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Investigation of chemotherapy-induced brain structural alterations in breast cancer patients with generalized q-sampling MRI and graph theoretical analysis
Tsung-Yuan Li1 na1,
Vincent Chin-Hung Chen2,3 na1,
Dah-Cherng Yeh4,
Shu-Ling Huang5,
Cheng-Nan Chen1,
Jyh-Wen Chai1,6,
Clayton Chi-Chang Chen1,7 &
Jun-Cheng Weng ORCID: orcid.org/0000-0001-7616-62163,8
BMC Cancer volume 18, Article number: 1211 (2018) Cite this article
Breast neoplasms are the most common cancer among women in Taiwan. Cognitive deficits are common complications of breast cancer survivors treated with chemotherapy. The most frequently observed disorders involve executive function and memory impairment. With improvements in tumor intervention and the consequent increase in the number of cancer survivors, the quality of life of patients has become an important issue. We are interested in the early effects of chemotherapy on the brain structures of patients. In addition, generalized q-sampling imaging (GQI), a wide range of q-space datasets for a more accurate and sophisticated diffusion MR approach, was first used in this topic.
As diffusion tensor imaging (DTI) is associated with restrictions in the resolution of crossing fibers, we attempted to use GQI, which can overcome these difficulties and is advantageous over DTI for tractography of the crossing fibers. This cross-sectional study included two groups: breast cancer survivors who had completed their chemotherapy (n = 19) and healthy controls (n = 20). All participants underwent diffusion MRI exams and neuropsychological assessments. We included four parts in our image analysis, i.e., voxel-based statistical analysis, multiple regression analysis, graph theoretical analysis and network-based statistical analysis.
The results from the voxel-based statistical analysis showed significantly lower GFA and NQA values in the breast cancer group than those in the control group. We found significant positive correlations between the FACT-Cog and GQI indices. In the graph theoretical analysis, the breast cancer group demonstrated significantly longer characteristic path length. Adjuvant chemotherapy affected the integrity of white matter and resulted in poor cognitive performance, as indicated by the correlations between the neuropsychological assessment scales and the GQI indices. In addition, it was found that the characteristic path lengths in the breast cancer group increased, indicating that the brain network integration became worse.
Our study demonstrated alterations in structural brain networks and associated neuropsychological deficits among breast cancer survivors.
The most common cancer among women in Taiwan is breast neoplasms. There are more than 10,000 women suffering from breast cancer, and nearly 2000 women die of breast cancer annually [1, 2]. The stage of breast cancer is based on the tumor size, the axillary lymph nodes that are involved, and distant metastasis. If breast cancer can be diagnosed and treated earlier, the five-year survival rate would be projected to increase to a maximum of 90%. There are various treatments for breast cancer, including traditional surgery, adjuvant chemotherapy, radiation therapy, targeted therapy and hormonal therapy.
Cognitive function in breast cancer survivors
Breast cancer is a common cause of mortality; however, treatments have improved, and consequently, the interest in the quality of life and function among survivors has increased. Therefore, depression, anxiety and psychiatric symptoms among breast cancer survivors need to be investigated. Breast cancer patients receive different treatments based on the size of the tumor, and these treatments often result in physical or cognitive deficits in patients. A range of 15 to 50% of patients with malignant tumors show persistent cognitive impairments after chemotherapy [3]. Many studies have also reported that breast cancer patients often appear to develop the phenomenon of chemo-brain after chemotherapy. In this condition, patients often complain of problems regarding memory, concentration, multiple operation, processing speed, and word retrieval [4, 5]. This cognitive impairment in patients can affect social relationships and even work performance [5].
One study tracked changes in the cognitive function of three groups, which included breast cancer patients with chemotherapy combined with radiotherapy, breast cancer patients with radiotherapy only, and a control group, over 3 years. The breast cancer patients treated with chemotherapy and radiotherapy (CTRT; n = 62) or radiotherapy only (RT; n = 67) completed neuropsychological assessments 6 months after completing treatment and then again 36 months later. The control group (n = 184) was assessed over a similar interval. There was also a significant difference in executive function (p = 0.006) among the three groups. This difference indicated that the control group performed better than the CTRT and RT groups [6].
Diffusion magnetic resonance imaging of the brain
With the improvements in tumor intervention and the increase in the number of cancer survivors, the cognition of patients has become an important issue for patients, physicians and researchers. One study evaluated the long-term effect of chemotherapy on brain microstructural integrity by comparing the brains of chemotherapy-exposed breast cancer survivors to those of healthy women. There were two groups of participants: 187 breast cancer survivors treated with CMF (cyclophosphamide, methotrexate, and 5-flourouracil) and 374 age-matched healthy women. Diffusion tensor imaging (DTI) was analyzed with tract-based spatial statistics. In addition, the authors used linear regression analysis to explore the impact of the length of time after chemotherapy. The results showed that the length of time after chemotherapy was inversely associated with fractional anisotropy (FA), mean diffusivity (MD) and radial diffusivity (RD) among breast cancer survivors. The authors reported that adjuvant chemotherapy had an adverse effect on the integrity of the white matter microstructure of breast cancer survivors who had survived more than 20 years on average [7].
In this study, we evaluated the early effects of chemotherapy on the brain structures of patients. Since diffusion tensor imaging is associated with restrictions in the resolution of crossing fibers, we tried to use generalized q-sampling imaging (GQI), which can overcome these difficulties and is advantageous over DTI for the tractography of crossing fibers [8].
This study was a cross-sectional study, and participants were recruited from the department of breast surgery of Taichung Veterans General Hospital. The study included 19 women with a history of breast cancer (stage I-IIIA) who had completed their primary chemotherapy less than 6 months before study entry and were currently without evidence of active cancer. There were 4 patients received radiation therapy, and 1 patient received hormone treatment. The number of menopausal women in the patients and controls were 5:5. The average age of the breast cancer survivors was 43.8± 6.4 years. The only chemotherapeutic drugs used by the patients were taxotere and epirubicin. Another 20 healthy women aged 50.1± 2.5 years served as the control group. All participants underwent magnetic resonance imaging (MRI) examinations on a 1.5 T scanner (Aera, Siemens, Germany) and neuropsychological assessments. The clinical characteristics and neuropsychological assessments are shown in Table 1.
Table 1 Group differences in clinical characteristics and neuropsychological assessment
The inclusion criteria were as follows: breast cancer survivors (within 6 months after chemotherapy) 20–55 years of age and healthy female 20–55 years of age. There were no other cancer types present in the breast cancer survivors other than breast cancer. If the participants were diagnosed with psychiatric, neurologic, or comorbid medical conditions that are known to affect cognitive function, they were excluded.
This study was approved by the Institutional Review Board at Taichung Veterans General Hospital. The review number was SF14185A. Participants were recruited from the department of breast surgery of Taichung Veterans General Hospital. The research assistant explained the research proposal to participants so that the participants could understand the research purpose, process and both their rights and interests. Clinical physicians assessed the physiological status of each participant to ensure she could participate in the MRI examination. All participants provided written informed consent before the examination. A clinical psychologist performed the neuropsychological assessment, and a radiologic technologist performed the subsequent MRI examination. The overall process took approximately 90 min.
Neuropsychological assessments
We designed the questionnaire to understand the basic information of the participants and used objective and subjective psychological tests to evaluate the cognitive function, emotion, mindfulness and psychological trauma of the participants. The neuropsychological tests included the Mini-Mental State Examination (MMSE), Functional Assessment of Cancer Therapy-Cognitive Function (FACT-Cog), Hospital Anxiety and Depression Scale (HADS), Impact of Event Scale-Revised (IES-R), and Cognitive and Affective Mindfulness Scale-Revised (CAMS-R). All statistics were performed with Microsoft Excel 2010. The results of the neuropsychological assessments are shown in Table 1.
Diffusion imaging parameters
For diffusion imaging, we performed a single-shot, diffusion-weighted spin echo-planar imaging sequence with the following parameters: magnetic field strength = 1.5 Tesla, repetition time = 7200 msec, echo time = 107 msec, field of view = 256 mm, matrix = 128 × 128, slice thickness = 4 mm, resolution = 2 × 2 × 4 mm3, b-values = 0, 1000, and 2000 s/mm2 in 129 noncollinear directions, number of excitations = 1, and the acquisition time was 16 min.
Generalized q-sampling imaging
Based on the Fourier transform between the diffusion magnetic resonance (MR) signals and the diffusion displacement, a new relationship can be deduced by directly estimating the spin distribution function (SDF) from the diffusion MR signals. This relationship leads to a new reconstructed method called generalized q-sampling imaging. GQI can provide directional and quantitative information about crossing fibers.
GQI is a model-free method that quantifies the density of water, which diffuses in different orientations. Model-free methods estimate the empirical distribution of the water diffusion, and there is no hypothesis on the distribution. The SDF is the density of diffusing water in different directions and is a kind of diffusion orientation distribution function (ODF). GQI provides information of the relation between the diffusion signals of water and the SDF. GQI can be applied to grid or shell sampling schemes, q-ball imaging (QBI) and diffusion spectrum imaging (DSI). Studies have shown that GQI has good sensitivity and specificity for white matter properties and pathology [9].
The GQI indices included generalized fractional anisotropy (GFA), quantitative anisotropy (QA), normalized quantitative anisotropy (NQA) and the isotropic value of the orientation distribution function (ISO). GFA is defined as the standard deviation divided by the root mean square of the ODF, indicating a measurement of the anisotropy. QA is defined as the amount of anisotropic spins that diffuse along the fiber orientation. NQA is the normalized QA. ISO is the minimum distribution value of an ODF, and thus ISO represents the background isotropic diffusion [9].
The human brain is a complex nervous system with highly segregated and integrated functions. We can construct a complex neural network model through the connections among brain regions. Graph theory is the mathematical study of graphs that model objects ("nodes") and their connections ("edges"), where nodes represent brain regions and edges represent structural or functional connections between regions [10]. According to the related information, the brain network is divided into the white matter network and the gray matter network. The white matter network represents the connection of cerebral nerve fibers between brain regions, whereas the gray matter network represents the functional connectivity among brain regions.
Research on the white matter network of the brain by modern mathematical graph theory has proven that the structural network of the brain has the characteristics of a "small-worldness" topological structure, which means that it has high clustering of nodes and short path lengths between nodes [11]. The topology indices of graph theory include the mean clustering coefficient, gamma, local efficiency, characteristic path length, lambda, global efficiency and the small-worldness index. We used graph theoretical analysis and generalized q-sampling imaging to measure brain network connectivity.
We used four methods, namely, voxel-based statistical analysis, graph theoretical analysis, network-based statistical analysis and multiple regression analysis, to analyze the diffusion data. We considered covariates in all the analyses.
Voxel-based statistical analysis
Diffusion imaging was first corrected for eddy currents by FSL (FMRIB software library). The spin distribution function was reconstructed using a model-free reconstruction method with DSI studio (DSI studio was developed by Fang-Cheng (Frank) Yeh). Through this mathematical algorithm, we obtained the diffusion indices of generalized q-sampling imaging, including generalized fractional anisotropy (GFA), quantitative anisotropy (QA), normalized quantitative anisotropy (NQA) and the isotropic value of the orientation distribution function (ISO). Independent t-tests were performed with the Statistical Parametric Mapping (SPM) software to find the differences between the two groups. In addition, a significant difference in age between the two groups (p < 0.001) was found; thus, we considered age a covariate of no interest.
Multiple regression analysis
In statistical modeling, regression analysis is a set of statistical processes for estimating the relationships among variables. It includes many techniques for modeling and analyzing several variables when the focus is on the relationship between a dependent variable and one or more independent variables. Multiple regression analysis is an extension of the application of simple linear regression that seeks to understand the function of a dependent variable and two or more sets of independent variables. Multiple regression analysis through SPM was used to detect the correlations between the neuropsychological scales and the indices of GQI for all participants. We also used age as a covariate in the multiple regression analysis.
Graph theoretical analysis
Generalized q-sampling MRI can noninvasively detect the direction of water molecule diffusion in the white matter of the brain. We reconstructed the pathways of nerve fibers in the brain using fiber assignment by continuous tracking (FACT) with DSI studio. Network edges were established using FACT and the Automated Anatomical Labeling (AAL) templates, which divided the brain into 90 brain regions in Montreal Neurological Institute (MNI) space. The number of virtual fibers, or "edges", connecting each pair of regions of interest (ROIs) was determined, resulting in a 90 × 90 weighted connectivity matrix for each participant [10]. We defined network edges as follows (1):
$$ \mathrm{E}=\frac{Fiber\ count}{Fiber\ length}\times NQA $$
Finally, the graph theoretical algorithm was used to obtain the topological properties of the complex network measures. The area under the curve (AUC) for each connectivity metric of the topology indices was compared between the groups. The network density range was calculated from 0.05 to 0.26, in 0.01 increments. The minimum value was defined by the limit density of the individual network not to be fragmented, and the maximum value was defined by the density when the topology indices that remained unchanged [12]. Since the differences between groups in network measures below the network density which depend on the number of individual networks that fragment in each group, group comparisons below the density are not meaningful [13]. The density means the ratio of existing connections to all possible connections. To identify the statistically significance differences between groups in the network topology indices, graph theoretical analysis toolbox was used to execute the two-sample t-test and non-parametric permutation test with 1000 repetitions. We evaluated the network segregation with the mean clustering coefficient, gamma, and local efficiency, and the network integration with the characteristic path length, lambda, and global efficiency [14].
Network-based statistical analysis
Network-based statistic (NBS, Melbourne Neuropsychiatry Centre, The University of Melbourne and Melbourne Health, Australia) is the graph analogue of cluster-based statistical methods used in mass univariate testing on all pixels in an image. NBS analysis was used to identify the significance of any connected sub-networks obvious in the set of altered connections [15]. NBS analysis is used to identify any potentially connected structures formed by an appropriately chosen set of supra-threshold links. The topological extent of any such structure is used to examine its significance. The test statistic (i.e., primary threshold) computed for each pairwise combination is used to construct a set of supra-threshold links. The null distribution of the number of edges was empirically acquired using non-parametric permutation (5000 permutations) to evaluate the significance of each of the connected edges. Finally, we used the BrainNet viewer (The MathWorks Inc., Natick, MA, US) to visualize the significant sub-networks revealed by NBS.
A total of 39 participants were recruited for the study including 19 chemotherapy treated women and 20 healthy controls. All participants were aged between 20 and 55 years old. The average age of patients and healthy women were 43.8 ± 6.4 and 50.1 ± 2.5 years old. Due to wide range and significant difference between groups in age, we had added age as one of covariant factors in statistical analysis to reduce the impact of age. Two patients suffered from breast cancer stage I, 14 patients suffered from breast cancer stage II, and 3 patients suffered from breast cancer stage III, respectively. There were 4 patients received radiation therapy and 1 patient received hormonal treatment among 19 patients treated with chemotherapy. The number of menopausal women in the patients and controls were 5:5. The chemotherapy treated patients did not differ from the healthy controls with regard to education, MMSE, CAMS-R, HADS and IES-R. However, the breast cancer survivors showed significantly lower perceived cognitive impairments and impacts on quality of life, as revealed by paired t-tests (p < 0.05). The chemotherapy-treated patients revealed worse cognitive function. The participant demographic information and neuropsychological assessment results are presented in Table 1.
The results from the voxel-based statistical analysis showed significantly lower GFA and NQA values in the breast cancer group than those in the control group (p < 0.05 corrected by false discovery rate, FDR). The brain regions with differences included the right postcentral blade, left superior corona radiate, right superior temporal gyrus, right inferior frontal blade and left middle temporal gyrus. The results of the voxel-based statistical analysis are presented in Fig. 1.
The GFA values of the breast cancer survivors were lower than those of the healthy controls in a the right postcentral blade, and lower NQA values were found in the brain regions of the b left superior corona radiate, c right superior temporal gyrus, d right inferior frontal blade and e left middle temporal gyrus
These neuropsychological scales (i.e., MMSE, CAMS-R, HADS, IES-R and FACT-Cog) were selected for the correlation analysis with changes in the indices of GQI. The results of the multiple regression analysis are shown in Table 2 and Fig. 2. It is worth mentioning that significant positive correlations between the perceived cognitive impairments and the GQI indices (GFA and NQA) were found in the regions of the left anterior corona radiate and the right cingulate gyrus (p < 0.01 corrected by FDR). In addition, significant positive correlations between the impact on quality of life and the GQI indices (GFA and NQA) were found in the regions of the right middle frontal gyrus, left postcentral blade and splenium of the corpus callosum (p < 0.01 corrected by FDR).
Table 2 Correlation between neuropsychological assessment scales and GQI indices
The results of the brain regions included in the multiple regression analysis. The brain regions (a to x) in Figure 2 correspond to the second column of Table 2
