Citations

Purpose: The electronic Medical Records and Genomics (eMERGE) Phase III study was undertaken to assess clinical utility of returning medically actionable genomic screening results. We assessed pediatric clinical outcomes following return of pathogenic/likely pathogenic (P/LP) variants in autosomal dominant conditions with available effective interventions. Methods: The two eMERGE III pediatric sites collected outcome data and assessed changes in medical management at 6 and 12 months. Results: We returned P/LP results to 29 participants with outcome data. For 23 of the 29 participants, the P/LP results were previously unknown. Five of the 23 participants were already followed for conditions related to the P/LP variant. Of those receiving novel results and not being followed for the condition related to the P/LP result (n = 18), 14 (77.8%) had a change in healthcare after return of results (RoR). Following RoR, cascade testing of family members occurred for 10 of 23 (43.5%). Conclusions: The most common outcomes post-RoR included imaging/laboratory testing and health behavior recommendations. A change in healthcare was documented in 77.8% of those receiving results by 6 months. Our findings demonstrate how return of genomic screening results impacts healthcare in pediatric populations.

Albumin-interferon-α (alb-IFN) is a novel recombinant protein derived from IFN-α2b genetically fused to human albumin. The resulting single polypeptide combines in one molecule the antiviral properties of IFN-α with the long serum half-life of albumin. IFN-mediated biological responses stem from the engagement of IFN-α with its target receptor and subsequent modulation of IFN-specific gene (ISG) expression. To evaluate the pharmacodynamics of alb-IFN during the Phase I/II study conducted in patients with chronic hepatitis C (CHC) who had previously failed IFN-α-containing regimens, ISG induction was evaluated in peripheral blood and compared with antiviral response. Whole blood was obtained at day 0, day 7 and day 28 from 21 patients enrolled in the higher dose (500–900 μg) alb-IFN cohort, who received two injections on day 0 and day 14. Taqman real-time PCR was used to assess candidate ISG expression. There was sustained induction on day 7 and day 28 of the ISG's OAS1, IRF-7, IFI44 and IFI27. Although all patients showed a molecular response to alb-IFN, individual variability in pretreatment gene expression levels and fold of modulation during treatment was observed. At day 28, induction of OAS1, IFI44 and IRF7 showed pairwise correlation in individual patients ( P<0.05). Moreover, the induction of expression at day 28, and pretreatment levels of OAS1 and IFI44 correlated with hepatitis C virus RNA reduction at day 28 ( P<0.05). In conclusion, alb-IFN demonstrated robust induction of ISG that was consistent with the response associated with an IFN-α.

Albumin-interferon-α (IFN-α) is a novel 85.7–kDa recombinant protein consisting of IFN-α that is genetically fused to human serum albumin. In this Phase I/II, multicentre, open-label study, we evaluated the safety and tolerability, pharmacokinetics and pharmacodynamics of albumin-IFN-α in IFN-α-experienced patients with chronic hepatitis C. Albumin-IFN-α was administered in 22 escalating doses (7–900 μg) in a single injection or in two injections 14 days apart. In the 119 patients studied, there were no discontinuations because of adverse events, and albumin-IFN-α had a favourable safety profile at doses up to 900 μg. The most common adverse events were headache (56%), fatigue (52%), injection site erythema (38%), arthralgias (32%) and pyrexia (27%). Reduced clearance resulted in a mean elimination half-life of 159h, which supports dosing at 2- to 4-week intervals. Induction of the IFN-specific gene OAS1 was maintained for ≥28 days following a single injection of albumin-IFN-α at doses of ≥40 μg. Dose-dependent antiviral activity was observed in this IFN-α-experienced study population. Antiviral activity of ≥1.0–log reductions in HCV RNA was observed in 47% (37/78) of patients in the 120- to 900-μg cohorts and in 59% (16/27) in the 400- to 900-μg double-injection cohorts. These results support further clinical studies of albumin-IFN-α for the treatment of patients with chronic hepatitis C.

