Coordinating an Oncology Precision Medicine Clinic Within an Integrated Health System: Lessons Learned in Year One

Precision medicine is a term describing strategies to promote health and prevent and treat disease based on an individual’s genetic, molecular, and lifestyle characteristics. Oncology precision medicine (OPM) is a cancer treatment approach targeting cancer-specific genetic and molecular alterations. Implementation of an OPM clinical program optimally involves the support and collaboration of multiple departments, including administration, medical oncology, pathology, interventional radiology, genetics, research, and informatics. In this review, we briefly introduce the published evidence regarding OPM’s potential effect on patient outcomes and discuss what we have learned over the first year of operating an OPM program within an integrated health care system (Aurora Health Care, Milwaukee, WI) comprised of multiple hospitals and clinics. We also report our experience implementing a specific OPM software platform used to embed molecular panel data into patients’ electronic medical records

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe

Genomic investigations of unexplained acute hepatitis in children

Since its first identification in Scotland, over 1,000 cases of unexplained paediatric hepatitis in children have been reported worldwide, including 278 cases in the UK1. Here we report an investigation of 38 cases, 66 age-matched immunocompetent controls and 21 immunocompromised comparator participants, using a combination of genomic, transcriptomic, proteomic and immunohistochemical methods. We detected high levels of adeno-associated virus 2 (AAV2) DNA in the liver, blood, plasma or stool from 27 of 28 cases. We found low levels of adenovirus (HAdV) and human herpesvirus 6B (HHV-6B) in 23 of 31 and 16 of 23, respectively, of the cases tested. By contrast, AAV2 was infrequently detected and at low titre in the blood or the liver from control children with HAdV, even when profoundly immunosuppressed. AAV2, HAdV and HHV-6 phylogeny excluded the emergence of novel strains in cases. Histological analyses of explanted livers showed enrichment for T cells and B lineage cells. Proteomic comparison of liver tissue from cases and healthy controls identified increased expression of HLA class 2, immunoglobulin variable regions and complement proteins. HAdV and AAV2 proteins were not detected in the livers. Instead, we identified AAV2 DNA complexes reflecting both HAdV-mediated and HHV-6B-mediated replication. We hypothesize that high levels of abnormal AAV2 replication products aided by HAdV and, in severe cases, HHV-6B may have triggered immune-mediated hepatic disease in genetically and immunologically predisposed children

Promising outcomes of screening for pancreatic cancer by genetic testing and endoscopic ultrasound

OBJECTIVE: This study aimed to determine if screening patients based on certain cancer syndromes or family history criteria can lead to early detection of pancreatic cancer. METHODS: This was a cohort study from 2008 to 2011 at a large tertiary referral center. A total of 30 patients met high-risk criteria after genetic counseling and were referred to a gastroenterologist for possible endoscopic ultrasound (EUS). RESULTS: Of the 30 patients, 16 underwent EUS. Subsequently, 3 patients had fine needle aspiration. Two patients had pancreatic adenocarcinoma, and 1 patient had an intraductal papillary mucinous neoplasm with low-grade dysplasia. The 2 patients with pancreatic adenocarcinoma both had breast cancer and BRCA2 mutations. The patient with the intraductal papillary mucinous neoplasm had Peutz-Jeghers syndrome. All 3 patients underwent surgery and have remained cancer free. CONCLUSIONS: Genetic risk assessment with EUS +/- fine needle aspiration in high-risk patients may lead to earlier detection of pancreatic cancer and potentially improve overall morbidity and mortality. Greater emphasis should be placed on screening patients for hereditary cancer syndromes that increase the risk of pancreatic cancer

Coordinating an Oncology Precision Medicine Clinic Within an Integrated Health System: Lessons Learned in Year One

Precision medicine is a term describing strategies to promote health and prevent and treat disease based on an individual’s genetic, molecular, and lifestyle characteristics. Oncology precision medicine (OPM) is a cancer treatment approach targeting cancer-specific genetic and molecular alterations. Implementation of an OPM clinical program optimally involves the support and collaboration of multiple departments, including administration, medical oncology, pathology, interventional radiology, genetics, research, and informatics. In this review, we briefly introduce the published evidence regarding OPM’s potential effect on patient outcomes and discuss what we have learned over the first year of operating an OPM program within an integrated health care system (Aurora Health Care, Milwaukee, WI) comprised of multiple hospitals and clinics. We also report our experience implementing a specific OPM software platform used to embed molecular panel data into patients’ electronic medical records

Splicing profile by capture RNA-seq identifies pathogenic germline variants in tumor suppressor genes

Germline variants in tumor suppressor genes (TSGs) can result in RNA mis-splicing and predisposition to cancer. However, identification of variants that impact splicing remains a challenge, contributing to a substantial proportion of patients with suspected hereditary cancer syndromes remaining without a molecular diagnosis. To address this, we used capture RNA-sequencing (RNA-seq) to generate a splicing profile of 18 TSGs (APC, ATM, BRCA1, BRCA2, BRIP1, CDH1, CHEK2, MLH1, MSH2, MSH6, MUTYH, NF1, PALB2, PMS2, PTEN, RAD51C, RAD51D, and TP53) in 345 whole-blood samples from healthy donors. We subsequently demonstrated that this approach can detect mis-splicing by comparing splicing profiles from the control dataset to profiles generated from whole blood of individuals previously identified with pathogenic germline splicing variants in these genes. To assess the utility of our TSG splicing profile to prospectively identify pathogenic splicing variants, we performed concurrent capture DNA and RNA-seq in a cohort of 1000 patients with suspected hereditary cancer syndromes. This approach improved the diagnostic yield in this cohort, resulting in a 9.1% relative increase in the detection of pathogenic variants, demonstrating the utility of performing simultaneous DNA and RNA genetic testing in a clinical context