Citations

We present a novel case of acute ischemic stroke in the postoperative setting of open septal myectomy. A 24-year-old woman developed acute left hemiparesis and rightward eye deviation the morning after surgery. She underwent emergent endovascular stoke therapy by mechanical embolectomy with successful retrieval of a fragment of myocardium that was obstructing the right middle cerebral artery. To our knowledge there has been no previous case described of a myocardial fragment causing a proximal intracranial artery occlusion with resulting ischemia and infarction.

PurposeTo investigate the feasibility of utilizing brain stiffness as a potential biomarker for behavioral variant frontotemporal dementia (bvFTD) patients. Magnetic resonance elastography (MRE) is a noninvasive technique for evaluating the mechanical properties of brain tissue in vivo. MRE has demonstrated decreased brain stiffness in patients with Alzheimer's disease.Materials and MethodsWe examined five male subjects with bvFTD and nine cognitively normal age‐matched male controls (NC) with brain 3T MRE. Stiffness was calculated in nine regions of interest (ROIs): whole brain (entire cerebrum excluding cerebellum), frontal lobes, occipital lobes, parietal lobes, temporal lobes, deep gray matter / white matter (GM/WM; insula, deep gray nuclei and white matter tracts), cerebellum, sensorimotor cortex (pre‐ and postcentral gyri), and a composite region labeled FT (frontal and temporal lobes excluding the pre‐ and postcentral gyri).ResultsSignificantly lower stiffness values were observed in the whole brain (P = 0.007), frontal lobe (P = 0.001), and temporal lobes (P = 0.005) of bvFTD patients compared to NC. No significant stiffness differences were observed in any other ROIs of bvFTD patients compared to NC (P > 0.05). These results demonstrate that statistically significant brain softening occurs in the frontal and temporal lobes of bvFTD patients, which corresponds to the expected pathophysiology of bvFTD.ConclusionFuture studies evaluating the feasibility of brain MRE for early disease detection and monitoring disease progression could shed new insights into understanding the mechanisms involved in bvFTD. J. Magn. Reson. Imaging 2016;43:474–478.

Abstract Many somatic mutations have been detected in pancreatic ductal adenocarcinoma (PDAC), leading to the identification of some key drivers of disease progression, but the involvement of large genomic rearrangements has often been overlooked. In this study, we performed mate pair sequencing (MPseq) on genomic DNA from 24 PDAC tumors, including 15 laser-captured microdissected PDAC and 9 patient-derived xenografts, to identify genome-wide rearrangements. Large genomic rearrangements with intragenic breakpoints altering key regulatory genes involved in PDAC progression were detected in all tumors. SMAD4, ZNF521, and FHIT were among the most frequently hit genes. Conversely, commonly reported genes with copy number gains, including MYC and GATA6, were frequently observed in the absence of direct intragenic breakpoints, suggesting a requirement for sustaining oncogenic function during PDAC progression. Integration of data from MPseq, exome sequencing, and transcriptome analysis of primary PDAC cases identified limited overlap in genes affected by both rearrangements and point mutations. However, significant overlap was observed in major PDAC-associated signaling pathways, with all PDAC exhibiting reduced SMAD4 expression, reduced SMAD-dependent TGFβ signaling, and increased WNT and Hedgehog signaling. The frequent loss of SMAD4 and FHIT due to genomic rearrangements strongly implicates these genes as key drivers of PDAC, thus highlighting the strengths of an integrated genomic and transcriptomic approach for identifying mechanisms underlying disease initiation and progression. Cancer Res; 76(3); 749–61. ©2015 AACR.