In the graph theoretical analysis, we divided the individual topology network measurement into the BC and healthy control group. If the density was below 0.05, the individual network in both groups began to fragment which resulted in different numbers of nodes for individual network. Therefore, group comparisons below the density were not meaningful. The highest density was defined by the topology network measurement remained unchanged. The density we calculated is from 0.05 to 0.26. These results were confirmed by AUC analysis across network densities. The BC group demonstrated significantly longer characteristic path lengths across densities than those of the control group (p < 0.05 corrected by FDR, Fig. 3a). Longer characteristic path length represents worse global integration in the BC group. As shown in Fig. 3b, both groups of women demonstrated connectomes with the small-world properties (small-worldness index > 1) of complex networks when compared to random networks. Although both groups maintained the small-worldness brain network, the network was more like a regular network in the BC group.
The breast cancer (BC) group (blue points) showed significantly longer characteristic path lengths in (a) than those of the controls (orange points), and both groups of women showed connectomes with the small-world properties of complex networks in (b)
In NBS analysis, we compared the edges of the brain networks between the BC group and the healthy controls. The results of the network-based statistics showed that some brain structure network connections were decreased in the breast cancer group compared to those in the control group (p < 0.01 corrected by FDR), as shown in Fig. 4. The lower connected sub-network comprised edges between left inferior occipital and left fusiform, right post-central, right superior parietal, and left supra-marginal; between right cuneus and right post-central; between left fusiform and right superior parietal; between left supra-marginal and right putamen.
The brain structure network connections of the breast cancer group were decreased in the links between left inferior occipital and left fusiform, right post-central, right superior parietal, and left supra-marginal; between right cuneus and right post-central; between left fusiform and right superior parietal; between left supra-marginal and right putamen
Neuroimaging studies have shown that cognitive impairment results in subtle and diffuse brain damage [7, 16,17,18]. The cerebral white matter mediates communication among different brain regions, and the integrity of the cerebral white matter is important for the optimal performance of the brain. Injury to any part of the white matter connections can lead to changes in cognitive performance [19]. A study demonstrated that breast cancer survivors (3 to 5 months after chemotherapy) showed significantly worse performance in terms of attention, concentration, memory and psychomotor speed, as well as decreases in the FA of major white matter structures associated with cognitive function, such as the superior longitudinal fasciculus and the corpus callosum [20]. The control group showed higher scores on the FACT-Cog than those of the BC group, indicating that the cognitive function of breast cancer survivors decreased generally in our study. However, there were significant differences between the groups in perceived cognitive impairments and impact on quality of life. The effects of chemotherapy may lead to deficits in behavior and neuropsychological performance [21]. In our study, we did not find any significant differences between the groups in terms of the neuropsychological assessments, such as the MMSE, CAMS-R, HADS and IES-R.
The mechanisms mediating cognitive impairment after chemotherapy are unknown. There are several potential reasons for white matter vulnerability and cognitive function decline after chemotherapy, notably the direct white matter toxicity of chemotherapeutic drugs [7, 22]. There is evidence that the commonly used chemotherapeutic drug 5-fluorouracil (5-FU) crosses the blood brain barrier (BBB) by simple diffusion [23, 24]. Murine models have indicated that clinically relevant concentrations of 5-FU has been shown to cause injury to white matter tracts of the central nervous system; this finding was also reported in a case report on humans [25, 26]. Taxane-derived agents are chemotherapy drugs widely adopted in cancer treatment. Despite taxotere and epirubicin cross the BBB poorly [27], neurotoxicity is the major adverse effect of taxotere. They often manifested as painful neuropathy experienced during treatment, and it is sometimes irreversible [28]. There were 51 studies reported taxane-related gastrointestinal, hematological and neurological toxicities in adult patients with solid tumors [29]. In addition, epirubicin frequently induced toxicities including anemia, fever, myalgias, and neurotoxicity [30]. Therefore, we inferred that the effect of neurotoxicity was on the brain areas of the right post-central blade, left superior corona radiate, right superior temporal gyrus, right inferior frontal blade and left middle temporal gyrus. One study demonstrated decreased FA in the frontal and temporal white matter tracts of post-chemotherapy breast cancer patients compared to the tracts of healthy controls [31]. Another study showed decreased network connectivity in the frontal, striatal and temporal regions of cancer survivors 10 years after chemotherapy compared to that of healthy controls [32]. It has been demonstrated that medial temporal lobe toxicity has adverse effects on both recognition and working memory [33]. Our results were consistent with those of previous studies of the frontal and temporal regions.
A study examined the effect of adjuvant chemotherapy on white matter in women with breast cancer using DTI. It was found that positive correlation existed between the FA in the genu and processing speed [34]. Another study showed significant positive correlations between the domains of attention and processing/psychomotor speed and FA in the regions of the temporal and parietal white matter tracts. Moreover, the self-report cognitive failure questionnaire (CFQ) scores negatively correlated with the FA in the frontal and parietal regions [31]. We observed that the impact on quality of life was positively correlated with GFA and NQA in the splenium of the corpus callosum and the right middle frontal gyrus. Furthermore, the CAMS-R scores positively correlated with GFA in the right middle temporal gyrus and the left middle frontal gyrus. Our results were similar to those of previous studies.
The effect of menopause associated with cognitive function is uncertain [35]. Therefore, we did not consider menopause a covariate in this study. One study found no negative effects of therapy-induced menopause on cognitive function in breast cancer survivors [36]. Most studies divide breast cancer into 4 major molecular subtypes including Luminal A, Luminal B, Triple-negative, HER2 positive [37]. Whether breast cancer itself affects cognitive function is unknown. There is no literature to investigate this issue until now. Because the sample size is small and this is a preliminary research, we did not consider breast cancer subtypes in this study.
Cognitive deficits are common complications of breast cancer survivors treated with chemotherapy, and the incidence of cognitive deficits can reach 75% [38]. Chemotherapy-treated patients were found to be eight times more likely to have cognitive deficits than nonchemotherapy-treated patients [39, 40]. The most frequently observed disorders involve executive function and memory impairment. One study consisted of two groups of participants, including 34 breast cancer survivors who had completed chemotherapy more than 5.35 years before on average and 27 healthy women. The researchers explored changes in resting-state functional connectivity networks with graph theoretical analysis between breast cancer survivors treated with chemotherapy and healthy women. In addition, they evaluated the relationships among network measures, the length of time after chemotherapy, age, and breast cancer stage using linear regression analysis. The results showed that the clustering coefficient, characteristic path length and small-worldness index were lower in the breast cancer survivors than in the healthy controls. Compared with the control group, the breast cancer survivors had significantly lower nodal degree values in the left amygdala, left caudate, right inferior frontal gyrus, bilateral medial orbital frontal gyrus, and bilateral superior temporal gyrus. Linear regression analysis showed that the regional degree in the left hippocampus and right hippocampus were negatively correlated with the time since treatment. The impact of chemotherapy on the connectivity of these brain areas is permanent and may worsen over time [41].
Complex networks of the brain can be economical by minimizing the wiring cost, such as by possessing multiple nearby and fewer remote connections [42]. In our study, both groups of women demonstrated connectomes with the small-world properties of complex networks when compared to the properties of random networks. A small-worldness network has high local efficiency and global efficiency so that the brain network can effectively transfer information [43]. The human brain has been demonstrated to possess connectomes with the small-world properties that not only have the ability to segregate and integrate information [44] but also have low energy consumption and high efficiency in transmitting and processing information [42, 45].
This study used GQI and graph theoretical analysis to evaluate the brain structure and networks of chemotherapy-treated breast cancer survivors in comparison with controls. The results showed that the reduction in white matter connectivity in patients with breast cancer after treatment may lead to large-scale brain network reorganization, leading to increases in segregation and decreases in integration of the brain structural network. The changes in the small-world properties could reflect a compensatory mechanism, meaning the brain strives to maintain the integrity of the entire network at the expense of other networks, such as network integration [10]. Breast cancer survivors are usually able to perform a variety of cognitive tasks (intact segregation) but need more time, more effort or different strategies than before (damaged integration) [46, 47]. We found that the decreasing network integration in the breast cancer survivors was the result of the characteristic path length. The ability of the brain network is weak in transmitting messages. This finding was consistent with the concept that the white matter pathway plays a role in brain information transmission [48]. There were no significant differences between the groups in terms of network segregation in our study. Due to compensatory neuroplasticity, the cognitive function of breast cancer survivors may remain unchanged or may only slightly deteriorate [49].
The study was a preliminary study and more comprehensive investigations will be performed in the near future. There were some limitations in this study including small sample of participants, the cross-sectional design, and lack of a non-chemotherapy treated patient group. Therefore, we cannot distinguish the toxicity of chemotherapeutic drugs and the breast cancer itself on white matter structures. In addition, there was also variability in breast cancer stage, breast cancer subtypes, hormonal treatment, and menopause status that are likely to contribute to the effects of chemotherapy on cognitive function.
Our results provide further evidence that adjuvant chemotherapy is associated with demyelination of white matter. In addition, adjuvant chemotherapy affected the integrity of white matter and resulted in poor cognitive performance, as indicated by the correlation between the neuropsychological assessment scales and the GQI indices. We found that the characteristic path lengths of breast cancer survivors were longer than those of healthy controls, as assessed by graph theoretical analysis. This result indicated that the brain network integration of breast cancer survivors became worse. Our study demonstrated alterations in the structural brain networks of breast cancer survivors. Therefore, changes in GQI indices and network topological properties may serve as neuropathological biomarkers of treatment-induced neurotoxicity. This is the first study to investigate chemotherapeutic effects on brain structural changes in breast cancer survivors with a generalized q-sampling image. Further studies of this issue with larger samples and longitudinal designs are required to determine the long-term effects of altered brain network organization.
5-FU:
AAL:
Automated Anatomical Labeling
BBB:
Blood brain barrier
CAMS-R:
Cognitive and Affective Mindfulness Scale-Revised
CFQ:
Cognitive failure questionnaire
CMF:
Cyclophosphamide, methotrexate, and 5-flourouracil
DSI:
Diffusion spectrum imaging
DTI:
Diffusion tensor imaging
FA:
Fractional anisotropy
Fiber assignment by continuous tracking
FACT-Cog:
Functional Assessment of Cancer Therapy-Cognitive Function
GFA:
Generalized fractional anisotropy
GQI:
HADS:
Hospital Anxiety and Depression Scale
IES-R:
Impact of Event Scale-Revised
Isotropic value of the orientation distribution function
MD:
Mean diffusivity
MMSE:
Mini-Mental State Examination
MNI:
Montreal Neurological Institute
MRI:
NBS:
Network-based statistic
NQA:
Normalized quantitative anisotropy
ODF:
Orientation distribution function
QA:
Quantitative anisotropy
QBI:
Q-ball imaging
RD:
Radial diffusivity
Region of interest
SDF:
Spin distribution function
SPM:
Statistical Parametric Mapping
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Bourke RS, West CR, Chheda G, Tower DB. Kinetics of entry and distribution of 5-fluorouracil in cerebrospinal fluid and brain following intravenous injection in a primate. Cancer Res. 1973;33(7):1735–46.
Kerr IG, Zimm S, Collins JM, O'Neill D, Poplack DG. Effect of intravenous dose and schedule on cerebrospinal fluid pharmacokinetics of 5-fluorouracil in the monkey. Cancer Res. 1984;44(11):4929–32.
Han R, Yang YM, Dietrich J, Luebke A, Mayer-Proschel M, Noble M. Systemic 5-fluorouracil treatment causes a syndrome of delayed myelin destruction in the central nervous system. J Biol. 2008;7(4):12.
Moore-Maxwell CA, Datto MB, Hulette CM. Chemotherapy-induced toxic leukoencephalopathy causes a wide range of symptoms: a series of four autopsies. Mod Pathol. 2004;17(2):241–7.
Postma TJ, Heimans JJ. Neurological complications of chemotherapy to the peripheral nervous system. Handbook of Clinical Neurology. 2012;105:917-936.
Velasco R, Bruna J. Taxane-induced peripheral neurotoxicity. Toxics. 2015;3(2):152–69.
Frederiks CN, Lam SW, Guchelaar HJ, Boven E. Genetic polymorphisms and paclitaxel- or docetaxel-induced toxicities: a systematic review. Cancer Treat Rev. 2015;41(10):935–50.
Del Mastro L, Levaggi A, Michelotti A, Cavazzini G, Adami F, Scotto T, Piras M, Danese S, Garrone O, Durando A, et al. 5-fluorouracil, epirubicin and cyclophosphamide versus epirubicin and paclitaxel in node-positive early breast cancer: a phase-III randomized GONO-MIG5 trial. Breast Cancer Res Treat. 2016;155(1):117–26.
Deprez S, Amant F, Yigit R, Porke K, Verhoeven J, Van den Stock J, Smeets A, Christiaens MR, Leemans A, Van Hecke W, et al. Chemotherapy-induced structural changes in cerebral white matter and its correlation with impaired cognitive functioning in breast cancer patients. Hum Brain Mapp. 2011;32(3):480–93.
Hosseini SM, Koovakkattu D, Kesler SR. Altered small-world properties of gray matter networks in breast cancer. BMC Neurol. 2012;12:28.
Olson IR, Moore KS, Stark M, Chatterjee A. Visual working memory is impaired when the medial temporal lobe is damaged. J Cogn Neurosci. 2006;18(7):1087–97.
Abraham J, Haut MW, Moran MT, Filburn S, Lemiuex S, Kuwabara H. Adjuvant chemotherapy for breast cancer: effects on cerebral white matter seen in diffusion tensor imaging. Clin Breast Cancer. 2008;8(1):88–91.
Will MA, Randolph JF. The influence of reproductive hormones on brain function in the menopausal transition. Minerva Ginecol. 2009;61(6):469–81.
Hermelink K, Henschel V, Untch M, Bauerfeind I, Lux MP, Munzel K. Short-term effects of treatment-induced hormonal changes on cognitive function in breast cancer patients: results of a multicenter, prospective, longitudinal study. Cancer. 2008;113(9):2431–9.
Anderson WF, Rosenberg PS, Prat A, Perou CM, Sherman ME. How many etiological subtypes of breast cancer: two, three, four, or more? J Natl Cancer Inst. 2014;106(8). https://doi.org/10.1093/jnci/dju165.
Janelsins MC, Kohli S, Mohile SG, Usuki K, Ahles TA, Morrow GR. An update on cancer- and chemotherapy-related cognitive dysfunction: current status. Semin Oncol. 2011;38(3):431–8.
Schagen SB, Muller MJ, Boogerd W, Mellenbergh GJ, van Dam FS. Change in cognitive function after chemotherapy: a prospective longitudinal study in breast cancer patients. J Natl Cancer Inst. 2006;98(23):1742–5.
Stewart A, Collins B, Mackenzie J, Tomiak E, Verma S, Bielajew C. The cognitive effects of adjuvant chemotherapy in early stage breast cancer: a prospective study. Psycho-Oncology. 2008;17(2):122–30.
Bruno J, Hosseini SM, Kesler S. Altered resting state functional brain network topology in chemotherapy-treated breast cancer survivors. Neurobiol Dis. 2012;48(3):329–38.
Achard S, Bullmore E. Efficiency and cost of economical brain functional networks. PLoS Comput Biol. 2007;3(2):e17.
Latora V, Marchiori M. Efficient behavior of small-world networks. Phys Rev Lett. 2001;87(19):198701.
Sporns O, Zwi JD. The small world of the cerebral cortex. Neuroinformatics. 2004;2(2):145–62.
Kaiser M, Hilgetag CC. Nonoptimal component placement, but short processing paths, due to long-distance projections in neural systems. PLoS Comput Biol. 2006;2(7):e95.
Von AD, Habermann B, Carpenter JS, Schneider BL. Impact of perceived cognitive impairment in breast cancer survivors. Eur J Oncol Nurs. 2013;17(2):236–41.
Kesler SR, Bennett FC, Mahaffey ML, Spiegel D. Regional brain activation during verbal declarative memory in metastatic breast cancer. Clin Cancer Res. 2009;15(21):6665–73.
Filley CM. White matter: organization and functional relevance. Neuropsychol Rev. 2010;20(2):158–73.
Andryszak P, Wiłkość M, Izdebski P, Żurawski B. A systemic literature review of neuroimaging studies in women with breast cancer treated with adjuvant chemotherapy. Contemp Oncol. 2017;21(1):6–15.
This study was supported in part by the research programs MOST107–2221-E-182-054-MY3, MOST106–2221-E-182-079, MOST104–2314-B-040-001 and NSC103–2420-H-040-002, which were sponsored by the Ministry of Science and Technology, Taipei, Taiwan. This study was also supported by the grant (BMRPD1H0101, BMRPD1G1321) of Chang Gung University, Taoyuan, Taiwan, and the grant (CORPG6G0101, CORPG6G0121) of Chang Gung Memorial Hospital, Chiayi, Taiwan. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
The datasets generated and/or analyzed during the current study are not publicly available due owing to data privacy policy at our facility, but are available from the corresponding author on reasonable request.
Tsung-Yuan Li and Vincent Chin-Hung Chen contributed equally to this work.
Department of Radiology, Taichung Veterans General Hospital, Taichung, Taiwan
Tsung-Yuan Li, Cheng-Nan Chen, Jyh-Wen Chai & Clayton Chi-Chang Chen
School of Medicine, Chang Gung University, Taoyuan, Taiwan
Vincent Chin-Hung Chen
Department of Psychiatry, Chang Gung Memorial Hospital, Chiayi, Taiwan
Vincent Chin-Hung Chen & Jun-Cheng Weng
Breast Medical Center, Cheng Ching Hospital Chung Kang Branch, Taichung, Taiwan
Dah-Cherng Yeh
Department of Psychology, Chung Shan Medical University, Taichung, Taiwan
Shu-Ling Huang
College of Medicine, China Medical University, Taichung, Taiwan
Jyh-Wen Chai
Department of Medical Education, Taichung Veterans General Hospital, Taichung, Taiwan
Clayton Chi-Chang Chen
Department of Medical Imaging and Radiological Sciences, Chang Gung University, No. 259, Wenhua 1st Rd., Guishan Dist., Taoyuan City, 33302, Taiwan
Jun-Cheng Weng
Tsung-Yuan Li
Cheng-Nan Chen
TYL: data collection, data analysis, writing article; VCHC: project idea, study design, manuscript revision; DCY: study design, data collection; SLH: data collection, data analysis; CNC: data collection; JWC: data collection; CCCC: data collection; JCW: project idea, study design, software development, data analysis, writing article, manuscript revision. All authors read and approved the final manuscript.
Correspondence to Jun-Cheng Weng.
This study was approved by the Institutional Review Board at Taichung Veterans General Hospital. The review number was SF14185A. All participants provided written informed consent before the examination.
Li, TY., Chen, V.CH., Yeh, DC. et al. Investigation of chemotherapy-induced brain structural alterations in breast cancer patients with generalized q-sampling MRI and graph theoretical analysis. BMC Cancer 18, 1211 (2018). https://doi.org/10.1186/s12885-018-5113-z


