Citations

Abstract Aims Calmodulinopathies are rare life-threatening arrhythmia syndromes which affect mostly young individuals and are, caused by mutations in any of the three genes (CALM 1–3) that encode identical calmodulin proteins. We established the International Calmodulinopathy Registry (ICalmR) to understand the natural history, clinical features, and response to therapy of patients with a CALM-mediated arrhythmia syndrome. Methods and results A dedicated Case Report File was created to collect demographic, clinical, and genetic information. ICalmR has enrolled 74 subjects, with a variant in the CALM1 (n = 36), CALM2 (n = 23), or CALM3 (n = 15) genes. Sixty-four (86.5%) were symptomatic and the 10-year cumulative mortality was 27%. The two prevalent phenotypes are long QT syndrome (LQTS; CALM-LQTS, n = 36, 49%) and catecholaminergic polymorphic ventricular tachycardia (CPVT; CALM-CPVT, n = 21, 28%). CALM-LQTS patients have extremely prolonged QTc intervals (594 ± 73 ms), high prevalence (78%) of life-threatening arrhythmias with median age at onset of 1.5 years [interquartile range (IQR) 0.1–5.5 years] and poor response to therapies. Most electrocardiograms (ECGs) show late onset peaked T waves. All CALM-CPVT patients were symptomatic with median age of onset of 6.0 years (IQR 3.0–8.5 years). Basal ECG frequently shows prominent U waves. Other CALM-related phenotypes are idiopathic ventricular fibrillation (IVF, n = 7), sudden unexplained death (SUD, n = 4), overlapping features of CPVT/LQTS (n = 3), and predominant neurological phenotype (n = 1). Cardiac structural abnormalities and neurological features were present in 18 and 13 patients, respectively. Conclusion Calmodulinopathies are largely characterized by adrenergically-induced life-threatening arrhythmias. Available therapies are disquietingly insufficient, especially in CALM-LQTS. Combination therapy with drugs, sympathectomy, and devices should be considered.

Background. Individuals after solid organ transplant may develop secondary malignancies. In our clinical practice, we noted an increasing number of individuals who developed colorectal cancers after solid organ transplantation. The primary aim of this study was to describe the characteristics and outcomes of the patients who developed colorectal cancer after solid organ transplant. Materials and Methods. Data was gathered and merged from several registries at Mayo Clinic to identify all patients who received a diagnosis of colon or rectal cancer and solid organ transplant. Continuous variables were summarized as mean (standard deviation) and median (range), while categorical variables were reported as frequency (percentage). Time to colorectal cancer after transplant and overall survival after cancer diagnosis were estimated using Kaplan-Meier method. Results. Initially, 115 colorectal cancer patients who also had a transplant were identified. The diagnosis of colorectal cancer was noted after solid organ transplant in 63 patients. The mean age at transplant was 57 years. Majority had received a kidney transplant (44.4%) followed by liver (36.5%). The median time to develop colorectal cancer was 59.3 months (range: 4.4-251.4 months). 15 (24.6%) were stage 4 at diagnosis and 13 (21.3%) had stage 3 colorectal cancer. Median overall survival was 30.8 months; 5-, 10- and 15-year survival were noted to be 42.5%, 17.9%, and 7.5%, respectively. None of the stage 4 patients were alive at 5 years; 5-year survival rate for stage 1, 2, and 3 patients was 77%, 50%, and 42%, respectively. Conclusions. Our study reports on one of the largest cohorts of patients of colorectal cancer that developed the cancer after solid organ transplant. Survival is extremely poor for advanced cases. However, long-term survivors are noted who developed the cancer at a relatively early stage. Colorectal screening recommendations may need to be revised for patients after solid organ transplant.

