A computable pathology report for precision medicine: extending an observables ontology unifying SNOMED CT and LOINC

Background The College of American Pathologists (CAP) introduced the first cancer synoptic reporting protocols in 1998. However, the objective of a fully computable and machine-readable cancer synoptic report remains elusive due to insufficient definitional content in Systematized Nomenclature of Medicine – Clinical Terms (SNOMED CT) and Logical Observation Identifiers Names and Codes (LOINC). To address this terminology gap, investigators at the University of Nebraska Medical Center (UNMC) are developing, authoring, and testing a SNOMED CT observable ontology to represent the data elements identified by the synoptic worksheets of CAP. Methods Investigators along with collaborators from the US National Library of Medicine, CAP, the International Health Terminology Standards Development Organization, and the UK Health and Social Care Information Centre analyzed and assessed required data elements for colorectal cancer and invasive breast cancer synoptic reporting. SNOMED CT concept expressions were developed at UNMC in the Nebraska Lexicon© SNOMED CT namespace. LOINC codes for each SNOMED CT expression were issued by the Regenstrief Institute. SNOMED CT concepts represented observation answer value sets. Results UNMC investigators created a total of 194 SNOMED CT observable entity concept definitions to represent required data elements for CAP colorectal and breast cancer synoptic worksheets, including biomarkers. Concepts were bound to colorectal and invasive breast cancer reports in the UNMC pathology system and successfully used to populate a UNMC biobank. Discussion The absence of a robust observables ontology represents a barrier to data capture and reuse in clinical areas founded upon observational information. Terminology developed in this project establishes the model to characterize pathology data for information exchange, public health, and research analytics

Metabolic Alterations in Pancreatic Cancer Progression

Pancreatic cancer is the third leading cause of cancer-related deaths in the USA. Pancreatic tumors are characterized by enhanced glycolytic metabolism promoted by a hypoxic tumor microenvironment and a resultant acidic milieu. The metabolic reprogramming allows cancer cells to survive hostile microenvironments. Through the analysis of the principal metabolic pathways, we identified the specific metabolites that are altered during pancreatic cancer progression in the spontaneous progression (KPC) mouse model. Genetically engineered mice exhibited metabolic alterations during PanINs formation, even before the tumor development. To account for other cells in the tumor microenvironment and to focus on metabolic adaptations concerning tumorigenic cells only, we compared the metabolic profile of KPC and orthotopic tumors with those obtained from KPC-tumor derived cell lines. We observed significant upregulation of glycolysis and the pentose phosphate pathway metabolites even at the early stages of pathogenesis. Other biosynthetic pathways also demonstrated a few common perturbations. While some of the metabolic changes in tumor cells are not detectable in orthotopic and spontaneous tumors, a significant number of tumor cell-intrinsic metabolic alterations are readily detectable in the animal models. Overall, we identified that metabolic alterations in precancerous lesions are maintained during cancer development and are largely mirrored by cancer cells in culture conditions

Are ulcers a marker for invasive carcinoma in barrett's esophagus? data from a diagnostic variability study with clinical follow-up

