123 results on '"Raghavan SS"'
Search Results
2. An assessment of interactions between global health initiatives and country health systems
- Author
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Samb, B., Evans, T., Dybul, M., Atun, R., Moatti, Jp, Nishtar, S., Wright, A., Celletti, F., Hsu, J., Kim, Jy, Brugha, R., Russell, A., Etienne, C., De, S, Mwase, T., Wang, Wj, Wright, J., Dare, L., Delfraissy, Jf, Boillot, F., Miege, P., Zhang, Xl, Rhatigan, J., Weintraub, R., Pun, S., Abe, C., Caceres, C., Camara, M., Coriat, B., D Almeida, C., Aleshkina, J., Murzalieva, G., Kadzandira, J., Hammami, N., Mwapasa, V., Chkhatarashvili, K., Buch, E., Miti, K., Kamenga, C., Elouma, Mse, Schwalbe, N., Greenberg, A., Frehywot, S., Markus, A., Goeman, L., Khan, A., Amati, J., Mwaura-Muiru, E., Ivers, Lc, Ellner, A., Shakow, A., Kley, Nc, Irwin, A., Sullivan, E., Baker, B., Cohn, J., Davis, P., Headley, J., Siplon, P., Dickinson, C., Pearson, M., Waddington, C., Boyer, S., Eboko, F., Orsi, F., Larouze, B., Le Loup, G., Ndubani, P., Simbaya, J., Boelaert, M., Cavalli, A., Ooms, G., Pirard, M., Polman, K., Damme, W., Dormael, M., Vermeiren, P., Teokul, W., Dlodlo, R., Fujiwara, P., Ruppol, S., Vella, S., Semigina, T., Corbett, E., Godfrey-Faussett, P., Spicer, N., Walt, G., Kanchanachitra, C., Philips, M., Riva, G., Kabuayi, Jp, Kiputsu, Ak, Ndongosieme, A., Koulla-Shiro, S., Samake, S., Bamba, Si, Coulibaly, Y., Traore, Mn, Berthe, Ibi, Wibulpolprasert, S., Chunharas, S., Jerome, G., Mukherjee, J., Nguini, Meo, Rao, Kd, Reddy, S., Nyirenda, L., Biesma, R., Bruen, C., Dicker, P., Walsh, A., Parsons, A., Mathole, T., Sanders, D., Raghavan, Ss, Mwanza, F., Michael, Eb, Richard, W., Banati, P., Blakley, M., Ingenkamp, N., Lansang, Ma, Low-Beer, D., Shakarishvili, G., Kayongo, A., Buse, K., Martineau, T., Dehne, K., Pett, I., Salama, P., Chilundo, B., Ndumbe, P., Atashili, J., Sow, Ps, Peter Hill, Brenzel, L., Babaley, M., Dayrit, M., Zoysa, I., Dyrhauge, J., Galichet, B., Kadama, P., Porignon, D., Russell, S., Tata, H., and Lerberghe, W.
- Abstract
Since 2000, the emergence of several large disease-specific global health initiatives (GHIs) has changed the way in which international donors provide assistance for public health. Some critics have claimed that these initiatives burden health systems that are already fragile in countries with few resources, whereas others have asserted that weak health systems prevent progress in meeting disease-specific targets. So far, most of the evidence for this debate has been provided by speculation and anecdotes. We use a review and analysis of existing data, and 15 new studies that were submitted to WHO for the purpose of writing this Report to describe the complex nature of the interplay between country health systems and GHIs. We suggest that this Report provides the most detailed compilation of published and emerging evidence so far, and provides a basis for identification of the ways in which GHIs and health systems can interact to mutually reinforce their effects. On the basis of the findings, we make some general recommendations and identify a series of action points for international partners, governments, and other stakeholders that will help ensure that investments in GHIs and country health systems can fulfil their potential to produce comprehensive and lasting results in disease-specific work, and advance the general public health agenda. The target date for achievement of the health-related Millennium Development Goals is drawing close, and the economic downturn threatens to undermine the improvements in health outcomes that have been achieved in the past few years. If adjustments to the interactions between GHIs and country health systems will improve efficiency, equity value for money, and outcomes in global public health, then these opportunities should not be missed.
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- 2009
3. Effects of HIV disease on lipid, glucose and insulin levels: results from a large antiretroviral-naive cohort
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El-Sadr, WM, primary, Mullin, CM, additional, Carr, A, additional, Gibert, C, additional, Rappoport, C, additional, Visnegarwala, F, additional, Grunfeld, C, additional, and Raghavan, SS, additional
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- 2005
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4. Sex differences in the associations of HIV disease characteristics and body composition in antiretroviral-naive persons.
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Visnegarwala F, Raghavan SS, Mullin CM, Bartsch G, Wang J, Kotler D, Gibert CL, Shlay J, Grunfeld C, Carr A, El-Sadr W, and Terry Beirn Community Program for Clinical Research on AIDS
- Abstract
BACKGROUND: Data on associations of body composition with HIV disease characteristics are limited. OBJECTIVE: We compared sex-specific associations between HIV disease characteristics and body composition in an racially-ethnically diverse cohort of antiretroviral-naive patients. DESIGN: The study was a cross-sectional analysis of participants enrolled in a metabolic substudy of a multicenter trial. Regional fat was measured, and total body fat (TBF) was derived by using the Durnin-Womersley formula (DWF) and bioelectrical impedance analysis (BIA). Body cell mass (BCM) was measured by BIA. RESULTS: Among 422 participants, 22% were women, 60% were African American, and 36% had prior AIDS-defining illnesses. Mean (+/-SD) age was 38.2 +/- 9.6 y, CD4+ count was 215 +/- 184 cells/mm3, and HIV RNA log10 was 5.0 +/- 0.8 copies/mL. On multivariate analysis, women with AIDS-defining illness had significantly (P < 0.005) lower regional body fat and TBF (BIA: -9.5 kg; DWF: -7.3 kg) but nonsignificantly lower BCM (-1.3 kg) than did women without such illnesses, whereas men with AIDS-defining illness had significantly (P < 0.005) lower BCM (-1.7 kg) but nonsignificantly lower TBF (BIA: -1.3 kg; DWF: -1.83 kg) than did men without such illnesses (P < 0.05 for sex differences in TBF). Significant negative associations of HIV RNA with BCM (-0.9 kg/log RNA; P = 0.03), TBF by BIA (-1.4 kg/log RNA; P = 0.05) and by DWF (-1.6 kg/log RNA; P = 0.01), and regional fat were observed in men only. CONCLUSIONS: The effect of prior AIDS illness on body fat differed significantly between the sexes: women with prior AIDS-defining illness had significantly less fat than did women without such illnesses. An independent effect of HIV viremia on BCM and fat was seen in men. These distinctions may be due to inherent biological differences between the sexes. Copyright © 2005 American Society for Clinical Nutrition [ABSTRACT FROM AUTHOR]
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- 2005
5. PRAME Expression in Merkel Cell Carcinoma.
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Miller E, Biesemier A, Coomes DM, and Raghavan SS
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- Humans, Male, Female, Aged, Middle Aged, Aged, 80 and over, Retrospective Studies, Immunohistochemistry, Antigens, Viral, Tumor analysis, Prognosis, Polyomavirus Infections virology, Polyomavirus Infections pathology, Polyomavirus Infections mortality, Antigens, Neoplasm, Carcinoma, Merkel Cell virology, Carcinoma, Merkel Cell pathology, Carcinoma, Merkel Cell mortality, Skin Neoplasms virology, Skin Neoplasms pathology, Skin Neoplasms mortality, Biomarkers, Tumor analysis, Merkel cell polyomavirus isolation & purification
- Abstract
Merkel cell carcinoma (MCC) is a rare and aggressive neuroendocrine tumor of the skin. Risk factors include extensive sun damage, infection with Merkel cell polyomavirus, and an immunocompromised state. PRAME, also known as preferentially expressed antigen in melanoma, is a cancer-testis antigen recently found to be a useful diagnostic tool in the workup of melanocytic neoplasms. However, the expression pattern of PRAME in Merkel cell carcinoma is unknown. In this study, we examine PRAME expression in Merkel cell carcinoma and explore its prognostic implications. The institutional archives at the University of Virginia were used to search for tumors classified as Merkel cell carcinoma from 2004 to 2022. All potential cases were reviewed to confirm the diagnosis, and electronic medical records were searched for clinical and demographic data. Tumors were subsequently immunostained for PRAME and Merkel cell polyomavirus. Cox proportional hazards regression models were used to estimate relative (all-cause) survival of PRAME positivity and MCPyV positivity in our study as well as MCC-specific survival of PRAME positivity. Univariate and multivariable models were created for each outcome related to all-cause survival. A total of 39 cases were included in the study. Twenty-eight percent (11 cases) demonstrated strong PRAME expression, and 27% of cases were positive for Merkel cell polyomavirus. There was no statistically significant correlation between PRAME expression and virus positivity. With respect to PRAME, the adjusted all-cause mortality hazard ratio was 11.4 (95% CI: 1.8, 70.8). The unadjusted MCC-specific hazard ratio was 4.6 (95% CI: 0.8, 27.5). The adjusted hazard ratio pertaining to Merkel cell polyomavirus infection was 0.25 (95% CI: 0.02, 2.96). In this limited cohort, PRAME expression appears to correlate with worse outcomes in Merkel cell carcinoma., Competing Interests: Conflicts of Interest and Source of Funding: The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)
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- 2024
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6. Histopathology underlying environmental enteric dysfunction in a cohort study of undernourished children in Bangladesh, Pakistan, and Zambia compared with United States children.
