Citations

Abstract Background Pathogenic variants in ryanodine receptor 1 ( RYR 1, MIM # 180901) are the cause of congenital myopathy with fiber‐type disproportion, malignant hyperthermia susceptibility type 1, central core disease of muscle, multiminicore disease and other congenital myopathies. Methods We present a patient with global developmental delay, hypotonia, myopathy, joint hypermobility, and multiple other systemic complaints that were noted early in life. Later she was found to have multiple bone deformities involving her spine, with severe scoliosis that was corrected surgically. She was also diagnosed with ophthalmoplegia, chronic hypercapnic respiratory failure, and hypertension. At 22 years of age she presented to the genetics clinic with a diagnosis of mitochondrial myopathy and underwent whole exome sequencing ( WES ). Results Whole exome sequencing revealed two novel compound heterozygous variants in RYR 1 (c.7060_7062del, p.Val2354del and c.4485_4500del, p.Tyr1495X). Conclusion Review of her clinical, pathologic, and genetic findings pointed to a diagnosis of a congenital myopathy with fiber‐type disproportion.

AbstractSerum‐derived bovine immunoglobulin/protein isolate (SBI), an oral nutritional therapy, is efficacious in diverse diarrheal diseases. In an open‐label study in 15 patients with irritable bowel syndrome‐diarrhea (IBS‐D), we evaluated effects of SBI (5.0 g, twice a day) for 8 weeks on safety, on bowel function and abdominal pain, tryptophan metabolism (K:T ratio), intestinal permeability (13C‐mannitol and lactulose excretion), bile acid synthesis (fasting serum FGF‐19 and C4), duodenal and stool microbiome, and the expression of 90 genes related to inflammation, immune function, and tight junctions in duodenal mucosa. Statistical analysis (paired tests, baseline vs. treatment) was based on intention to treat (ITT) principles. One of 15 Caucasian patients (13F, 2M, age 40.3 ± 2.3y, BMI 34.3 ± 3.0 kg/m2) withdrew without completing studies. There were improvements in stools/day (decrease, P < 0.001), ease of passage (P = 0.035), and evacuation (P = 0.004) with SBI therapy. Worst pain severity was numerically reduced in last 2 weeks' treatment (P = 0.078). Duodenal mucosal mRNA expression; serum C4, FGF‐19, and KT ratio; small bowel or colon permeability; and stool microbiome were not significantly different after SBI therapy, compared to baseline. In duodenal brushings, there was considerable microbiota structure difference (β diversity analysis P = 0.072, UniFrac) and, on taxonomic analysis, increased abundance of Proteobacteria Burkholderiales, Firmicutes Catonella, and unclassified genus organisms with SBI therapy. Thus, SBI therapy for 8 weeks in IBS‐D patients is associated with improved bowel function; the mechanism of benefit is unclear, though there were microbiota structure differences in duodenal brushings. Further studies in patients with low‐grade inflammation and intestinal barrier dysfunction at baseline are indicated.

Abstract Background: In Minnesota, the 2012 Cancer Report by the Department of Health reported both the incidence of liver cancer and mortality rates due to liver cancer among Blacks were significantly higher than Caucasians. African immigration to Minnesota is the third highest by percentage of state population in the US. Given that viral hepatitis disproportionately affects sub-Saharan Africans and that these individuals are emigrating from countries where childhood HBV vaccination has only recently been implemented on a national scale, we speculate that this unique immigrant community may be a major contributor to the increased burden of viral hepatitis and liver cancer complications in the state. Limited research exists on the burden of viral hepatitis and hepatocellular carcinoma among African immigrants. Thus, we conducted a prospective community-wide screening to assess the rates of chronic HBV and HCV infections among Somali, Liberian and Kenyan immigrants in Minnesota. Methods: Several African community health centers and organizations in Minnesota were selected for the study. Individuals of Somali, Liberian or Kenyan descent were enrolled in a prospective screening study for chronic HBV and HCV infection. Blood samples were collected and tested for hepatitis B surface antigen (HBsAg), hepatitis B core antibody (HBcAb), hepatitis B surface antibody (HBsAb), and anti-hepatitis C virus antibody (anti-HCV). Follow-up testing, health education, counseling, and referral were provided to participants. Results: 853 participants provided blood specimens. 13.5% of participants had chronic HBV infection while 32.4% had prior HBV exposure with spontaneous viral clearance. 7% of participants had chronic HCV infection. Follow up and linkage to care were provided to participants with chronic hepatitis while preventive advice was provided to those who were negative for both infections. In particular, participants susceptible to HBV were informed about the availability of HBV vaccine in order to protect against future HBV infection. Conclusions: Chronic HBV and HCV are major health problems among recent African immigrants in Minnesota. Community-based screening is an effective way to identify and provide health education and linkage to care for individuals with or at risk for viral hepatitis. Citation Format: Essa A. Mohamed, Nasra H. Giama, Hassan M. Shaleh, Abdul M. Oseini, Hager Ahmed Mohammed, Jessica Cvinar, Ibrahim A. Waaeys, Hamdi A. Ali, Loretta K. Allotey, Lewis R. Roberts. Community-wide outreach and screening to reduce hepatitis B, hepatitis C and liver cancer disparities among African immigrants in Minnesota. [abstract]. In: Proceedings of the Ninth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2016 Sep 25-28; Fort Lauderdale, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2017;26(2 Suppl):Abstract nr C76.