Abstract Purpose: The expression of programmed cell death ligand 1 (PD-L1) provides limited predictive value in identifying patients most likely to respond to immunotherapy. As the heterogeneity of PD-L1 expression may lead to sampling error and the misclassification of PD-L1 status, we assessed the distribution of PD-L1 expression in paired, resected multifocal lung cancers. Experimental Design: PD-L1 was assessed by IHC. Paired lesions were defined as independent primaries or related lesions using mate pair next-generation sequencing. Agreement statistics were used for analysis. Results: Sixty-seven multifocal lung cancers from 32 patients were sequenced and stained for PD-L1. There was agreement of PD-L1 expression by the tumor cells in paired lesions of 20 patients and disagreement of PD-L1 expression by the tumor cells in paired lesions of 12 patients (κ = 0.01). Sequencing identified that 23 patients had independent primary lung cancers and that 9 patients had related cancers. In paired lesions of patients with independent cancers, there was agreement of PD-L1 expression by the tumor cells in 12 patients and disagreement in 11 patients (κ = 0.31). In paired lesions of patients with related lung cancers, there was agreement of PD-L1 expression by the tumor cells in 8 patients and disagreement in 1 patient (κ = 0.73). Conclusions: The expression of PD-L1 is heterogeneous among paired independent lung cancers, but there are high levels of agreement in intrapulmonary metastasis. Clin Cancer Res; 22(9); 2177–82. ©2015 AACR.

OBJECT Endoscopic approaches to the anterior craniocervical junction are increasing in frequency. Choice of oral versus endoscopic endonasal approach to the odontoid often depends on the relationship of the C1–2 complex to the hard palate. However, it is not known how this relevant anatomy changes with age. We hypothesize that there is a dynamic relationship of C-2 and the hard palate, which changes with age, and potentially affects the choice of surgical approach. The aim of this study was to characterize the relationship of C-2 relative to the hard palate with respect to age and sex. METHODS Emergency department billing and trauma records from 2008 to 2014 were reviewed for patients of all ages who underwent cervical or maxillofacial CT as part of a trauma evaluation for closed head injury. Patients who had a CT scan that allowed adequate visualization of the hard palate, opisthion, and upper cervical spine (C-1 and C-2) were included. Patients who had cervical or displaced facial/skull base fractures, a history of rheumatoid arthritis, or craniofacial anomalies were excluded. The distance from McGregor's palatooccipital line to the midpoint of the inferior endplate of C-2 (McL–C2) was measured on midsagittal CT scans. Patients were grouped by decile of age and by sex. A 1-way ANOVA was performed with each respective grouping. RESULTS Ultimately, 483 patients (29% female) were included. The mean age was 46 ± 24 years. The majority of patients studied were in the 2nd through 8th decades of life (85%). Significant variation was found between McL–C2 and decile of age (p < 0.001) and sex (p < 0.001). The mean McL–C2 was 27 mm in the 1st decade of life compared with the population mean of 37 mm. The mean McL–C2 was also noted to be smaller in females (mean difference 4.8 mm, p < 0.0001). Both decile of age (p = 0.0009) and sex (p < 0.0001) were independently correlated with McL–C2 on multivariate analysis. CONCLUSIONS The relationship of C-2 and the hard palate significantly varies with respect to age and sex, descending relative to the hard palate a full centimeter on average in adulthood. These findings may have relevance in determining optimal surgical approaches for addressing pathology involving the anterior craniocervical junction.

Recent applications of the clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 system have greatly improved the efficiency of genome editing in pigs. However, in some cases, genetically modified pig models need an additional modification to improve their application. The objective of this experiment was to determine whether a combination of somatic cell NT (SCNT) by using a previously modified donor cell line and subsequent zygote injection with CRISPR/Cas9 guide RNA to target a second gene would result in embryos and offspring successfully containing both modifications. Fibroblast cell lines were collected from fumarylacetoacetate hydrolase deficient (FAH–/–) fetuses and used as the donor cell line. Somatic cell NT was performed by standard technique. A CRISPR guide RNA specific for recombination activating gene 2 (RAG2) was designed and in vitro transcribed from a synthesised gBlock (IDT) containing a T7 promoter sequence, the CRISPR Guide RNA (20 bp), and 85 bp of tracer RNA. The gBlock was PCR amplified with Q5 polymerase (NEB, Ipswich, MA, USA) and in vitro transcribed with the MEGAshortscript™ T7 Transcription Kit (Life Technologies, Grand Island, NY, USA). Guide RNA (20 ng µL–1) and polyadenylated Cas9 (20 ng µL–1, Sigma, St. Louis, MO, USA) were co-injected into the cytoplasm of SCNT zygotes at 14 to 16 h after fusion and activation. Injected SCNT were then cultured in vitro in PZM3 + 1.69 mM arginine medium (MU1) to Day 5. Three embryo transfers were performed surgically into recipient gilts on Day 4 or 5 of oestrus (50, 62, or 70 embryos per pig) to evaluate in vivo development. The remaining embryos were cultured in MU1 to Day 7 and analysed for the presence of modifications to the RAG2 gene. Embryos were classified as modified if they contained an INDEL as measured by both gel electrophoresis and DNA sequencing of PCR amplicons spanning the targeted exon. The RAG2 modification rate was 83.3% (n = 6), of which 50% (n = 3) of the embryos contained biallelic modifications. All control embryos contained a wild-type RAG2 gene (n = 5). Embryo transfer resulted in a 33.3% pregnancy rate (1/3). The combination of SCNT and CRISPR/Cas9 zygote injection can be a highly efficient tool to successfully create pig embryos with an additional modification. This additional technique further improves the usefulness of already created genetically modified pig models. This study was funded by the National Institutes of Health via U42 OD011140.