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Kelly P, VanBuskirk K, Coomes D, Mouksassi S, Smith G, Jamil Z, Hossain MS, Syed S, Marie C, Tarr PI, Sullivan PB, Petri WA Jr, Denno DM, Ahmed T, Mahfuz M, Ali SA, Moore SR, Ndao IM, Tearney GJ, Ömer H Yilmaz, Raghavan SS, Moskaluk CA, and Liu TC
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- Humans, Bangladesh epidemiology, Pakistan epidemiology, Zambia epidemiology, Cohort Studies, Child, Female, Male, Infant, Child, Preschool, United States epidemiology, Biopsy, Intestinal Diseases pathology, Celiac Disease pathology, Intestinal Mucosa pathology, Goblet Cells pathology, Child Nutrition Disorders epidemiology, Child Nutrition Disorders pathology, Duodenum pathology
- Abstract
Background: Environmental enteric dysfunction (EED) is an asymptomatic intestinal disorder associated with growth impairment, delayed neurocognitive development, and impaired oral vaccine responses., Objectives: We set out to develop and validate a histopathologic scoring system on duodenal biopsies from a cohort study of children with growth failure in Bangladesh, Pakistan, and Zambia ("EED") with reference to biopsies from United States children with no clinically reported histologic pathology (referred to hereafter as "normal") or celiac disease., Methods: Five gastrointestinal pathologists evaluated 745 hematoxylin and eosin slide images from 291 children with EED (mean age: 1.6 y) and 66 United States children (mean age: 6.8 y). Histomorphologic features (i.e., villus/crypt architecture, goblet cells, epithelial and lamina propria acute/chronic inflammation, Brunner's glands, Paneth cells, epithelial detachment, enterocyte injury, and foveolar metaplasia) were used to score each histopathologic slide. Generalized estimating equations were used to determine differences between EED, normal, and celiac disease, and receiver operating characteristic curves were used to assess predictive value., Results: Biopsies from the duodenal bulb showed higher intramucosal Brunner's gland scores and lower intraepithelial lymphocyte scores than from the second or third parts of the duodenum (D2/3), so only D2/3 were included in the final analysis. Although 7 parameters differed significantly between EED and normal biopsies in regression models, only 5 (blunted villus architecture, increased intraepithelial lymphocytosis, goblet cell depletion, Paneth cell depletion, and reduced intramucosal Brunner's glands) were required to create a total score percentage (TSP-5) that correctly identified EED against normal biopsies (AUC: 0.992; 95% CI: 0.983, 0.998). Geographic comparisons showed more severe goblet cell depletion in Bangladesh and more marked intraepithelial lymphocytosis in Pakistan., Conclusions: This scoring system involving 5 histologic parameters demonstrates very high discrimination between EED and normal biopsies, indicating that this scoring system can be applied with confidence to studies of intestinal biopsies in EED., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)
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- 2024
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7. Hematoxylin and Eosin Architecture Uncovers Clinically Divergent Niches in Pancreatic Cancer.
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Guo JL, Lopez DM, Mascharak S, Foster DS, Khan A, Davitt MF, Nguyen AT, Burcham AR, Chinta MS, Guardino NJ, Griffin M, Miller E, Januszyk M, Raghavan SS, Longacre TA, Delitto DJ, Norton JA, and Longaker MT
- Abstract
Pancreatic ductal adenocarcinoma (PDAC) represents one of the only cancers with an increasing incidence rate and is often associated with intra- and peri-tumoral scarring, referred to as desmoplasia. This scarring is highly heterogeneous in extracellular matrix (ECM) architecture and plays complex roles in both tumor biology and clinical outcomes that are not yet fully understood. Using hematoxylin and eosin (H&E), a routine histological stain utilized in existing clinical workflows, we quantified ECM architecture in 85 patient samples to assess relationships between desmoplastic architecture and clinical outcomes such as survival time and disease recurrence. By utilizing unsupervised machine learning to summarize a latent space across 147 local (e.g., fiber length, solidity) and global (e.g., fiber branching, porosity) H&E-based features, we identified a continuum of histological architectures that were associated with differences in both survival and recurrence. Furthermore, we mapped H&E architectures to a CO-Detection by indEXing (CODEX) reference atlas, revealing localized cell- and protein-based niches associated with outcome-positive versus outcome-negative scarring in the tumor microenvironment. Overall, our study utilizes standard H&E staining to uncover clinically relevant associations between desmoplastic organization and PDAC outcomes, offering a translatable pipeline to support prognostic decision-making and a blueprint of spatial-biological factors for modeling by tissue engineering methods.
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- 2024
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8. Metastatic Undifferentiated Melanoma Mimicking a Primary Bone Tumor: A Potential Diagnostic Pitfall.
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Wills A, Dibbern M, Frierson HF, and Raghavan SS
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- Humans, DNA Mutational Analysis, Mutation, Proto-Oncogene Proteins B-raf genetics, Melanoma diagnosis, Melanoma genetics, Melanoma pathology, Skin Neoplasms diagnosis, Skin Neoplasms genetics, Skin Neoplasms pathology, Bone Neoplasms diagnosis, Bone Neoplasms genetics
- Abstract
Abstract: Undifferentiated melanoma (UM) is defined by the loss of classic morphologic and immunohistochemical melanocytic markers. Reports in the literature are rare and show that UM usually occurs as a metastasis in the setting of a known primary cutaneous melanoma. The most common mutations in UM include those involving BRAF , NRAS , and KIT , which are almost invariably present in the parent melanoma. In this study, we report a case of a primary sinonasal melanoma with metastatic UM presenting with osteoclast-like giant cells and resembling a primary bone tumor. The retention of an unusual KRAS mutation in UM that was also present in the primary lesion provided critical information for the diagnosis. Our report highlights the importance of considering mutational analysis to identify undifferentiated melanomas in patients with metastatic tumors which do not have the typical histopathologic and immunohistochemical features of melanoma., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)
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- 2024
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9. PRAME Expression in Melanocytic Proliferations in Special Sites.
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Maniaci JL and Raghavan SS
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- Humans, Skin pathology, Diagnosis, Differential, Antigens, Neoplasm, Melanoma diagnosis, Melanoma pathology, Skin Neoplasms pathology, Nevus, Pigmented diagnosis, Nevus, Pigmented pathology, Nevus diagnosis, Nevus pathology
- Abstract
The subset of nevi occurring at special sites (eg, acral skin, anogeni-tal region, breast, ear, flexural surfaces) have normal histologic variations that preclude the use of routinely used diagnostic criteria for malignancy. Suggested criteria for differentiating malignant special-site lesions from benign lesions have been described, but there is an unmet need for a validated test aiding in the delineation of benign and malignant lesions at special sites. Preferentially expressed antigen of melanoma (PRAME) expression has been characterized as a relatively specific marker of melanoma, but not within the specific population of special-site lesions. This study aimed to determine if PRAME may serve as a specific marker of melanoma within the population of special-sites lesions.
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- 2024
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10. Immunoglobulin G4 in eosinophilic esophagitis: Immune complex formation and correlation with disease activity.
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Medernach JG, Li RC, Zhao XY, Yin B, Noonan EA, Etter EF, Raghavan SS, Borish LC, Wilson JM, Barnes BH, Platts-Mills TAE, Ewald SE, Sauer BG, and McGowan EC
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- Adult, Female, Animals, Cattle, Humans, Antigen-Antibody Complex, Immunoglobulin G, Allergens, Milk Proteins, Eosinophilic Esophagitis pathology
- Abstract
Background: Recent studies have shown deposition of immunoglobulin G4 (IgG4) and food proteins in the esophageal mucosa of eosinophilic esophagitis (EoE) patients. Our aims were to assess whether co-localization of IgG4 and major cow's milk proteins (CMPs) was associated with EoE disease activity and to investigate the proteins enriched in proximity to IgG4 deposits., Methods: This study included adult subjects with EoE (n = 13) and non-EoE controls (n = 5). Esophageal biopsies were immunofluorescence stained for IgG4 and CMPs. Co-localization in paired samples from active disease and remission was assessed and compared to controls. The proteome surrounding IgG4 deposits was evaluated by the novel technique, AutoSTOMP. IgG4-food protein interactions were confirmed with co-immunoprecipitation and mass spectrometry., Results: IgG4-CMP co-localization was higher in the active EoE group compared to paired remission samples (Bos d 4, p = .02; Bos d 5, p = .002; Bos d 8, p = .002). Co-localization was also significantly higher in the active EoE group compared to non-EoE controls (Bos d 4, p = .0013; Bos d 5, p = .0007; Bos d 8, p = .0013). AutoSTOMP identified eosinophil-derived proteins (PRG 2 and 3, EPX, RNASE3) and calpain-14 in IgG4-enriched areas. Co-immunoprecipitation and mass spectrometry confirmed IgG4 binding to multiple food allergens., Conclusion: These findings further contribute to the understanding of the interaction of IgG4 with food antigens as it relates to EoE disease activity. These data strongly suggest the immune complex formation of IgG4 and major cow's milk proteins. These immune complexes may have a potential role in the pathophysiology of EoE by contributing to eosinophil activation and disease progression., (© 2023 The Authors. Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)
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- 2023
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11. Evaluation of action of steroid molecules on SARS-CoV-2 by inhibiting NSP-15, an endoribonuclease.
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Dhanabalan AK, Raghavan SS, Rajendran S, Ramasamy V, Abdul SAA, Narayanasamy N, and Krishnasamy G
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- Humans, SARS-CoV-2 metabolism, Molecular Docking Simulation, Antiviral Agents chemistry, Endoribonucleases, Dexamethasone pharmacology, COVID-19, Cortisone
- Abstract
Many countries in the world have recently experienced an outbreak of COVID-19, turned out to be a pandemic which significantly affected the world economy. Among many attempts to treat/control infection or to modulate host immunity, many small molecules including steroids were prescribed based on their use against other viral infection or inflammatory conditions. A recent report established the possibility of usage of a corticosteroid against the virus through inhibiting NSP-15; an mRNA endonuclease of SARS-CoV-2 and thereby viral replication. This study aimed to identify potential anti-viral agents for the virus through computational approaches and to validate binding properties with the protein target through molecular dynamics simulation. Unlike the conventional approaches, dedicated data base of steroid like compounds was used for initial screening along with dexamethasone and cortisone, which are used in the treatment of COVID-19 affected population in some countries. Molecular docking was performed for three compounds filtered from data base in addition to dexamethasone and Cortisone followed by molecular dynamics simulation analysis to validate the dynamics of binding at the active site. In addition, analysis of ADME properties established that these compounds have favorable drug-like properties. Based on docking, molecular dynamics simulation studies and various other trajectory analyses, compounds that are identified could be suggested as therapeutics or precursors towards designing new anti-viral agents against SARS-CoV-2, to combat COVID-19. Also, this is an attempt to study the impact of steroid compounds on NSP-15 of SARS-CoV-2, since many steroid like compounds are used during the treatment of COVID-19 patients., (© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)
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- 2023
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12. Desmoplastic stromal signatures predict patient outcomes in pancreatic ductal adenocarcinoma.