Most notably, the two-hour, 18-song performance included the entirety of the group's 2006 album, The Crane Wife. In fact, the entire show seemed like a gift to New York City with a longer, more expansive setlist than anything (I think) has been delivered to other cities on the Decemberists' 2018 "Your Girl/Your Ghost" tour.
And while the BRIC Celebrate Brooklyn! Festival grounds were a little on the muddy side due to a monsoon-like thunderstorm earlier in the afternoon, the Decemberists opened up with two strong tracks from their latest album, I'll Be Your Girl, that are familiar to FUV listeners. The first, "Severed," was anchored by Chris Funk's vintage synth, while the second, "Sucker's Prayer," featured Kelly Hogan and Nora O'Connor on backing vocals (the pair elevated the songs of the core five-piece all evening).
Following crowd pleasers "Make You Better" and "The Rake's Song," Jenny Conlee gave her accordion the first, but not the last, workout of the concert on "Down By The Water." Then came full immersion in the fantasy and folklore of The Crane Wife. The narrative, which fuses a Japanese folk tale with Shakespeare's The Tempest, is as idiosyncratic as any in the band's catalog and was highlighted by the dramatic dynamics of the epic song cycle "The Island."
During the encore, Meloy mentioned the poignant Autumn de Wilde-directed video released last month for "Once In My Life," a song that samples Yo La Tengo's "Barnaby, Hardly Working." Meloy then gave FUV some love before excluding the radio audience on the profanity-laced, extremely FCC-unfriendly "Ben Franklin's Song," written with Lin-Manuel Miranda for the Hamildrops series. The exclamation mark on the night came in the form of the rousing "The Mariner's Revenge Song," complete with an inflatable whale that hovered over the crowd before crashing into the back of the stage.
You won't be able to see the whale, but you can listen on-demand to the whole show now, minus a cussy Mr. Franklin. The next "Summer of FUV" live broadcast happens this Friday, August 17, at 7 p.m. EDT with Ben Folds and Cake at Forest Hills Stadium, airing on 90.7FM WFUV and streaming via WFUV.org. Check out our full line-up of shows here.


