Citations

Abstract Structural grey matter covariance networks provide an individual quantification of morphological patterns in the brain. The network integrity is disrupted in sporadic Alzheimer’s disease, and network properties show associations with the level of amyloid pathology and cognitive decline. Therefore, these network properties might be disease progression markers. However, it remains unclear when and how grey matter network integrity changes with disease progression. We investigated these questions in autosomal dominant Alzheimer’s disease mutation carriers, whose conserved age at dementia onset allows individual staging based upon their estimated years to symptom onset. From the Dominantly Inherited Alzheimer Network observational cohort, we selected T1-weighted MRI scans from 269 mutation carriers and 170 non-carriers (mean age 38 ± 15 years, mean estimated years to symptom onset −9 ± 11), of whom 237 had longitudinal scans with a mean follow-up of 3.0 years. Single-subject grey matter networks were extracted, and we calculated for each individual the network properties which describe the network topology, including the size, clustering, path length and small worldness. We determined at which time point mutation carriers and non-carriers diverged for global and regional grey matter network metrics, both cross-sectionally and for rate of change over time. Based on cross-sectional data, the earliest difference was observed in normalized path length, which was decreased for mutation carriers in the precuneus area at 13 years and on a global level 12 years before estimated symptom onset. Based on longitudinal data, we found the earliest difference between groups on a global level 6 years before symptom onset, with a greater rate of decline of network size for mutation carriers. We further compared grey matter network small worldness with established biomarkers for Alzheimer disease (i.e. amyloid accumulation, cortical thickness, brain metabolism and cognitive function). We found that greater amyloid accumulation at baseline was associated with faster decline of small worldness over time, and decline in grey matter network measures over time was accompanied by decline in brain metabolism, cortical thinning and cognitive decline. In summary, network measures decline in autosomal dominant Alzheimer’s disease, which is alike sporadic Alzheimer’s disease, and the properties show decline over time prior to estimated symptom onset. These data suggest that single-subject networks properties obtained from structural MRI scans form an additional non-invasive tool for understanding the substrate of cognitive decline and measuring progression from preclinical to severe clinical stages of Alzheimer’s disease.

Background: The aim of this aortic stenosis registry was to investigate the changes of routine echocardiographic indices and strain in patients with moderate-to-severe aortic stenosis over a 6-month follow-up period. Methods: Our aortic stenosis registry is observational, prospective, multicenter registry of nine countries, with 197 patients with aortic valve area less than 1.5 cm 2 . The enrolment took place from January to August 2017. We excluded patients with uncontrolled atrial arrhythmias, pulmonary hypertension or cardiomyopathies, as well as those with hemodynamically significant valvular disease other than aortic stenosis. We included patients who did not require intervention and who had a complete follow-up study. Results: In patients with preserved ejection fraction, left ventricular mass has significantly increased between baseline and follow-up studies (218 ± 34 grams vs 253 ± 29 grams, p = 0.02). However, when indexed to body surface area, there was no significant difference. Left ventricular global longitudinal strain significantly decreased (-19.7 ± -4.8 vs (-16.4 vs -3.8, p = 0.01). Left atrial volume was significantly higher at follow-up (p = 0.035). Right ventricular basal diameter and mid-cavity diameter were greater at the follow-up (p = 0.04 and p = 0.035, respectively). Patients with low-flow low-gradient aortic stenosis had significantly lower global longitudinal strain (-12.3% ± -3.9% vs -19.7% ± -4.8%, p = 0.01). Conclusion: Left atrial dilatation is one of the first changes to take place in low-flow low-gradient aortic stenosis patients even when left ventricular dimensions and function remains intact. Global longitudinal strain is an important determinant of left ventricular systolic and diastolic dysfunction and right ventricular function is an important parameter of aortic stenosis assessment. Accordingly, our registry has further shed the light on these indices role as multisite follow-up of aortic stenosis.

SUMMARY OBJECTIVES To bring summarized information about what has been published so far regarding Covid-19, facilitating the access to information and a better understanding of this pandemic, and to contribute to the medical community in the decision-making against this virus. METHODS This review article brings collected information from different articles published since the beginning of the pandemic of the 2019 novel coronavirus. KEY RESULTS This paper aggregates and consolidates some epidemiological parameters and clinical knowledge about the novel coronavirus and brings what is new in the search for pandemic control. MAJOR CONCLUSIONS Governments and health authorities are under increased pressure to control the COVID-19 spreading. In this scenario, the scientific community is working hard to produce relevant papers which will help in the next steps against coronavirus. Our review summarized the latest news about SARS-CoV2, evidencing what we know about COVID-19 until now.