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Mascharak S, Guo JL, Foster DS, Khan A, Davitt MF, Nguyen AT, Burcham AR, Chinta MS, Guardino NJ, Griffin M, Lopez DM, Miller E, Januszyk M, Raghavan SS, Longacre TA, Delitto DJ, Norton JA, and Longaker MT
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- Humans, Extracellular Matrix pathology, Tumor Microenvironment, Carcinoma, Pancreatic Ductal drug therapy, Pancreatic Neoplasms drug therapy
- Abstract
Pancreatic ductal adenocarcinoma (PDAC) is projected to become the second leading cause of cancer-related death. Hallmarks include desmoplasia with variable extracellular matrix (ECM) architecture and a complex microenvironment with spatially defined tumor, stromal, and immune populations. Nevertheless, the role of desmoplastic spatial organization in patient/tumor variability remains underexplored, which we elucidate using two technologies. First, we quantify ECM patterning in 437 patients, revealing architectures associated with disease-free and overall survival. Second, we spatially profile the cellular milieu of 78 specimens using codetection by indexing, identifying an axis of pro-inflammatory cell interactions predictive of poorer outcomes. We discover that clinical characteristics, including neoadjuvant chemotherapy status, tumor stage, and ECM architecture, correlate with differential stromal-immune organization, including fibroblast subtypes with distinct niches. Lastly, we define unified signatures that predict survival with areas under the receiver operating characteristic curve (AUCs) of 0.872-0.903, differentiating survivorship by 655 days. Overall, our findings establish matrix ultrastructural and cellular organizations of fibrosis linked to poorer outcomes., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)
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- 2023
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13. Cutaneous lesions in the setting of hypophosphatasia.
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Shen NW, Yi LG, Omesiete W, Peroutka CM, Raghavan SS, and Greer KE
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Competing Interests: None disclosed.
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- 2023
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14. Endothelial protein C receptor binding induces conformational changes to severe malaria-associated group A PfEMP1.
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Rajan Raghavan SS, Turner L, Jensen RW, Johansen NT, Jensen DS, Gourdon P, Zhang J, Wang Y, Theander TG, Wang K, and Lavstsen T
- Abstract
Severe Plasmodium falciparum malaria infections are caused by microvascular sequestration of parasites binding to the human endothelial protein C receptor (EPCR) via the multi-domain P. falciparum erythrocyte membrane protein 1 (PfEMP1) adhesion ligands. Using cryogenic electron microscopy (Cryo-EM) and PfEMP1 sequence diversity analysis, we found that group A PfEMP1 CIDRα1 domains interact with the adjacent DBLα1 domain through central, conserved residues of the EPCR-binding site to adopt a compact conformation. Upon EPCR binding, the DBLα1 domain is displaced, and the EPCR-binding helix of CIDRα1 is turned, kinked, and twisted to reach a rearranged, stable EPCR-bound conformation. The unbound conformation and the required transition to the EPCR-bound conformation may represent a conformational masking mechanism of immune evasion for the PfEMP1 family., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)
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- 2023
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15. Widespread livedo racemosa.
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Zhao P, Luu LA, Gish TJ, Raghavan SS, Gru AA, and Zlotoff BJ
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- Humans, Livedo Reticularis
- Abstract
Competing Interests: Conflicts of interest The authors declare they have no conflicts of interest.
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- 2023
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16. Regressing Papules on the Sole of the Foot: Challenge.
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Kreher MA, Wills AC, Duran J, Raghavan SS, and Zlotoff BJ
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- Humans, Lower Extremity, Foot, Skin Abnormalities
- Abstract
Competing Interests: The authors declare no conflicts of interest.
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- 2023
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17. Regressing Papules on the Sole of the Foot: Answer.
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Kreher MA, Wills AC, Duran J, Raghavan SS, and Zlotoff BJ
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- Humans, Lower Extremity, Foot, Skin Abnormalities
- Abstract
Competing Interests: The authors declare no conflicts of interest.
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- 2023
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18. Polyacrylamide-based hydrogel coatings improve biocompatibility of implanted pump devices.
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Chan D, Maikawa CL, d'Aquino AI, Raghavan SS, Troxell ML, and Appel EA
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- Rats, Mice, Humans, Animals, Polymers, Hydrogels, Acrylamides, Inflammation, Insulins
- Abstract
The introduction of transcutaneous and subcutaneous implants and devices into the human body instigates fouling and foreign body responses (FBRs) that limit their functional lifetimes. Polymer coatings are a promising solution to improve the biocompatibility of such implants, with potential to enhance in vivo device performance and prolong device lifetime. Here we sought to develop novel materials for use as coatings on subcutaneously implanted devices to reduce the FBR and local tissue inflammation in comparison to gold standard materials such as poly(ethylene glycol) and polyzwitterions. We prepared a library of polyacrylamide-based copolymer hydrogels, which were selected from materials previously shown to exhibit remarkable antifouling properties with blood and plasma, and implanted them into the subcutaneous space of mice to evaluate their biocompatibility over the course of 1 month. The top performing polyacrylamide-based copolymer hydrogel material, comprising a 50:50 mixture of N-(2-hydroxyethyl)acrylamide (HEAm) and N-(3-methoxypropyl)acrylamide (MPAm), exhibited significantly better biocompatibility and lower tissue inflammation than gold standard materials. Moreover, when applied to polydimethylsiloxane disks or silicon catheters as a thin coating (45 ± 1 μm), this leading copolymer hydrogel coating significantly improved implant biocompatibility. Using a rat model of insulin-deficient diabetes, we showed that insulin pumps fitted with HEAm-co-MPAm hydrogel-coated insulin infusion catheters exhibited improved biocompatibility and extended functional lifetime over pumps fitted with industry standard catheters. These polyacrylamide-based copolymer hydrogel coatings have the potential to improve device function and lifetime, thereby reducing the burden of disease management for people regularly using implanted devices., (© 2023 Wiley Periodicals LLC.)
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- 2023
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19. Malignant undifferentiated and rhabdoid tumors of the gastroesophageal junction and esophagus with SMARCA4 loss: a case series.
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Gupta S, Noona SW, Pambuccian SE, Robinson B, Martin LW, Williams E, Stelow EB, and Raghavan SS
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- Humans, Esophagogastric Junction pathology, Biomarkers, Tumor metabolism, DNA Helicases genetics, Nuclear Proteins, Transcription Factors, Rhabdoid Tumor pathology, Carcinoma pathology
- Abstract
Undifferentiated SMARCA4-deficient carcinoma of the esophagus and gastroesophageal junction is a rare, highly aggressive, and diagnostically challenging malignancy. Here we present a case series of high-grade undifferentiated malignant neoplasms of the esophagus and gastroesophageal junction that share SMARCA4 loss by immunohistochemistry and demonstrate a rhabdoid phenotype. Five cases are presented, including 4 men and 1 woman with an age range of 48-79 years. Interestingly, only one case showed intestinal metaplasia (Barrett's esophagus) and no cases demonstrated glandular dysplasia or glandular differentiation. In all, the lesional cells were immunoreactive with antibodies to keratins (3/5), CD34 (2/4), and CD138 (4/5). SMARCA4 expression was diffusely lost in all cases, whereas SMARCB1 expression was intact. OncoScan™ assay demonstrated loss of SMARCA4 in all cases analyzed. Additional OncoScan™ findings included abnormalities of CDKN2A in 2 of 3 cases, abnormalities of TP53 in 2 of 3 cases, and abnormalities of PTPRD in 2 of 3 cases, among other abnormalities., (Copyright © 2022 Elsevier Inc. All rights reserved.)
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- 2023
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20. Histopathologic and molecular characterization of BAP-1-inactivated melanoma.
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Miller EM, Linos K, Bacchi CE, Gru AA, and Raghavan SS
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- Female, Humans, Male, Mutation, Neoplasm Recurrence, Local, Proto-Oncogene Proteins B-raf genetics, Retrospective Studies, Aged, Melanoma, Cutaneous Malignant, Melanoma genetics, Melanoma pathology, Skin Neoplasms pathology
- Abstract
Background: BRCA1-associated protein 1 (BAP-1) is a deubiquitylase that functions as a tumor suppressor, regulating multiple cellular processes including cell cycle control, differentiation, cell death, and DNA repair. BAP-1-inactivated melanocytic tumors (BIMTs) have recently been described and are characterized by epithelioid cytomorphology, are often clonal in appearance, and typically do not recur or show malignant transformation on follow-up., Aim: To describe the histopathologic and molecular characterization of five cases of BAP-1-inactivated cutaneous malignant melanomas., Methods: The archives at two separate institutions were retrospectively searched for tumors classified as melanoma with loss of BAP-1 via immunohistochemistry. Five cases were identified. These cases were classified as malignant melanoma based on cytomorphology, immunohistochemistry, and ancillary molecular testing. The clinical demographics were recorded, along with the histomorphologic features of each case. Genomic analysis for all cases was performed via OncoScan., Results: The five reviewed cases consisted of two females and three males ranging from 67 to 74 years in age. Molecular characterization of each case was performed using OncoScan. Microarray assay showed that there was a complete deletion of 3p in all cases, BRAF V600E mutation in two cases, NRAS missense variant in one case, and loss of 9p in three cases. All cases showed malignant copy number alterations., Conclusions: Herein we describe five cases of BAP-1-inactivated melanomas confirmed by histomorphology and immunohistochemistry, all of which show malignant copy number profiles including loss of 3p. In addition, we provide a case of a likely BIMT showing progression to BAP-1-inactivated melanoma on a 16-year follow-up., (© 2022 The Authors. Journal of Cutaneous Pathology published by John Wiley & Sons Ltd.)
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- 2023
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21. A rapidly growing nodule on the leg of an adolescent: A unique presentation of a non-neural granular cell tumor.
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Hobbs LK, Kozak MD, Gradecki SE, McGahren ED, and Raghavan SS
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- Adolescent, Humans, Leg pathology, Anaplastic Lymphoma Kinase, Granular Cell Tumor pathology, Skin Neoplasms pathology
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- 2022
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22. Histopathology of primary cutaneous adenoid cystic carcinoma of the scrotum presenting with predominantly solid growth.
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Gradecki SE, Gru AA, Rieger KE, and Raghavan SS
- Subjects
- Diagnosis, Differential, Humans, Male, Scrotum pathology, Carcinoma, Adenoid Cystic pathology, Skin Neoplasms pathology
- Published
- 2022
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23. Deep Learning Mechanism for Predicting the Axillary Lymph Node Metastasis in Patients with Primary Breast Cancer.