Leigh Magar makes some of the most sensational hats in Charleston, South Carolina—a city where a hat really means something. She outfits cookbook authors Matt Lee and Ted Lee in fedoras for a wonderful outdoor dinner party.
Whether it's a baseball cap or a straw boater, a cloche or a four-foot-wide church bonnet, Southerners love the blast of self-expression—and the shade—of a great hat. Our friend Leigh Magar designs ravishing ones for Magar Hatworks in Charleston.
Leigh Magar and Johnny Tucker. Photo © Fredrika Stjärne.
We first met Leigh and her architect husband, Johnny Tucker, at a crab boil on the banks of a creek south of the city. The two of them appeared to have stepped out of a 1930s film. Her hat, a spray of feathers, was perched rakishly over an immaculate bob; he wore a three-piece suit and a leopard-print fedora. And then Leigh pulled from her handbag a red polka-dot apron, tied it on over her vintage dress, and proceeded to pick apart and devour the crabs on the table with a gusto unmatched by any of the good ol' boys in their camouflage caps.
At any party, Leigh and Johnny are always the first to hit the oyster-shucking table and the last dancing on the porch, even when the candelabra above has begun to drip wax on everyone's heads. When she shows her hat collections, she turns that into a party, too. People come to the garden of her studio to drink tea (and quite a lot of wine), eat pimento-cheese sandwiches and watch models circulate among the fig and mulberry trees wearing Magar Hatworks's latest trilbies, fedoras and cocktail hats. Recently, Leigh packed up her fall collections and sent them on their way to Barneys New York and the Tokyo retailer Isetan. There was a brief lull before she would embark on a series of exclusive designs for New York designer Gary Graham. As her occasional cohosts, it seemed to us as good a time as any for a party in her garden.
When guests arrived and began to gather on the porch, we passed around lacy squash blossoms stuffed with red-pepper ricotta—our riff on Leigh's pimento-cheese sandwiches and a tribute to Tuscany, where she and Johnny tied the knot. Leigh ladled out a fiery watermelon gazpacho with crab and avocado—a twist on Mary Randolph's "gaspacho," from the seminal Southern cookbook The Virginia Housewife, and our nod to Johnny's home state.


