Citations

AbstractThe high discard rate of pediatric donor hearts presents a major challenge for children awaiting heart transplantation. Recent literature identifies several factors that contribute to the disparities in pediatric donor heart usage, including regulatory oversight, the absence of guidelines on pediatric donor heart acceptance, and variation among transplant programs. However, a likely additional contributor to this issue are the behavioral factors influencing transplant team decisions in donor offer scenarios, a topic that has not yet been studied in detail. Behavioral economics and decision psychology provide an excellent foundation for investigating decision‐making in the pediatric transplant setting, offering key insights into the behavior of transplant professionals. We conducted a systematic review of published literature in pediatric heart transplant related to behavioral economics and the psychology of decision‐making. In this review, we draw on paradigms from these two domains in order to examine how existing aspects of the transplant environment, including regulatory oversight, programmatic variation, and allocation systems, may precipitate potential biases surrounding donor offer decisions. Recognizing how human decision behavior influences donor acceptance is a first step toward improving utilization of potentially viable pediatric donor hearts.

Background: Insight into type 5 long QT syndrome (LQT5) has been limited to case reports and small family series. Improved understanding of the clinical phenotype and genetic features associated with rare KCNE1 variants implicated in LQT5 was sought through an international multicenter collaboration. Methods: Patients with either presumed autosomal dominant LQT5 (N = 229) or the recessive Type 2 Jervell and Lange-Nielsen syndrome (N = 19) were enrolled from 22 genetic arrhythmia clinics and 4 registries from 9 countries. KCNE1 variants were evaluated for ECG penetrance (defined as QTc >460 ms on presenting ECG) and genotype-phenotype segregation. Multivariable Cox regression was used to compare the associations between clinical and genetic variables with a composite primary outcome of definite arrhythmic events, including appropriate implantable cardioverter-defibrillator shocks, aborted cardiac arrest, and sudden cardiac death. Results: A total of 32 distinct KCNE1 rare variants were identified in 89 probands and 140 genotype positive family members with presumed LQT5 and an additional 19 Type 2 Jervell and Lange-Nielsen syndrome patients. Among presumed LQT5 patients, the mean QTc on presenting ECG was significantly longer in probands (476.9±38.6 ms) compared with genotype positive family members (441.8±30.9 ms, P <0.001). ECG penetrance for heterozygous genotype positive family members was 20.7% (29/140). A definite arrhythmic event was experienced in 16.9% (15/89) of heterozygous probands in comparison with 1.4% (2/140) of family members (adjusted hazard ratio [HR] 11.6 [95% CI, 2.6–52.2]; P =0.001). Event incidence did not differ significantly for Type 2 Jervell and Lange-Nielsen syndrome patients relative to the overall heterozygous cohort (10.5% [2/19]; HR 1.7 [95% CI, 0.3–10.8], P =0.590). The cumulative prevalence of the 32 KCNE1 variants in the Genome Aggregation Database, which is a human database of exome and genome sequencing data from now over 140 000 individuals, was 238-fold greater than the anticipated prevalence of all LQT5 combined (0.238% vs 0.001%). Conclusions: The present study suggests that putative/confirmed loss-of-function KCNE1 variants predispose to QT prolongation, however, the low ECG penetrance observed suggests they do not manifest clinically in the majority of individuals, aligning with the mild phenotype observed for Type 2 Jervell and Lange-Nielsen syndrome patients.

Management of febrile neutropenia (FN) is an integral part of supportive care for patients undergoing cancer treatment. The NCCN Guidelines for Hematopoietic Growth Factors provide suggestions for appropriate evaluation, risk determination, prophylaxis, and management of FN. These NCCN Guidelines are intended to guide clinicians in the appropriate use of growth factors for select patients undergoing treatment of nonmyeloid malignancies. These NCCN Guidelines Insights highlight important updates to the NCCN Guidelines regarding the incorporation of newly FDA-approved granulocyte-colony stimulating factor biosimilars for the prevention and treatment of FN.