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Ashokkumar N, Meera S, Anandan P, Murthy MYB, Kalaivani KS, Alahmadi TA, Alharbi SA, Raghavan SS, and Jayadhas SA
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- Female, Humans, Lymph Nodes pathology, Lymphatic Metastasis pathology, Reproducibility of Results, Sensitivity and Specificity, Breast Neoplasms diagnosis, Breast Neoplasms pathology, Deep Learning
- Abstract
The second largest cause of mortality worldwide is breast cancer, and it mostly occurs in women. Early diagnosis has improved further treatments and reduced the level of mortality. A unique deep learning algorithm is presented for predicting breast cancer in its early stages. This method utilizes numerous layers to retrieve significantly greater amounts of information from the source inputs. It could perform automatic quantitative evaluation of complicated image properties in the medical field and give greater precision and reliability during the diagnosis. The dataset of axillary lymph nodes from the breast cancer patients was collected from Erasmus Medical Center. A total of 1050 images were studied from the 850 patients during the years 2018 to 2021. For the independent test, data samples were collected for 100 images from 95 patients at national cancer institute. The existence of axillary lymph nodes was confirmed by pathologic examination. The feed forward, radial basis function, and Kohonen self-organizing are the artificial neural networks (ANNs) which are used to train 84% of the Erasmus Medical Center dataset and test the remaining 16% of the independent dataset. The proposed model performance was determined in terms of accuracy (Ac), sensitivity (Sn), specificity (Sf), and the outcome of the receiver operating curve (Roc), which was compared to the other four radiologists' mechanism. The result of the study shows that the proposed mechanism achieves 95% sensitivity, 96% specificity, and 98% accuracy, which is higher than the radiologists' models (90% sensitivity, 92% specificity, and 94% accuracy). Deep learning algorithms could accurately predict the clinical negativity of axillary lymph node metastases by utilizing images of initial breast cancer patients. This method provides an earlier diagnostic technique for axillary lymph node metastases in patients with medically negative changes in axillary lymph nodes., Competing Interests: The authors declare that there are no conflicts of interest regarding the publication of this paper., (Copyright © 2022 N. Ashokkumar et al.)
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- 2022
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24. Insights in the structural understanding of amyloidogenicity and mutation-led conformational dynamics of amyloid beta (Aβ) through molecular dynamics simulations and principal component analysis.
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Raghavan SS, Iqbal S, Ayyadurai N, and Gunasekaran K
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- Humans, Molecular Dynamics Simulation, Mutation, Peptide Fragments chemistry, Principal Component Analysis, Alzheimer Disease metabolism, Amyloid beta-Peptides chemistry
- Abstract
Abnormal protein aggregation in the nervous tissue leads to several neurodegenerative disorders like Alzheimer's disease (AD). In AD, accumulation of the amyloid beta (Aβ) peptide is proposed to be an early important event in pathogenesis. Significant research efforts are devoted so as to understand the Aβ misfolding and aggregation. Molecular dynamics (MD) simulations complement experiments and provide structural information at the atomic level with dynamics without facing the same experimental limitations. Artificial missense mutations are employed experimentally and computationally for providing insights into the structure-function relationships of amyloid-β in relation to the pathologies of AD. Present work describes the MD simulations for 100 ns so as to probe the structural and conformational dynamics of Aβ1-42 assemblies and its mutants. Essential dynamics analysis with respect to conformational deviation of C
α was evaluated to identify the largest residual fluctuation of Cα. Conformational stability of all Aβ mutants was analyzed by computing RMSD, deciphering the convergence is reached in the last 20 ns in all replicas. To highlight the low frequency mode of motion corresponding to the highest amplitude, atomic displacements seen in trajectory, distance pair principal component analysis (dpPCA) was performed, which adumbrated mutations strongly affect the conformational dynamics of investigated model when compared with wild type. Dynamic cross correlation matrix (DCCM) also suggests the conserved interactions of wild Aβ and imply mutations in β3-β4 loop region induce deformity and residual fluctuations as observed from simulation. Present study indicate the mutational energy landscape which induces deformation leading to fibrillation.Communicated by Ramaswamy H. Sarma.- Published
- 2022
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25. Targeting oxidized phospholipids by AAV-based gene therapy in mice with established hepatic steatosis prevents progression to fibrosis.
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Upchurch CM, Yeudall S, Pavelec CM, Merk D, Greulich J, Manjegowda M, Raghavan SS, Bochkis IM, Scott MM, Perez-Reyes E, and Leitinger N
- Subjects
- Animals, Fibrosis, Genetic Therapy, Hepatocytes metabolism, Liver metabolism, Mice, Mice, Inbred C57BL, Oxidation-Reduction, Non-alcoholic Fatty Liver Disease genetics, Non-alcoholic Fatty Liver Disease metabolism, Non-alcoholic Fatty Liver Disease therapy, Phospholipids metabolism
- Abstract
Oxidized phosphatidylcholines (OxPCs) are implicated in chronic tissue damage. Hyperlipidemic LDL-R--deficient mice transgenic for an OxPC-recognizing IgM fragment (scFv-E06) are protected against nonalcoholic fatty liver disease (NAFLD). To examine the effect of OxPC elimination at different stages of NAFLD progression, we used cre-dependent, adeno-associated virus serotype 8-mediated expression of the single-chain variable fragment of E06 (AAV8-scFv-E06) in hepatocytes of albumin-cre mice. AAV8-induced expression of scFv-E06 at the start of FPC diet protected mice from developing hepatic steatosis. Independently, expression of scFv-E06 in mice with established steatosis prevented the progression to hepatic fibrosis. Mass spectrometry-based oxophospho-lipidomics identified individual OxPC species that were reduced by scFv-E06 expression. In vitro, identified OxPC species dysregulated mitochondrial metabolism and gene expression in hepatocytes and hepatic stellate cells. We demonstrate that individual OxPC species independently affect disease initiation and progression from hepatic steatosis to steatohepatitis, and that AAV-mediated expression of scFv-E06 is an effective therapeutic intervention.
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- 2022
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26. Immunohistochemistry in melanocytic lesions: Updates with a practical review for pathologists.
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Saleem A, Narala S, and Raghavan SS
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- Biomarkers, Tumor, Humans, Immunohistochemistry, Melanocytes metabolism, Melanocytes pathology, S100 Proteins metabolism, Pathologists, Skin Neoplasms diagnosis, Skin Neoplasms pathology
- Abstract
This review provides a summary of the immunohistochemical markers pertinent to the diagnosis of melanocytic lesions. There is considerable morphologic overlap between benign and malignant melanocytic lesions, and given the significant differences in clinical management, the diagnostic workup becomes crucial. Immunohistochemistry aids in the distinction between various melanocytic proliferations and recent contributions to the literature have furthered our optimization of panels in the diagnostic workup. In recent years, SOX10 has been considered as the optimal marker for melanocytic lesions given the similar sensitivity but higher specificity than S100. HMB-45 is less sensitive than S100 but demonstrates utility in confirmation of deceptively banal small cell and nevoid melanoma variants where deep nests of melanocytes are highlighted. Melan-A (MART-1) and MiTF show similar sensitivity to S100 however there is a lack of expression in spindle cell and desmoplastic melanomas., (Copyright © 2021 Elsevier Inc. All rights reserved.)
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- 2022
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27. Use of Ultrasensitive RNA In Situ Hybridization for Determining Clonality in Cutaneous B-Cell Lymphomas and Lymphoid Hyperplasia Decreases Subsequent Use of Molecular Testing and Is Cost-effective.
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Craddock AP, Kane WJ, Raghavan SS, Williams ES, Gru AA, and Gradecki SE
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- Cost-Benefit Analysis, Humans, Hyperplasia, Immunoglobulin Heavy Chains, In Situ Hybridization, Molecular Diagnostic Techniques, Lymphoma, B-Cell diagnosis, Lymphoma, B-Cell genetics, Lymphoma, B-Cell pathology, RNA
- Abstract
Primary cutaneous B-cell lymphomas (PCBCLs) are diagnostically challenging entities due to significant overlap in clinical and morphologic features with reactive lymphoid proliferations. Traditional methods for evaluating clonality such as immunohistochemistry (IHC) and chromogenic in situ hybridization (CISH) are limited by low sensitivity, which leads to additional costly and time-consuming molecular clonality assays. More recent technology has introduced ultrasensitive bright-field RNA in situ hybridization (BRISH) to the field, which can detect single molecules of light-chain mRNA. The current study evaluated 274 cases of PCBCL in addition to atypical and reactive lymphoid infiltrates, with CISH or BRISH performed on 180 (65.7%). CISH was performed on 105 (58.3%), and BRISH was performed on 75 (41.7%). Significantly fewer immunoglobulin heavy-chain (IGH) rearrangement studies were performed on cases that were evaluated with BRISH as compared with CISH (P=0.02). Subgroup analysis demonstrated that cases with restriction by BRISH were significantly less likely to have subsequent IGH studies performed (P=0.01). The expected costs of cases using CISH versus BRISH were $1053.89 versus $810.32 to the patient and $245.63 versus $225.23 to the laboratory. The use of ultrasensitive BRISH to evaluate clonality in PCBCL reduced the use of IGH rearrangement studies when compared with CISH. In particular, cases with light-chain restriction by BRISH did not result in confirmatory molecular testing. Despite slightly higher costs to the laboratory to perform BRISH, routine use of this methodology can result in cost savings to both the patient and laboratory by decreasing the use of expensive molecular methods., Competing Interests: Conflicts of Interest and Source of Funding: A.A.G. currently acts as a consultant and investigator as Seattle Genetics, an investigator at Innate Pharma, an investigator and consultant at StemLine Therapeutics, and an investigator at CRISPR Therapeutics. These companies did not provide funding for this work, nor did they play any role in the study design, analysis, or manuscript preparation. For the remaining authors none were declared., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)
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- 2022
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28. Machine Learning Approach for Cardiovascular Risk and Coronary Artery Calcification Score.