text:
Lope hace referencia a varios artículos:

Etimología
Lope es un nombre de pila español del que procede el apellido patronímico López. Proviene del latín lupus, lobo. Su variante portuguesa es Lopo. Se celebra su onomástica el 2 de diciembre.

Nombre
 Siglo XI
Lope Íñiguez

 Siglo XII
Lope Díaz I de Haro
Lope Díaz II de Haro
Lope Díaz III de Haro
Lope Fernando de Ayn

 Siglo XIV
Lope de Barrientos
Lope Fernández de Luna
Lope García de Salazar

 Siglo XV
Lope de Stúñiga
Lope Machado

 Siglo XVI
Lope de Aguirre
Lope de Deza
Lope de Moscoso Osorio
Lope de Rueda
Lope de Ulloa y Lemos
Lope de Vega
Lope Díez de Aux de Armendáriz
Lope García de Castro

 Siglo XIX
Lope Recio Loynaz
Sergio Lope

 Siglo XXI
Lope Serrano

Además
Lope (película), de 2010 dirigida por Andrucha Waddington.

Referencias

redpajama_set_name: RedPajamaWikipedia


text:
Arts Notes
Arts Choices
Eastside Culture Crawl
PuSh Festival
Visual Arts Reviews
Arts Spot
Roger Waters's Another Brick in the Wall: The Opera to open 2020 Vancouver Opera Festival
by Janet Smith on February 11th, 2019 at 2:37 PM
Vancouver Opera Festival will get an infusion of Pink Floyd next year.
In its season announcement for 2019-20, the VO announced it would kick off the fourth annual celebration in spring 2020 with Another Brick in the Wall: The Opera. Written by composer Julien Bilodeau and librettist Roger Waters, it's based on the concept album The Wall, and the plot is taken almost directly from the 1982 movie. Amped up with spectacular video projections, it premiered at Opéra de Montréal in March 2017 as part of the city's 375th-anniversary celebration.
General director Kim Gaynor offsets that contemporary work with two classics during the regular season.
A "sumptuous new version" of Giuseppe Verdi's La Traviata kicks off next season in October, and it's the result of five Canadian opera companies joining forces to produce the lavish, 1920s-Paris sets and costumes. The production is directed by Alain Gauthier and designed by Christina Poddubiuk, and features Canadian Emily Dorn as Violetta and tenor Andrew Haji as Alfredo.
February 2020 brings Gioachino Rossini's The Barber of Seville, with new Arts Club Theatre artistic director Ashlie Corcoran making her VO directing debut at the helm of the production; Corcoran was assistant director on the same opera at the VO seven years ago. (She's directed such other operas as Canadian Opera Company 's The Magic Flute.) The role of Rosina will be sung by French-Canadian mezzo-soprano Julie Boulianne, with tenor Isaiah Bell taking on Count Almaviva. Local favourite Ken MacDonald, now based in Toronto, designed the sets.
The 2020 Vancouver Opera Festival is scheduled to run April 23 to May 3, 2020, opening with Another Brick in the Wall at the Queen Elizabeth Theatre stage, alternating with Wolfgang Amadeus Mozart's Cosi fan Tutte at the Vancouver Playhouse.
Meanwhile, Vancouver Opera is creating a new opera for young audiences that will tour the province's school's next year. The Flight of the Hummingbird, based on the graphic novel of the same name by renowned Haida artist Michael Nicoll Yahugulanaas, addresses climate change and personal responsibility. The libretto and creative design are by Yahugulanaas and Barry Gilson, with original music composed by French-Canadian composer Maxime Goulet. Glynis Leyshon directs.
For the immediate future, La Boheme is set to open Thursday night [February 14] at the Queen Elizabeth Theatre).
Current subscribers can lock in their reserved seats for the upcoming season from now until April 26 at vancouveropera.ca, while new subscriptions will be available beginning May 14. Single tickets will be available beginning July 2.
Visionary duo André Barbe and Renaud Doucet take Vancouver Opera's La Bohème to 1920s Paris

