environments.

Head motion is a common cause of image degradation in brain MR imaging. Motion artifacts negatively impact MR image quality and therefore radiologists’ capacity to read the images, ultimately affecting patient clinical care.¹ Motion artifacts are more common in noncompliant patients,² but even in compliant adults, intrascan movement is reported in at least 10% of cases.³ For children who require high-resolution MR images, obtaining optimal image quality can be challenging, owing to the requirement to stay still over long durations needed for acquisition.⁴ Sedation can be an option, but it carries higher risks, costs, and preparation and recovery time.⁵In conditions such as intractable focal epilepsy, identification of an epileptogenic lesion is clinically important to guide surgical treatment. However, these lesions can be visually subtle, particularly in children in whom subtle cortical dysplasias are more common.⁶ Dedicated epilepsy MR imaging protocols use high-resolution 3D sequences to allow better cortical definition and free reformatting of orientation but involve acquisition times in the order of minutes, so data collection becomes more sensitive to motion.⁷For children in particular, multiple strategies are available for minimizing motion during MR examinations. Collaboration with play specialists using mock scanners and training or projecting a cartoon are good approaches to reduce anxiety.^8,9 These tools are not always available in clinical radiology and, even with these strategies, motion can still be an issue.¹⁰ Different scanning approaches to correct for intrascan motion have been proposed. Broadly, prospective methods track head motion in real time and modify the acquisition directions accordingly.¹¹ These approaches are applicable to a wide range of sequences but require optical systems with external tracking markers, sometimes uncomfortable or impractical, and extra setup can ultimately result in longer examinations. Furthermore, these approaches may also not be robust to continuous motion.^11-13 Retrospective techniques have also been proposed, in some cases relying on imaging navigators that are not compatible with all standard sequences or contrasts.¹²Here, we use a more general retrospective motion correction technique: Distributed and Incoherent Sample Orders for Reconstruction Deblurring by using Encoding Redundancy (DISORDER). In this method, k-space samples are reordered to enable retrospective motion correction during image reconstruction.¹⁴ Our hypothesis is that DISORDER improves clinical MR imaging quality and readability. To assess its use for clinical sequences, we acquired a dedicated epilepsy MR imaging protocol in 32 children across a wide age range. We used both objective image quality metrics and expert neuroradiologist ratings to evaluate the outcome after motion correction.     

Impact on Health-Related Quality of Life of Induction Chemotherapy Compared With Concurrent Cisplatin and Radiation Therapy in Patients With Head and Neck Cancer

AimsOrgan preservation, an important goal in the treatment of head and neck squamous cell carcinoma (HNSCC), may include induction chemotherapy and cisplatin with radiation therapy (CRT). To our knowledge, no reports have directly compared the impact of induction chemotherapy with that of CRT on health-related quality of life (HRQOL).Materials and methodsIn a phase II trial, we assessed the HRQOL of patients treated with induction chemotherapy followed by CRT. Eligible patients had stage III–IV HNSCC. HRQOL questionnaires were administered at baseline, the end of induction (EOI), the end of CRT (EOCRT) and after CRT. Functional Assessment of Cancer Therapy (FACT version 4) assessed HRQOL. We carried out a comparison of changes in HRQOL from baseline to EOI and from EOI to EOCRT. This trial is registered with ClinicalTrials.gov (NCT01566435).ResultsThirty patients were enrolled in the study. Most HRQOL questionnaires were completed (88%). The mean total FACT scores did not differ from baseline to EOI (general: 83.8 versus 79.1, P = 0.08; head and neck: 109.7 versus 105.8, P = 0.33; Total Outcome Index: 69.7 versus 62.3, P = 0.03; respectively, using P ≤ 0.01 to adjust for multiple simultaneous tests of differences). However, total FACT scores significantly worsened from EOI to EOCRT (79.1 versus 62.3, P = 0.01; 105.8 versus 74.2, P < 0.01; 62.3 versus 34.2, P = 0.01; respectively). Within domains, the head and neck cancer subscale score did not differ from baseline to EOI (median 28.5 versus 27.0, P = 0.69), but significantly worsened from EOI to EOCRT (27.0 versus 9.5, P < 0.01). Swallowing, oral pain and voice quality improved from baseline to EOI, but worsened from EOI to EOCRT. Physical and functional scores worsened from baseline to EOI and from EOI to EOCRT. The emotional well-being score improved from baseline to EOI but worsened from EOI to EOCRT.ConclusionsOverall, HRQOL did not significantly change from baseline to EOI but dramatically worsened from EOI to EOCRT.