Citations

SummaryBackgroundCongenital diaphragmatic hernia (CDH) is a rare anomaly with high mortality and long‐term comorbid conditions.AimsOur aim was to describe the presenting characteristics, treatment, and outcomes of consecutive patients with CDH treated at our institution.MethodsWe performed a retrospective cohort study and identified consecutive neonates treated for CDH from 2001 to 2015 at our institution. For all patients identified, we reviewed hospital and postdischarge data for neonatal, disease, and treatment characteristics. We determined hospital survival overall and also according to the presence of prenatal diagnosis, liver herniation into the chest (liver up), and the use of extracorporeal membrane oxygenation (ECMO) in addition to surgery. We evaluated postdischarge chronic conditions in patients with at least one year of follow‐up.ResultsThirty‐eight neonates were admitted for treatment during the study period. In three who were in extremis, life support was withdrawn. The other 35 underwent surgical repair, of whom eight received ECMO. The overall survival was 79% (30/38). Survival for those who had surgical correction of CDH but did not need ECMO was 89% (24/27); it was 75% (6/8) for those who received ECMO and had surgery. Hospital survival was lower for liver‐up vs liver‐down CDH (61% [11/18] vs 95% [19/20]; odds ratio, 0.08; 95% CI, 0.01–0.77; P = 0.01). Among survivors, the median duration of hospitalization was 31 (interquartile range, 20–73) days. Major chronic pulmonary and gastrointestinal disorders, failure to thrive, and neurodevelopmental delays were the most noted comorbid conditions after discharge, and all were more prevalent in those who required ECMO.ConclusionThe overall survival of neonates with CDH was 79%. Intrathoracic liver herniation was associated with more frequent use of ECMO and greater mortality. A substantial number of survivors, especially those who required ECMO, experienced chronic conditions after discharge.

AbstractThe 2016 World Health Organization (WHO) diagnostic criteria for myeloproliferative neoplasms (MPN) underscore the prognostically‐relevant distinction between essential thrombocythemia (ET) and prefibrotic primary myelofibrosis (pre‐PMF). In addition, leukocytosis has been identified as an important prognostic marker in otherwise WHO‐defined ET. However, controversy remains regarding the objectivity of morphologic criteria in distinguishing ET from pre‐PMF and the precise prognostic cutoff values for leukocytosis. Serum lactate dehydrogenase (LDH) level might be a biologically more accurate measure of leukocyte turnover and a more sensitive marker of pre‐PMF, in otherwise WHO‐defined ET. In the current study of 183 consecutive patients with WHO‐defined ET, the presence of grade 1 bone marrow (BM) fibrosis did not affect presenting clinical or laboratory features; in contrast, increased serum LDH at diagnosis was associated with leukocytosis (p = .002), thrombocytosis (p < .001), palpable splenomegaly (p = .03) and higher international prognostic score (IPSET) (p = .002); serum LDH did not correlate with BM fibrosis, JAK2/CALR/MPL or TET2/ASXL1 mutations. In univariate analysis, risk factors for survival included age ≥60 years (p = .002; HR 10.2, 95% CI 2.3‐44.6), male sex (p = .02; HR 3.2, 95% CI 1.2‐8.2), leukocyte count ≥15 × 109/L (p = .007; HR 4.7, 95% CI 1.5‐14.6), and increased serum LDH (p = .002; HR 3.7, 95% CI 1.5‐9.1), but not BM fibrosis (p = .17). In multivariable analysis, age, sex and serum LDH remained significant; serum LDH also remained significant, in the context of IPSET (p = .003) and in patients with leukocytosis (p = .003). We conclude that serum LDH level carries an independent prognostic value for survival in ET and might represent a biologically more accurate surrogate for leukocytosis.