redpajama_set_name: RedPajamaCommonCrawl


The East Lawn occupies the former kitchen and dairy.
There are two spacious bedrooms, one with a king size bed that can, on request, be split into two singles, and the other with a double bed that provides an outlook across the lawn and the valley to the Duchess Drive and Fastheugh Hill.
The sitting room includes an open log fire, perfect for relaxing on autumn and winter evenings.
There are french doors which lead onto a terraced area which can be used for outside dining or simply relaxing.


text:
Q: Differential Operator Invertible Good evening,
I have a little problem with the invertibility of an operator $A : W^{1,2}(S^1,\mathbb{R}^{2n})\longrightarrow L^2(S^1,\mathbb{R^{2n}})$ defined as $$(A\zeta)(t) = \dot{\zeta}(t)-\dot{\Psi}(t)\cdot\Psi^{-1}(t)\cdot\zeta(t),$$
where $\Psi(t)\in \mathbb{R}^{2n\times 2n}$ is a path of symplectic matrices with $\Psi(0)=Id$.
The claim then is that $A$ is invertible if and only if $1$ is not an eigenvalue of $\Psi(t)$ for any $t$.
In the paper, it sounds like this is obvious, so I started to show that $\ker A = \{0\}$: If $A\zeta = 0$ (i.e. $(A\zeta)(t) = 0$ a.e.), we have
$$\dot{\Psi}(t)\cdot\underbrace{\Psi^{-1}(t)\cdot\zeta(t)}_{=:\alpha(t)} =\dot{\zeta}(t)  .$$
So setting $\alpha (t) := \Psi^{-1}(t)\cdot\zeta(t)$, this simplifies to
\begin{align}
\dot{\Psi}(t)\cdot\alpha(t) &=\frac{d}{dt}(\Psi(t)\cdot\alpha(t)) \\ \Leftrightarrow \dot{\Psi}(t)\cdot\alpha(t) &=\dot{\Psi}(t)\cdot\alpha(t)+\Psi(t)\dot{\alpha}(t) \\ \Leftrightarrow \Psi(t)\cdot\dot{\alpha}(t) &= 0
\end{align}
Since $\Psi(t)$ is invertible (as a symplectic matrix), this means $\dot{\alpha}(t) = 0$, so $\alpha(t)$ is a constant vector and so by definition of $\alpha$ we get that
$$ \zeta(t)=\Psi(t)\cdot\alpha $$
is actually an element of the kernel. This seems be the place where the claim with $1$ (not) being an eigenvalue of $\Psi(t)$ should come into play, however I don't really see how. Of course, maybe my steps have an error somewhere, so I would really like to hear other people's opinions on it.

A: $\Rightarrow$: Let $v \in \mbox{ker}(\Phi(\tilde{t}) - id) \neq \lbrace 0 \rbrace$ for some $\tilde{t} \in [0,1]$ i.e.
\begin{equation}
\Phi(\tilde{t})v = v
\end{equation}
Define
\begin{equation}
v(t) = \Phi(t)v
\end{equation}
assume w.l.o.g. $\tilde{t} = 1$ then
$v(1) = \Phi(1)v = v = v(0)$ hence $v \in W^{1,2}(S^1, \mathbb{R}^{2n})$. Now
\begin{equation}
Av = 0
\end{equation}
means
\begin{equation}
\frac{d}{dt}v = -S v
\end{equation}
where $S = \dot{\Phi}(t)\Phi^{-1}(t)$ or equivalent
\begin{equation}
\frac{d}{dt}v = \left(\frac{d}{dt}\Phi\right) \Phi^{-1}v = -\Phi \frac{d}{dt}(\Phi^{-1})v
\end{equation}
which can be rephrased by saying $\frac{d}{dt}(\Phi^{-1}v) = 0$ or
\begin{equation}
v(t) = \Phi(t)v_0
\end{equation}
for $v \in \mathbb{R}^{2n}$. Since $v$ is a loop we obtain
$v(0) = v(1) = \Phi(1)v(0)$. This shows that $v \in \mbox{ker} A$ hence $\mbox{ker} A \neq \lbrace 0 \rbrace$ and $A$ is not invertible.
$\Leftarrow$: Let $v \in L^2(S^1, \mathbb{R}^{2n})$. We wish to find a unique $u \in W^{1,2}(S^1, \mathbb{R}^{2n})$ such that
\begin{equation}
Au = v.
\end{equation}
This implies
\begin{equation}
\dot{u} =(Su - v)
\end{equation}
We can construct a solution $u_x$ for any $x \in \mathbb{R}^{2n}$ satisfying $Au_x = v$ and $u_x(0) = x$ by defining
\begin{equation}
u_x(t) = \Phi(t)\left(x - \int^{t}_{0}{\Phi^{-1}(s)}v(s)ds \right)
\end{equation}
for any $x \in \mathbb{R}^{2n}$. Now the periodicity of $u_x$ is the case if
\begin{equation}
x = \Phi(1)\left( x- \int^{1}_{0}{\Phi(s)^{-1}v(s) ds} \right).
\end{equation}
Rewriting
\begin{equation}
(\Phi(1) - id)x = \Phi(1)\int^{1}_{0}{\Phi^{-1}(s)v(s)ds}.
\end{equation}
This can be solved by $\Phi(1) - id$ is invertible hence $A$ is invertible.

redpajama_set_name: RedPajamaStackExchange


text:
Comments, Questions & Concerns
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Updated On: Sep 16, 2013
Brian David Frantz, formerly of Allentown, PA, died September 4, 2013, after a five-year valiant battle with Metastatic Melanoma; his devoted wife Ronnie was with him. Brian was 52 years old. He was the youngest son of Shirley R. Frantz and the late Eugene P. Frantz, Sr. of Coplay, PA.
From an early age, Brian wanted to be a firefighter. At only 16 years old he volunteered with the Western Salisbury Volunteer Fire Department in Lehigh Vounty, PA. After high school graduation he joined the U.S. Air Force serving 4 years as a firefighter at Pope Air Force Base, NC and Chanute Air Force Base, IL. At Chanute AFB Brian was an Air Training Command Instructor at the USAF Fire Protection School. After service with the USAF, Brian joined the Arlington County Fire Department (ACFD) and worked there for 22 years. During that time he achieved the rank of Captain and earned his degree in Fire Administration. Among his various assignments with the ACFD, he was most proud of his time as a Fire Instructor at the ACFD Fire Training Academy, training 4 recruit classes.
Brian was a first responder on September 11, 2001, and received the Arlington County Chamber of Commerce Valor award for performance at the Pentagon on 9-11. His fire rescue is depicted in the book FIREFIGHT, INSIDE THE BATTLE TO SAVE THE PENTAGON ON 9/11 by Patrick Creed and Rick Newman.
Brian was also a brilliant photo-artist, capturing on 35mm film the beauty in the everyday. Some of his recent photos were selected by juried competition for the Penn Medicine "Celebration of Art and Life 2013" and are currently on exhibition at Penn Medicine through January 2014.
In 2005 he met his soul mate Veronica "Ronnie" Gunderson and a year later they were married on a beach at sunset.
In 2008 Brian was diagnosed with Stage III Metastatic Melanoma which progressed to Stage IV two years later. In 2010, through the resolute efforts of the University of Pennsylvania's Dr. Lynn Schuchter, he was enrolled in a Phase III Randomized Clinical Trial of the BRAF-Inhibitor VEMURAFINIB (FDA approved August 2011; marketed as ZELBORAF). In the clinical trial Brian was one of only 86 people enrolled in North Americal; one out of 337 enrolled in the entire world. On VEMURAFINIB he benefited for over 2 1/2 years, far exceeding typical overall survival time.
In lieu of flowers and to honor Brian's battle against cancer, donations can be made in his name to the Melanoma Program at the Abramson Cancer Center. Donations should be made payable to the Trustees of the University of Pennsylvania and sent to Abramson Cancer Development, 3535 Market St Suite 750, Philadelphia PA 19104. Support is needed to continue clinical research and education.
See more at: http://www.legacy.com/obituaries/mcall/obituary.aspx?n=brian-frantz&pid=166909938&fhid=3060#fbLoggedOut
Arlington Fire Fighters