Abstract Background: While genomic alterations are central players in tumor progression, proteins are the targets for precision therapy. The degree by which “actionable” genomic alterations translate into activated/altered proteins and pathway is still under investigation. Using a multi-OMIC approach from the SideOut 2 metastatic breast cancer (MBC) trial, this study explored the concordance between selected “actionable” genomic alterations and protein expression/activation. Methods: Snap frozen biopsies from 29 MBC patients enrolled in a prospective phase II trial were used for this analysis. Exome WES and RNASeq data was processed using an in-house developed pipeline and identified amplification of CCND1 (6/29), FGFR1 (4/29), and FGF 3, 4, 5, and 19 (4/29) as some of most frequent “actionable” genomic alterations in our MBC cohort. Signaling analysis of the 29 cases was performed using Reverse Phase Protein Microarray coupled with Laser Capture Microdissection. Protein expression/phosphorylation was measured in a continuous scale and classified based on quartile distribution. Concordance between CCND1 amplification and Cyclin D1 expression, along with the activation of FOXM1 T600 and Rb S780, was explored. Amplification of the FGFR1 locus or its ligands was correlated with the level of activation/phosphorylation of FGFR1 Y653/654. Results: While Cyclin D1 protein expression was greater than the population mean for 4/6 (67%) patients with CCND1 amplification, only 2/6 (33%) patients with CCND1 amplification had Cyclin D1 level within the top quartile of the population (n=29). FOXM1 T600 activation was independent from CCND1 amplification, with high levels of FOXM1 T600 predominantly in the CCND1 wild-type population. Only 1/6 (17%) patients with CCND1 amplification had FOXM1 T600 level similar to the top quartile of the population while a second patient was above the population median. Activation of Rb S780 was above the population median, but below the top quartile, in 2/6 (33%) CCND1 amplified patients. Similarly, none of the patients with activation of FGFR Y653/654 equal to the top quartile harbored an FGFR1 amplification. Only 1/4 (25%) patients carrying an FGFR1 amplification had an activation of FGFR Y653/654 above the population median. Similarly, 1/4 (25%) patients with FGF ligand amplification showed FGFR Y653/654 level within the top quartile while three patients had FGFR Y653/654 activation below the population median. No significant results were found between proteomic (below/above the median) and genomic characteristics by Fisher test (p&gt;0.05). Conclusion: Molecular genotyping of “actionable” cancer targets alone may be insufficient in predicting whether the actual drug target protein is expressed and/or activated in any given patient's tumor. Although these results need further validation, the combination of genomic and proteomic data may represent a more informative approach for identifying real molecular drivers of individual lesions as well as “actionable” protein/phosphoprotein targets in the absence of genomic events. Multi-OMIC approaches may lead to more effective stratification in precision medicine trials. Citation Format: Pierobon M, Wong S, Reeded A, Anthony S, Robert N, Northfelt DW, Jahanzeb M, Vocila L, Wulfkuhle J, Dunetz B, Aldrich J, Byron S, Craig D, Liotta L, Carpten J, Petricoin EF. A multi-OMIC analysis to explore the impact of “actionable” genomic alterations on protein pathway activation: Clinical implication for precision medicine in metastatic breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P1-07-09.

