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Background: Survivors of childhood cancer are at risk for therapy-related subsequent malignant neoplasms (SMN), including thyroid SMN. Telomere length (TL) is associated with cancer risk, but the relationship between TL and SMN risk among survivors is less clear. Methods: We conducted a nested, matched case–control study of radiation-exposed 15-year+ adult survivors of childhood cancer with thyroid SMN (cases) and without SMN (controls). Forty-six cases were matched to 46 controls by primary diagnosis, chemotherapy (yes/no), radiation field, and follow-up duration. Lymphocyte TL (LTL) was measured by telomere flow-FISH cytometry using blood samples banked at a mean of 38.9 years (cases), 39.2 years (controls). Genetic variation in telomere genes was assessed by whole genome sequencing. Point estimates for LTL Results: Cases had shorter median LTL than controls in three out of four leukocyte subsets. Cases were more likely to have NK cell LTL Conclusions: Long-term survivors have shorter than expected LTL, a finding that is more pronounced among survivors with thyroid SMN. Impact: The long-term impact of childhood cancer treatment on immune function is poorly understood. Our findings support immune function studies in larger survivor cohorts to assess long-term deficits in adaptive and innate immunity that may underlie SMN risk.

Radiation therapy, a mainstay of treatment for head and neck cancer, is not always curative due to the development of treatment resistance; additionally, multi-institutional trials have questioned the efficacy of concurrent radiation with cetuximab, the epidermal growth factor receptor (EGFR) inhibitor. We unraveled a mechanism for radiation resistance; that is, radiation induces EGFR, which phosphorylates TRIP13 (thyroid hormone receptor interactor 13) on tyrosine 56. Phosphorylated (phospho-)TRIP13 promotes non-homologous end joining (NHEJ) repair to induce radiation resistance. NHEJ is the main repair pathway for radiation-induced DNA damage. Tumors expressing high TRIP13 do not respond to radiation but are sensitive to cetuximab or cetuximab combined with radiation. Suppression of phosphorylation of TRIP13 at Y56 abrogates these effects. These findings show that EGFR-mediated phosphorylation of TRIP13 at Y56 is a vital mechanism of radiation resistance. Notably, TRIP13-pY56 could be used to predict the response to radiation or cetuximab and could be explored as an actionable target.

PURPOSE Early identification of childhood cancer survivors at high risk for treatment-related cardiomyopathy may improve outcomes by enabling intervention before development of heart failure. We implemented artificial intelligence (AI) methods using the Children's Oncology Group guideline–recommended baseline ECG to predict cardiomyopathy. MATERIAL AND METHODS Seven AI and signal processing methods were applied to 10-second 12-lead ECGs obtained on 1,217 adult survivors of childhood cancer prospectively followed in the St Jude Lifetime Cohort (SJLIFE) study. Clinical and echocardiographic assessment of cardiac function was performed at initial and follow-up SJLIFE visits. Cardiomyopathy was defined as an ejection fraction < 50% or an absolute drop from baseline ≥ 10%. Genetic algorithm was used for feature selection, and extreme gradient boosting was applied to predict cardiomyopathy during the follow-up period. Model performance was evaluated by five-fold stratified cross-validation. RESULTS The median age at baseline SJLIFE evaluation was 31.7 years (range 18.4-66.4), and the time between baseline and follow-up evaluations was 5.2 years (0.5-9.5). Two thirds (67.1%) of patients were exposed to chest radiation, and 76.6% to anthracycline chemotherapy. One hundred seventeen (9.6%) patients developed cardiomyopathy during follow-up. In the model based solely on ECG features, the cross-validation area under the curve (AUC) was 0.87 (95% CI, 0.83 to 0.90), whereas the model based on clinical features had an AUC of 0.69 (95% CI, 0.64 to 0.74). In the model based on ECG and clinical features, the cross-validation AUC was 0.89 (95% CI, 0.86 to 0.91), with a sensitivity of 78% and a specificity of 81%. CONCLUSION AI using ECG data may assist in the identification of childhood cancer survivors at increased risk for developing future cardiomyopathy.