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Aditya CR, Sattaru NC, Gopal K, Rahul R, Chandra Shekara G, Nasif O, Alharbi SA, Raghavan SS, and Jayadhas SA
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- Coronary Angiography methods, Heart Disease Risk Factors, Humans, Machine Learning, Risk Factors, Cardiovascular Diseases, Coronary Artery Disease diagnostic imaging, Coronary Artery Disease epidemiology
- Abstract
Coronary artery calcification (CAC) could assist in the discovery of new risk elements for coronary artery disorder. CAC evaluation, on the other hand, is difficult due to the wide range of CAC in the populations. As a reason, evaluating and analysing data among research have become complicated. In the Research of Inherited Risk Factors for Coronary Atherosclerosis, we used CAC information to test the effects of different analytical methodologies on the correlation with recognized cardiovascular risk elements in asymptomatic patients. Cardiac computed tomography (CT) is also seeing an increase in examinations, and machine learning (ML) could assist with the growing amount of extracted data. Furthermore, there are other sectors in cardiac CT where machine learning could be crucial, including coronary calcium scoring, perfusion, and CT angiography. The establishment of risk evaluation algorithms based on information from CAC utilizing machine learning could assist in the categorization of patients undergoing cardiovascular into distinct risk groups and effectively adapt their treatments to their unique situations. Our findings imply that for forecasting CVD occurrences in asymptomatic people, age-sex segmentation by CAC percentile rank is as effective as absolute CAC scoring. Longitudinal population-based investigations are currently underway and would offer further definitive findings. While machine learning is a strong technology with a lot of possibilities, its implementations in the domain of cardiac CAC are generally in the early stages of development and are not currently commonly accessible in medical practise because of the requirement for substantial verification. Enhanced machine learning will, however, have a significant effect on cardiovascular and coronary artery calcification in the upcoming years., Competing Interests: The authors declare that there are no conflicts of interest regarding the publication of this paper., (Copyright © 2022 C. R. Aditya et al.)
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- 2022
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29. A Deep Learning Framework for Earlier Prediction of Diabetic Retinopathy from Fundus Photographs.
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Gunasekaran K, Pitchai R, Chaitanya GK, Selvaraj D, Annie Sheryl S, Almoallim HS, Alharbi SA, Raghavan SS, and Tesemma BG
- Subjects
- Fundus Oculi, Humans, Neural Networks, Computer, Photography methods, Deep Learning, Diabetes Mellitus, Diabetic Retinopathy diagnostic imaging
- Abstract
Diabetic patients can also be identified immediately utilizing retinopathy photos, but it is a challenging task. The blood veins visible in fundus photographs are used in several disease diagnosis approaches. We sought to replicate the findings published in implementation and verification of a deep learning approach for diabetic retinopathy identification in retinal fundus pictures. To address this issue, the suggested investigative study uses recurrent neural networks (RNN) to retrieve characteristics from deep networks. As a result, using computational approaches to identify certain disorders automatically might be a fantastic solution. We developed and tested several iterations of a deep learning framework to forecast the progression of diabetic retinopathy in diabetic individuals who have undergone teleretinal diabetic retinopathy assessment in a basic healthcare environment. A collection of one-field or three-field colour fundus pictures served as the input for both iterations. Utilizing the proposed DRNN methodology, advanced identification of the diabetic state was performed utilizing HE detected in an eye's blood vessel. This research demonstrates the difficulties in duplicating deep learning approach findings, as well as the necessity for more reproduction and replication research to verify deep learning techniques, particularly in the field of healthcare picture processing. This development investigates the utilization of several other Deep Neural Network Frameworks on photographs from the dataset after they have been treated to suitable image computation methods such as local average colour subtraction to assist in highlighting the germane characteristics from a fundoscopy, thus, also enhancing the identification and assessment procedure of diabetic retinopathy and serving as a skilled guidelines framework for practitioners all over the globe., Competing Interests: The authors declare that there are no conflicts of interest regarding the publication of this paper., (Copyright © 2022 K. Gunasekaran et al.)
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- 2022
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30. Cutaneous Neurocristic Hamartoma Mimicking Basal Cell Carcinoma in a Patient With Xeroderma Pigmentosum.
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Finberg A, Martin S, Gradecki S, Zlotoff B, and Raghavan SS
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- Child, Comparative Genomic Hybridization, Female, Humans, Carcinoma, Basal Cell complications, Carcinoma, Basal Cell diagnosis, Carcinoma, Basal Cell genetics, Hamartoma complications, Hamartoma diagnosis, Hamartoma genetics, Skin Neoplasms complications, Skin Neoplasms diagnosis, Skin Neoplasms genetics, Xeroderma Pigmentosum complications, Xeroderma Pigmentosum diagnosis, Xeroderma Pigmentosum genetics
- Abstract
Abstract: Neurocristic hamartomas (NCH) of cutaneous origin are especially rare congenital or acquired neoplasms that often arise through aberrant embryologic development of pluripotent neural crest cells. Clinically, they often present as pigmented macules or papules on the scalp with associated alopecia. NCHs are characterized histopathologically by dermal melanocytic, fibroblastic, and neurosustentacular components. Correct identification of this etiology is critical because of potential for malignant transformation, particularly in acquired NCHs. Our patient was a 6-year-old girl with xeroderma pigmentosum and confirmed XPC mutation followed in our dermatology clinic since the age of 3. She had a history of multiple actinic keratoses but no prior skin cancers. A 4-mm homogenous pink papule on the left frontal scalp concerning for basal cell carcinoma was noted during routine skin examination. After a 3-month course of 3 times weekly topical imiquimod, the lesion had grown to a 6 mm diameter. The patient was then referred to plastic surgery for definitive excision. Histologically, the lesion showed a well-circumscribed proliferation of spindle cells with a trabecular and nested growth pattern. Perivascular pseudorosettes were identified, as were areas that resembled well-differentiated neural tissue. The spindle cells diffusely expressed S100 protein, SOX10, and CD34, with patchy expression of Melan-A and HMB-45. PRAME was negative, and p16 was retained. Array comparative genomic hybridization was performed, and no clinically significant copy number or single nucleotide variants were detected. To the best of our knowledge, this is the first documented case in the literature of a cutaneous neurocristic hamartoma arising in a patient with xeroderma pigmentosum., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)
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- 2022
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31. Next-generation sequencing confirms T-cell clonality in a subset of pediatric pityriasis lichenoides.
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Raghavan SS, Wang JY, Gru AA, Marqueling AL, Teng JMC, Brown RA, Novoa RA, Kim Y, Zehnder J, Zhang BM, and Rieger KE
- Subjects
- Adolescent, Child, Child, Preschool, Female, High-Throughput Nucleotide Sequencing, Humans, Male, Cloning, Molecular, Genes, T-Cell Receptor beta genetics, Genes, T-Cell Receptor gamma genetics, Pityriasis Lichenoides genetics
- Abstract
Background: Pityriasis lichenoides (PL) is a papulosquamous disease that affects both adults and children. Previous studies have shown a subset of this entity to have clonal T-cell populations via PCR-based assays. In this study, we sought to implement next-generation sequencing (NGS) as a more sensitive and specific test to examine for T-cell clonality within the pediatric population., Methods: We identified 18 biopsy specimens from 12 pediatric patients with clinical and histopathologic findings compatible with PL. Patient demographics, clinical features, management, and histopathologic findings were reviewed. All specimens were analyzed for clonality with NGS of T-cell receptor beta (TRB) and gamma (TRG) genes., Results: Of the 12 patients, 9 (75%) had complete resolution of lesions at the time of data collection (mean follow-up 31 months). The remaining three patients significantly improved with methotrexate (with or without acitretin). Interestingly, 7 of 12 patients (58%) and 9 of 17 biopsy specimens (53%) showed evidence of T-cell clonality. Two patients showed matching TRB clones from different anatomic sites., Conclusions: T-cell clonality is a common finding in PL, probably representing a "reactive clonality" rather than a true lymphoproliferative disorder. Clonality alone cannot be used as a means to distinguish PL from lymphomatoid papulosis or cutaneous lymphoma., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)
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- 2022
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32. Clonal cutaneous and neurosyphilis: A pitfall in pseudolymphoma diagnosis.
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Yi LG, Rusu CA, Cropley TG, Marchi E, Gru AA, Greer KE, and Raghavan SS
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- Aged, Cloning, Molecular, Diagnosis, Differential, Genes, T-Cell Receptor gamma genetics, Humans, Lymphoma, T-Cell diagnosis, Male, Uveitis, Anterior microbiology, Syphilis diagnosis
- Abstract
Syphilis is a sexually transmitted infectious disease caused by the bacterium Treponema pallidum and can cause a wide variety of cutaneous manifestations, most commonly, a papulosquamous eruption of the trunk and extremities. Treatment with penicillin is curative. We report a case of a 69-year-old man who presented with recent onset of blurry vision and a nonpainful, nonpruritic eruption of pink-to-violaceous dermal nodules on his upper trunk and upper extremities. Biopsies of two separate locations revealed a dense superficial and deep perivascular atypical lymphocytic infiltrate with admixed plasma cells, histiocytes, and eosinophils. Some scattered cells expressed CD30, PD1, BCL-6, and ICOS. T-cell receptor (TCR)-rearrangement showed an identical TCR-gamma clone between both biopsy specimens. The patient was subsequently seen by ophthalmology and diagnosed with acute anterior uveitis. Rapid plasma reagin was reactive and cerebrospinal fluid studies showed findings consistent with a diagnosis of neurosyphilis. A T. pallidum immunostain of the skin biopsies was performed upon re-review, and was diffusely positive for spirochetes at the dermal-epidermal junction and within injured vessels. The patient was treated with penicillin G with near-resolution of his skin lesions. This case highlights the unusual ability of syphilis to mimic a T-cell lymphoma with matching clones across two different biopsy sites., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)
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- 2022
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33. Reproducible Histopathologic Features in Cases of Basal Cell Carcinoma With Neuroendocrine Expression: A Clinicopathologic Study of 24 Cases With a Potential Diagnostic Pitfall.
- Author
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Plaza JA, Pootrakul L, Raghavan SS, Sangueza M, and Gru AA
- Subjects
- Biomarkers, Tumor analysis, Carcinoma, Neuroendocrine diagnosis, Carcinoma, Neuroendocrine pathology, Diagnosis, Differential, Female, Humans, Male, Carcinoma, Basal Cell diagnosis, Carcinoma, Basal Cell pathology, Skin Neoplasms diagnosis, Skin Neoplasms pathology
- Abstract
Abstract: Basal cell carcinomas (BCCs) are common malignancies that usually show clear histomorphologic features, but in certain instances, it can display different patterns of differentiation leading to potential diagnostic confusion. BCCs with neuroendocrine differentiation/expression have been mentioned only briefly in the literature. In this study, we present cases of BCCs with neuroendocrine differentiation/expression that demonstrate reproducible histopathological features. Twenty-four cases were included in the study. All tumors showed conventional histopathologic features that are seen in BCCs, but in addition, all the tumors showed large, hyperchromatic, pleomorphic, mononuclear, and multinucleate cells with intracytoplasmic inclusions and intranuclear cytoplasmic invaginations, with rare cases showing stippled nuclei (salt-and-pepper appearance). These histologic features were somewhat concerning for a neuroendocrine carcinoma; thus, immunohistochemistry studies were performed in all cases at the time of diagnosis. By immunohistochemistry, all tumors showed expression of neuroendocrine markers. CD56 was expressed in all cases 24/24, chromogranin was positive in 17/24 cases, and synaptophysin 8/24 was positive in cases. This study confirms a subset of histopathologic features that are present in cases of BCC that are associated with neuroendocrine expression that can potentially be interpreted differently and can create a diagnostic pitfall. Neuroendocrine expression in BCCs is yet uncertain, and further studies are required to fully understand this phenomenon. To avoid diagnostic pitfalls, dermatopathologists must be aware of these unusual histopathologic features and aberrant immunostaining in such tumors; hence, it is advised to perform a thorough histologic inspection., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)
- Published
- 2021
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34. Primary Cutaneous Monomorphic Post-transplant Lymphoproliferative Disorder Mimicking Squamous Cell Carcinoma In Situ.