463 Background: The genomic assessment of cancer has been revolutionized by next-generation sequencing and is increasingly being applied in the clinic to guide therapeutic decision-making. Time to reporting of results, specimen quantity, and analyte quality have constrained initial clinical applications to gene panels and whole exome based strategies. Methods: Patients underwent surgical resection, excisional or core biopsies, or bone marrow biopsy. Samples were analyzed by whole genome or exome sequencing and RNA sequencing, bioinformatics analysis, and therapeutic target prioritization by a multi-disciplinary Clinical Genomics Board. All prioritized targets were CLIA validated using Sanger sequencing, RT-qPCR, FISH, or IHC as appropriate. Treatment was delivered using off-label FDA approved drugs, clinical trials, or single patient INDs. Results: We have enrolled 40 patients with advanced, treatment-refractory cancers of whom sequencing data is available on 33. The initial 6 patients were evaluated in a non-CLIA pilot phase and 27 in the CLIA enabled phase. Upon availability of the initial report, identified targets of putative therapeutic relevance were then prioritized by the CGB in 22/27 patients (81%) for subsequent CLIA validation. Eleven patients have been treated with genomically selected therapy with partial response in 3/10 assessed patients. A testicular cancer patient had aberrations in two testes specific genes, a copy number gain in TSSK6 and a novel gene fusion between thyroid hormone receptor associated protein 3 (THRAP3) and Tektin 2 (TEKT2). Additionally, a case of papillary renal cell carcinoma had an amplification of YAP1 and a previously unreported P287T mutation in CCND1, suggesting potential benefit with a CDK4/6 inhibitor. Treatment is ongoing and results will be reported. Conclusions: Integrated whole genome analysis in a CLIA setting is feasible. Integration of SNV, copy number and transcriptional data may allow for selection of putative driver genes to enhance targeted therapy decisions. Barriers for future broader implementation include the need for reduced time from biopsy to report and availability of therapies.

165 Background: The Hematology Hospital Outpatient service at Rochester Methodist Hospital provides ambulatory outpatient care to patients who would normally be hospitalized on our inpatient services due to cytopenias and need for infusion/transfusion support. A quality project was conducted to streamline our process and decrease wait times. Methods: This project was a part of a Mayo Lean Collaborative initiative to increase customer satisfaction and eliminate waste. The first step was to collect baseline measurements to capture the non-value added waiting time of our entire outpatient process. These benchmark times were collected from 65 patients over 4 days. We evaluated these wait times to identify gaps in care and factors contributing to delays in our process. Data collected "before and after" each implementation phase determined if the change was beneficial. Results: Through our data collection, one major area of opportunity we identified was the wait time for CBC results. At baseline, patients were waiting in a room for 61.9 minutes for lab results. A major contributor to delay was the lack of carriers to send blood samples through the tube system being stocked in the outpatient area. We also discovered that the time from when the sample was placed in the carrier to the time it arrived in our lab was significant. Through a process analysis it was identified that the CBC tubes were being sent to a central lab prior to their final destination in the Hematology lab. We were able to re-route our CBCs directly to the hem lab. Data collected after the intervention showed we were receiving results at 51 minutes, therefore, eliminating 10.9 minutes off of an appointment. We also identified additional opportunities such as pre-assigning rooms, scheduling, exam room organization, and communication that were able to be addressed. Conclusions: As a result of this lean collaborative project we reduced patient wait time by 20.1 minutes and increased patient satisfaction. We were able to order interventions sooner thereby increasing patient safety. By process analysis, we identified multiple areas in our process that could be shortened with no additional cost.

