Abstract
In the treatment of glioblastoma (GBM), MRI is used to determine location and extent of cancer. It is poorly understood how far tumor invasion may exist outside of contrast enhancement (CE) ...and FLAIR hyperintensity (FL). This study identifies presumed non-enhancing tumor invasion using SOX2 staining on tissue collected at autopsy, which may highlight invading glioma cells. Three patients with primary GBM were included for this study. Patient 1 (P1) with an overall survival (OS) of 148 days received no treatment following sub-total resection. Patient 2 (P2) (OS = 1601) and patient 3 (P3) (OS = 629 days) underwent the clinical standard of care treatment including chemo-radiation and bevacizumab at recurrence. At autopsy, brains were sliced axially to match patients’ last MRI scan. Samples were obtained including regions suspicious of tumor and regions appearing normal. SOX2 positive cells were identified visually on digitized autopsy histology. Samples were visually matched to the patient’s last T1C and FLAIR MRI acquisition prior to death. Approximate distance from CE and FL from SOX2 positive cells was measured digitally, limited to the same MRI slice (2D assessment). For P1 who received no treatment, SOX2 positive cells were identified 3.9cm from CE and 4.1cm from FL within the same hemisphere as the primary tumor, and 2.1cm and 2.3cm within the opposite hemisphere, respectively. For P2 and (P3), SOX2 positive cells were identified approximately 4.4cm (5.2 cm) from CE and 4.0cm (2.0cm) from FL within the same hemisphere as primary tumor, and 4.7cm (4.4cm) from CE and 4.1 cm (4.7cm) from FL within the opposite hemisphere. This study uses SOX2 to identify presumed GBM cells well beyond clinically identified regions of tumor, on T1C and FLAIR imaging. Additional research is necessary to determine SOX2 sensitivity and specificity for identifying GBM cells outside regions with readily identifiable GBM characteristics.
Abstract
Perfusion MRI, using both contrast-based techniques such as dynamic susceptibility imaging (DSC) and non-contrast-based techniques like arterial spin labeling (ASL) have been used to monitor ...blood flow as a marker of angiogenic glioma presence, and showed substantial potential in the differentiation of true progression from pseudoprogression post-treatment. This study uses radio-pathomic maps of cellularity sensitive to areas of non-enhancing tumor to test the hypothesis that perfusion-derived markers of tumor probability will associate with tumor presence within contrast-enhancement but not beyond the enhancing margin. This study included pre-surgical relative cerebral blood volume (rCBV) estimates derived from DSC perfusion data from the PENN-GBM dataset (n=456) and presurgical ASL images from the UCSF-PDGM dataset (n=426) for analyses. The T1, T1C, FLAIR, and ADC images from each patient were used to generate radio-pathomic cell density maps using a previously validated model that excels at accurate detection of non-enhancing tumor presence. Mean cell density, rCBV, and ASL were computed for each corresponding patient within included segmentations for contrast-enhancement (excluding necrotic core) and FLAIR hyperintensity (excluding both necrotic core and enhancement). Pearson’s correlations were then used to quantify the association between perfusion-derived estimates and mean cell density within each region of interest. Both rCBV and ASL showed positive associations with cell density within contrast enhancement (rCBV: R=0.280, p< 0.001; ASL: R=0.117, p=0.016). However, both perfusion metrics also showed no association with cell density within the non-enhancing, FLAIR hyperintense region (rCBV: R=0.0162, p=0.731; ASL: R=-0.213, p=0.634). These results suggest that perfusion imaging successfully identifies angiogenic tumor but may be less efficacious in detecting non-enhancing tumor presence. Future studies should examine how perfusion’s relationship with hypercellular tumor presence evolves in the presence of treatment, as well as in relation to other advanced imaging metrics such as MR spectroscopy and CEST imaging.
Abstract
PURPOSE
Apparent diffusion coefficient (ADC) maps offer tremendous insight into cellularity and local tissue environment. Proliferation of tumor cells results in increased local cellularity ...and cell density, thus impairing the free diffusion of water molecules. Therefore, hypointense ADC signals are thought to reflect regions of increased cellularity, and are useful imaging markers for distinguishing neoplastic cellular processes. In this study, we tested the hypothesis that changes in ADC intensity over the course of disease progression differ in progressing gliomas within the tumor-delineated region.