text:
Review: The Lumineers shine on "BRIGHTSIDE"
By RAGAN CLARK - Associated Press
This cover image released by Dualtone shows "Brightside" by The Lumineers.
Uncredited - handout one time use, Dualtone
"BRIGHTSIDE," The Lumineers (Dualtone Records)
It will be hard for The Lumineers to top their immersive 2019 masterpiece "III" — a three-part concept album and accompanying short film exploring the cycle of addiction through generations. So, they didn't try to.
Instead, the Denver band, consisting of founding members and songwriters Wesley Shultz and Jeremiah Fraites, went in a different direction entirely on their fourth LP, "BRIGHTSIDE."
If their last album was lightning in a bottle, this album is a drop of concentrate — it is shorter (nine tracks), with quiet moments that are quieter, loud moments that are louder and a sense of urgency that propels each track into the next.
It's a typical Lumineers album in many ways. Shultz and Fraites are masters of storytelling and "BRIGHTSIDE" is no exception. The catchy "WHERE WE ARE" is vivid in its imagery: "Crashed the car in Arizona on the interstate/ People pullin' over cryin' thinkin' we were dead."
What separates "BRIGHTSIDE" from albums past is a raw quality, like sitting in on a jam session. Strings are sparse, instead relying on piano, percussion and guitar to carry the record. Songs like the stripped down "A.M. RADIO" with its acoustic guitar lead in have a simplicity that allow the craftsmanship to shine.
The Lumineers may not have toured for "III" in 2020 as planned, but they chose to look on the bright side of a difficult situation, giving fans some playful tracks bristling with hopefulness as society peers forward to a life beyond the pandemic.
Music Review-the Lumineers
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Jon Stewart to receive 2022 Mark Twain Prize for American Humor
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Fun and Entertainment
Jimmy Buffett looks at 50 years after his 1st Key West gig
KEY WEST, Fla. (AP) — A profane phone call and Jimmy Buffett's inability to keep his daily planner organized 50 years ago in Miami set in motion events that changed the music world. Those events made the singer-songwriter one of the most beloved entertainers in America. And one of the wealthiest, with a net worth around $600 million.
Works entering the public domain offer the chance for a new chapter for classic works
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Hundreds of doctors petition Spotify to address Joe Rogan's 'history of broadcasting misinformation'
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Drew Minard brings Iowa cred to Broadway's big 'Music Man' revival
As the only Iowan in the cast of the Broadway revival of "The Music Man," Drew Minard has been asked more than once if "Iowa Stubborn" holds true.
Betty White's assistant shares one of her final photos
"She was radiant and beautiful and as happy as ever," the post read. See how Betty White was celebrated on what would have been her 100th birthday.
About Town: Bucktown Revue returns, explore the world of beer with a five-course dinner pairing, and more
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Betty White would be 100 today. Here's how to watch her tribute movie
A film meant to celebrate White's birthday still will screen in 900 theaters across the country. Find out how to see it. Plus, watch a Betty White blooper reel here.
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Quad-Cities honors Betty White with favorite treats
Finns Grill is offering the Betty White Meal, including a hot dog, fries, potato chips and Red Vines, throughout January.
DUBAI, United Arab Emirates (AP) — Auction house Sotheby's Dubai has unveiled a diamond that's literally from out of this world.
Colombian author García Márquez had secret Mexican daughter
BOGOTA, Colombia (AP) — For decades renowned Colombian author Gabriel García Márquez kept the public from knowing about an intimate aspect of his life: He had a daughter with a Mexican writer, with whom he had an extramarital affair in the early 1990s.


Today, if we take a look around us; we can find various travel agencies. The number of online travel firms is also increasing day by day. Be it an online or offline travel company; each of them have to manage several business functions. We can find various travel apps, social media websites and other travel technology solutions. However, installing separate software for every function leads to increase in costs. As a result; Travel ERP system came into existence.
These ERP systems serve as a unique solution for all issues. It has various competitive advantages. So, now whether you want to generate supplier invoice, bill an agency commission or calculate vendor's commission; ERP does this all. Oneview ERP is an appropriate system that helps travel agencies across the globe to manage their tasks smoothly. It is used to market an improved travel management and expense solution.
Above cost, there are many more advantages of having an ERP system in your travel agency. It saves time thus making every process automatic. OneView ERP is one of the most advanced ERP systems rendering highly efficient and scalable application suite.
Change is the law of life but willingness to change is all that matters. Join the travel revolution, having an ERP in your organization will help you to manage tours and travel trips easily. Go ahead with travel technology. There's no reason why any travel firm must not have an ERP. The one that wants to boost its productivity and profitability will definitely have the same. Are you one among those? Contact us today to clear your doubts.


Yesterday's hearing (Monday, October 31, 2005) at the Massachusetts State House was clearly an attempt to delay adoption of OpenDocument Format (ODF) --- delivering a swipe at Peter Quinn, CIO and Director of the state's Information and Technology Division.
On Oct 19 I began the first trip in many years that wasn't primarily for the sake of my work. Tania asked me to go to Bogota to be with her in her thesis presentation. I was happy that my presence was important to her, so of course I said yes. After various schedule changes, we settled finally on Oct 19 to 28. That would give me a fair amount of time after her presentation, when she would be more relaxed.
EFF urges a fresh inquiry into the ramifications of DRM.
Please send your nominations by 30 November 2005.


Mum of Five Staying Sane: Our review of the fab Mattel Amigami craft and creativity kits. Including the Panda, Dog and Bird kits. Release you creativity to make your own designs. Fab and fun arts and crafts with endless design opportunities.
Our review of the fab Mattel Amigami craft and creativity kits. Including the Panda, Dog and Bird kits. Release you creativity to make your own designs. Fab and fun arts and crafts with endless design opportunities.
We were recently sent a lovely selection of Amigami toys to review with a little help from our friends! We had lovely invites to send out asking our friends to come and help us try out the Amigami kits and put them to the test!
Amigami are fab little kits. The animals are solid plastic bodies and each one comes with it's own selection of crafty add ons including colourful shapes, wings and eyes to twist, stick, clip on and style.
We were sent the Dog, Panda and Bird kits which came with full instructions for each animal, a full set of colourful shapes, paper stripes to curl and stickers. Each child can then style their animal in their own unique way meaning that no animal will ever look the same once your child has released their creativity.
There are other animals in the Amigami range too which are available from many toy stores.
We had a lovely creative session out in the garden. I set out a blanket with all of the kits on and instructions and just let the children help themselves. It was fab as there is no need for glue or scissors etc.... so you can really just let them get on with what they are doing and there is no mess or cutting involved in order to create.
Curling the colourful strips to make springy shapes to attach to the animals was so quick and easy. Each animal came with a curling bar where you attach one end of your strip of card to the small point on the bar and just twist around. You can the use it to make crazy hair on your animal or a curly tail.
Curling the colourful card strips around the handy and easy to use curling bar. All coloured card is pre cut and easy to separate and use.
All of the colourful shapes came on one sheet of card and were easy to just push out of the card and were instantly ready to use. They had holes already punched into them and they attached to the main animal body using small plastic shaped clips. These was so easy to do and also meant that if they changed their mind on something it was easy to remove and change. We were also sent the star puncher tool which allows you to make star shapes in the colourful card, adding even more detail to your designs.
There is endless possibilities with these kits and quite a few different animals to choose from. We love cracft in this house but sometimes it nice not to have to get the scissors, glue and paint out in order to have fun. These were an instant hit and I could really just sit back and watch them create without having to help out with cutting out shapes or punching holes in things. It meant they could really get creative without having to keep asking for help and at the end they had something they had made and put their own unique design into as well.
I would highly recommend these for crafty days, party favours, presents for friends etc.... They are excellent, fun, colourful and creative.
The children had a fab time. We had lots of unique creations made and they didn't all look the same which was good. You don't have to follow a strict set of instructions in order to make it and then it ends up looking exactly the same as your friends one that she made! Lots of positive comments from the children including the fact that they can go home and restyle over and over again which is great.
There are endless possibilities to make and create. This bird was made by my almost 3 year old. The recommended age is from 6+ years but with my supervision I just wanted to show what he could do and how easy it is. He could have added a lot more.
Four more of the many other designs available from Amigami. Each comes with over 70 reusable stickers. 30 different colourful paper parts and 6 shaped plastic pins to attach the paper parts for endless creative fun.