703 Background: In metastatic colorectal cancer (CRC), pharmacogenomics (PGx) testing presents a unique opportunity to improve outcomes since the genes DPYD & UGT1A1 encoding the enzymes metabolizing the chemotherapy drugs, 5-fluorouracil and irinotecan, are already well known. In the TRIBE clinical trial, proportion of patients with serious adverse events (SAEs) was higher in those with DPYD/UGT1A1 aberrations and were dose dependent. Critical barrier has been integration into clinical practice. We aimed to report on the feasibility and results of incorporating PGx testing into clinical practice. Methods: As a quality improvement initiative, we integrated the use of OneOme RightMed comprehensive test through funding from our center of individualized medicine, which reports on 28 genes and over 350 medications of interest. Pharmacists provided dosage recommendations based on test results real-time. Results: 126 patients have had the PGx testing since November 2017. Results have been available within 3-5 days. The table outlines the analyzed results thus far of variants in UGT1A1 and the DPYD-genes alongside the CYP450 genes. Of these, 59% had a DPYD/UGT1A1 aberration and 100% had at least one actionable aberration related to supportive care medications from all possible medications listed on their PGx report. Conclusions: Preemptive comprehensive PGx testing can be integrated into clinical practice in real-time for cancer patients. This sets the stage for a prospective randomized clinical trial to demonstrate the amount of benefit this can result in these patients. [Table: see text]

660 Background: Adverse toxicities to chemotherapy remain a limiting factor for patients receiving treatment for malignancies. In gastrointestinal cancers, particularly metastatic colorectal cancer, the majority of front line treatment remains chemotherapy containing 5-fluorouracil and/or irinotecan. One particular cause that can predispose a patient to increased toxicity from 5-fluorouracil is genetic variation in the DPYD gene, as well as TYMS gene. Similarly, genetic variation in the UGT1A1 gene can increase the risk of irinotecan toxicity. These gene variations may have major implications when deciding on treatment regimens for these types of patients; however, they are not routinely checked. Methods: In Mayo Clinic Florida, patients with metastatic colorectal cancer receiving 5-fluorouracil and/or irinotecan chemotherapy during the period of July 2017-July 2018 were tested for genetic variants in DPYD/TYMS and UGT1A1. This testing was done during routine clinic visit either by buccal swab or blood test. The DPYD/TYMS and UGT1A1 variant results were evaluated together with a pharmacist for recommendations regarding dose reductions on 5-fluorouracil and irinotecan respectively. Results: A total of 292 patients were tested. Total number of patients who had a variation in the DPYD/ TYMS and/or UGT1A1 gene was 169 (57.9%). The UGT1A1 variation was the most prevalent with 154 (52.7%) patients having a variant (115 heterozygous variant, 34 homozygous variant and 5 double heterozygous variant). Specifically there were 3 patients with both UGT1A1 and DPYD variants and 3 patients with both UGT1A1 and TYMS variants. One patient had both DPYD and TYMS variations. Conclusions: Routine pharmacogenomic testing for UGT1A1 and DPYD/TYMS genetic variants should be done in all patients receiving irinotecan and 5-fluorouracil chemotherapy respectively. Avoiding or preemptively dose reducing these agents in patients with gene variations may help prevent toxic adverse events and make treatment more tolerable.