We correlated follow-up information from 138 patients with Barrett's esophagus and varying degrees of dysplasia with the presence of ulcers. Methods A group of pathologist participants were asked to contribute patients’ initial biopsy slides showing Barrett's esophagus (BE) without dysplasia and with epithelial changes indefinite for dysplasia, low grade dysplasia (LGD), high grade dysplasia (HGD), and adenocarcinoma. From the initial 250 cases used for a diagnostic reproducibility study, follow-up information was available for 138 patients. Results There were 44 cases submitted as BE, 22 as BE with epithelial changes indefinite for dysplasia, 26 as BE with LGD, 33 as BE with HGD, and 13 as BE with adenocarcinoma. Ulcers were present in 35/138 cases (25%), including 3/44 cases of BE without dysplasia (7%), 2/22 cases of BE with epithelial changes indefinite for dysplasia (9%), 0/26 cases of BE with LGD (0%), 10/33 cases of BE with HGD (30%), and 7/13 cases of BE with adenocarcinoma (54%). On follow-up, there were no invasive carcinomas detected among the BE without dysplasia group (median follow-up = 38.5 months). Adenocarcinomas were detected in 4/22 cases (18%) submitted as BE with epithelial changes indefinite for dysplasia at 19, 55, 60, and 62 months and in 4/26 cases (15%) of BE with LGD at 9, 9, 11, and 60 months. None of these carcinomas occurred in cases in which an ulcer was present in the initial biopsy specimen. Among the 33 HGD cases, 20 (60%) were found to have adenocarcinoma on subsequent resection specimens. The presence of an ulcer with HGD increased the likelihood of finding carcinoma in the resection specimen, as 8/10 biopsies (80%) of HGD patients with ulcers had carcinoma, compared to 12/23 biopsies (52%) of HGD patients without ulcers. All of the cases interpreted as adenocarcinomas on biopsy were found either to have invasive carcinoma on esophageal resection or to have metastases that were demonstrated in unresectable patients. Conclusion If an ulcer accompanies HGD in a biopsy specimen from a patient with BE, it is likely that invasive carcinoma is also present at that time.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/75186/1/j.1572-0241.2002.05420.x.pd

Incidence of Gastric Cancer in Marrakech and Casablanca, Morocco

Gastric cancer is the fifth most common cancer globally with over 70% of new cases occurring in developing countries. In Morocco, oncologists in Marrakech suspected higher frequency of gastric cancer compared to Casablanca, a city 150 kilometers away. This study calculated age-specific, sex-specific, and total incidence rates of gastric cancer in Marrakech and was compared to the Casablanca population-based cancer registry. Using medical records from Center Hospital University Mohammad VI and reports from 4 main private pathology laboratories in Marrakech, we identified 774 patients for the period 2008–2012. Comparison of rates showed higher age-specific incidence in Marrakech in nearly all age groups for both genders. A higher total incidence in Marrakech than in Casablanca was found with rates of 5.50 and 3.23 per 100,000, respectively. Incidence was significantly higher among males in Marrakech than males in Casablanca (7.19 and 3.91 per 100,000, resp.) and females in Marrakech compared to females in Casablanca (3.87 and 2.58 per 100,000, resp.). Future studies should address possible underestimation of gastric cancer in Marrakech, estimate incidence in other regions of Morocco, and investigate possible risk factors to explain the difference in rates

Na mira do sucesso : estratégias de combate ao insucesso escolar de alunos estrangeiros

Trabalho de projeto de mestrado, Ciências da Educação (Área de especialização Formação de Adultos), Universidade de Lisboa, Instituto de Educação, 2017Considerando a importância da integração no contexto escolar e consequentemente no sucesso educativo, o presente trabalho projeto, desenvolvido no âmbito do Mestrado em Ciências da Educação, área de especialidade em Formação de Adultos, centra-se na integração de alunos estrangeiros no ensino português, assim como na dinamização de atividades de promoção do seu sucesso escolar. Deste modo, o relatório apresenta como principais temáticas a integração de estrangeiros em Portugal, o insucesso escolar dos alunos estrangeiros e as políticas educativas de combate a este fenómeno, culminando na definição e desenvolvimento de um projeto de combate ao insucesso escolar destinado a este público. O trabalho desenvolvido junto destes jovens nos últimos nove anos e o diagnóstico elaborado no Agrupamento de Escolas João de Barros permitiu compreender a importância de intervir junto da população estrangeira, fomentando o sucesso educativo e a integração no país de acolhimento, uma vez que a taxa de retenção destes jovens está muito acima dos seus colegas autóctones.Considering the importance of integration in the school context, and consequently in educational success, this project, developed in the scope of the master’s degree in Educational Sciences, specialization in Adult Education, focuses on foreign students’ integration at the Portuguese educational system and activities that could be developed to promote their school success. Therefore, the main themes of the report are the integration of foreigners in Portugal, the lack of academic experience from foreign students and educational policies to reduce this barrier, in order to define and develop a project to combat school failure among this cases. The work developed for the last nine years with this students, the diagnostic elaborated in João de Barros Group of Schools, allowed me to understand the importance of an intervention among foreign students, to foment educational success and integration in the host country, bearing in mind that the retention rate in those cases is far above the native students’ average

Metabolic Rewiring by Loss of Sirt5 Promotes Kras-induced Pancreatic Cancer Progression.