Background: Lung cancer, the most common cause of cancer-related death in adults, has not been well studied as a subsequent malignant neoplasm (SMN) in childhood cancer survivors. We assessed prevalence, risk factors, and outcomes for lung SMN in the Childhood Cancer Survivor Study (CCSS) cohort. Methods: Among 25,654 5-year survivors diagnosed with childhood cancer ( Results: Forty-two survivors developed a lung SMN [SIR, 4.0; 95% confidence interval (CI), 2.9–5.4] with a cumulative incidence of 0.16% at 30 years from diagnosis (95% CI, 0.09%–0.23%). In a treatment model, chest radiation doses of 10–30 Gy (HR, 3.4; 95% CI, 1.05–11.0), >30–40 Gy (HR, 4.6; 95% CI, 1.5–14.3), and >40 Gy (HR, 9.1; 95% CI, 3.1–27.0) were associated with lung SMN, with a monotone dose trend (Ptrend < 0.001). Survivors of Hodgkin lymphoma (SIR, 9.3; 95% CI, 6.2–13.4) and bone cancer (SIR, 4.4; 95% CI, 1.8–9.1) were at greatest risk for lung SMN. Conclusions: Survivors of childhood cancer are at increased risk for lung cancer compared with the general population. Greatest risk was observed among survivors who received chest radiotherapy or with primary diagnoses of Hodgkin lymphoma or bone cancer. Impact: This study describes the largest number of observed lung cancers in childhood cancer survivors and elucidates need for further study in this aging and growing population.

Achieving an optimal surgical result in patients with major aortopulmonary collateral arteries (MAPCAs) requires a thorough preoperative evaluation of the anatomy and physiology of the pulmonary circulation. This review provides a detailed description of diagnostic catheterization in patients with MAPCAs, including a summary of catheterization techniques, an overview of commonly used terms, and a review of MAPCA and pulmonary artery angiographic anatomy.

ALSUntangled reviews alternative and off label treatments with a goal of helping patients make more informed decisions about them. Here we review ketogenic diets. We shows that these have plausible mechanisms, including augmenting cellular energy balance and reducing excitotoxicity, neuroinflammation and oxidative stress. We review a mouse model study, anecdotal reports and trials in ALS and other diseases. We conclude that there is yet not enough data to recommend ketogenic diets for patients with ALS, especially in light of the many side effects these can have.

BACKGROUND AND PURPOSE We previously evaluated late cardiac disease in long-term survivors in the Childhood Cancer Survivor Study (CCSS) based on heart radiation therapy (RT) doses estimated from an age-scaled phantom with a simple atlas-based heart model (HAtlas). We enhanced our phantom with a high-resolution CT-based anatomically realistic and validated age-scalable cardiac model (HHybrid). We aimed to evaluate how this update would impact our prior estimates of RT-related late cardiac disease risk in the CCSS cohort. METHODS We evaluated 24,214 survivors from the CCSS diagnosed from 1970 to 1999. RT fields were reconstructed on an age-scaled phantom with HHybrid and mean heart dose (Dm), percent volume receiving ≥ 20 Gy (V20) and ≥ 5 Gy with V20 = 0 ( [Formula: see text] ) were calculated. We reevaluated cumulative incidences and adjusted relative rates of grade 3-5 Common Terminology Criteria for Adverse Events outcomes for any cardiac disease, coronary artery disease (CAD), and heart failure (HF) in association with Dm, V20, and [Formula: see text] (as categorical variables). Dose-response relationships were evaluated using piecewise-exponential models, adjusting for attained age, sex, cancer diagnosis age, race/ethnicity, time-dependent smoking history, diagnosis year, and chemotherapy exposure and doses. For relative rates, Dm was also considered as a continuous variable. RESULTS Consistent with previous findings with HAtlas, reevaluation using HHybrid dosimetry found that, Dm ≥ 10 Gy, V20 ≥ 0.1%, and [Formula: see text] ≥ 50% were all associated with increased cumulative incidences and relative rates for any cardiac disease, CAD, and HF. While updated risk estimates were consistent with previous estimates overall without statistically significant changes, there were some important and significant (P