Background Anesthesia-focused short courses might be an effective and sustainable way to further the ongoing training and evidence-based practice skills of anesthesia professionals in low- and middle-income countries (LMICs). Instructional design, the process by which formalized learning theory is incorporated into education planning and delivery, is a tool that can strengthen learning in these short courses. As part of an ongoing multilateral project between the University of Minnesota (UMN) and Kabul University of Medical Sciences (KUMS), this project sought to identify the feasibility and potential educational impact of a newly designed postoperative analgesia short-course employing instructional design principles. The Afghan faculty learners’ subjective viewpoint of the short course experience was also investigated and is described in this article. Methods Afghan learners and United States based faculty met in Bangalore, India in August 2018 for this short course. During the 6-day course, learners participated in didactics and workshops discussing regional anesthesia techniques, multimodal analgesia, safety, pain assessment and management, and the influence of ethno-cultural context on pain control. Interactive games, model-based nerve block simulations, and flipped classroom approaches were educational strategies used in the course. The Afghan faculty also participated in instructional design workshops designed to strengthen their teaching skills for use with both students and faculty colleagues. Pretests, posttests, and opinion surveys were completed by the Afghan faculty learners. Results All learners completed the course with full participation. A median of 5 out of 10 technical questions were answered correctly by the learners on the pretest; this score improved to a median of 6.5 on the posttest. The number of learners who ranked their understanding of the role of regional anesthesia in their perioperative care practice as “very well” increased from 2 to 5 faculty. Likewise, the number of learners who described their understanding of postoperative pain and their ability to perform regional anesthesia as “not well at all” decreased from 2 to 0 in both categories. Further, the majority of the participants agreed that at the end of the course their ability to understand and apply instructional design concepts had improved. Conclusions The short course in postoperative pain management appeared to improve short-term knowledge among Afghan faculty participants. Afghan faculty had a favorable opinion of the course and increased confidence in their ability to use instructional design best practices. The results of this project suggest that short courses based in instructional design can be useful and effective for short-term knowledge gain in an LMIC setting such as Afghanistan.

AbstractThis review discusses the definition and major categories of cutaneous T‐cell lymphoma, Sézary syndrome and mycosis fungoides, and the role of immunophenotyping in their diagnosis. The following key points are raised: (a) Sézary syndrome and mycosis fungoides cells most often have a characteristic CD3+ CD4+ CD7− and/or CD26− immunophenotype. (b) This immunophenotype is not specific, but can assist in the distinction from non‐neoplastic T cells and other subtypes of mature T‐cell neoplasm. (c) However, small subsets of normal and reactive T‐cells can have an overlapping immunophenotype, and can be distinguished by evaluating for additional changes in antigen expression.

TPS11570 Background: Soft tissue sarcoma (STS) is a heterogenous malignancy of mesenchymal origin and includes more than 50 biologically distinct subtypes. Leiomyosarcoma (LMS), a neoplasm of smooth muscle origin, represents up to 20% of STS. The uterus is the most common site of origin in women. Advanced uterine LMS (uLMS) is initially treated with gemcitabine + docetaxel or anthracycline-based chemotherapy but overall survival remains < 24 mos. Besides recurrent alterations in RB1, TP53 and ATRX, insight into cancer biology of uLMS remains limited. Recently, whole exome and transcriptomic sequencing studies suggest uLMS harbors characteristic defects in the homologous recombination (HR) DNA repair pathway and thus features of BRCAness. HR-deficient cancers are unable to efficiently repair double-stranded DNA breaks and appear sensitive to treatment with poly ADP-ribose polymerase (PARP) inhibitors. In preclinical studies, the combination of temozolomide (T), an alkylating agent, and olaparib (O), a PARP inhibitor, was synergistic and markedly suppressed proliferation of uLMS models. A recent phase II study in small cell lung cancer defined the RP2D for T + O where the chief toxicity was myelosuppression. Methods: NCI Protocol #10250 is a single-arm, open-label, multi-center phase II clinical trial of T + O in patients with advanced uLMS. Eligible pts have ECOG PS ≤ 2, progression on ≥ 1 prior line of therapy and disease measurable by RECIST v1.1 and amenable to image-guided biopsy. Pts receive T 75 mg/m2 PO daily + O 200 mg PO BID on days 1-7 in 21-day cycles. The 1° endpoint is objective response rate (ORR). A one-stage binomial design is used to evaluate for an ORR ≤ 10% (null hypothesis) versus ≥ 35% (alternative hypothesis). The design calls for 22 patients. If 5/22 respond, the treatment is promising. This design yields 93% power and 1-sided type I error of 6%. 2° endpoints include progression free survival and safety. All pts undergo tumor biopsies pre-treatment and during cycle 2. Tissue is used for correlative analysis interrogating uLMS for features of BRCAness through (a) whole exome sequencing/RNAseq to evaluate for alterations in HR pathway component genes, (b) RAD51 foci formation by immunohistochemistry as a functional marker of HR pathway activity and (c) protein expression of Schlafen family member number 11 (SLFN11), an emerging biomarker for PARPi. Tumors are also evaluated for MGMT protein expression, a known determinant of sensitivity to T. The study opened to accrual 10/2019. Clinical trial information: NCT03880019.

