bluuebunny/crossref_metadata_2025_split huggingface dataset:
Utility of Discordant Mismatch Repair-Deficiency (MMR)/Microsatellite Instability (MSI) Testing in Screening Uterine Leiomyosarcoma Patient for Lynch/Other Familial Cancer Syndromes
Authors: Reddy K S 
Published: October 2020

Abstract

Casestudy
Lynch Syndrome (LS) is primarily linked to colorectal and endometrial cancers. Occasional sarcomas, including leiomyosarcoma, have been recognized within the spectrum of LS demonstrating mismatch repair-deficiency (MMR)/microsatellite instability (MSI) in this context.

Results
A 67-year-old female of bilineal Ashkenazi Jewish descent was recently diagnosed with uterine leiomyosarcoma in addition to metastatic papillary thyroid carcinoma at age 58. She met NCCN criteria for LS and BRCA1/2 (brother with renal cancer at age 64, father with colon cancer at age 60, paternal half-sister with rectal cancer at age 50 and maternal aunt with breast cancer).
Studies have shown that immunohistochemistry (IHC) for MMR proteins and PCR-based MSI have comparable sensitivity and specificity with high concordance, but neither test alone is sufficient to capture all defective MMR tumors. Screening strategies vary depending on the level of clinical suspicion for LS. When high, a normal result by one method warrants testing via a second method or concurrent IHC plus PCR testing to minimize the impact of rare false normal results. Rarely, this strategy can yield discordant results, as in our case wherein MSI by PCR was stable (MSS) but IHC for MLH-1 and PMS-2 showed heterogeneous (patchy/focal) nuclear loss of protein expression. The latter is not always due to artefact but can correspond to MMR status differences within the tumor, requiring recognition to prevent false-positive/false-negative evaluations. Heterogenous MLH1 and/or PMS2 expression, may be suggestive of variable MLH1 methylation/second hit mutations, variable epitope expression or expression related to variable differentiation.

Conclusion
The clinical significance of this pattern was unclear in our patient whose initial genetic screen (including MLH1, PMS2, MSH2, MSH6, EPCAM) was negative. However, as studies have indicated that patients with indeterminate IHC findings can have MLH1 hypermethylation or germline mutations, she had justification to undergo extended genetic screening. A heterozygous pathogenic variant in BLM 2207_2212delinsTAGATTC (p.Tyr736Leufs*5) associated with autosomal recessive Bloom Syndrome (BS) was identified. Carriers of BS do not show symptoms of the disease, but they are at a greater than average risk of developing cancers.
Novel Gene Fusions in Rhabdomyosarcoma
Authors: Montoya-Cerrillo D M , Diaz-Perez J A , Rosenberg A E 
Published: October 2020

Abstract

Introduction/Objective
Rhabdomyosarcoma (RMS) encompasses a heterogeneous group of tumors with striated muscle morphology and/or immunophenotype. Molecular analysis of rhabdomyosarcoma has identified a number of aberrations useful for classification. Initially, fusion associated RMS was restricted to tumors with FOXO1 rearrangements, confirming the diagnosis of alveolar RMS, and identifying patients with poor-outcome. Spindle cell RMS, have been described with VGLL2 fusions, EWSR1/FUS-TFCP2 rearrangements, and myoD1 mutations. In addition, NCOA2-MEIS1 fusion gene was recently described in two primary intraosseous RMSs sharing primitive histology. Herein we report two cases of spindle cell RMS, harboring different novel fusion genes, one presenting EP300-VGLL3, and the second with NCOA2-MEIS1 and CAV1-MET.

Methods
Two cases of RMS were retrieved from the pathology files at the University of Miami Hospital (UMH) and Jackson Memorial Hospital (JMH). Morphology and immunohistochemistry were reviewed. A commercial genomic profiling test for both cases was also analyzed. The study was approved by the Institutional Review Board at UMH.

Results
Case #1 is a 36-year-old man presented with a 1.5 cm submucosal mass in the ventral left tongue. The biopsy revealed a malignant spindle cell neoplasm and immunohistochemistry showed tumor cells positive for desmin, SMA, myogenin and MYOD-1. A partial glossectomy was performed, achieving negative resection margins. Next- generation sequencing (NGS) identified an EP300-VGLL3 fusion. The patient is currently being followed and has been disease-free for 6 months. Case #2 is a 19-years-old male with no medical history admitted with lower extremities weakness and a large expansile pelvic bone lesion and multiple spinal metastases. Biopsy from the pelvic lesion revealed malignant primitive round cells and short spindle cells arranged in fascicles which were positive for desmin, MYOD-1, TLE-1 and CD99 and focally positive for myogenin and WT-1. NGS identified two fusion genes, NCOA2- MEIS1 and CAV1-MET.