A subset of rats that self-administer 3,4-methylenedioxypyrovalerone (MDPV) develop unusually high levels of drug taking. A history of responding maintained by cocaine, but not food, prevents the development of this high-responder phenotype; however, it is unclear how histories of noncontingent cocaine exposure or self-administering drugs from other pharmacological classes would affect its development. In the current studies, 5 groups of male Sprague-Dawley rats were used to determine whether histories of responding maintained by drugs from different pharmacological classes (e.g., MDPV, cocaine, fentanyl, nicotine, or ketamine) would differentially impact the development of the high-responder phenotype when MDPV was available for self-administration. Two additional groups were used to determine whether noncontingent exposure to cocaine would prevent the development of the high-responder phenotype when MDPV was available for self-administration, and whether noncontingent exposure to MDPV would facilitate the development of the high-responder phenotype when cocaine was available for self-administration. Consistent with previous reports, a history of response-contingent cocaine, and to a lesser extent noncontingent cocaine, prevented the MDPV high-responder phenotype; however, when responding was initially maintained by fentanyl, nicotine, or ketamine, the MDPV high-responder phenotype developed in ∼45% of rats. By manipulating behavioral and pharmacological histories prior to evaluating MDPV self-administration, the current studies provide additional evidence that a history of response-contingent (or noncontingent) cocaine can prevent the transition from well regulated to aberrant drug-taking when responding is maintained by MDPV. Although the mechanism(s) that underlies this novel high-responder phenotype are unknown, elucidation may provide insight into individual differences relating to substance use disorder. SIGNIFICANCE STATEMENT A subset of outbred Sprague-Dawley rats self-administer high levels of the synthetic cathinone 3,4-methylenedioxypyrovalerone (MDPV). Understanding the behavioral and/or pharmacological factors that can prevent the development of dysregulated MDPV self-administration may provide insight into individual differences in vulnerability to develop a substance use disorder.

BACKGROUND: The development of post-traumatic heterotopic ossification (HO) is a common, undesirable sequela in patients with high-energy (war-related) extremity injuries. While inflammatory and osteoinductive signaling pathways are known to be involved in the development and progression of post-traumatic HO, features of the structural microenvironment within which the ectopic bone begins to form remain poorly understood. Thus, increasing our knowledge of molecular and structural changes within the healing wound may help elucidate the pathogenesis of post-traumatic HO and aid in the development of specific treatment and/or prevention strategies. METHODS: In this study, we performed high-resolution microscopy and biochemical analysis of tissues obtained from traumatic war wounds to characterize changes in the structural microenvironment. In addition, using an electrospinning approach, we modeled this microenvironment to reconstitute a three-dimensional type I collagen scaffold with non-woven, randomly oriented nanofibers where we evaluated the performance of primary mesenchymal progenitor cells. RESULTS: We found that traumatic war wounds are characterized by a disorganized, densely fibrotic collagen I matrix that influences progenitor cells adhesion, proliferation and osteogenic differentiation potential. CONCLUSION: Altogether, these results suggest that the structural microenvironment present in traumatic war wounds has the potential to contribute to the development of post-traumatic HO. Our findings may support novel treatment strategies directed towards modifying the structural microenvironment after traumatic injury.

Eosinophilic myocarditis, a rare and under-recognized disease process, occurs due to cytotoxic inflammation of the endomyocardium that over time may lead to a restrictive cardiomyopathy. We report clinical, multimodality imaging, and pathologic findings in a 45-year-old woman over a 17-month period as she progressed from suspected acute eosinophilic myocarditis to phenotypic endomyocardial fibrosis resulting in recurrent ascites. Interval echocardiograms demonstrate definitive pathologic structural changes that reflect the hemodynamic consequences of the underlying cardiomyopathy. Despite a negative myocardial biopsy, characteristic findings on cardiovascular magnetic resonance imaging clarified the diagnosis which led to successful treatment with endomyocardial resection and valve replacements.