e22024 Background: Disease surveillance in high risk melanoma patients using PET/CT is recommended every 6 months, an algorithm that is extremely expensive and often difficult to access. Biomarkers capable of detecting recurrence and low volume metastasis have application in tools to improve the cost effectiveness of surveillance. Towards this long term goal, our aim was to discover melanoma-specific methylated DNA markers (MDMs). Methods: Candidate MDMs were identified by reduced representation bisulfite sequencing of selected age- and sex-balanced snap frozen metastatic melanoma, benign control skin and white blood cells. Sequences were filtered for highest methylation difference, lowest control methylation background ( < 1%), and highest discrimination by variance inflated logistic regression. Using formalin-fixed tissues, the top 32 MDMs were further evaluated in metastatic melanoma from 35 patients, primary melanoma from 26 patients, and 73 control samples (47 benign precursor lesions or normal skin, and 26 healthy buffy coat samples to assess for background DNA in circulation). Candidate markers were blindly assayed by quantitative methylation specific PCR. After normalization by within sample ACTB level, random forest modeling with cross-validation identified marker combinations with greatest predictive accuracy. Results: On receiver operator characteristics analyses of individual marker candidates, areas under the curve (AUCs) ranged from 0.43 to 0.97. Median AUC was 0.835. At 100% specificity, a cross-validated panel of five MDMs (see Table), yielded a sensitivity of 33/35 cases (94.3%; 95% CI, 86.6-100%) for metastatic melanoma and 22/26 cases (84.6%; 95% CI, 70.7-98.5%) for primary melanoma. Furthermore, none of the 5 markers were detected in normal buffy coat samples. Conclusions: A panel of five novel MDMs assayed on tissue and undetectable in normal buffy coat achieves very high discrimination between melanoma and benign control tissues. This panel can be assessed in blood or other bodily fluids for application in melanoma surveillance. [Table: see text]

5584 Background: The timing of systemic therapy in relation to radiotherapy (RT) is important in most malignancies. In contrast, androgen deprivation therapy (ADT) has largely been investigated in relation to its duration rather than its sequencing with RT. Herein, we conduct the first combined individual patient analysis of two phase III randomized trials to determine the optimal timing of ADT with RT in localized prostate cancer (PCa). Methods: Individual patient data was obtained from the Malone et al trial (JCO 2019), which randomized patients to receive neoadjuvant/concurrent or concurrent/adjuvant ADT for 6 months with prostate only RT. This was combined with the prostate only RT arms of RTOG 9413 that randomized patients to 4 months of neoadjuvant/concurrent or adjuvant ADT. The neoadjuvant/concurrent arms of both trials were combined into the “neoadjuvant” group, and the concurrent/adjuvant (Malone) and adjuvant arm (RTOG 9413) were combined in the “adjuvant” group. The Kaplan-Meier method was used to estimate overall survival (OS) and progression-free survival (PFS). Cumulative incidence of distant metastasis (DM), PCa-specific mortality (PCSM) and biochemical failure (BF) were calculated using the Fine-Gray method with non-PCa deaths as competing events. Late genitourinary (GU) and gastrointestinal (GI) toxicity are also reported. Results: The median follow-up was 14.9 years (yrs) and 1065 patients were included (n=531 neoadjuvant, 534 adjuvant). Groups were well balanced for all baseline characteristics. Adjuvant ADT was superior to neoadjuvant ADT in terms of BF (15yr: 33% vs 43%, HR: 1.37 (95%CI: 1.12-1.68), p=0.002), DM (15yr: 12% vs 18%, HR: 1.40 (95%CI: 1.00-1.95), p=0.04), and PFS (15yr: 36% vs 29%, HR: 1.25 (95%CI: 1.07-1.47), p=0.01). Adjuvant ADT yielded lower PCSM (15yr: 15% vs 20%, HR: 1.29 (95%CI: 0.95-1.75), p=0.10), but did not reach statistical significance. This approached statistical significance in high risk PCa (HR 1.39 (95%CI 1.00-1.93), p=0.053). OS was not significantly different between arms (15yr: 39% vs 34%, HR: 1.11 (95%CI: 0.95-1.30), p=0.20). There was no significant difference in either late grade ≥3 GI (p=0.21) or GU (p=0.98) toxicity. Conclusions: We demonstrate for the first time that sequencing of ADT with RT significantly impacts long-term oncologic outcomes in localized PCa, favoring an adjuvant rather than neoadjuvant approach, without increasing late toxicity. This data has important implications to ongoing and future clinical trial design. Clinical trial information: NCT00769548 .