- Author
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Craddock AP, Gru AA, Mannschreck D, Wilson BB, and Raghavan SS
- Subjects
- Aged, Carcinoma, Squamous Cell diagnosis, Diagnosis, Differential, Female, Humans, Lymphoproliferative Disorders immunology, Lymphoproliferative Disorders pathology, Postoperative Complications diagnosis, Postoperative Complications pathology, Skin Diseases immunology, Skin Diseases pathology, Skin Neoplasms diagnosis, Immunocompromised Host, Kidney Transplantation adverse effects, Lymphoproliferative Disorders diagnosis, Postoperative Complications immunology, Skin Diseases diagnosis
- Abstract
Abstract: Post-transplant lymphoproliferative disorder (PTLD) is a term used to describe a range of lymphoproliferative disorders that occur after solid organ transplant. Although the clinical presentation is variable, primary cutaneous PTLD typically presents as isolated nodules that appear as dermal-based proliferations. We present a case of a 70-year-old woman with a history of a kidney transplant who presented with a 2-month history of an asymptomatic, erythematous plaque on the right shin, clinically suspected to be squamous cell carcinoma in situ. Histomorphology demonstrated a dermal proliferation of atypical plasma cells with dense chromatin, variable nucleoli, and irregular nuclear borders. The atypical plasma cells were positive for Epstein-Barr virus by in situ hybridization and markedly kappa-restricted by RNAscope in situ hybridization. A diagnosis of cutaneous monomorphic PTLD, plasma cell neoplasm variant, was rendered, a rare diagnosis in the skin. Treatment for PTLD typically involves reduction of immunosuppression, although our patient progressed and developed new lesions despite this intervention. In this study, we present an atypical presentation of cutaneous PTLD, plasma cell neoplasm variant, presenting as squamous cell carcinoma in situ., Competing Interests: A. A. Gru currently acts as a consultant and investigator as Seattle Genetics, an investigator at Innate Pharma, an investigator and consultant at StemLine Therapeutics, and an investigator at CRISPR Therapeutics. These companies did not provide funding for this work, nor did they play any role in the study design, analysis, or manuscript preparation. The remaining authors declare no conflicts of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)
- Published
- 2021
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35. Clinicopathologic characterization of enfortumab vedotin-associated cutaneous toxicity in patients with urothelial carcinoma.
- Author
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Hirotsu KE, Rana J, Wang JY, Raghavan SS, Rieger KE, Srinivas S, Fan AC, Kwong BY, Novoa RA, and Zaba LC
- Subjects
- Antibodies, Monoclonal therapeutic use, Humans, Lymphatic Metastasis, Skin pathology, Urinary Bladder Neoplasms secondary, Antibodies, Monoclonal adverse effects, Antineoplastic Agents, Immunological adverse effects, Carcinoma, Transitional Cell drug therapy, Drug Eruptions etiology, Skin drug effects, Urinary Bladder Neoplasms drug therapy
- Abstract
Competing Interests: Conflicts of interest Dr Kwong is a consultant for Genentech, Oncoderm, Happy 2nd Birthday, and is on the advisory board of Kyowa Kirin. Drs Hirotsu, Rana, Wang, Raghavan, Rieger, Srinivas, Fan, Novoa, and Zaba have no conflicts of interest to disclose.
- Published
- 2021
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36. Pemphigus erythematosus: A case series from a tertiary academic center and literature review.
- Author
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Hobbs LK, Noland MB, Raghavan SS, and Gru AA
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Child, Preschool, Diagnosis, Differential, Ethnicity statistics & numerical data, Female, Fluorescent Antibody Technique methods, Humans, Lupus Erythematosus, Systemic diagnosis, Lupus Erythematosus, Systemic immunology, Lupus Erythematosus, Systemic pathology, Male, Middle Aged, Pemphigus epidemiology, Pemphigus immunology, Pemphigus pathology, Prevalence, Skin Diseases, Vesiculobullous immunology, Tertiary Care Centers, Autoimmune Diseases pathology, Erythema pathology, Pemphigus diagnosis, Skin Diseases, Vesiculobullous pathology
- Abstract
Background: Pemphigus erythematosus (PE) is a rare autoimmune skin condition with clinical, histopathological, and serological features that show overlap between lupus erythematosus and pemphigus foliaceus. It typically presents with erythematous, scaly plaques and has a female predominance., Methods: After Institutional Review Board (IRB) approval, we searched the internal pathology database for "pemphigus erythematosus" in the diagnostic line between 1 January 2000 and 30 July 2020. A comprehensive chart review was performed to collect patient demographics, clinical presentation, and treatment course. We performed a review of the literature and clinical, histopathological, and serological features were collected for comparison to our case series., Results: Five patients in the case series and 87 patients in the literature were diagnosed with PE. Clinical, histopathological, and serological features were consistent with what has been reported in the literature, although our cohort demonstrated a younger age at presentation, along with a higher proportion (80%) of Black patients. Of the 25 patients in the literature whose race was reported, only five patients (20%) were reported to be Black., Conclusion: This is the first case series of PE that has shown an increased prevalence among middle-aged Black patients. No specific trend in regards to race was seen in the review of the literature., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)
- Published
- 2021
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37. Hemophagocytic lymphohistiocytosis secondary to progressive disseminated histoplasmosis presenting as cellulitis.
- Author
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Puing AG, Raghavan SS, Aleshin MA, and Ho DY
- Abstract
Histoplasmosis-associated hemophagocytic lymphohistiocytosis is a rate but lethal disease in immunocompromised hosts. Unusual clinical presentations make diagnosing invasive fungal infection even more challenging. Here we present a case of hemophagocytic lymphohistiocytosis secondary to progressive disseminated histoplasmosis presenting as cellulitis in a patient with systemic lupus erythematous. A high index of suspicion combined with histopathology and molecular diagnostic techniques are important to establish an accurate and timely diagnosis of opportunistic infections in immunocompromised patients., Competing Interests: There are none., (© 2021 The Authors.)
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- 2021
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38. Spindle-cell (Sarcomatoid) Variant of Cutaneous Anaplastic Large-cell Lymphoma (C-ALCL): An Unusual Mimicker of Cutaneous Malignant Mesenchymal Tumors-A Series of 11 Cases.
- Author
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Gru AA, Bhagat G, Subtil A, Raghavan SS, Pulitzer M, Chung C, Sangueza M, and Plaza JA
- Subjects
- Adult, Aged, Aged, 80 and over, Biomarkers, Tumor analysis, Biomarkers, Tumor genetics, Diagnosis, Differential, Female, Humans, Immunohistochemistry, Immunophenotyping, In Situ Hybridization, Fluorescence, Lymphoma, Primary Cutaneous Anaplastic Large Cell genetics, Lymphoma, Primary Cutaneous Anaplastic Large Cell immunology, Male, Mesenchymoma genetics, Mesenchymoma immunology, Middle Aged, Predictive Value of Tests, Skin Neoplasms genetics, Skin Neoplasms immunology, Lymphoma, Primary Cutaneous Anaplastic Large Cell pathology, Mesenchymoma pathology, Skin Neoplasms pathology
- Abstract
Cutaneous anaplastic large-cell lymphoma (C-ALCL) represents one of the entities within the group of CD30-positive lymphoproliferative disorders of the skin. Most cases are ALK-negative, though isolated cases of ALK-positive C-ALCL have also been reported. By definition, the diagnosis of C-ALCL requires the expression of CD30 in >75% of the cells. Histopathologically, C-ALCL shows a dermal-based nodular and circumscribed proliferation of large pleomorphic cells with vesicular nuclei, prominent nucleoli, and eosinophilic cytoplasm, including hallmark cells. Since 1990, isolated case reports of a so-called "sarcomatoid" variant have been published in the literature. Herein, we present a series of 11 cases of spindle (sarcomatoid) C-ALCL, with comprehensive histopathologic, immunophenotypic, and molecular data. Spindle C-ALCL represents a potential mimicker of malignant mesenchymal or hematopoietic tumors in the skin and should always be considered in the differential diagnosis when assessing cutaneous pleomorphic spindle cell neoplasms., Competing Interests: Conflicts of Interest and Source of Funding: The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)
- Published
- 2021
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39. Reactivation of Chagas Disease in a Patient With an Autoimmune Rheumatic Disease: Case Report and Review of the Literature.
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Czech MM, Nayak AK, Subramanian K, Suarez JF, Ferguson J, Jacobson KB, Montgomery SP, Chang M, Bae GH, Raghavan SS, Wang H, Miranti E, Budvytiene I, Shoor SM, Banaei N, Rieger K, Deresinski S, Holubar M, and Blackburn BG
- Abstract
Reactivation of Chagas disease has been described in immunosuppressed patients, but there is a paucity of literature describing reactivation in patients on immunosuppressive therapies for the treatment of autoimmune rheumatic diseases. We describe a case of Chagas disease reactivation in a woman taking azathioprine and prednisone for limited cutaneous systemic sclerosis (lcSSc). Reactivation manifested as indurated and erythematous cutaneous nodules. Sequencing of a skin biopsy specimen confirmed the diagnosis of Chagas disease. She was treated with benznidazole with clinical improvement in the cutaneous lesions. However, her clinical course was complicated and included disseminated CMV disease and subsequent septic shock due to bacteremia. Our case and review of the literature highlight that screening for Chagas disease should be strongly considered for patients who will undergo immunosuppression for treatment of autoimmune disease if epidemiologically indicated., (© The Author(s) 2021. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)
- Published
- 2021
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40. DDIT3 Immunohistochemistry Is a Useful Tool for the Diagnosis of Myxoid Liposarcoma.