Conclusion
Different types of rhabdomyosarcoma are associated with a variety of different gene fusions and some may be of prognostic significance. Our two cases are the first reported with EP300-VGLL3 and CAV1-MET fusion genes. CAV1-MET oncogenic potential has been described only in lung cancer. The prognostic significance of rhabdomyosarcoma with novel gene fusions requires longer follow-up and the identification of additional cases.
Criticality Of Adequate Quality Monitoring Of Pre-Type And Screen Orders For The Operating Room: Role Of The Education, Proactive Communication At VAMC
Authors: Patel V , Petersen J M , Jhala D 
Published: October 2020

Abstract

Introduction/Objective
Ordering pre-operative type and screen specimens before the day of surgery is very important to prevent delays in provision of blood products due to unexpected alloantibody findings, unexpected ABO discrepancies, or need for a repeat ABO-RH testing due to lack of historical testing. However, the important pre- operative type and screen was not always ordered prior to the day of surgery by the clinician. Due to this observation, after discussion and collaboration with the Blood Utilization Committee (BUC), an educational and mentoring intervention for the pre-operative clinicians was undertaken.

Methods
Education and mentoring of clinicians involved in the pre-operative clinics, surgical services, and new incoming physicians on an ongoing basis was undertaken through the BUC since March 2018. As part of quality assurance, to track the results of this widespread educational effort, the daily OR lists from January 2017 to December 2019 were examined with the medical record to determine if a pre-operative type and screen was ordered prior to the day of surgery. The established Maximum Surgery Blood order Schedule (MSBOS) for the facility was used to determine if a pre-operative type and screen would be indicated for the listed procedure.

Results
As we started reinforced pre type and screen should be ordered there has been significant increase in percent of compliance rate average from 76% (2017), 87% (2018), and 95.6% (2019). By the T-test, there was a statistically significant change in the monthly ordering rates (p-value &lt; 0.05). The VAMC’s preferred threshold value of at least 95% with pre-operative type and screen prior to the day of procedure was achieved in the 2019 calendar year with no operating room delays.

Conclusion
Appropriately performing the pre-operative type and screen prior to the day of the elective surgical procedure would reduce the risk of delays due to unexpected findings or lack of a historical ABO-RH type. Educational interventions help tremendously in ensuring this critical patient care practice is followed. The value of collaborating and educating clinicians cannot be understated as it is both cheap, simple, and highly effective.
Utility Of Ebus-Tbna In Diagnosis And Staging Of Lung Nodules In The Setting Of Known Second Malignancy In Veterans - A Quality Assurance Study
Authors: Dalal S , Jhala D 
Published: October 2020

Abstract

Introduction/Objective
Endobronchial ultrasound guided transbronchial needle aspiration (EBUS-TBNA) is minimally invasive procedure for diagnosis/staging/restaging of lung nodules, recommended by the National Comprehensive Cancer Network (NCCN) 2017 Clinical Practice Guidelines. Veteran patients are an elderly patient cohort with multiple comorbidities and many have existing known 2nd malignancy. It will be crucial to diagnose and appropriately stage lung nodules. Our primary aim was to assess the efficacy of EBUS-TBNA in diagnosis/nodal staging in elderly patients with known 2nd malignancy. Our secondary aim was to evaluate the safety of this procedure for veterans.

Methods
A retrospective search for cases of EBUS-TBNA in patients with known second malignancy was carried out in Vista/Fileman at the Corporal Michael J Crescenz VA Medical Center between the period of June 2019 to January 2020. Sites included lung, cervical lymph nodes, mediastinum and hilar region.

Results
Of total 93 EBUS-TBNA procedures performed; EBUS-TBNA targeted both the lung and lymph node (62 cases), lymph nodes alone (28 cases) and only lung (3 cases). Total 53 were diagnosed malignant; with primary being lung (39 cases) and pleura (2 cases); and diagnosis of new metastatic carcinomas to lung was made in (12 cases).
The metastatic neoplasms included 2 urothelial carcinoma, 7 squamous carcinoma, 2 metastatic adenocarcinoma, and 1 prostatic adenocarcinoma. 32/53 (60.3%) had the history of prior extrapulmonary second malignancy.
Immunohistochemical studies was able to be performed in 50/53 (94%) of malignant cases, predictive marker PD-L1 on 50/53 (94%) cases, molecular testing on 23/53(43.3%) cases and Foundation One testing (Cambridge, MA, NGS) on 11/53(20.7%) cases. In all 93 cases, there were no complications (0/93) (0%) of the procedure.

