Pan-cancer Landscape of Programmed Death Ligand-1 and Programmed Death Ligand-2 Structural Variations.

PURPOSE: Programmed cell death protein-1 (PD-1) receptor and ligand interactions are the target of immunotherapies for more than 20 cancer types. Biomarkers that predict response to immunotherapy are microsatellite instability, tumor mutational burden, and programmed death ligand-1 (PD-L1) immunohistochemistry. Structural variations (SVs) in PD-L1 (CD274) and PD-L2 (PDCD1LG2) have been observed in cancer, but the comprehensive landscape is unknown. Here, we describe the genomic landscape of PD-L1 and PD-L2 SVs, their potential impact on the tumor microenvironment, and evidence that patients with these alterations can benefit from immunotherapy. METHODS: We analyzed sequencing data from cancer cases with PD-L1 and PD-L2 SVs across 22 publications and four data sets, including Foundation Medicine Inc, The Cancer Genome Atlas, International Cancer Genome Consortium, and the Oncology Research Information Exchange Network. We leveraged RNA sequencing to evaluate immune signatures. We curated literature reporting clinical outcomes of patients harboring PD-L1 or PD-L2 SVs. RESULTS: Using data sets encompassing 300,000 tumors, we curated 486 cases with SVs in PD-L1 and PD-L2 and observed consistent breakpoint patterns, or hotspots. Leveraging The Cancer Genome Atlas, we observed significant upregulation in PD-L1 expression and signatures for interferon signaling, macrophages, T cells, and immune cell proliferation in samples harboring PD-L1 or PD-L2 SVs. Retrospective review of 12 studies that identified patients with SVs in PD-L1 or PD-L2 revealed > 50% (52/71) response rate to PD-1 immunotherapy with durable responses. CONCLUSION: Our findings show that the 3'-UTR is frequently affected, and that SVs are associated with increased expression of ligands and immune signatures. Retrospective evidence from curated studies suggests this genomic alteration could help identify candidates for PD-1/PD-L1 immunotherapy. We expect these findings will better define PD-L1 and PD-L2 SVs in cancer and lend support for prospective clinical trials to target these alterations.

Immunophenotypic Characterization of Canine Nodal T-Zone Lymphoma.

T-zone lymphoma (TZL) is an indolent nodal T-cell lymphoma most commonly observed in submandibular lymph nodes in dogs. The diagnosis is based on its distinct morphology and expression of CD3. TZL has been reported to have a low Ki67 index and to lack expression of CD45. The latter feature has been used to diagnose this type of lymphoma via fine needle aspirate and flow cytometry without confirmation of the characteristic tissue architecture. The goal of this study was to characterize the immunophenotype of canine nodal TZL in greater detail. Twenty-seven TZLs were selected based on their characteristic morphology. A tissue microarray was generated, and immunohistochemical expression of CD3, CD5, CD20, CD21, CD25, CD45, Bcl-6, and Ki67 was evaluated. Neoplastic T cells in all cases were positive for CD3, CD5, and CD25, and negative for CD20, CD21, and Bcl-6. Positive labelling for CD45 was detected in 2 of the 27 cases with the remaining 25 cases being negative. All cases had a low Ki67 index with an average index of 19.56%. For the CD45-positive TZLs, clonality of the T-cell antigen receptor gamma gene was confirmed in only one of these cases. The observed immunophenotype of canine TZL is similar to previous publications with the exception that 2 cases expressed CD45. Expression of CD45 in TZLs in this study emphasizes the importance of interpreting immunophenotypic findings in conjunction with histopathology to reach an accurate diagnosis and not to use lack of expression of a particular antigen as the sole diagnostic criterion.

Squamous cell carcinoma with clear cell differentiation in an equine eyelid.