- Author
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Scapa JV, Cloutier JM, Raghavan SS, Peters-Schulze G, Varma S, and Charville GW
- Subjects
- Humans, Immunohistochemistry, Transcription Factor CHOP biosynthesis, Biomarkers, Tumor analysis, Liposarcoma, Myxoid diagnosis, Soft Tissue Neoplasms diagnosis, Transcription Factor CHOP analysis
- Abstract
Myxoid liposarcoma is a malignant adipogenic neoplasm characterized by prominent arborizing capillaries, occasional lipoblasts, and primitive-appearing spindle cells in a myxoid background. A recurrent translocation in myxoid liposarcoma results in an oncoprotein consisting of full-length DDIT3 (CHOP) fused to an N-terminal segment of either FUS (TLS) or, less often, EWSR1. Here, we explore the diagnostic significance of DDIT3 expression in myxoid liposarcoma using a mouse monoclonal antibody recognizing an epitope in the N-terminal region. Studying a total of 300 tumors, we find diffuse, moderate-to-strong nuclear-localized anti-DDIT3 immunoreactivity in all 46 cases of myxoid liposarcoma representing 36 unique tumors, including 6 cases with high-grade (round cell) morphology. DDIT3 immunohistochemistry also highlighted a distinctive vasculocentric growth pattern in 7 myxoid liposarcomas treated with neoadjuvant radiation. In contrast, the vast majority of other examined lipomatous and myxoid neoplasms exhibited no DDIT3 expression; limited, weak immunoreactivity in <10% of cells was infrequently observed in dedifferentiated liposarcoma (6/39, 15%), solitary fibrous tumor (3/12, 25%), pleomorphic liposarcoma (1/15, 7%), and high-grade myxofibrosarcoma (2/17, 12%). Although this minimal DDIT3 expression did not correlate with DDIT3 amplification or myxoid liposarcoma-like morphology in dedifferentiated liposarcoma, there was evidence among sarcomas (excluding myxoid liposarcoma) of a relationship between expression and exposure to neoadjuvant radiation or cytotoxic chemotherapy. The constellation of findings indicates that DDIT3 immunohistochemistry may have utility in the evaluation of myxoid and lipomatous neoplasms to support the diagnosis of myxoid liposarcoma., Competing Interests: Conflicts of Interest and Source of Funding: G.W.C. is supported in part by the Stanford University School of Medicine Clinical and Translational Science Award Program (National Center for Advancing Translational Sciences, KL2TR003143). For the remaining authors none were declared., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)
- Published
- 2021
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41. ALK-positive compound Spitz nevus with extensive perineural and intraneural neurotropism.
- Author
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Brown RA, Wang JY, Raghavan SS, Zhang J, Wan DC, Born D, Koo M, Hazard FK, Novoa RA, and Rieger KE
- Subjects
- Child, Preschool, Female, Humans, Lip pathology, Mutation, Nevus, Epithelioid and Spindle Cell genetics, Peripheral Nerves pathology, Skin Neoplasms genetics, Anaplastic Lymphoma Kinase genetics, Nevus, Epithelioid and Spindle Cell pathology, Skin Neoplasms pathology
- Abstract
Historically recognized by their characteristic histopathologic features, Spitz neoplasms are now known to be molecularly defined by mutually exclusive recurrent abnormalities that cause activation of the MAPK pathway. Spitz neoplasms with ALK rearrangements frequently demonstrate polypoid growth with a plexiform arrangement of nested, fusiform melanocytes in intersecting fascicles. Although neurotropism has been described in indolent Spitz neoplasms, this feature is not frequently mentioned in publications on histopathologic assessment of this group of melanocytic tumors. Here, we present an unusual case of a 3-year-old female with an ALK-positive compound Spitz nevus with extensive perineural and intraneural neurotropism occurring on the vermilion border of the lower lip., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)
- Published
- 2021
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42. BODIPY based realtime, reversible and targeted fluorescent probes for biothiol imaging in living cells.
- Author
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He R, Zhang Y, Madhu S, Gao Q, Lian Q, Raghavan SS, and Geng J
- Subjects
- Humans, Boron Compounds chemistry, Fluorescent Dyes chemistry, Sulfhydryl Compounds chemistry
- Abstract
Real-time live cell imaging and quantification of biothiol dynamics are important for understanding pathophysiological processes. However, the design and synthesis of rational probes that have reversible and real-time capabilities is still challenging. In this work, we have prepared boron-dipyrrolemethene (BODIPY) based fluorescent molecules as ratiometric probes that allow the real-time biothiol dynamics to be observed in living cells. The Michael reaction between α-formyl-BODIPY (BOD-JQ) and GSH exhibited a reversible fluorogenic mechanism with fluorescent emission shifting from 592 nm to 544 nm with t
1/2 = 16 ms. In particular, we showed that the probes with targeting agents are capable of detecting biothiols in mitochondria and the endoplasmic reticulum (ER) with high temporal resolution.- Published
- 2020
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43. Histopathologic Characterization of Mogamulizumab-associated Rash.
- Author
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Wang JY, Hirotsu KE, Neal TM, Raghavan SS, Kwong BY, Khodadoust MS, Brown RA, Novoa RA, Kim YH, and Rieger KE
- Subjects
- CD4-CD8 Ratio, Drug Eruptions genetics, Drug Eruptions immunology, Drug Eruptions pathology, Exanthema genetics, Exanthema immunology, Exanthema pathology, Female, Genes, T-Cell Receptor, High-Throughput Nucleotide Sequencing, Humans, Male, Skin immunology, Skin pathology, T-Lymphocytes immunology, Antibodies, Monoclonal, Humanized adverse effects, Antineoplastic Agents adverse effects, Drug Eruptions etiology, Exanthema chemically induced, Skin drug effects, T-Lymphocytes drug effects
- Abstract
Rash is one of the most common adverse events observed with mogamulizumab, an anti-C-C chemokine receptor 4 monoclonal antibody approved for previously treated mycosis fungoides (MF) and Sezary syndrome (SS). Given the nonspecific clinical presentations of this rash, histopathologic distinction from MF/SS is critical for informing clinical management. We performed a comprehensive characterization of the histopathologic findings in mogamulizumab-associated rash (MAR) with the integration of high-throughput sequencing of T-cell receptor (TCR) genes. Fifty-two biopsy specimens from 19 patients were evaluated retrospectively. Three major histologic reaction patterns were identified: spongiotic/psoriasiform dermatitis (33/52), interface dermatitis (11/52), and granulomatous dermatitis (8/52). Almost half of the specimens (21/52) showed at least 2 of these reaction patterns concurrently. Dermal eosinophils were not a consistent feature, being present in only half (27/52) of specimens and prominent in only 3. Features mimicking MF/SS, including lymphocyte exocytosis, lamellar fibroplasia, and adnexal involvement, were commonly seen but tended to be focal and mild. In 38/43 specimens with available immunohistochemistry, intraepidermal lymphocytes demonstrated a CD4:CD8 ratio ≤1 : 1. Low background levels of the patient's previously identified MF/SS-associated TCR sequence(s) were demonstrated in 20/46 specimens analyzed by high-throughput sequencing of TCR. We conclude that MAR may demonstrate diverse histologic features. Findings that may distinguish MAR from MF/SS include the inverted or normalized CD4:CD8 ratio within intraepidermal lymphocytes and demonstration of absent or nondominant levels of disease-associated TCR sequences. Correlation with the clinical findings and immunohistochemical and molecular characterization of the patient's MF/SS before mogamulizumab, when possible, may facilitate recognition of MAR.
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- 2020
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44. Diffuse PRAME expression is highly specific for malignant melanoma in the distinction from clear cell sarcoma.
- Author
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Raghavan SS, Wang JY, Toland A, Bangs CD, Rieger KE, Novoa RA, Charville GW, and Brown RA
- Subjects
- Antigens, Neoplasm analysis, Biomarkers, Tumor analysis, Biomarkers, Tumor metabolism, Diagnosis, Differential, Humans, Sensitivity and Specificity, Melanoma, Cutaneous Malignant, Antigens, Neoplasm biosynthesis, Melanoma diagnosis, Sarcoma, Clear Cell diagnosis, Skin Neoplasms diagnosis
- Published
- 2020
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- View/download PDF
45. PRAME expression in melanocytic proliferations with intermediate histopathologic or spitzoid features.
- Author
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Raghavan SS, Wang JY, Kwok S, Rieger KE, Novoa RA, and Brown RA
- Subjects
- Adult, Aged, Carrier Proteins genetics, Cohort Studies, Diagnosis, Differential, Dysplastic Nevus Syndrome genetics, Dysplastic Nevus Syndrome pathology, Female, Humans, Immunohistochemistry methods, Male, Melanoma pathology, Nevus, Epithelioid and Spindle Cell genetics, Nevus, Epithelioid and Spindle Cell pathology, Skin Neoplasms pathology, Tumor Suppressor Proteins genetics, Ubiquitin Thiolesterase genetics, Melanoma, Cutaneous Malignant, Antigens, Neoplasm genetics, Cell Proliferation genetics, Melanocytes pathology, Melanoma genetics, Skin Neoplasms genetics
- Abstract
Background: PRAME (PReferentially expressed Antigen in MElanoma) has shown utility in distinguishing melanoma from benign melanocytic lesions, but knowledge of its expression pattern in intermediate melanocytic and spitzoid proliferations is limited., Methods: Immunohistochemical expression of PRAME was examined in 112 melanocytic proliferations with intermediate histopathologic or spitzoid features., Results: Any intensity of nuclear PRAME staining in at least 60% of lesional melanocytes was determined as the best threshold for diffuse staining in this cohort. Nearly all non-spitzoid melanomas (23/24; 95.8%) demonstrated diffuse PRAME expression. PRAME was completely negative in 95.6% (43/45) of mitotically-active nevi, traumatized nevi, nevi with persistent/recurrent features, and dysplastic nevi. Most Spitz nevi (15/20) and atypical Spitz tumors (10/13) entirely lacked PRAME expression. One Spitz nevus, one atypical Spitz tumor, and one spitzoid melanoma (1/2) demonstrated diffuse PRAME expression., Conclusions: Although diffuse PRAME expression is generally limited to malignant melanoma, benign Spitz nevi and atypical Spitz tumors can infrequently express diffuse PRAME. PRAME immunohistochemistry can be useful in the evaluation of atypical melanocytic proliferations with intermediate histopathologic features but should be interpreted with caution in the setting of spitzoid neoplasms., (© 2020 John Wiley & Sons A/S . Published by John Wiley & Sons Ltd.)