289 Background: Cholangiocarcinoma (CC), hepatocellular carcinoma (HCC), and pancreatic ductal adenocarcinoma (PDAC) are all devastating malignancies. Limited data exists about PD-1 and PDL1 expression in these cancers. We assessed expression of PD1/PDL1 in a large cohort of patients with hepato-pancreatico-biliary (HPB) cancers and explored the existence of accompanying genomic mutations associated with expression of PD-1/PD-L1. Methods: 524 patients with HPB cancers (354 PDAC, 58 HCC, 54 intrahepatic (ICC), 18 extrahepatic (ECC), and 40 gallbladder (GBC)) were included in the study and tumors tested centrally at a CLIA lab (Caris Life Sciences, Phoenix, AZ). Tests included one or more of the following: gene sequencing (next generation sequencing, Illumina TruSeq), protein expression (immunohistochemistry [IHC]) and gene amplification). PD-1 (SP142 antibody) and PD-L1 (MRQ-22 antibody) status was tested in all samples. Two-tailed Fisher's exact test was performed to test where proportions of positive results were different by subgroup (p²0.05). Results: Among those with PDAC, HCC, ICC, ECC, and GBC, rates of PD1 expression on tumor infiltrating lymphocytes (TILs) and PD-L1 expression on tumor cells is detailed in the Table. In PD-1+, compared with PD-1- HPB cancers, mutations in the following were more prevalent, though not statistically significant: BRCA2, ATM, CTNNB1, and PIK3CA. Among all theranostic biomarkers tested, TOP2A expression (IHC) was significantly increased in PD-L1+ versus PD-L1- tumors (82% vs 60%; p=0.0083). Conclusions: HPB tumors express PD-L1 at a frequency of 4-18%, and PD-1 at a frequency of 29-45%. A statistically significant association of mutations with PD-1+ or PD-L1+ tumors was not identified in this group of tumors. PD-L1 expression associates with TOP2a expression, a marker of proliferation and also anthracycline sensitivity. Further evaluation of this correlation and PDL1/PD-1 + anthracycline combination therapy may be warranted. [Table: see text]

64 Background: The goals of our Lymphoma Survivorship Clinic (SC) are to coordinate care, educate patients, and create a survivorship care plan (SCP). The aim of this study was to determine if patient-centered outcomes are improved after a SC visit. Methods: From 11/13-5/15, surveys were mailed to recently-treated lymphoma patients who were within 4 weeks of their last visit and in remission. Quality of life (QOL) was measured with PROMIS and distress was measured with the Impact of Events scale. Responses between those who attended SC and those who were eligible but did not attend were analyzed. Results: There were 96 surveys sent to the SC group; 59 were returned (61% response rate). Of the non-SC group, 140 surveys were sent and 84 were returned (60% response rate). Mean age was 57 years (range 23-77) in the SC group and 59 years (23-88) in the non-SC group. There were more females in the SC group (52% vs 30%) but no differences in race, marital status, education, or health literacy. Those who attended the SC were more likely to recall receiving a summary of cancer treatment and recommendations for follow-up care (90% SC vs. 75% non-SC, p = 0.03). Furthermore, SC attendees were more likely to “definitely” recall discussion on improving health or preventing illness (89% vs. 53%), getting help in making changes in habits/lifestyle (76% vs. 50%), diet (80% vs. 31%), and exercise (82% vs. 51%), all p < 0.001. There were no differences in discussions regarding smoking, follow-up testing, and symptom monitoring. The SC group was less likely to need more information regarding sexuality (6% vs 20%, p = 0.045). There were no differences in need for information regarding anxiety, fitness, familial cancer risk, fertility, complementary therapies, and social issues. The SC group was slightly more confident that they could get information or advice related to cancer (completely confident 76% vs. 61%, p = 0.07). There were no differences in QOL or distress. Conclusions: A Lymphoma SC visit increased receipt of SCP and provided more information on survivorship issues, particularly health behaviors, but did not improve QOL or distress. Further study is needed to determine if this leads to long-term health benefits.

Abstract Welander distal myopathy is a rare autosomal dominant disorder characterized by muscle weakness in the hands and feet. Exome sequencing of affected families discovered a segregating p.Glu384Lys pathogenic variant in TIA-1 as the main genetic cause of Welander distal myopathy. TIA-1 encodes an RNA-binding protein which serves as a key component of stress granules. This protein also regulates splicing and translation of mRNA. Our patient developed progressive weakness in his hands and feet during his late 40s that was misdiagnosed as a neuropathy that caused muscle atrophy. Follow-up genetic testing revealed a p.Glu384Lys pathogenic variant in TIA-1, and he was then diagnosed with Welander distal myopathy. Our case report underlines the importance of electrodiagnostic and genetic testing of patients.