Enzyme-linked immunosorbent assays (ELISAs) have been developed to diagnose Helicobacter pylori infection. However, the methods are not standardized. We therefore prospectively evaluated the sensitivities and specificities of ELISAs developed in the United States and the United Kingdom in a study population comprising 41 consecutive symptomatic outpatients and 35 volunteers. At endoscopy, multiple biopsies were obtained for histology and culture and stained sections were graded for chronic gastritis, active chronic gastritis, and density of H. pylori. Serum samples were analyzed for H. pylori by ELISA. The first set of assays for immunoglobulin G (IgG) and IgA used a pool of sonicated isolates of H. pylori from five patients in the United States (antigen A). The second set of assays, developed in the United Kingdom, used three different antigens: antigen 1, an acid-extractable surface antigen; antigen 2, an acid-extractable antigen from an aflagellate variant; and antigen 3, a urease-containing fraction. Cutoff scores for positive results were determined a priori on the basis of previous serological studies. There was close agreement between histology and culture. In the study population, 36% of the individuals were H. pylori positive. The diagnostic value of the different ELISAs were highly comparable, and the crude antigens performed as well as the more purified antigens. The antigen A IgG had a sensitivity and specificity of 96 and 94%, respectively; the values for antigen 1 were 93 and 96%, respectively. The antigen A IgA and antigen 3 assays were the least sensitive tests.(ABSTRACT TRUNCATED AT 250 WORDS)

Spontaneous portosystemic shunts (SPSSs) have been associated with worse clinical outcomes in the pre–liver transplantation (LT) setting, but little is known about their post‐LT impacts. Our aim was to compare LT candidates with and without SPSSs and assess the impact of SPSSs on patient mortality and graft survival in the post‐LT setting. Patients 18 years or older with abdominal imaging done prior to LT were included. Exclusion criteria were the presence of pre‐LT surgical shunts, LT indications other than cirrhosis, and combined solid organ transplantations. SPSSs were classified as absent, small, or large according to their maximum diameter (8 mm). Multiple variables that could influence the post‐LT course were extracted for analysis. Patient and graft survival were estimated using the Kaplan‐Meier method and were compared between groups using a log‐rank test. The project received institutional review board approval. We extracted data from 326 patients. After comparing patients without SPSS or with small or large SPSSs, no statistical difference was found for overall patient survival: no SPSS (n = 8/63), reference; small SPSS (n = 18/150), hazard ratio (HR), 1.05 (95% confidence interval [CI], 0.45‐2.46); and large SPSS (n = 6/113), HR, 0.60 (95% CI, 0.20‐1.78); P = 0.20. Also, no difference was found for graft survival: no SPSS (n = 11/63), reference; small SPSS (n = 21/150), HR, 0.80 (95% CI, 0.38‐1.70); large SPSS (n = 11/113), HR, 0.59 (95% CI, 0.25‐1.40); P = 0.48. Similarly, no statistical significance was found for these variables when comparing if the graft used was procured from a donation after circulatory death donor versus a donation after brain death donor. In conclusion, the previously described association between SPSSs and worse clinical outcomes in pre‐LT patients seems not to persist once patients undergo LT. This study suggests that no steps to correct SPSS intraoperatively are necessary.

AbstractHistological transformation in Waldenström macroglobulinemia (WM) is an uncommon complication, with limited data, particularly regarding the impact of MYD88 L265P mutation on transformation. We examined risk factors and outcomes associated with transformation in WM, highlighting the role of MYD88 L265P mutation. Patients with WM seen at Mayo Clinic, Rochester, USA and University Hospital of Reims, France, between 01/01/1996 and December 31, 2017 were included; 50 (4.3%) of 1147 patients transformed to a high‐grade lymphoma, with median time‐to‐transformation of 4.5 (range 0‐21) years in the transformed cohort. The MYD88 L265P mutation status was known in 435/1147 (38%) patients (406 with non‐transformed WM and 29 patients in transformed cohort). On multivariate analysis, MYD88 WT status alone was an independent predictor of transformation (odds ratio, 7[95%CI: 2.1‐23]; P = .003). Additionally, the MYD88 WT status was independently associated with shorter time‐to‐transformation (HR 7.9 [95%CI: 2.3‐27; P = .001]), with a 5‐year transformation rate of 16% for MYD88 WT vs 2.8% with MYD88 L265P mutated patients. Patients with transformation demonstrated a significant increase in risk of death compared to patients who did not transform (HR 5.075; 95%CI: 3.8‐6.8; P < .001). In conclusion, the MYD88 WT status is an independent predictor of transformation and associated with a shorter time‐to‐transformation. Additionally, transformation conferred an inferior overall survival in patients with WM.