Gastric cancer is the third leading cause of cancer-related deaths worldwide. Over 95% of gastric cancers are adenocarcinomas, which are typically classified based on anatomic location and histologic type. Gastric cancer generally carries a poor prognosis because it is often diagnosed at an advanced stage. Systemic therapy can provide palliation, improved survival, and enhanced quality of life in patients with locally advanced or metastatic disease. The implementation of biomarker testing, especially analysis of HER2 status, microsatellite instability (MSI) status, and the expression of programmed death-ligand 1 (PD-L1), has had a significant impact on clinical practice and patient care. Targeted therapies including trastuzumab, nivolumab, and pembrolizumab have produced encouraging results in clinical trials for the treatment of patients with locally advanced or metastatic disease. Palliative management, which may include systemic therapy, chemoradiation, and/or best supportive care, is recommended for all patients with unresectable or metastatic cancer. Multidisciplinary team management is essential for all patients with localized gastric cancer. This selection from the NCCN Guidelines for Gastric Cancer focuses on the management of unresectable locally advanced, recurrent, or metastatic disease.

Abstract The public health impact of genomic screening can be enhanced by cascade testing. However, cascade testing depends on communication of results to family members. While the barriers and facilitators of family communication have been researched following clinical genetic testing, the factors impacting the dissemination of genomic screening results are unknown. Using the pragmatic Electronic Medical Records and Genomics Network‐3 (eMERGE‐3) study, we explored the reported sharing practices of participants who underwent genomic screening across the United States. Six eMERGE‐3 sites returned genomic screening results for mostly dominant medically actionable disorders and surveyed adult participants regarding communication of results with first‐degree relatives. Across the sites, 279 participants completed a 1‐month and/or 6‐month post‐results survey. By 6 months, only 34% of the 156 respondents shared their results with all first‐degree relatives and 4% did not share with any. Over a third (39%) first‐degree relatives were not notified of the results. Half (53%) of participants who received their results from a genetics provider shared them with all first‐degree relatives compared with 11% of participants who received their results from a non‐genetics provider. The most frequent reasons for sharing were a feeling of obligation (72%) and that the information could help family members make medical decisions (72%). The most common reasons indicated for not sharing were that the family members were too young (38%), or they were not in contact (25%) or not close to them (25%). These data indicate that the professional returning the results may impact sharing patterns, suggesting that there is a need to continue to educate healthcare providers regarding approaches to facilitate sharing of genetic results within families. Finally, these data suggest that interventions to increase sharing may be universally effective regardless of the origin of the genetic result.

Multiple myeloma (MM) is characterized by clonal expansion of malignant plasma cells (PCs) and aberrant production of monoclonal immunoglobulin detected as an M spike using serum protein electrophoresis. In the United States, MM represents ~15% of hematologic malignancies and is one of the few cancers increasing in incidence (e.g., 14,400 in 1996 to 32,270 in 2020, from SEER). Despite recent treatment advances, patients diagnosed with high risk/refractory MM (hrrMM) have an overall survival of only three years. Recently, our lab developed the first genetically engineered NrasQ61R; Myc-driven myeloma model (VQ mice). The VQ model recapitulates most biological and clinical features of hrrMM. VQ cells are serially transplantable into syngeneic recipients and can be propagated in vitro. As such, the VQ model could serve as a robust pre-clinical platform for drug screening and in vivo testing of new therapies to treat hrrMM. Whole exome sequencing (WES) of CD138+ cells from five primary VQ mice identified eight recurrently mutated genes. Of these eight genes, two have been previously identified as recurrently mutated in MM patients while the remainder appear to be unique to VQ myeloma. Meanwhile, RNA sequencing of CD138+ cells taken from both primary VQ mice and secondary VQ recipients show differential gene expression for five of these eight genes. Gene ontology analysis of recurrently mutated genes indicates that these genes play a role in interferon signaling, as well as receptor tyrosine kinase signaling. Here, we report the results of a high-throughput repurposing screen using the NCI's AOD IX library, which consists of 147 FDA-approved anti-cancer drugs. VQ cells were treated with 0.1 and 1µM of each compound in the presence or absence of 10nM of Trametinib (Tra), a potent MEK inhibitor. Screening results returned expected positive hits that were previously FDA approved for MM treatment (green dots, Panel 1B), such as proteasome inhibitors, histone deacetylase inhibitors, and chemotherapy drugs. Importantly, VQ cells were resistant to some compounds currently used to treat MM, including the BCL-2 inhibitor Venetoclax, the alkylating agent Melphalan, and the topoisomerase II inhibitor Etoposide (red dots, Panel 1B). De novo resistance to these therapies further indicates that the VQ cells model a multi-drug resistant MM. Two compounds were chosen for further testing: the protein translation inhibitor Omacetaxine (Oma) based on its single agent efficacy, and the multi-receptor tyrosine kinase inhibitor Ponatinib (Pot) based on its high synergy with Tra. Combination Index testing confirmed initial drug screening results but showed some antagonism between combination Oma and Pot treatment. We proceeded with in vivo testing of two novel combination therapies, in which 3-week treatment cycles were followed by a 1-week rest period between cycles: Three weeks of daily Tra and Pot treatment (TP), or two weeks of Tra and Pot treatment followed by one week of Oma (TPO) treatment. Vehicle (Veh) treated and Tra only treated mice were used as controls. Treatment efficacy was assessed against VQ-D1 MM, which grows primarily in the bone marrow (BM) and metastasizes to the spleen and liver of recipient mice. Four weeks post-treatment, myeloma growth in the BM was significantly reduced in both combo treatment groups, while MM burden in the spleen was also reduced. Overall, both TP and TPO treatment significantly extended survival compared to Veh or Tra treated mice, and significantly reduced liver extramedullary disease. To further test the range of Tra/Pot synergy in vivo, Tra dosage was reduced and treatment was administered daily. Interestingly, both low dose Tra monotherapy and TP combo therapy significantly extended survival compared to Veh control or Pot alone, and TP treated mice had increased survival compared to the Tra only treated mice. Taken together, our results show that low dose daily Trametinib treatment is superior to cycling dosage, and that Ponatinib treatment synergizes with both dosing schedules to extend survival in vivo. Our study demonstrates the utility of the VQ model for identifying new treatments for hrrMM and testing their efficacy in vivo. As part of our ongoing drug repurposing experiments, we have expanded our screening to a panel of 2,580 FDA-approved drugs, including but not limited to anti-cancer and anti-inflammatory drugs. Figure Disclosures Callander: Cellectar: Research Funding; University of Wisconsin: Current Employment.