PURPOSE To determine the incidence of serious chronic health conditions among survivors of pediatric Hodgkin lymphoma (HL), compare by era of therapy and by selected cancer therapies, and provide estimates of risks associated with contemporary therapy. METHODS Assessing 2,996 5-year HL survivors in the Childhood Cancer Survivor Study diagnosed from 1970 to 1999, we examined the cumulative incidence of severe to fatal chronic conditions (grades 3-5) using self-report conditions, medically confirmed subsequent malignant neoplasms, and cause of death based on the National Death Index. We used multivariable regression models to estimate hazard ratios (HRs) per decade and by key treatment exposures. RESULTS HL survivors were of a mean age of 35.6 years (range, 12-58 years). The cumulative incidence of any grade 3-5 condition by 35 years of age was 31.4% (95% CI, 29.2 to 33.5). Females were twice as likely (HR, 2.1; 95% CI, 1.8 to 2.4) to have a grade 3-5 condition compared with males. From the 1970s to the 1990s, there was a 20% reduction (HR, 0.8; 95% CI, 0.7 to 0.9) in decade-specific risk of a grade 3-5 condition ( P trend = .002). In survivors who had a recurrence and/or hematopoietic cell transplant, the risk of a grade 3-5 condition was substantially elevated, similar to that of survivors treated with high-dose, extended-field radiotherapy (HR, 1.2; 95% CI, 0.9 to 1.5). Compared with survivors treated with chest radiotherapy ≥ 35 Gy in combination with an anthracycline or alkylator, a contemporary regimen for low-intermediate risk HL was estimated to lead to a 40% reduction in risk of a grade 3-5 condition (HR, 0.6; 95% CI, 0.4 to 0.8). CONCLUSION This study demonstrates that risk-adapted therapy for pediatric HL has resulted in a significant reduction in serious long-term outcomes.

BACKGROUND Obesity may affect efficacy and safety of biologic treatments for ulcerative colitis (UC). Tofacitinib is an oral, small molecule Janus kinase inhibitor for the treatment of UC. AIMS To assess efficacy and safety of tofacitinib in patients with UC, by baseline body mass index (BMI). METHODS This post hoc analysis evaluated patients with UC receiving placebo or tofacitinib from the 8-week OCTAVE Induction 1 and 2 (NCT01465763, NCT01458951) and 52-week OCTAVE Sustain (NCT01458574) studies. Patients were stratified by BMI at OCTAVE Induction 1 and 2 baseline (

Background Comorbidity indices have been used to represent the overall medical complexity of patient populations in clinical research; however, it is not known how well they capture the comorbidities of patients with a stroke or brain injury admitted to inpatient rehabilitation facilities (IRFs). Objective To determine how well commonly used comorbidity indices capture the comorbidities of patients admitted to IRFs after a stroke or brain injury. Design Cross-sectional, retrospective study. Setting IRFs nationwide. Participants Adults from four impairment groups: (1) hemorrhagic stroke, (2) ischemic stroke, (3) nontraumatic brain injury (NTBI), and (4) traumatic brain injury (TBI). Main outcome measures International Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10-CM) codes were extracted from the Uniform Data System for Medical Rehabilitation (UDSMR) for IRF discharges from October 1, 2015 to December 31, 2017. The percentage of discharges captured by Deyo-Charlson, Elixhauser, and Centers for Medicare and Medicaid Services (CMS) tiers was determined, as was the percentage of comorbidities captured. These measures were also compared with respect to their ability to capture chronic medical complexity by examining the percentage of codes captured after removal of codes deemed to represent hospital complications or sequela of the admission diagnosis. Results The percentage of discharges without at least one ICD-10-CM code captured by any index ranged from 0.3%-3.8%. The percentage of comorbidities with a prevalence exceeding 1% captured by at least one index ranged from 37.1%-43.6%. Chronic comorbidities were most likely to be captured by Elixhauser (40.7%-44.4%), followed by Deyo-Charlson (7.8%-9.6%), then CMS tiers (4.5%-6.9%). Existing comorbidity measures capture most IRF discharges related to a brain injury or stroke, whereas most medical comorbidities escape representation. Several common, functionally relevant diagnoses were not captured. Conclusion The use of comorbidity indices in the IRF neurologic injury population should account for the fact that these measures miss several common, important comorbidities.