AbstractRelapsed indolent lymphoma often becomes refractory to standard chemoimmunotherapy and requires new therapeutic strategies. Targeting the PI3K/mTOR pathway in several types of lymphoma has shown preclinical and clinical efficacy providing the rationale to test this strategy in the treatment of relapsed/refractory indolent lymphomas. We investigated in a phase II open label clinical trial the efficacy and safety of single agent everolimus, an inhibitor of mTORC1, in patients with relapsed/refractory indolent lymphomas. Eligible patients received oral everolimus 10 mg daily on a 28 day‐cycle schedule. The primary endpoint was to evaluate the overall response rate (ORR) and safety of single‐agent everolimus in this patient population. Fifty‐five patients with indolent lymphoma were accrued. The median age was 67 years (range: 33‐85) with a median of five prior therapies (range: 1‐10). The ORR was 35% (19/55; 95% CI: 24‐48%), with complete response unconfirmed in 4% (2/55), and partial response in 31% (17/55). The ORR was 61% (14/23) in the patients with FL. The median time to response was 2.3 months (range: 1.4‐14.1), median duration of response of 11.5 months (95%‐CI: 5.7‐30.4), and a median progression‐free survival of 7.2 months (95%‐CI: 5.5‐12.5). The most common toxicity was hematologic with grades 3‐4 anemia, neutropenia, and thrombocytopenia documented in 15% (8/55), 22% (12/55), and 33% (18/55), respectively. There were no cases of febrile neutropenia, and eight patients discontinued therapy because of adverse events. Everolimus monotherapy is a valid therapeutic option in the relapsed and/or refractory indolent non‐Hodgkin lymphoma patients and is well tolerated.

ABSTRACTNext‐generation sequencing technologies have afforded unprecedented characterization of low‐frequency and rare genetic variation. Due to low power for single‐variant testing, aggregative methods are commonly used to combine observed rare variation within a single gene. Causal variation may also aggregate across multiple genes within relevant biomolecular pathways. Kernel‐machine regression and adaptive testing methods for aggregative rare‐variant association testing have been demonstrated to be powerful approaches for pathway‐level analysis, although these methods tend to be computationally intensive at high‐variant dimensionality and require access to complete data. An additional analytical issue in scans of large pathway definition sets is multiple testing correction. Gene set definitions may exhibit substantial genic overlap, and the impact of the resultant correlation in test statistics on Type I error rate control for large agnostic gene set scans has not been fully explored. Herein, we first outline a statistical strategy for aggregative rare‐variant analysis using component gene‐level linear kernel score test summary statistics as well as derive simple estimators of the effective number of tests for family‐wise error rate control. We then conduct extensive simulation studies to characterize the behavior of our approach relative to direct application of kernel and adaptive methods under a variety of conditions. We also apply our method to two case‐control studies, respectively, evaluating rare variation in hereditary prostate cancer and schizophrenia. Finally, we provide open‐source R code for public use to facilitate easy application of our methods to existing rare‐variant analysis results.

Abstract Background Anti–tumor necrosis factor alpha ( TNF ‐α) agents are used to treat a variety of autoimmune and inflammatory conditions, including psoriasis. Paradoxically, numerous reports have documented new‐onset or exacerbation of psoriasis or psoriasiform skin lesions ( PSO ) in patients treated with these agents for conditions other than PSO—particularly in adults with inflammatory bowel disease ( IBD ). Not much is known regarding similar cases in children. Methods A retrospective chart review was performed on children younger than 19 years of age with IBD seen at the Mayo Clinic between 2003 and 2015 who developed new‐onset or recurrent PSO while undergoing anti‐ TNF ‐α therapy. Results Fourteen children developed PSO while undergoing anti‐ TNF ‐α therapy for IBD . All three anti‐ TNF ‐α agents (infliximab, adalimumab, certolizumab) used to treat IBD in this series led to induction or recurrence of PSO lesions. The median time to development of PSO was 11 months (range 0–48 mos), the median age was 15 years (range 12.5–17.5 yrs), and 57% of patients were male. IBD activity was quiescent in 93% of cases at PSO onset. Seven patients (50%) discontinued their initial anti‐ TNF ‐α therapy because of their skin disease. Ultimately, four patients (29%) had to discontinue all anti‐ TNF ‐α therapy to induce PSO resolution. Conclusion TNF ‐α antagonist–induced PSO in children with IBD is a rarely reported adverse reaction. PSO onset has a variable latency, but usually occurs during IBD remission, with a slight male bias. Nearly half of patients required a change in their initial anti‐ TNF ‐α agent despite conventional skin‐directed therapies, and one‐third of patients discontinued all anti‐ TNF ‐α therapy because of PSO .