Nonhemorrhagic neurological deficits are underrecognized symptoms of intracranial dural arteriovenous fistulas (dAVFs) having cortical venous drainage. These symptoms are the consequence of cortical venous hypertension and portend a clinical course with increased risk of neurological morbidity and mortality. One rarely documented and easily misinterpreted type of nonhemorrhagic neurological deficit is progressive dementia, which can result from venous hypertension in the cortex or in bilateral thalami. The latter, which is due to dAVF drainage into the deep venous system, is the less common of these 2 dementia syndromes. Herein, the authors report 4 cases of dAVF with venous drainage into the vein of Galen causing bithalamic edema and rapidly progressive dementia. Two patients were treated successfully with endovascular embolization, and the other 2 patients were treated successfully with endovascular embolization followed by surgery. The radiographic abnormalities and presenting symptoms rapidly resolved after dAVF obliteration in all 4 cases. Detailed descriptions of these 4 cases are presented along with a critical review of 15 previously reported cases. In our analysis of these 19 published cases, the following were emphasized: 1) the clinical and radiographic differences between dAVF-induced thalamic versus cortical dementia syndromes; 2) the differential diagnosis and necessary radiographic workup for patients presenting with a rapidly progressive thalamic dementia syndrome; 3) the frequency at which delays in diagnosis occurred and potentially dangerous and avoidable diagnostic procedures were used; and 4) the rapidity and completeness of symptom resolution following dAVF treatment.

BackgroundTrastuzumab has substantially improved overall survival and reduced the risk of disease recurrence in patients with human epidermal growth factor receptor type II (HER‐II)–positive breast cancer. However, this benefit may be at the increased risk of cardiotoxicity. We aimed to explore the early subclinical left and right ventricular as well as atrial dysfunction, in trastuzumab‐treated patients with HER‐II–positive breast cancer, using velocity vector imaging.MethodsEchocardiography images were acquired in 50 patients with HER‐II–positive breast cancer undergoing trastuzumab therapy. All patients had baseline and 3–6 months and 12–15 months of follow‐up echocardiograms after initiation of trastuzumab therapy. Subendocardial borders of all the cardiac chambers were traced from the apical views to obtain volumetric and deformation indices.ResultsMean age was 60 ± 13 years. Left ventricular (LV) ejection fraction as well as conventional indices of right ventricular (RV) function did not change with trastuzumab. The RV peak systolic global longitudinal strain (GLε) significantly decreased (−24.53 ± 6.03 vs. −21.28 ± 5.11 vs. −21.84 ± 5.15, baseline vs. first and second follow‐ups, P = 0.01). LV peak systolic GLε was reduced by 1.19 at early follow‐up (P < 0.05). Left atrial reservoir and booster pump functions as well as right atrial reservoir function were reduced through follow‐up as well.ConclusionsThe RV exhibited greater change in strain after trastuzumab treatment when compared to the LV. Atria function was reduced by trastuzumab as well. The repercussion of these findings and their potential implication will warrant further study.