Boylesque star Joshua Dean. Photo by Mark Shelby Perry.
It was so popular last year that they're comin' back for 2016…the producers of New York City's Boylesque Festival (now 5 years old), Jen Gapay of Thirsty Girl Productions and Daniel Nardicio, are giving Seattle what they crave: The 2nd Annual Seattle Boylesque Festival, returning to Re-bar and The Triple Door on April 28th & 29th!
The festival kicks off on Thursday April 28th with it's Teaser Party, hosted by Seattle's own Ernie Von Schmaltz at the legendary Re-Bar! The party features over a dozen local and national performers and is sure to get your motor started for the weekend! Performers include The Brotherhood of Boylesque (Colorado) Al Lykya (Seattle), Beau Creep (Canada), Jesus La Pinga (Seattle), Major Suttle Tease (UK), Willy LaQueue (Chicago), Marquis Facade (Seattle), Jimmie Swagger (Chicago) EmpeRoar Fabulous (Seattle), Fosse Jack & Apollo Vidra (Seattle), and TheGla Monster (Chicago) and Will Longfellow, (Portland)!
Join us Friday April 29th for the festivals Main Event at The Triple Door, hosted by BenDeLaCreme! This stellar line up features international, national and local superstars including: Waxie Moon (Seattle), Tito Bonito (LA), 2 to Fly (NYC) Mod Carousel (Seattle), Izohnny (Portland),Jacques Patriaque (Vienna) Paris Original (Seattle), The Luminous Pariah (Seattle), Trojan Original (Seattle), Isaiah Esquire (Portland) Johnny Nuriel (Portland) Jonny Porkpie (NYC), Eddie Van Glam (Seattle), Ambrose Martos (NYC), Joshua Dean (NYC), Ben Franklin (NYC), Ernie Von Schmaltz (Seattle) and Matt Knife (NYC)!
The Teaser Party is hosted by Ernie Von Schmaltz at Re-bar, (1104 Howell Street in the Heart of Seattle's Meat District). Doors are at 7pm/Show at 8pm. $15 in advance and $20 at the door. 21+ w/ID.
The Main Event will be hosted by BenDeLaCreme at The Triple Door, 216 Union Street, with doors at 5:30 pm and 10 pm/shows at 7 pm and 10:30 pm respectively. Tickets $25 GA, $30 at the door and $40 VIP adv, $45 at the door.


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Bangladesh Wicketkeeper Congratulates Kohli for Reaching To 10,000 ODI Runs
by admin/ November 6, 2018/ news, Bangladesh, India Cricket Team, Virat Kohli/ No Comments/
Mushfiqur Rahim, the wicketkeeper-batsman from Bangladesh recently congratulated Indian skipper Virat Kohli for entering the elite club of batsmen by scoring 10,000 ODI runs.
Cricket News: Kohli reached from 9,000 runs to 10,000 runs in a span of 11 innings
Kohli had scored 140 runs in the first ODI against the Windies, and he was expected to score 81 runs, which was required to reach the milestone of 10K in the second ODI at Visakhapatnam.
India won the toss and elected to bat first and the skipper had to come out in the middle early once again as both the openers Shikhar Dhawan and Rohit Sharma did not last long.
Kohli then started to repair the innings with No. 4 batsman Ambati Rayudu. Although he started his innings cautiously, he soon started taking big hits after reaching his half-century.
He proved virtually unstoppable as he picked up yet another century, his 37th ODI ton, and eventually remained unbeaten on 157, which is his third highest score in ODIs.
But the historic moment came in the 37th over when he took a single off Ashley Nurse's delivery as he marched into the 10K club and did so with insane numbers. He beat the previous record holder Sachin Tendulkar by a big margin of 54 innings.
Moreover it took Virat exact 11 innings to reach the 10K mark from 9K mark and thus he became the fastest man to reach the coveted milestone, all that in just 205 innings.
Countless wishes started to pour in from all around the world and veteran Bangladesh cricketer Mushfiqur Rahim also took to Twitter to congratulate Kohli. He wrote, "Congratulations to one and only sir virat kohli for reaching 10k runs in the blink of an eye."
Tendulkar Had Predicted Long Before about Prithvi Shaw's International Future
BCCI Reveals 14-Man Squad for First Two ODIs against the Windies
Awards List of IPL 2018
CSK Coach Fleming Praises His Captain


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Creating a sense of belonging
The power of diversity, equity, and inclusion
Home Our Insights The power of diversity, e…
We strive to create a culture where each person feels accepted and valued. We believe that each person's ultimate potential begins with first acknowledging their inherent dignity. When we can recognize — and celebrate — our many human differences, we're able to create a workplace where all staff feel a sense of belonging and an opportunity to succeed. This allows us to attract and retain the best talent, serve clients through diverse thinking, and better represent and support the various communities in which we live and work.
What does diversity, equity, and inclusion mean at Plante Moran?
Diversity: We value the unique identities and experiences of our staff.
Equity: Everyone has an equitable and fair opportunity to succeed.
Inclusion: Each staff member can proudly say, "I know I belong here."
2022 Diversity, Equity, and Inclusion Annual Report.
Our DEI team
DEI Council: Creating an environment where all staff members can grow and succeed
Formed in 2003, Plante Moran's DEI Council was established to guide the firm toward long-term success and growth in diversity practices. We recognize that when you increase your retention of diverse staff, you build a pipeline of diverse future leaders of the firm. The Council integrates our staff resource groups, Women in Leadership, and our WorkFlex Committee under one umbrella to ensure we're effectively leveraging staff and sharing best practices, tools, and resources across the firm.
"We've made tremendous strides in this space, and I'm proud of that. I'm equally excited to build on that momentum to move forward," said DEI Council Chair Lou Longo. "This is not a destination. It's a journey we're all on together with opportunities for continuous learning. I see this position as an honor and a responsibility, and I hope to do right by the firm."
What's the key to integrating DEI efforts among the firm and our workforce? SRGs
Our staff resource groups (SRGs) are designed to help group members feel a sense of inclusion and belonging. We do this through a variety of efforts that help them expand their networks, nurture their professional development, and provide career support. This grassroots effort is staff-driven, so groups are requested and led by staff versus firm leaderships.
"Though autonomous, all of our SRGs have a similar vision: to help our diverse staff feel seen, heard, and supported," said DEI Leader Hawzien Gebremedhin. "We currently have four SRGs: Pride, African American, Veterans, and Satellite, and have plans to add three more in 2022. We understand that our SRGs are crucial to help our diverse staff members feel a deeper sense of community while building a more inclusive workspace for all."
Women in Leadership: Bringing increased equity to career advancement
Our Women in Leadership (WIL) initiative is aimed at increasing the visibility of women leaders internally and externally, providing targeted developmental career opportunities to retain and advance women leaders, and supporting partners in giving high-potential female staff growth and development opportunities.
And is this initiative making a difference? Absolutely. Women now make up 27.9% of all partners, compared to 17% when WIL was first formed. And our female mentoring program has seen a 300% increase in participation.
WorkFlex Committee: Because the whole person comes to work
An essential component of the WorkFlex Committee is the idea that we all need to be flexible. What works one week for work-life balance might look different the following week or the following year. The key is to be adaptable and open to changing circumstances.
That's where WorkFlex comes in. Developed to support staff in their ongoing quest for work-life balance, the program has been the catalyst for a number of initiatives, from our business casual dress policy, to a host of alternative working arrangements, to a "buddy" program to support new parents — all in the name of helping staff find their balance.
Looking for a place where you belong?
Diversity, equity, and inclusion insights:
Satellite staff: Working remotely, but connected and happier than ever
Article October 15, 2021 5 min read
There's value in diversity
September 6, 2021 2 min read
Track internship helps student discover, learn, and lead
Article September 3, 2021 2 min read
Women in Leadership: Why intentionality spurs progress
Alejandro Rodriguez shows how a strong culture can bridge any distance
Article August 26, 2021 4 min read
Beyond fast food: Students with autism find careers through the Exceptional Academy
Article May 27, 2021 4 min read
Hawzien Gebremedhin
Hawzien.Gebremedhin@plantemoran.com 303-846-3464
Lou Longo
lou.longo@plantemoran.com 312-602-3676
Beth Bialy
Group Managing Partner
beth.bialy@plantemoran.com 248-223-3377