- Published
- 2020
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46. Concurrent Trypanosoma cruzi and Cytomegalovirus Reactivation in an Immunosuppressed Patient With Limited Cutaneous Systemic Sclerosis.
- Author
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Chang MS, Bae GH, Almazan T, Raghavan SS, Wang JY, Czech MM, Wang H, Banaei N, Blackburn BG, Novoa RA, and Rieger KE
- Abstract
Chagas disease, a multisystem infection caused by the protozoan Trypanosoma cruzi, is primarily found in Latin America. In recent years, prevalence has increased in the United States, where reactivation is the most common clinical scenario. Here, we describe cutaneous reactivation of T. cruzi in a patient with limited cutaneous systemic sclerosis on immunosuppression therapy who simultaneously presented with cytomegalovirus reactivation. Histopathology showed parasitized histiocytes in the superficial and deep dermis. Occasional epidermal keratinocytes were also parasitized, and rare organisms were also seen in the walls of blood vessels. Also noted were viral cytopathic changes within the vascular endothelium, and immunostaining confirmed cytomegalovirus. In this report, we describe the difference in cutaneous findings between reactivated and acute Chagas disease, and we also review the histopathologic features that help distinguish T.cruzi from other intracellular organisms.
- Published
- 2020
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47. Eruptive Spitz nevus, a striking example of benign metastasis.
- Author
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Raghavan SS, Kapler ES, Dinges MM, Bastian BC, and Yeh I
- Subjects
- Female, Humans, Melanoma genetics, Middle Aged, Prognosis, Protein-Tyrosine Kinases genetics, Proto-Oncogene Proteins genetics, Skin Neoplasms genetics, Melanoma pathology, Nevus, Epithelioid and Spindle Cell pathology, Oncogene Proteins, Fusion genetics, Skin Neoplasms secondary
- Abstract
Metastasis is generally considered a characteristic of malignant tumors. Herein, we describe a patient with more than one hundred discrete Spitz nevi scattered all over her skin. Molecular analysis from three of the lesions identified a ROS1 fusion oncogene with identical genomic breakpoints, indicating that the nevi arose from a single transformed melanocyte and then disseminated throughout the integument. The demonstration of widespread distribution of a benign tumor with limited proliferative capability indicates that metastatic dissemination is not contingent on full malignant transformation. Thus, eruptive Spitz nevus is a striking example of benign metastasis, demonstrating that metastasis can occur before malignant transformation.
- Published
- 2020
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48. Diagnostic Utility of LEF1 Immunohistochemistry in Differentiating Deep Penetrating Nevi From Histologic Mimics.
- Author
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Raghavan SS, Saleem A, Wang JY, Rieger KE, Brown RA, and Novoa RA
- Subjects
- Adult, Diagnosis, Differential, Female, Humans, Immunohistochemistry, Lymphoid Enhancer-Binding Factor 1 analysis, Male, Middle Aged, Nevus, Blue diagnosis, beta Catenin analysis, beta Catenin biosynthesis, Biomarkers, Tumor analysis, Lymphoid Enhancer-Binding Factor 1 biosynthesis, Nevus, Pigmented diagnosis, Skin Neoplasms diagnosis
- Abstract
Deep penetrating nevi (DPNs) are intermediate grade lesions which have the capacity to recur, metastasize, or progress to melanoma. Differentiating DPN from other melanocytic lesions including blue and cellular blue nevi can be diagnostically challenging, and markers to distinguish these entities can be useful. Mutations of the β-catenin and mitogen-activated protein kinase pathways have recently been elucidated as distinctive of DPN. This pathway can subsequently activate lymphoid enhancer-binding factor 1 (LEF1), a transcription factor shown to facilitate the epithelial-mesenchymal transition to propagate tumorigenesis. Seventy-two cases in total were examined on hematoxylin and eosin sections and with β-catenin and LEF1 immunohistochemistry. This included: DPN (14), cellular blue nevi (19), blue nevi (15), congenital melanocytic nevi (12), and melanoma (12). Nuclear expression of LEF1, present throughout the entire depth of the lesion, was noted in 13/14 (93%) of DPN, 0/19 (0%) of cellular blue nevi, 0/15 (0%) of blue nevi, 1/12 (8%) of congenital melanocytic nevi, and 9/12 (75%) of melanoma cases. Nuclear expression of β-catenin, present throughout the entire depth of the lesion, was noted in 14/14 (100%) of DPN, 0/18 (0%) of cellular blue nevi, 0/15 (0%) of blue nevi, 1/12 (8%) of congenital melanocytic nevi, and 1/12 (8%) of melanoma cases. A majority of congenital melanocytic nevi demonstrated a gradient of LEF1 and β-catenin expression with more intense staining superficially and loss of staining with increasing depth. Deep, uniform nuclear LEF1 combined with β-catenin immunohistochemical staining can be useful in distinguishing DPN from histologic mimics.
- Published
- 2020
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49. Molecular profiling of a primary cutaneous signet-ring cell/histiocytoid carcinoma of the eyelid.
- Author
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Raghavan SS, Clark M, Louie CY, Jensen KC, Dietrich B, Beadle BM, El-Sawy T, Baik F, Kunder CA, and Brown RA
- Subjects
- Aged, 80 and over, Antineoplastic Agents, Hormonal therapeutic use, Biopsy, Carcinoma, Signet Ring Cell diagnosis, Carcinoma, Signet Ring Cell therapy, Combined Modality Therapy, Eyelid Neoplasms pathology, High-Throughput Nucleotide Sequencing methods, Histiocytes pathology, Humans, Male, Mutation, Radiotherapy, Adjuvant methods, Skin Neoplasms pathology, Surgical Flaps, Treatment Outcome, Antigens, CD genetics, Cadherins genetics, Carcinoma, Signet Ring Cell genetics, Eyelid Neoplasms genetics, Keratin-7 metabolism, Receptors, Androgen metabolism
- Abstract
Primary cutaneous signet-ring cell/histiocytoid carcinoma of the eyelid is a rare and aggressive neoplasm. Fewer than 50 cases have been reported in the literature, and the genetic driving mutations are unknown. Herein, we present a case of this rare disease along with the results of molecular profiling via targeted next-generation sequencing. The patient is an 85-year-old man who presented with left eyelid swelling initially thought to be a chalazion. After no response to incision and drainage and antibiotics, an incisional biopsy was performed. Histopathologic sections revealed a proliferation of cells with signet-ring and histiocytoid morphology arranged singly and in cords infiltrating the dermis, subcutaneous tissue, and muscle. The lesional cells strongly expressed cytoplasmic cytokeratin 7 and nuclear androgen receptor. Next-generation sequencing revealed a CDH1 mutation, which is known to confer signet-ring morphology in other carcinomas. Pathogenic mutations in NTRK3, CDKN1B, and PIK3CA were also detected. To our knowledge, this is the first documented genetic analysis of this rare disease with findings that offer insights into disease pathogenesis and potential therapeutic targets., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)
- Published
- 2020
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50. Smooth muscle tumors of the gastrointestinal tract: an analysis of prognostic features in 407 cases.
- Author
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Alpert L, Al-Sabti R, Graham RP, Pai RK, Gonzalez RS, Zhang X, Smith V, Wang HL, Westbrook L, Goldblum JR, Bakhshwin A, Shetty S, Klimstra DS, Shia J, Askan G, Robert ME, Thomas C, Frankel WL, Alsomali M, Hagen C, Mostafa ME, Feely MM, Assarzadegan N, Misdraji J, Shih AR, Agostini-Vulaj D, Meis JM, Tang S, Chatterjee D, Kang LI, Hart J, Lee SM, Smith T, Yantiss RK, Hissong EM, Gao ZH, Wu J, Resnick MB, Wu EY, Pai RK, Zhao L, Doyle LA, Chopra S, Panarelli NC, Hu S, Longacre TA, Raghavan SS, Lauwers GY, Ghayouri M, Cooper HS, Nagarathinam R, Bellizzi AM, Kakar S, Hosseini M, Rong J, Greenson JK, Lamps LW, Dong Z, and Bronner MP
- Subjects
- Adult, Aged, Aged, 80 and over, Disease Progression, Female, Humans, Male, Middle Aged, Prognosis, Progression-Free Survival, Gastrointestinal Neoplasms pathology, Smooth Muscle Tumor pathology
- Abstract
Smooth muscle tumors represent the second most common mural mesenchymal neoplasm in the gastrointestinal tract, but established criteria for prognostic assessment of these tumors are lacking. A large cohort of surgically resected intramural gastrointestinal smooth muscle tumors from 31 institutions was analyzed to identify potential prognostic features. Pathologic features were assessed by expert gastrointestinal and/or soft tissue pathologists at each center. Immunohistochemical confirmation was required. A total of 407 cases from the esophagus (n = 97, 24%), stomach (n = 180, 44%), small bowel (n = 74, 18%), and colorectum (n = 56, 14%) were identified. Patients ranged in age from 19 to 92 years (mean 55 years), with a slight female predominance (57%). Mean tumor size was 5.4 cm, with the largest tumor measuring 29 cm. Disease progression following surgery, defined as local recurrence, metastasis, or disease-related death, occurred in 56 patients (14%). Colorectal tumors were most likely to progress, followed by small bowel and gastric tumors. None of the esophageal tumors in this series progressed. Receiver operator characteristic analysis identified optimal cutoffs of 9.8 cm and 3 mitoses/5 mm
2 for discriminating between progressive and non-progressive tumors. Histologic features strongly associated with progression by univariate analysis included moderate-to-severe atypia, high cellularity, abnormal differentiation (defined as differentiation not closely resembling that of normal smooth muscle), tumor necrosis, mucosal ulceration, lamina propria involvement, and serosal involvement (P < 0.0001 for all features). Age, sex, and margin status were not significantly associated with progression (P = 0.23, 0.82, and 0.07, respectively). A risk assessment table was created based on tumor site, size, and mitotic count, and Kaplan-Meier plots of progression-free survival for each subgroup revealed progression-based tiers. Based on our findings, it appears that nonesophageal gastrointestinal smooth muscle tumors measuring >10 cm and/or showing ≥3 mitoses/5 mm2 may behave aggressively, and therefore close clinical follow-up is recommended in these cases.- Published
- 2020
- Full Text
- View/download PDF
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