METHODS
Sixty-three glioma patients from our brain bank were separated into two groups. Group 1 included patients with Grade 1-3 gliomas at surgical diagnosis and progressed to a Grade 4 glioma at autopsy. The second group of patients were those with an initial and final Grade 4 glioma diagnosis. Contrast-enhancing tumor regions on MRI sequences were annotated with an established machine-learning algorithm for each patient on their initial and final MRIs. Average ADC intensity within the contrast enhancing regions was extracted and change in signal intensity between the first and last MRI was calculated for each patient. Finally, the mean intensity difference between Group 2 and Group 1 were evaluated using a linear mixed model.
RESULTS
We report a negative mean difference between the Group 2 and Group 1s change in ADC intensity over time (p=0.03).
CONCLUSIONS
These findings suggest changes in cellularity, identified by ADC, are greater in patients who progress from low-to-high grade gliomas. With these results, it may be concluded that change in ADC hypointensity, as a proxy for cellularity, may be a defining imaging characteristic to identify progressing gliomas.
The COVID-19 pandemic required genetic counseling services, like most outpatient healthcare, to rapidly adopt a telemedicine model. Understanding the trends in patients’ preferences for telemedicine ...relative to in-person service delivery both before and after the advent of the COVID-19 pandemic may aid in navigating how best to integrate telemedicine in a post-COVID-19 era. Our study explored how respondents’ willingness to use, and preference for, telemedicine differed from before to after the onset of the COVID-19 pandemic. Respondents included patients, or their parent/guardian, seen in a general medical genetics clinic in 2018, prior to the COVID-19 pandemic, and in 2021, during the COVID-19 pandemic. Respondents were surveyed regarding their willingness to use telemedicine, preference for telemedicine relative to in-person care, and the influence of various factors. Among 69 pre-COVID-19 and 40 current-COVID-19 respondents, there was no shift in willingness to use, or preference for, telemedicine across these time periods. About half of respondents (50.6%) preferred telemedicine visits for the future. Of the 49.4% who preferred in-person visits, 79.1% were still willing to have visits via telemedicine. Predictors of these preferences included comfort with technology and prioritization of convenience of location. This study suggests that a hybrid care model, utilizing telemedicine and in-person service delivery, may be most appropriate to meet the needs of the diverse patients served. Concern for COVID-19 was not found to predict willingness or preference, suggesting that our findings may be generalizable in post-pandemic contexts.
The human zoonotic pathogen
O157:H7 is defined by its extensive prophage repertoire including those that encode Shiga toxin, the factor responsible for inducing life-threatening pathology in humans. ...As well as introducing genes that can contribute to the virulence of a strain, prophage can enable the generation of large-chromosomal rearrangements (LCRs) by homologous recombination. This work examines the types and frequencies of LCRs across the major lineages of the O157:H7 serotype. We demonstrate that LCRs are a major source of genomic variation across all lineages of
O157:H7 and by using both optical mapping and Oxford Nanopore long-read sequencing prove that LCRs are generated in laboratory cultures started from a single colony and that these variants can be recovered from colonized cattle. LCRs are biased towards the terminus region of the genome and are bounded by specific prophages that share large regions of sequence homology associated with the recombinational activity. RNA transcriptional profiling and phenotyping of specific structural variants indicated that important virulence phenotypes such as Shiga-toxin production, type-3 secretion and motility can be affected by LCRs. In summary,
O157:H7 has acquired multiple prophage regions over time that act to continually produce structural variants of the genome. These findings raise important questions about the significance of this prophage-mediated genome contingency to enhance adaptability between environments.
Abstract
PDAC is typically resistant to chemotherapy and immunotherapy; therefore, novel strategies are needed to enhance therapeutic response. BXCL701 is a well-studied inhibitor of dipeptidyl ...peptidases 4, 8, 9, and Fibroblast Activation Protein, and has been postulated to work through cytokine induction and macrophage pyroptosis. We examined the effects of BXCL701 and/or PD1 therapy in murine models of PDAC. In the mT3-2D PDAC model, combination therapy of established (~75mm3) sc tumors reduced tumor growth to a greater extent (PBS: 1349±230 mm3 on day 42 vs B + PD1: 355±161mm3, p<0.0001) following a 28-day treatment program of PBS, B (1mg/kg by daily oral gavage), PD1 (10mg/kg ip weekly) or the combination of B + PD1. Treatment with either B or PD1 alone had minimal anti-tumor effects. B + PD1 therapy was accompanied by significant tumor infiltration of NK cells by IHC, flow cytometry and Nanostring analysis. A dramatic reduction of tumor stromal fibrosis by Masson's trichrome staining was found in tumors treated with B alone or B + PD1. These findings suggest that the combination of BXCL701 with anti-PD1 antibody therapy can exert anti-tumor effects associated with increased intratumoral NK cell content and the loss of fibrosis that may facilitate immunotherapy efficacy.