Abstract Pediatric large B-cell lymphomas (LBCLs) share morphological and phenotypic features with adult types but have better prognosis. The higher frequency of some subtypes such as LBCL with IRF4 rearrangement (LBCL-IRF4) in children suggests that some age-related biological differences may exist. To characterize the genetic and molecular heterogeneity of these tumors, we studied 31 diffuse LBCLs (DLBCLs), not otherwise specified (NOS); 20 LBCL-IRF4 cases; and 12 cases of high-grade B-cell lymphoma (HGBCL), NOS in patients ≤25 years using an integrated approach, including targeted gene sequencing, copy-number arrays, and gene expression profiling. Each subgroup displayed different molecular profiles. LBCL-IRF4 had frequent mutations in IRF4 and NF-κB pathway genes (CARD11, CD79B, and MYD88), losses of 17p13 and gains of chromosome 7, 11q12.3-q25, whereas DLBCL, NOS was predominantly of germinal center B-cell (GCB) subtype and carried gene mutations similar to the adult counterpart (eg, SOCS1 and KMT2D), gains of 2p16/REL, and losses of 19p13/CD70. A subset of HGBCL, NOS displayed recurrent alterations of Burkitt lymphoma–related genes such as MYC, ID3, and DDX3X and homozygous deletions of 9p21/CDKN2A, whereas other cases were genetically closer to GCB DLBCL. Factors related to unfavorable outcome were age &gt;18 years; activated B-cell (ABC) DLBCL profile, HGBCL, NOS, high genetic complexity, 1q21-q44 gains, 2p16/REL gains/amplifications, 19p13/CD70 homozygous deletions, and TP53 and MYC mutations. In conclusion, these findings further unravel the molecular heterogeneity of pediatric and young adult LBCL, improve the classification of this group of tumors, and provide new parameters for risk stratification.

Abstract Aims/Objective:Congenital antithrombin (AT) deficiency, estrogen-containing oral contraceptive pills (OCPs) and pregnancy are associated with increased risk of venous thromboembolism (VTE). Little is known about reproductive decision-making in women with AT deficiency. We sought to explore the attitudes and choices regarding reproductive health in this population. Study Design/Methods:We conducted a provider-administered survey of women identified from the Mayo Clinic congenital AT deficiency database. Participants were asked to discuss their diagnosis of AT deficiency (age at diagnosis and VTE history including diagnosis and treatment) and questioned about (1) any lifetime methods of contraception, (2) pregnancies and pregnancy outcomes, (3) use of assisted reproductive technology, (4) history of menorrhagia, and (5) how their AT diagnosis had impacted each reproductive health experience and how this impact made them feel (open-ended question). Results:Of 31 women with congenital AT deficiency, 18 (58%) were reached, 8 (26%) were not reachable and 5 (16%) were deceased. Of the 18 women who completed the survey, median age at AT deficiency diagnosis was 40 years (range 7 - 65). Twelve (67%) women had experienced a VTE; 2 and 5 women had VTE in the setting of pregnancy OCP use, respectively. Reported contraceptive methods included OCPs, intrauterine device (IUD), and male condoms. Of the 5 women diagnosed with AT deficiency while taking OCPs, three switched to IUD, one to condoms, and one did not report an alternative method of contraception. Fifteen (83% ) women reported at least one pregnancy (median number of pregnancies = 2; range 1 - 6). Of 42 total pregnancies among the 18 women, 33 (79%) resulted in live term birth, 3 (7%) in live preterm birth, and 6 (14%) in miscarriage/spontaneous abortion at a median of 12 weeks into the pregnancy. Four women (22%) reported the use of anticoagulation during pregnancy (presumed to be low molecular weight heparin, but most women could not specify), and 1 woman reported use of assisted reproductive technology leading to a successful pregnancy. Eleven women (61%) reported menorrhagia, 4 (36%) while on anticoagulation for VTE events. Ten of 18 women (56%) reported that the AT deficiency diagnosis had affected their reproductive health in at least one way. Patient-reported comments are presented in Table 1, and a "word cloud" diagram (an image composed