Abstract Introduction: CD56+ lymphocytes (a defining marker of natural killer cells) have a predominantly cytotoxic phenotype and a hypothetical role in breast tumor immunosurveillance. Here we investigate whether CD56+ staining density varies in nonmalignant breast lobules according to confirmed breast cancer risk factors- age, and histologic features of fibrocystic change and lobular involution. Methods: Archived breast tissue samples were obtained from 94 women with benign breast disease (BBD). The sample set was selected as a nested case-control study (47 cases, 47 controls) from within a large BBD cohort; cases were those who developed breast cancer subsequent to their benign breast biopsy; controls were matched to cases on age at biopsy, year of biopsy, and length of breast cancer free follow-up at least as long as the time-to-cancer in the matched case. Up to 10 representative lobules in each sample were characterized by H&E for fibrocystic changes and the degree of epithelial proliferation (normal, nonproliferative, proliferative, atypia) and for degree of lobular involution (none, partial, complete). Consecutive sections were immunostained for CD56 and hematoxylin. Using digital image analysis, CD56 staining was quantified on a per lobule basis by pixel ratio (PR) (positive stain:total lobule). Statistical analysis was performed using linear mixed effects regression on the rank transformed density to account for correlations among multiple lobules from the same patient in assessing the association of density with lobule characteristics and using conditional logistic regression for association with case-control status. Results: Among 94 women (median age 52, range 35-73), 876 lobules were evaluated: 431 in BBD cases and 445 in BBD controls. Overall, 391 lobules (45%) were normal and the remaining 485 (55%) demonstrated fibrocystic changes. Among fibrocystic lobules, 247 (51%) had nonproliferative changes, 218 (45%) had epithelial proliferation, and 20 (4%) had atypical hyperplasia. Among normal lobules, 61 (16%) had no involution, 139 (36%) had partial involution, and 191 (49%) had complete involution. The vast majority of lobules (861/876, 98%) demonstrated presence of CD56+ cells, while only 15 of 876 lobules in 11 patients had zero CD56+ cells [7 cases (15%) versus 4 controls (8.5%) OR 1.75, p = 0.37]. The median CD56+ PR was 0.55% overall. Fibrocystic lobules as a group showed significantly lower median CD56+ PR compared to normal lobules (0.37% vs 0.85%, p &lt; 0.0001). Among subcategories of fibrocystic lobules, the median CD56+ PR was lower in proliferative lobules (0.29%) compared to non-proliferative (0.42%), but this difference was not statistically significant (p = 0.55). Older women (age &gt; 55) showed the highest CD56+ PR (median of 0.92%), as compared to 0.38% in women 45-55 (p=0.02), and 0.52% in women age &lt;45 (p = 0.26). Among normal lobules, median CD56+ PR was similar between lobules with no involution (0.55%) and partial involution (0.52%) but was considerably higher among lobules with complete involution (1.3%, p = 0.09 and p = 0.05, respectively). In a multivariable model, CD56+ PR differences between fibrocystic and normal lobules remained significant (p = 0.0002) and also remained significant between age groups of &gt; 55 and 45-55 (p = 0.02), while involution was non-significant. Median CD56+ PR was lower in cases (0.43%) compared to controls (0.72%), but this was not statistically significant (p=0.19) in our sample of 47 case-control pairs. Conclusions: Breast lobules with fibrocystic changes show less CD56+ cells, raising a question of possible immune suppression induced by early epithelial abnormalities. These findings encourage further investigation to improve understanding of the immune microenvironment in premalignant breast tissues. Citation Format: Rushin D. Brahmbhatt, Daniel Kerekes, Tanya L. Hoskin, Alvaro Pena, Daniel W. Visscher, Melody L. Stallings-Mann, Derek C. Radisky, Linda M. Murphy, Vernon Shane Pankratz, Keith L. Knutson, Marlene Frost, Amy C. Degnim. CD56+ immune cell infiltration is decreased in benign breast lobules with fibrocystic changes. [abstract]. In: Proceedings of the Thirteenth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2014 Sep 27-Oct 1; New Orleans, LA. Philadelphia (PA): AACR; Can Prev Res 2015;8(10 Suppl): Abstract nr B34.