Citation Format: Shangzi Wang, Allison Fitzgerald, Reham Ajina, Sandra A. Jablonsk, Louis M. Weiner, John MacDougall, Veena Agarwal, Vince J. O'Neill. Therapy with BXCL701 (B), a DPP8, DPP9, DPPIV and FAP inhibitor, in combination with anti-PD1 antibody (PD1) in a syngeneic murine pancreatic ductal adenocarcinoma (PDAC) model improves treatment outcomes and induces intratumoral NK cell infiltrates and a marked reduction in tumor stromal fibrosis abstract. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6636.
Aim
We compared preschool age children born very preterm with term‐born controls to: (1) understand the association between very preterm birth and community participation, (2) determine if motor ...impairment or social risk affect participation differently between groups, and (3) understand environmental barriers and supports to participation for parents.
Method
Forty‐eight children born very preterm (<30wks’ gestation; 22 males, 26 females) and 96 controls (47 males, 49 females) were assessed at 4 to 5 years’ corrected age for community participation using the Young Children’s Participation and Environment Measure. Motor skills were assessed using the Movement Assessment Battery for Children, Second Edition and the Little Developmental Coordination Disorder Questionnaire.
Results
Children born very preterm participated less frequently than term‐born children (difference in means=–0.28, 95% confidence interval CI –0.54 to –0.03, p=0.029). Social risk was associated with lower frequency (interaction p<0.001) and involvement (interaction p=0.05) in community activities for children in the very preterm group only. Parents of children born very preterm perceived more barriers (odds ratio=4.32, 95% CI 1.46–12.77, p=0.008) and environmental factors to be less supportive of participation than parents of controls (difference in medians=–6.21, 95% CI –11.42 to –1.00, p=0.02).
Interpretation
Children born very preterm may benefit from ongoing support to promote participation, especially in families of higher social risk.
Barreras y facilitadores para la participación comunitaria de niños en edad preescolar nacidos muy prematuros: un estudio de cohorte prospectivo
Objetivo
Comparamos los niños en edad preescolar nacidos muy prematuros con los controles nacidos a término para: (1) comprender la asociación entre el nacimiento muy prematuro y la participación comunitaria, (2) determinar si el deterioro motor o el riesgo social afectan la participación de manera diferente entre los grupos y (3) comprender las barreras ambientales y el apoyo a la participación de los padres.
Método
Cuarenta y ocho niños nacidos muy prematuros (<30 semanas de gestación; 22 varones, 26 mujeres) y 96 controles (47 varones, 49 mujeres) fueron evaluados a la edad corregida de 4 a 5 años para la participación comunitaria utilizando la Participación y el Ambiente de Niños Pequeños. Las habilidades motoras se evaluaron utilizando la Batería de evaluación del movimiento para niños, segunda edición y el Cuestionario sobre trastornos de coordinación del desarrollo pequeño.
Resultados
Los niños nacidos muy prematuros participaron con menos frecuencia que los niños nacidos a término (diferencia de medias = –0,28, intervalo de confianza IC del 95% –0,54 a –0,03, p = 0,029). El riesgo social se asoció con una menor frecuencia (interacción p <0,001) y participación (interacción p = 0,05) en actividades comunitarias para los niños en el grupo muy prematuro solamente. Los padres de niños nacidos muy prematuros percibieron más barreras (razón de posibilidades = 4,32, IC del 95%: 1,46‐12,77, p = 0,008) y factores ambientales como menos favorables a la participación que los padres de los controles (diferencia en las medianas = –6,21, IC del 95% –11,42 a –1,00, p = 0,02).
Interpretación
Los niños que nacen muy prematuros pueden beneficiarse del apoyo continuo para promover la participación, especialmente en las familias de mayor riesgo social.