Background. The role of MZ phenotype of α 1 antitrypsin (α1AT) deficiency as a potential cofactor in advanced liver disease arising from other primary causes is not widely understood. In the general population, MZ phenotype accounts for 2%–4% in Europe and 2%–7.1% in North America. The aim of this study was to determine the prevalence of the MZ phenotype among various causes of cirrhosis in the United States in the modern era and its impact on pulmonary function before and after liver transplantation. Methods. This retrospective study included adult patients with cirrhosis who underwent liver transplantation at Mayo Clinic. Participants’ data including pathogenesis of cirrhosis, model for end-stage liver disease-Na score, α1AT phenotype, liver decompensation events, and pulmonary outcomes was determined by retrospective review of the liver transplantation database. Results. One hundred thirty of 1341 adult patients with cirrhosis (9.7%) were α1AT MZ carriers. When comparing the distribution of protease inhibitor (PI) MZ among different pathogenesis, the prevalence of MZ was significantly increased in nonalcoholic steatohepatitis (NASH), alcoholic liver disease (ALD), and cryptogenic cirrhosis compared with other causes. Thirty-seven of 171 with NASH (22%), 37 of 187 with ALD (20%), and 9 of 39 with cryptogenic cirrhosis (23.1%) were identified as PI MZ, while in other subgroups; we detected 18 of 320 with viral hepatitis, and 11 of 339 with primary biliary cholangitis/primary sclerosing cholangitis. Also, MZ patients were more likely to develop preoperative chronic obstructive lung disease, and postoperative pulmonary hypertension and pulmonary embolism than MM patients. Conclusions. The rates of preoperative and postoperative pulmonary complications were found to be higher in PI MZ patients than in PI MM patients. The MZ phenotype was significantly enriched in NASH, ALD, and cryptogenic cirrhosis.

A challenge in returning genomic test results to research participants is how best to communicate complex and clinically nuanced findings to participants in a manner that is scalable to the large numbers of participants enrolled. The purpose of this study was to examine the features of genetic results letters produced at each Electronic Medical Records and Genomics (eMERGE3) Network site to assess their readability and content. Letters were collected from each site, and a qualitative analysis of letter content and a quantitative analysis of readability statistics were performed. Because letters were produced independently at each eMERGE site, significant heterogeneity in readability and content was found. The content of letters varied widely from a baseline of notifying participants that results existed to more detailed information about positive or negative results, as well as materials for sharing with family members. Most letters were significantly above the Centers for Disease Control-suggested reading level for health communication. While continued effort should be applied to make letters easier to understand, the ongoing challenge of explaining complex genomic information, the implications of negative test results, and the uncertainty that comes with some types of test and result makes simplifying letter text challenging.