of words from the women's comments regarding contraception), in which the size of each word indicates its frequency) is presented in Figure 1. Conclusion:Women with AT deficiency require careful multidisciplinary management to avoid complications in the settings of hormonal contraception and pregnancy. Many women reported that their reproductive health experiences were impacted by their diagnosis, but also reported successful pregnancy outcomes. Validated questionnaires should be developed to assess women's reproductive health experiences. Strategies for reproductive risk management should be discussed carefully, and patient involvement in reproductive decision-making is key in this population. Word Cloud depicting frequency of women's comments regarding AT deficiency and contraception Word Cloud depicting frequency of women's comments regarding AT deficiency and contraception Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Abstract Background: Noonan syndrome, characterized by dysmorphic facies, webbed neck, short stature, chest deformity, developmental delay and congenital heart defects, occurs as a result of mutations affecting the RAS-MAPK signaling pathway. A wide range of coagulation abnormalities are observed in these patients including: thrombocytopenia, platelet dysfunction and coagulation factor deficiencies. Screening for coagulation defects is recommended in childhood and especially prior to surgical procedures. Data available is limited and the extent of the hemostatic evaluation needed is not clearly defined. We carried out this study to outline the spectrum of coagulation abnormalities seen in patients with Noonan syndrome and their impact on surgical outcomes. Methods: In this retrospective cohort study, the electronic medical record system was queried for patients with Noonan syndrome seen at Mayo Clinic between 2000 and 2016. A detailed chart review was undertaken. Results i) Phenotypic correlates: 142 patients (58% male) met our study criteria, median age 21 years (range 14 days to 68 years). The referral specialty for initial evaluation was: cardiology 69 (49%), endocrinology 10 (7%), urology 10 (7%), neurology 8 (6%), pulmonary 6 (4%), orthopedic surgery 3 (2%), gastroenterology 2 (1%), psychiatry 2 (1%) and other specialties 4 (3%). Ten patients (7%) were referred for developmental delay, 13 (9%) for dysmorphism and 4 (3%) after having a family member diagnosed with Noonan syndrome. One patient (1%) presented with hematochezia. Twenty-seven (52%) of the 52 patients screened with genetic testing had a Noonan-associated gene defect. Bleeding was reported by 22 patients (15%) with a median International Society on Thrombosis and Haemostasis Bleeding Assessment Tool (ISTH-BAT) score of 2 (range 1-8). Of those tested, 11/121 (9%) patients had thrombocytopenia (platelets < 150 x 10^9/L). Screening coagulation tests were done in 58 (41%) patients, and included PT/aPTT in 43 (74%) and extended coagulation panels (including platelet function studies) in 15 (26%). Of the 22 patients with history of bleeding, 20 (90%) had screening coagulation testing. Twenty-two (38%) of patients screened had one or more coagulation laboratory abnormality. Ten (66%) patients with clinically suspected platelet dysfunction had normal platelet function analyzer (PFA)-100 testing and normal light transmission aggregometry, while 5 (33%) had decreased platelet aggregation with epinephrine. Four patients (7%) (including 2 siblings) had low vWF levels consistent with type 1 vWD, 9 (16%) had mild clotting factor deficiencies ( FIX- 3, FXII-2 and multiple clotting factors-5) and 4 (7%) had a prolonged baseline PT and/or aPTT without additional coagulation factor assessment (Table 1). Thirteen patients (9%) had both a bleeding phenotype and abnormal coagulation laboratory results. ii) Surgical outcomes: A total of 274 surgical procedures were performed in 89 patients (63%). These included: cardiac 118 (43%), orthopedic 30 (11%), ENT 27 (10%), neurosurgical 26 (10%), abdominal 17 (6%), urologic 17 (6%), gynecologic 12 (4%) thoracic 8 (3%), ophthalmologic 7 (3%), plastic surgery 5 (2%), maxillofacial 4 (1%) and lymph node