Conclusion
EBUS-TBNA is an efficient, cost effective and minimally invasive modality in elderly veteran patient population with multiple co-morbidities. EBUS-TBNA is successful in procuring adequate material for diagnosis, molecular and predictive marker studies; thus, it can play a crucial role in precision oncology. EBUS-TBNA plays a pivotal role diagnosing and ruling out metastatic nodal disease in veteran patient population which has a high incidence of known 2nd extrapulmonary malignancy. EBUS-TBNA is deemed safe in veterans.
Comparism Of Cryoprecipitate Production Methods Using Fibrinogen And Factor VIII Assay
Authors: Bolarinwa A , Otokiti O E 
Published: October 2020

Abstract

Introduction/Objective
cryopecipiitate is of huge importance in the management of some Bleeding disorders especially in a low resource settings like ours where it is still the mainstay of management of disseminated Intravsacular coagulopathy, Haemophilia and Von willebrand Disease. In this study we aimed to compared the quality of cryoprecipitate produced using the Thaw-siphon method (no centrifugation) and the ones produced using the Slow- thawing (with centrifugation) methods

Methods
Ten units of newly prepared Fresh Frozen plasmas were randomly selected, five of were used to prepare cryoprecipitate using the Thaw-siphon method while cryoprecipitate were prepared using the slow-thawing plus centrifugation method. The Fibrinogen concentration in all the ten units were determined using the modified Claus tehcnique while the Factor Viii assay of each unit was done using the one-stage APTT based Assay method

Results
using the Thaw-siphon method, the mean fibrinogen concentration (152mg/bag) was found to be lower than that of units prepared with slow-thawing plus centrifugation methods (256mg/bag). In a similar manner Factor Viii concentrations were higher in the Slow-thawing with centrifugation methods, Mean Factor Viii concentration was 172Iu/bag when compared with 82 IU/bag in Thaw-siphon methods

Conclusion
We concluded that Cryoprecipiate produced usng the Thaw- centrifugation methods have higher Fibrinogen and factor Viii units and as such, smaller quantity will be required for correction of coagulopathy when compared with the Thaw-siphon methods. Despite this glaring and expected findings, it is worthy of note that the cryoprecipitate units produced by Thaw-siphon methods meets the required criteria for quality cryoprecipitate and will be very useful in a low resource settings.
Sirtuin-1 inhibits endothelin-2 expression in human granulosa-lutein cells via hypoxia inducible factor 1 alpha and epigenetic modifications†
Authors: Szymanska Magdalena , Manthe Sarah , Shrestha Ketan , Girsh Eliezer , Harlev Avi , Kisliouk Tatiana , Meidan Rina 
Published: October 2020

Abstract
Endothelin-2 (EDN2) expression in granulosa cells was previously shown to be highly dependent on the hypoxic mediator, hypoxia inducible factor 1 alpha (HIF1A). Here, we investigated whether sirtuin-1 (SIRT1), by deacetylating HIF1A and class III histones, modulates EDN2 in human granulosa-lutein cells (hGLCs). We found that HIF1A was markedly suppressed in the presence of resveratrol or a specific SIRT1 activator, SRT2104. In turn, hypoxia reduced SIRT1 levels, implying a mutually inhibitory interaction between hypoxia (HIF1A) and SIRT1. Consistent with reduced HIF1A transcriptional activity, SIRT1 activators, resveratrol, SRT2104, and metformin, each acting via different mechanisms, significantly inhibited EDN2. In support, knockdown of SIRT1 with siRNA markedly elevated EDN2, whereas adding SRT2104 to SIRT1-silenced cells abolished the stimulatory effect of siSIRT1 on EDN2 levels further demonstrating that EDN2 is negatively correlated with SIRT1. Next, we investigated whether SIRT1 can also mediate the repression of the EDN2 promoter via histone modification. Chromatin immunoprecipitation (ChIP) analysis revealed that SIRT1 is indeed bound to the EDN2 promoter and that elevated SIRT1 induced a 40% decrease in the acetylation of histone H3, suggesting that SIRT1 inhibits EDN2 promoter activity by inducing a repressive histone configuration. Importantly, SIRT1 activation, using SRT2104 or resveratrol, decreased the viable numbers of hGLC, and silencing SIRT1 enhanced hGLC viability. This effect may be mediated by reducing HIF1A and EDN2 levels, shown to promote cell survival. Taken together, these findings propose novel, physiologically relevant roles for SIRT1 in downregulating EDN2 and survival of hGLCs.
Targeted sequencing of Parkinson’s disease loci genes highlights SYT11, FGF20 and other associations
Authors: Rudakou Uladzislau , Yu Eric , Krohn Lynne , Ruskey Jennifer A , Asayesh Farnaz , Dauvilliers Yves , Spiegelman Dan , Greenbaum Lior , Fahn Stanley , Waters Cheryl H , Dupré Nicolas , Rouleau Guy A , Hassin-Baer Sharon , Fon Edward A , Alcalay Roy N , Gan-Or Ziv 
Published: October 2020