BACKGROUND & AIMS: SIRT5 plays pleiotropic roles via post-translational modifications, serving as a tumor suppressor, or an oncogene, in different tumors. However, the role SIRT5 plays in the initiation and progression of pancreatic ductal adenocarcinoma (PDAC) remains unknown. METHODS: Published datasets and tissue arrays with SIRT5 staining were used to investigate the clinical relevance of SIRT5 in PDAC. Furthermore, to define the role of SIRT5 in the carcinogenesis of PDAC, we generated autochthonous mouse models with conditional Sirt5 knockout. Moreover, to examine the mechanistic role of SIRT5 in PDAC carcinogenesis, SIRT5 was knocked down in PDAC cell lines and organoids, followed by metabolomics and proteomics studies. A novel SIRT5 activator was utilized for therapeutic studies in organoids and patient-derived xenografts. RESULTS: SIRT5 expression negatively regulated tumor cell proliferation and correlated with a favorable prognosis in PDAC patients. Genetic ablation of Sirt5 in PDAC mouse models promoted acinar-to-ductal metaplasia, precursor lesions, and pancreatic tumorigenesis, resulting in poor survival. Mechanistically, SIRT5 loss enhanced glutamine and glutathione metabolism via acetylation-mediated activation of GOT1. A selective SIRT5 activator, MC3138, phenocopied the effects of SIRT5 overexpression and exhibited anti-tumor effects on human PDAC cells. MC3138 also diminished nucleotide pools, sensitizing human PDAC cell lines, organoids, and patient-derived xenografts to gemcitabine. CONCLUSIONS: Collectively, we identify SIRT5 as a key tumor suppressor in PDAC, whose loss promotes tumorigenesis through increased non-canonical utilization of glutamine via GOT1, and that SIRT5 activation is a novel therapeutic strategy to target PDAC

Gastric adenocarcinoma with chief cell differentiation: a proposal for reclassification as oxyntic gland polyp/adenoma

Gastric adenocarcinoma with chief cell differentiation (GA-CCD) has been reported as a new, rare variant of gastric adenocarcinoma. Only 12 cases in Japanese patients have been described to date, but they demonstrate distinct clinicopathologic features. To further characterize these lesions, we have collected 10 additional cases. Patients ranged in age from 44 to 79 years (mean, 64.2 y) with a relatively equal sex distribution (6 women and 4 men). Stratified by race, 4 patients were Hispanic, 2 were White, 2 were African American, 1 was Asian (Chinese), and the race was unknown for 1 patient. All patients presented with gastroesophageal reflux that prompted an endoscopic examination. The majority of GA-CCDs were identified in the fundus (7 of 10, 70%) and the remaining in the cardia (n=3). Grossly, they were solitary and polypoid, ranging in size from 0.2 to 0.8 cm (mean, 0.4 cm). Histologically, all cases were centered in the deep mucosa, with focal involvement of surface foveolar epithelium in 3 (30%) cases but not the submucosa. The tumors consisted of clustered glands and irregular branching cords of oxyntic epithelium. Thin wisps of radiating smooth muscle separated the epithelium, but desmoplasia was distinctly absent in all cases. The oxyntic mucosa was 1 to 2 cells thick and composed of a mixture of mucous neck, parietal, and chief cells. In 7 of 10 (70%) cases, chief cells were the predominant cell type, whereas the remaining 3 cases consisted primarily of mucous neck cells. The nuclei were mildly enlarged with slight nuclear pleomorphism, but no mitotic figures were identified. In addition, necrosis, lymphovascular invasion, and perineural invasion were absent. Immunohistochemically, GA-CCDs were diffusely positive for MUC6 (10 of 10, 100%) and negative for MUC5AC (0%) and MUC2 (0%). Ki-67 immunolabeling demonstrated variable expression, with the highest areas ranging from 0.2% to 10%. Clinical follow-up was available for 9 of 10 (90%) patients and ranged from 6 to 39 months. One patient had persistence of lesion at 6 months because of incomplete removal, whereas the other 8 were disease free. In summary, GA-CCDs are solitary, mucosal lesions of the gastric cardia/fundus that arise in patients from multiple ethnic backgrounds. Considering that patients within this study and those reported previously have had neither true recurrence nor progression of disease, these lesions are best regarded as benign. Consequently, the term GA-CCD is contradictory and we prefer the descriptive term "oxyntic gland polyp/adenoma" until further studies can clarify the pathogenesis of these lesions and their natural history