dissection 3 (1%). Platelets were utilized in 26 procedures (10%), fresh frozen plasma in 19 (7%) and cryoprecipitate in 7 (3%). Two procedures were performed in patients with type 1 vWD using vWF concentrates. Abnormal intra or postoperative bleeding was seen in 5/274 procedures (1.8%) performed in 4 patients. One patient had a known functional platelet disorder, one had normal PT and aPTT and two were not screened for coagulation defects. Bleeding was managed with transfusional supportive care in 3 (60%) surgical cases, while in 2 (40%) cases patients required re-intervention to achieve surgical hemostasis (bleeding from femoral access site and pacemaker pocket hematoma). There was no mortality related to the excess perioperative bleeding. Conclusion: Varying hemostatic abnormalities are seen in patients with Noonan syndrome, ranging from thrombocytopenia to multiple coagulation factor deficiencies. Frank bleeding manifestations however are uncommon and when present are usually mild. Clinical evaluation focused on the bleeding history and basic coagulation screening allows for successful perioperative hemostatic support and good surgical outcomes. Disclosures No relevant conflicts of interest to declare.

Background The phase 3 trial A041202 solidified the Bruton's Tyrosine Kinase (BTK) inhibitor ibrutinib as a standard of care for older patients with previously untreated CLL by showing superior progression-free survival (PFS) as compared with bendamustine plus rituximab. While ibrutinib is highly effective in previously untreated CLL, there do remain disadvantages to this therapy, specifically the low rate of complete response (CR) and therefore the need for continuous administration, which increases cost and toxicity. In older patients especially, toxicities with ibrutinib are common; 17% of patients had atrial fibrillation and 29% had grade 3 or higher hypertension on the A041202 study. Thus, strategies to decrease the exposure time to ibrutinib are of interest. Venetoclax is an inhibitor of BCL2 that has shown efficacy as a single agent and in combination with monoclonal antibodies, specifically the anti-CD20 monoclonal antibody obinutuzumab for patients with previously untreated CLL. One significant advantage to venetoclax is the ability to produce CRs and minimal residual disease negative (MRD-) responses. In this study, we compare ibrutinib plus obinutuzumab (IO) to ibrutinib plus venetoclax plus obinutuzumab (IVO) with a response-dependent discontinuation. While other studies have been designed with the goal of discontinuation of ibrutinib through combinations with venetoclax, no other study has been presented using a response-dependent discontinuation strategy. Study Design and Methods A041702 is a randomized phase 3 study led by the Alliance for Clinical Trials in Oncology that is currently enrolling through the NCI National Clinical Trials Network (NCTN). CLL patients age 70 years or older who are previously untreated and in need of therapy are eligible. Previous treatment of autoimmune complications with steroids or rituximab is allowed. Patients must have intermediate- or high-risk Rai stage, ECOG performance status 0-2, ANC ≥ 1000/mm3 unless due to marrow involvement, and platelets ≥ 30,000/mm3. CrCl must be ≥ 40 mL/min and AST/ALT ≤ 2.5x upper limit of normal. Patients with hepatitis B must have undetectable viral load, and patients must not have an intercurrent illness that is expected to limit survival to < 5 years. Warfarin and strong inhibitors or inducers of CYP3A4/5 are not permitted. Patients are initially preregistered to the study and submit a peripheral blood sample for central FISH analysis of del(17p). Patients who are registered are randomized 1:1 to Arm 1 (IO) or Arm 2 (IVO), and are stratified by Rai stage and presence of del(17p). IO consists of I daily starting cycle 1 day 1, and O dosed as standard starting cycle 1 day 1 and continuing to cycle 6 day 1. IVO consists of IO as in Arm 1, with V starting cycle 3 day 1 with standard 5-week ramp-up and continuing until cycle 14 day 28. At the end of 14 cycles, patients in both arms undergo response evaluation with central peripheral