A 15-y-old Miniature horse mare had a 6-mo history of an ulcerated mass on the right lower eyelid. An incisional biopsy and a subsequent excisional biopsy were submitted to the Michigan State University Veterinary Diagnostic Laboratory for microscopic evaluation. Histologically, the incisional biopsy was composed of sheets of large neoplastic vacuolated polygonal cells. A few regions contained poorly differentiated neoplastic round-to-basaloid cells that rimmed the sheets of highly vacuolated polygonal cells. Both vacuolated and basaloid cells exhibited strong perimembranous and cytoplasmic immunoreactivity for E-cadherin and cytokeratin 5/6, respectively. Vacuolated polygonal cells were histochemically negative for periodic acid-Schiff, mucicarmine, and oil red O, consistent with a diagnosis of poorly differentiated carcinoma. Within the excisional biopsy specimen, there were anastomosing cords and nests of neoplastic squamous epithelial cells that merged with sheets of similar vacuolated polygonal cells. These findings are consistent with a squamous cell carcinoma with clear cell differentiation. In addition, in the adjacent dermis, there was solar elastosis suggestive of ultraviolet (UV) damage. A clear cell variant of squamous cell carcinoma is a rare entity in humans that previously has not been described in animals, to our knowledge, and is often associated with chronic UV exposure.

Immunophenotypic Characterization of Canine Splenic Follicular-Derived B-Cell Lymphoma.

Marginal zone lymphoma (MZL) and mantle cell lymphoma (MCL) belong to a subgroup of indolent B-cell lymphomas most commonly reported in the canine spleen. The goal of this study was to characterize the immunophenotype of splenic MZL and MCL in comparison to their human counterparts. Ten MCLs and 28 MZLs were selected based on morphology. A tissue microarray was generated, and expression of CD3, CD5, CD10, CD45, CD20, CD79a, Pax-5, Bcl-2, Bcl-6, cyclin D1, cyclin D3, MCL-1, MUM-1, and Sox-11 was evaluated. Neoplastic cells in all MCLs and MZLs were positive for CD5, CD20, CD45, CD79a, and BCL2 and negative for CD3, CD10, Bcl-6, cyclin D1, and cyclin D3. Positive labeling for Pax-5 was detected in 8 of 10 MCLs and 26 of 28 MZLs. Positive labeling for MUM-1 was detected in 3 of 10 MCLs, and 27 of 28 MZLs were positive for MUM-1. No MCLs but 8 of 24 MZLs were positive for MCL-1. Canine splenic MZL and MCL have a similar immunophenotype as their human counterparts. However, human splenic MCL overexpresses cyclin D1 due to a translocation. A similar genetic alteration has not been reported in dogs. In addition, in contrast to human MZL, canine splenic MZL generally expresses CD5. Following identification of B vs T cells with CD20 and CD3, a panel composed of BCL-2, Bcl-6, MUM-1, and MCL-1 combined with the histomorphological pattern can be used to accurately diagnose MZL and MCL in dogs. Expression of Bcl-2 and lack of MCL-1 expression in MCL may suggest a therapeutic benefit of BCL-2 inhibitors in canine MCL.

Sparse representation of electrodermal activity with knowledge-driven dictionaries.

Biometric sensors and portable devices are being increasingly embedded into our everyday life, creating the need for robust physiological models that efficiently represent, analyze, and interpret the acquired signals. We propose a knowledge-driven method to represent electrodermal activity (EDA), a psychophysiological signal linked to stress, affect, and cognitive processing. We build EDA-specific dictionaries that accurately model both the slow varying tonic part and the signal fluctuations, called skin conductance responses (SCR), and use greedy sparse representation techniques to decompose the signal into a small number of atoms from the dictionary. Quantitative evaluation of our method considers signal reconstruction, compression rate, and information retrieval measures, that capture the ability of the model to incorporate the main signal characteristics, such as SCR occurrences. Compared to previous studies fitting a predetermined structure to the signal, results indicate that our approach provides benefits across all aforementioned criteria. This paper demonstrates the ability of appropriate dictionaries along with sparse decomposition methods to reliably represent EDA signals and provides a foundation for automatic measurement of SCR characteristics and the extraction of meaningful EDA features.

Physiological and behavioral stress and anxiety in children with autism spectrum disorders during routine oral care.