Abstract
Genome-wide association studies (GWAS) have identified numerous loci associated with Parkinson’s disease. The specific genes and variants that drive the associations within the vast majority of these loci are unknown. We aimed to perform a comprehensive analysis of selected genes to determine the potential role of rare and common genetic variants within these loci. We fully sequenced 32 genes from 25 loci previously associated with Parkinson’s disease in 2657 patients and 3647 controls from three cohorts. Capture was done using molecular inversion probes targeting the exons, exon-intron boundaries and untranslated regions (UTRs) of the genes of interest, followed by sequencing. Quality control was performed to include only high-quality variants. We examined the role of rare variants (minor allele frequency &lt; 0.01) using optimized sequence Kernel association tests. The association of common variants was estimated using regression models adjusted for age, sex and ethnicity as required in each cohort, followed by a meta-analysis. After Bonferroni correction, we identified a burden of rare variants in SYT11, FGF20 and GCH1 associated with Parkinson’s disease. Nominal associations were identified in 21 additional genes. Previous reports suggested that the SYT11 GWAS association is driven by variants in the nearby GBA gene. However, the association of SYT11 was mainly driven by a rare 3′ UTR variant (rs945006601) and was independent of GBA variants (P = 5.23 × 10−5 after exclusion of all GBA variant carriers). The association of FGF20 was driven by a rare 5′ UTR variant (rs1034608171) located in the promoter region. The previously reported association of GCH1 with Parkinson’s disease is driven by rare non-synonymous variants, some of which are known to cause dopamine-responsive dystonia. We also identified two LRRK2 variants, p.Arg793Met and p.Gln1353Lys, in 10 and eight controls, respectively, but not in patients. We identified common variants associated with Parkinson’s disease in MAPT, TMEM175, BST1, SNCA and GPNMB, which are all in strong linkage disequilibrium with known GWAS hits in their respective loci. A common coding PM20D1 variant, p.Ile149Val, was nominally associated with reduced risk of Parkinson’s disease (odds ratio 0.73, 95% confidence interval 0.60–0.89, P = 1.161 × 10−3). This variant is not in linkage disequilibrium with the top GWAS hits within this locus and may represent a novel association. These results further demonstrate the importance of fine mapping of GWAS loci, and suggest that SYT11, FGF20, and potentially PM20D1, BST1 and GPNMB should be considered for future studies as possible Parkinson’s disease-related genes.
Clinical Characteristics and Outcomes of Breakthrough Candidemia in 71 Hematologic Malignancy Patients and/or Allogeneic Hematopoietic Stem Cell Transplant Recipients: A Single-center Retrospective Study From China, 2011–2018
Authors: Chen Xiao-Chen , Xu Jie , Wu De-Pei 
Published: October 2020

Abstract

Background
Antifungal prophylaxis may result in breakthrough infections in hematology patients with severe agranulocytosis, with few studies assessing risk factors and clinical outcomes of breakthrough candidemia. We described the distribution of Candida species, assessed risk factors for mortality in such patients, and determined differences in the incidence and mortality of breakthrough candidemia between patients who did or did not receive an allogeneic hematopoietic stem cell transplant.

Methods
We collected clinical and microbiological data of patients with hematologic malignancies and breakthrough candidemia from a single center. Seven-day and 30-day follow-up outcomes were recorded; the incidence and mortality of breakthrough candidemia between patients who did or did not undergo an allogeneic transplant were compared. Kaplan-Meier survival estimates were used to generate survival curves, and predictors were identified using Cox regression analyses.