Induction of pancreatic neoplasia in the KRAS/TP53 Oncopig

The 5-year survival of pancreatic cancer (PC) remains low. Murine models may not adequately mimic human PC and can be too small for medical device development. A large-animal PC model could address these issues. We induced and characterized pancreatic tumors in Oncopigs (transgenic swine containing KRAS(G12D) and TP53(R167H)). The oncopigs underwent injection of adenovirus expressing Cre recombinase (AdCre) into one of the main pancreatic ducts. Resultant tumors were characterized by histology, cytokine expression, exome sequencing and transcriptome analysis. Ten of 14 Oncopigs (71%) had gross tumor within 3 weeks. At necropsy, all of these subjects had gastric outlet obstruction secondary to pancreatic tumor and phlegmon. Oncopigs with injections without Cre recombinase and wild-type pigs with AdCre injection did not show notable effect. Exome and transcriptome analysis of the porcine pancreatic tumors revealed similarity to the molecular signatures and pathways of human PC. Although further optimization and validation of this porcine PC model would be beneficial, it is anticipated that this model will be useful for focused research and development of diagnostic and therapeutic technologies for PC. This article has an associated First Person interview with the joint first authors of the paper

Aberrant expression of mucin core proteins and o-linked glycans associated with progression of pancreatic cancer

PURPOSE: Mucin expression is a common feature of most adenocarcinomas and features prominently in current attempts to improve diagnosis and therapy of pancreatic cancer and other adenocarcinomas. We investigated the expression of a number of mucin core proteins and associated O-linked glycans expressed in pancreatic adenocarcinoma (PA) – sialyl Tn (STn), Tn, T antigen, sialyl Lewis A (CA19-9), sialyl Lewis C (SLeC), Lewis X (LeX) and sialyl Lewis X (SLeX) – during the progression of pancreatic cancer from early stages to metastatic disease. EXPERIMENTAL DESIGN: Immunohistochemical analyses of mucin and associated glycan expression on primary tumor and liver metastatic tumor samples were performed with matched sets of tissues from 40 autopsy patients diagnosed with PA, 14 surgically resected tissue samples, and 8 normal pancreata. RESULTS: There were significant changes in mucin expression patterns throughout disease progression. MUC1 and MUC4 were differentially glycosylated as the disease progressed from early PanINs to metastatic disease. De novo expression of several mucins correlated with increased metastasis indicating a potentially more invasive phenotype, and we demonstrate the expression of MUC6 in acinar cells undergoing acinar to ductal metaplasia. A “cancer field-effect” that included changes in mucin protein expression and glycosylation in the adjacent normal pancreas was also seen. CONCLUSIONS: There are significant alterations in mucin expression and post-translational processing during progression of pancreatic cancer from early lesions to metastasis. The results are presented in the context of how mucins influence the biology of tumor cells and their microenvironment during progression of pancreatic cancer