BACKGROUND: Children with autism spectrum disorders (ASD) commonly exhibit uncooperative behaviors which impede oral care. Previous studies have utilized dentist-report measures of uncooperative behaviors in children with ASD but none have utilized an objective measure of children's behavior or a physiological measure of distress. This study investigated behavioral and physiological distress in children with ASD during routine oral care and examined factors associated with this distress. METHODS: Participants were 44 children (n=22 typical, n=22 ASD) aged 6-12 receiving routine dental cleanings. Behavioral and physiological measures of stress and anxiety were collected during dental cleanings. RESULTS: Children with ASD exhibited greater distress, compared to the typical group, on dentist-report and researcher-coded measures of overt distress behaviors and on physiological measures. Correlations between physiological and behavioral measures of distress were found in the ASD but not in the typical group. Behavioral distress was correlated with age in the typical group and with expressive communication ability and sensory processing difficulties in the ASD group; physiological distress was correlated with parent-report of anxiety in the typical group and sensory processing difficulties in the ASD group. CONCLUSIONS: Novel strategies may be required to decrease behavioral and physiological distress in children with ASD in the dental clinic.

Oral care and sensory over-responsivity in children with autism spectrum disorders.

PURPOSE: The purpose of this study was to investigate the relationship between sensory sensitivities and oral care difficulties in children with autism spectrum disorders (ASDs) or typical development (TD). METHODS: Participants included 396 parents of 2- to 18-year-old children with ASDs or TD who completed a questionnaire about oral care in the home and dental office. Descriptive and bivariate analyses were conducted to examine the association between sensory sensitivities and oral care variables. RESULTS: Both hypotheses were supported: (1) ASDs children vs. TD children were reported to have a significantly greater prevalence of sensory over-responsivity across all sensory domains; and (2) ASDs children characterized as "sensory over-responders" exhibited a significantly greater prevalence of oral care difficulty in the home and dental office vs. ASDs children who responded more typically to sensory stimuli ("sensory not over-responders"). CONCLUSIONS: This study provides further evidence for the impact of sensory processing problems on oral care, both in the home and dental office. Methods to best serve children with autism spectrum disorders may include strategies that alter the sensory characteristics of the dental environment as well as interventions to reduce children's sensory sensitivities.

Oral care experiences and challenges in children with autism spectrum disorders.

PURPOSE: The purpose of this study was to investigate the differences between children with autism spectrum disorders (ASD) and their typically developing peers in relation to aspects of oral care. METHODS: Participants included 396 parents of ASD children or typically developing 2- to 18-year-olds. Parents completed a 37-item questionnaire designed by authors to elicit information about oral care in the home and dental office. Descriptive, bivariate, and multivariate regression analyses were conducted to examine the association between diagnostic group and oral care variables. RESULTS: Significantly more parents of ASD children than parents of typically developing children reported difficulty across almost all oral care variables explored, including oral care in the home, oral care at the dentist, and access to oral care. Following multivariate regression to control for possible confounders-including age, gender, Hispanic status, and paternal education level-all previously significant variables remained significant. CONCLUSION: This study indicates that children with autism spectrum disorders experience greater difficulties and barriers to care in both the home and dental office settings than their typically developing peers.

Oral care and sensory concerns in autism.

We examined sensory-related aspects of oral care at home and the dentist's office in children with autism spectrum disorders (ASD) and their typically developing (TD) peers. Results from parent questionnaires (n = 196 ASD, n = 202 TD) and one focus group were analyzed to determine whether sensory experiences were different between groups. Significantly more parents of children with ASD reported difficulties with sensory-related oral care variables in the home and dental office; this finding was supported by qualitative data. Using sensory strategies to modify the environment may enhance the dental experience and improve quality of life for children with ASD and their families.

Oral care and sensory sensitivities in children with autism spectrum disorders.

Children with autism spectrum disorders (ASD) are at high risk for oral disease. The aim of this study was to examine the contribution of sensory processing problems to challenges in receiving oral care for children with ASD. A questionnaire was sent to the parents of 206 children with disabilities to test the hypotheses that children with ASD, relative to children with other disabilities, experience greater difficulty with home-based and professional oral care, and that these difficulties may relate in part to sensory processing problems. The results partially supported these hypotheses. Compared to children with other disabilities, those with ASD had greater behavioral difficulties and sensory sensitivities that parents believed interfered with their child's oral care. Among children with ASD, sensory sensitivities were associated with oral care difficulties in the home and dental office, and with behavioral difficulties in the dental office. Utilizing strategies to modify the sensory environment may help facilitate oral care in children with ASD.