Results
Of 71 enrolled patients, 17 received allogeneic transplants. Incidences of breakthrough candidemia were 17 of 2924 (0.58%) and 54 of 12 015 (0.45%) in the transplant and nontransplant groups, respectively (P = .35). The most common isolate was Candida tropicalis, and antifungal agent combinations were the most common first-line treatment. Cumulative mortality rates of patients were 21.1% and 31.0% at days 7 and 30, respectively, and they significantly differed between both groups. Septic shock, central venous catheter removal, and granulocyte recovery were significantly associated with 7-day mortality; the latter 2 remained independent predictors of 30-day mortality.

Conclusions
Breakthrough candidemia-related mortality was higher in the allogeneic transplant group, although the incidence was not significantly different between the groups. Prompt and adequate antifungal treatment with catheter removal may reduce mortality.
Using a Composite Maternal–Infant Outcome Measure in Tuberculosis-Prevention Studies Among Pregnant Women
Authors: Montepiedra Grace , Kim Soyeon , Weinberg Adriana , Theron Gerhard , Sterling Timothy R , LaCourse Sylvia M , Bradford Sarah , Chakhtoura Nahida , Jean-Philippe Patrick , Evans Scott , Gupta Amita 
Published: October 2020

Abstract

Background
Tuberculosis (TB-)-preventive therapy (TPT) among pregnant women reduces risk of TB in mothers and infants, but timing of initiation should consider potential adverse effects. We propose an analytical approach to evaluate the risk–benefit of interventions.

Methods
A novel outcome measure that prioritizes maternal and infant events was developed with a 2-stage Delphi survey, where a panel of stakeholders assigned scores from 0 (best) to 100 (worst) based on perceived desirability. Using data from TB APPRISE, a trial among pregnant women living with human immunodeficiency virus (WLWH) that randomized the timing of initiation of isoniazid, antepartum versus postpartum, was evaluated.

Results
The composite outcome scoring/ranking system categorized mother–infant paired outcomes into 8 groups assigned identical median scores by stakeholders. Maternal/infant TB and nonsevere adverse pregnancy outcomes were assigned similar scores. Mean (SD) composite outcome scores were 43.7 (33.0) and 41.2 (33.7) in the antepartum and postpartum TPT initiation arms, respectively. However, a modifying effect of baseline antiretroviral regimen was detected (P = .049). When women received nevirapine, composite scores were higher (worse outcomes) in the antepartum versus postpartum arms (adjusted difference, 14.3; 95% confidence interval [CI], 2.4–26.2; P = .02), whereas when women received efavirenz there was no difference by timing of TPT (adjusted difference, .62; 95% CI, −3.2–6.2; P = .53).

Conclusions
For TPT, when used by otherwise healthy persons, preventing adverse events is paramount from the perspective of stakeholders. Among pregnant WLWH in high-TB-burden regions, it is important to consider the antepartum antiretroviral regimen taken when deciding when to initiate TPT.
Clinical Trials Registration. NCT01494038 (IMPAACT P1078).
Clustering Cases of Chlamydia psittaci Pneumonia in Coronavirus Disease 2019 Screening Ward Staff
Authors: Lei Jian-Hua , Xu Yun , Jiang Yong-Fang , Shi Zhi-Hui , Guo Tao 
Published: October 2020

Abstract
We describe 4 cases of Chlamydia psittaci pneumonia among medical staff in a coronavirus disease 2019 (COVID-19) screening ward, as well as the experience of dealing with this nosocomial infection event. Atypical pneumonia, in addition to COVID-19, should be considered when clustering cases occur, even during a COVID-19 pneumonia pandemic.
Translingual arts-based practices for language learners
Authors: Hirsu Lavinia , Zacharias Sally , Futro Dobrochna 
Published: October 2020

Abstract
In this article, we advocate for the enriching role of arts-based practices in the delivery of a translingual pedagogic approach. With a growing interest in translanguaging, ELT practitioners are searching for models and creative ideas that foster a translingual environment for their learners. We have responded to this call and developed a collaborative project entitled ‘Creative Language Practices: Exploring Translanguaging in Pedagogical Contexts and Beyond’. The project brought together language researchers from the University of Glasgow, creative artists, and school teachers. By sharing our approach and practices, we want to promote the adoption of translingual values and guiding principles through the use of arts as a methodology for language learning and meaning-making. Instead of feeling intimidated by the complexity and difficulty of the concept of translanguaging, teachers and practitioners could adopt an arts-based pedagogy as the catalyst for creative practice that will help learners to explore their creative resources.