Abdominal aortic aneurysm (AAA) is a complex disease which is incompletely accounted for. Basement membrane (BM) Collagen IV (COL4A1/A2) is abundant in the artery wall, and several lines of evidence indicate a protective role of baseline COL4A1/A2 in AAA development. Using Col4a1/a2 hemizygous knockout mice (Col4a1/a2+/−, 129Svj background) we show that partial Col4a1/a2 deficiency augmented AAA formation. Although unchallenged aortas were morphometrically and biomechanically unaffected by genotype, explorative proteomic analyses of aortas revealed a clear reduction in BM components and contractile vascular smooth muscle cell (VSMC) proteins, suggesting a central effect of the BM in maintaining VSMCs in the contractile phenotype. These findings were translated to human arteries by showing that COL4A1/A2 correlated to BM proteins and VSMC markers in non-lesioned internal mammary arteries obtained from coronary artery bypass procedures. Moreover, in human AAA tissue, MYH11 (VSMC marker) was depleted in areas of reduced COL4 as assessed by immunohistochemistry. Finally, circulating COL4A1 degradation fragments correlated with AAA progression in the largest Danish AAA cohort, suggesting COL4A1/A2 proteolysis to be an important feature of AAA formation. In sum, we identify COL4A1/A2 as a critical regulator of VSMC phenotype and a protective factor in AAA formation.

OBJECTIVE: To characterize the prevalence and predictors of concerns regarding future health and cancer risk among siblings of childhood cancer survivors. METHODS: This study reports longitudinal data (baseline and follow-up) from 3,969 adult siblings (median age = 29 [range 18 – 56] years) of long-term survivors of childhood cancer (median time since diagnosis 19.6 [9.6–33.8] years). Self-reported future health and cancer risk concerns (concerned vs not concerned) were assessed. Demographics and health data reported by both the siblings and their matched cancer survivors were examined as risk factors for health concerns using multivariable logistic regression. RESULTS: Percentage of siblings reporting future health and cancer risk concerns, respectively, decreased across decade of survivors’ diagnosis: 1970s (73.3%; 63.9%), 1980s (67.2%; 62.6%), 1990s (45.7%; 52.3%). Risk factors associated with future health concerns included sibling chronic health conditions (grade 2 Odds Ratio [OR]=1.57, 95% CI: 1.12–2.20; grade 3–4 OR=1.86, 95% CI: 1.18–2.94; compared to less than grade 2). Risk factors associated with future cancer concerns included sibling chronic health conditions (grade 2 OR=1.43, 95% CI: 1.05–1.94;’ grade 3–4 OR=1.64, 95% CI: 1.09–2.47; compared to less than grade 2). CONCLUSIONS: Sibling concerns regarding future health and cancer have diminished in recent decades. There are subgroups of siblings that are at-risk for future health and cancer risk concerns. IMPLICATIONS FOR CANCER SURVIVORS: Routine screening of concerns in at-risk siblings of survivors of childhood cancer may benefit the siblings of cancer survivors. These individuals may benefit from early interventions during diagnosis and treatment of their siblings.