blood and bone marrow MRD testing. Patients on IO then continue I indefinitely. Patients on IVO who are in a bone marrow MRD- CR discontinue all therapy, and those who are not continue I indefinitely. The primary objective of the study is to compare PFS between IO and IVO using the strategy of response-dependent discontinuation. There is 90% power to detect a hazard ratio for PFS of 0.55 (corresponding to 5-year PFS rates of 70% and 82.187% for IO and IVO, respectively), at a one-sided significance level of 0.025 by a log-rank test. This design requires 128 events and 431 total evaluable patients assuming uniform accrual over the course of 3 years and minimum follow-up of 5 years. The study includes two interim analyses for superiority when 50% and 75% of the expected number of events have been observed and three interim analyses for futility when 25%, 50%, and 75% of the expected number of events have been observed. Conclusions A041702 is an ongoing phase 3 clinical trial using a novel response-dependent discontinuation method. Results of this study have the potential to change the standard of care for older patients with previously untreated CLL. The study is expected to accrue for 3 years beginning January 2019, and we welcome participation from sites throughout the NCTN. Support: U10CA180821, U10CA180882, UG1CA189823, U24CA196171; U10CA180820 (ECOG-ACRIN); https://acknowledgments.alliancefound.org; ClinicalTrials.gov Identifier: NCT03737981 Disclosures Woyach: Janssen: Consultancy, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; AbbVie: Research Funding; Karyopharm: Research Funding; Loxo: Research Funding; Morphosys: Research Funding; Verastem: Research Funding. Lozanski:Beckman Coulter: Research Funding; Boehringer Ingelheim: Research Funding; Stemline Therapeutics Inc.: Research Funding; Genentec: Research Funding. Ding:Merck: Research Funding; DTRM Biopharma: Research Funding. Hill:Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Consultancy, Honoraria; Celegene: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria; Takeda: Research Funding; Amgen: Research Funding; TG therapeutics: Research Funding; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Consultancy, Research Funding; Kite: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Stone:Argenx, Celgene, Takeda Oncology: Other: Data and Safety Monitoring Board/Committee: ; Novartis, Agios, Arog: Research Funding; AbbVie, Actinium, Agios, Argenx, Arog, Astellas, AstraZeneca, Biolinerx, Celgene, Cornerstone Biopharma, Fujifilm, Jazz Pharmaceuticals, Amgen, Ono, Orsenix, Otsuka, Merck, Novartis, Pfizer, Sumitomo, Trovagene: Consultancy. Byrd:Janssen: Consultancy, Other: Travel Expenses, Research Funding, Speakers Bureau; BeiGene: Research Funding; Pharmacyclics LLC, an AbbVie Company: Other: Travel Expenses, Research Funding, Speakers Bureau; Gilead: Other: Travel Expenses, Research Funding, Speakers Bureau; Pharmacyclics LLC, an AbbVie Company: Other: Travel Expenses, Research Funding, Speakers Bureau; Genentech: Research Funding; Ohio State University: Patents & Royalties: OSU-2S; Janssen: Consultancy, Other: Travel Expenses, Research Funding, Speakers Bureau; Gilead: Other: Travel Expenses, Research Funding, Speakers Bureau; Novartis: Other: Travel Expenses, Speakers Bureau; Gilead: Other: Travel Expenses, Research Funding, Speakers Bureau; Pharmacyclics LLC, an AbbVie Company: Other: Travel Expenses, Research Funding, Speakers Bureau; TG Therapeutics: Other: Travel Expenses, Research Funding, Speakers Bureau; Novartis: Other: Travel Expenses, Speakers Bureau; Ohio State University: Patents & Royalties: OSU-2S; Acerta: Research Funding; Novartis: Other: Travel Expenses, Speakers Bureau; BeiGene: Research Funding; Ohio State University: Patents & Royalties: OSU-2S; TG Therapeutics: Other: Travel Expenses, Research Funding, Speakers Bureau; Acerta: Research Funding; Genentech: Research Funding; BeiGene: Research Funding; Genentech: Research Funding; Acerta: Research Funding; TG Therapeutics: Other: Travel Expenses, Research Funding, Speakers Bureau; Janssen: Consultancy, Other: Travel Expenses, Research Funding, Speakers Bureau.