525 Background: The hallmark of circulating tumor DNA (ctDNA) is its rapid turnaround and non-invasive nature. According to American Society of Clinical Oncology (ASCO) and College of American Pathologists joint ctDNA review published in March 2018, there is no sufficient evidence to support the use of ctDNA in practice for GI cancers. However, there were numerous studies presented at ASCO Annual Meeting supporting its value. We aimed to summarizing on its role in the management of gastrointestinal cancers based on the studies presented recently. Methods: We limited our search to keywords ‘ctDNA’, ‘circulating tumor DNA’, ‘cell-free DNA (cfDNA)’ and/or ‘liquid biopsy’, at the 2018 ASCO Annual Meeting library abstracts and presentations. Results: There were 35 studies that revolved around ctDNA as a diagnostic tool, prognostic marker and a measure of tumor heterogeneity in gastrointestinal cancers. Depending on the assay used, the results of several studies showed that ctDNA was able to identify relevant mutations including RAS, HER2/Neu, BRAF, MET, BRCA2, APC, TP53, ROS1, PTEN and NF1. The prognosis in terms of tumor mutation burden, objective response rate, metastasis and survival was also estimated based on ctDNA. The findings showed that higher baseline ctDNA levels and/or increased number of mutations detected in ctDNA were associated with poor survival and multi-site metastasis. Right-sided colon cancer was associated with higher number of mutations in ctDNA than left-sided colon and rectal cancers. Similarly, tubular adenocarcinoma subtype of gastric cancer was more likely to have higher ctDNA levels than signet-ring cell subtype. The response to therapy and the residual metastatic disease which was otherwise not detected on imaging could be detected by ctDNA as well. Conclusions: The research at ASCO 2018 report an increasingly promising role of ctDNA in many forms in patients with gastrointestinal malignancies. Experts at the meeting argued that this may well indeed be ready for prime time for certain GI malignancies including colorectal cancers. Prospective studies and studies showing its feasibility into practice can potentially help revise the current guidelines.

Background National prevalence and outcomes of Fontan operation in the USA is unknown. Study objective was to determine trends (temporal change) in the annual volume of Fontan operations, in-hospital mortality, postoperative complications and type of hospital discharge. Methods Review of the Nationwide Inpatient Sample for patients that underwent Fontan operation from 2001 to 2014 using the International Classification of Diseases-Ninth Revision, Clinical Modification procedure code for Fontan operation, that is, 35.94. To evaluate for change in patients’ demographics over the years, we divided the patient population into four groups based on procedure year (2001–2004, 2005–2008, 2009–2011 and 2012–2014). Results An estimated 15 934 Fontan operations were performed in the USA from 2001 to 2014. Median (Q1–Q3) age was 3 (2–4) years and 39.8% were female. Hypoplastic left heart syndrome was the most common (29%) congenital heart disease diagnosis. An estimated 1175 procedures were performed in 2001 and 1340 in 2014, but there was no significant change in the number of procedures per year (p=0.47). There was significant decline in in-hospital mortality from 4.5% (53/1175) in 2001 to 1.1% (15/1340) in 2014 (p=0.009). When we compared event rates between 2001–2004 and 2012–2014 periods, there was significant decline in postoperative cardiac complications (12.6% (459/3640) to 8% (378/4706), p=0.007) and respiratory complications (17.1% (623/3640) to 10.2% (481/4706), p<0.001). However, there was increase in the number of patients discharged to home with healthcare assistance or transferred to another acute care facility (5.8% (211/3640) to 9.4% (443/4706), p=0.01) and inflation-adjusted hospitalisation cost (US$46 978 to US$60 383, p<0.001), but no significant change in length of stay (p=0.73). Conclusion On the average, 1062 Fontan operations are performed annually in the USA with no change in volume of procedures but a decrease in in-hospital mortality and postoperative complications over a 15-year period.

Haploidentical stem cell transplantation provides a plausible alternative for the patients when a fully matched donor is unavailable. Historically, the decision of considering haploidentical transplant has remained elusive; however, with the recent advances, the consideration of haploidentical grafts as a treatment option has become more apparent for both allografting for diseases and engraftment failure. We are reporting here an anecdotal case of a successful haploidentical engraftment in a patient with the prior graft failure of an HLA-matched related donor. Since the patient was severely alloimmunized, desensitization protocol was utilized before the haploidentical transplant, and the patient after 8 months of her second allogeneic transplantation is doing great with successful engraftment, no relapse, and no graft-versus-host disease (GVHD). Numerous reports pertinent to haploidentical graft have shown favorable outcomes in the graft placement, a decline in the rate of GVHD, and an improvement in the morbidity and mortality in affected individuals. Based on the current reports, haploidentical transplantation might be more feasible and has meaningful implications in the situations where matched donors are infrequent.