Barreiras e facilitadores para a participação na comunidade para crianças pré‐escolares nascidas muito prematuras: um estudo de coorte prospectivo
Objetivo
Comparamos crianças em idade pré‐escolar nascidas muito prematuras com crianças nascidas a termo para: 1) entender a associação entre nascimento muito prematuro e participação na comunidade. 2) Determinar se a deficiência motora ou risco social afetam a participação de forma diferente entre gupos, e 3) compreender barreiras e suportes ambientais para a participação de acordo com os pais.
Método
Quarenta e oito crianças nascidas muito prematuras (<30 semanas de gestação; 22 do sexo masculino, 26 do sexo feminino) e 96 controles (47 do sexo masculino, 49 do sexo feminino) foram avaliadas nas idade de 4 a 5 anos de idade corrigida quanto à participação na comunidade usando a Medida da participação e do ambiente para crianças pequenas. Habilidades motoras foram avaliadas usando a Bateria de avaliação motora para crianças, segunda edição, e o Questionário de Transtorno do Desenvolvimento da Coordenação de Little.
Resultados
Crianças nascidas muito prematuras participaram com menor frequência do que crianças nascidas a termo (diferença na média=–0,28, intervalo de confiança IC a 95%–0,54 a –0,03, p=0,029). O risco social foi associado com menor frequência (interação p<0,001) e envolvimento (interação p=0,05) nas atividades da comunidade apenas para crianças no grupo muito prematuro. Os pais de crianças nascidas muito prematuras perceberam mais barreiras (taxa de risco=4,32, IC 95% 1,46–12,77, p=0,008) e menos apoios quanto aos fatores ambientais para a participação do que os pais dos controles (diferença na média=–6,21, IC 95% –11,42 a –1,00, p=0,02).
Interpretação
Crianças nascidas muito prematuras podem se beneficiar de suporte continuado para promover a participação, especialmente em famílias de maior risco social.
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Extracorporeal membrane oxygenation (ECMO) use in patients with cardiac arrest is increasing. Utilization remains variable between centers using ECMO as a rescue therapy or early protocolized ...extracorporeal cardiopulmonary resuscitation.
Single-center, retrospective evaluation of cardiac arrest with cardiopulmonary resuscitation and rescue ECMO support from 2011 through 2019. Study objectives included survival, non-neurologic, and neurologic outcomes; validation of the SAVE and modified SAVE (mSAVE) scores for survival and favorable neurologic outcome; and predictive factor identification in cardiac arrest with ECMO rescue therapy.
Eighty-nine patients were included. In-hospital survival was 38.2% and median CPC score was 2. Survivors had lower BMI (27.9 ± 4.2 kg/m2 vs. 32.3 ± 7.5 kg/m2, P = 0.003), less obesity (BMI ≥ 30 kg/m2) (26.5% vs. 49.1%, P = 0.035), shorter CPR duration (35.5 ± 31.7 m vs. 58.0 ± 49.5 m, P = 0.019), more tracheostomy (38.2% vs. 7.3%, P < 0.001), and less renal replacement therapy (RRT) (17.6% vs. 38.2%, P = 0.031). Patients with a favorable neurologic outcome had lower body weight (86.2 ± 17.9 kg vs. 98.1 ± 19.4 kg, P = 0.010), lower BMI (28.1 ± 4.5 kg/m2 vs. 33.9 ± 7.9 kg/m2, P < 0.001), and less obesity (29.7% vs. 56.3%, P = 0.026). mSAVE score predicted in-hospital survival (OR 1.11; 95%CI 1.03-1.19; P = 0.004) and favorable neurologic outcome (OR 1.11; 1.03-1.20; P = 0.009). Multivariate analysis for in-hospital survival included mSAVE, BMI, CPR-time, tracheostomy, and RRT (c-statistic: 0.864). Favorable neurologic outcome included mSAVE and BMI (c-statistic: 0.805).
mSAVE, BMI, RRT, and tracheostomy are predictors of in-hospital survival and mSAVE and BMI are predictors of favorable neurologic outcome in cardiac arrest with ECMO rescue therapy.
In February 2015, an outbreak of recently acquired HIV infections among people who inject drugs (PWID) was identified in Dublin, following similar outbreaks in Greece and Romania in 2011. We compared ...drug and risk behaviours among 15 HIV cases and 39 controls. Injecting a synthetic cathinone, snow blow, was associated with recent HIV infection (AOR: 49; p=0.003). Prevention and control efforts are underway among PWID in Dublin, but may also be needed elsewhere in Europe.
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