Exposure to cranial radiotherapy is associated with an increased risk of subsequent CNS neoplasms among childhood, adolescent, and young adult (CAYA) cancer survivors. Surveillance for subsequent neoplasms can translate into early diagnoses and interventions that could improve cancer survivors' health and quality of life. The practice guideline presented here by the International Late Effects of Childhood Cancer Guideline Harmonization Group was developed with an evidence-based method that entailed the gathering and appraisal of published evidence associated with subsequent CNS neoplasms among CAYA cancer survivors. The preparation of these guidelines showed a paucity of high-quality evidence and highlighted the need for additional research to inform survivorship care. The recommendations are based on careful consideration of the evidence supporting the benefits, risks, and harms of the surveillance interventions, clinical judgment regarding individual patient circumstances, and the need to maintain flexibility of application across different health-care systems. Currently, there is insufficient evidence to establish whether early detection of subsequent CNS neoplasms reduces morbidity and mortality, and therefore no recommendation can be formulated for or against routine MRI surveillance. The decision to start surveillance should be made by the CAYA cancer survivor and health-care provider after careful consideration of the potential harms and benefits of surveillance for CNS neoplasms, including meningioma.

We sought to compare oncologic and functional outcomes between thermal and nonthermal energy partial gland ablation (PGA) modalities. We conducted comprehensive, structured literature searches, and 39 papers, abstracts, and presentations met the inclusion criteria of pre-PGA magnetic resonance imaging, oncologic outcomes of at least 6 months, and systematic biopsies after PGA. Twenty-six studies used thermal ablation: high-intensity focused ultrasound (HIFU), cryotherapy, focal laser ablation, or radiofrequency ablation. In-field recurrence rates ranged from 0 to 36% for HIFU, 6 to 24% for cryotherapy, 4 to 50% for focal laser ablation, and 20 to 25% for radiofrequency ablation. Twelve studies used nonthermal technologies of focal brachytherapy, vascular-targeted photodynamic therapy, or irreversible electroporation. Focal brachytherapy had the lowest reported failure rate of 8%, vascular-targeted photodynamic therapy had >30% positive in-field biopsies, and irreversible electroporation had in-field recurrence rates of 12–35%. PGA was well tolerated, and nearly all patients returned to baseline urinary function 12 months later. Most modalities caused transient decreases in erectile function. Persistent erectile dysfunction was highest in patients who underwent HIFU. Although oncologic outcomes vary between treatment modalities, systematic review of existing data demonstrates that PGA is a safe treatment option for patients with localized prostate cancer., Highlights • Partial gland ablation (PGA) is an emerging prostate cancer treatment that targets the “index lesion,” defined as the largest lesion of the highest grade. • PGA methods can be broadly characterized by the type of energy used: thermal or nonthermal. • Patients treated with PGA have fewer treatment-related side effects than patients treated with radical therapies. • Long-term oncologic outcomes of patients with clinically significant disease are needed to verify the safety of PGA. • Clarity is needed regarding how to monitor these patients post-PGA, the need for repeat biopsies, and how to use PSA and MRI to monitor for disease progression.

Nodular regenerative hyperplasia (NRH) of the liver may lead to noncirrhotic portal hypertension with subsequent development of portosystemic shunts. While extrahepatic and macrovascular shunts are readily visualized with imaging or endoscopy, there is no standard technique to detect intrahepatic microvascular portosystemic shunting and quantitatively assess shunt burden. We present a case of a 53-year-old female with suspected NRH and hepatopulmonary syndrome with inconclusive liver biopsies and absent portosystemic shunts per abdominal imaging. A percutaneous transportal infusion of Technetium-99m labeled macroaggregated albumin (99mTc-MAA) successfully identified intrahepatic microvascular portosystemic shunting and quantified a lung shunt fraction of more than 30%. NRH was subsequently confirmed with a surgical wedge biopsy and the patient was successfuly treated with a liver transplant. Transportal 99mTc-MAA could be used to both identify and quantify otherwise occult microvascular portosystemic shunts in patients with clinical sequelae of portal hypertension.

A diagnosis of traumatic brain injury (TBI) is typically based on patient medical history, a clinical examination, and imaging tests. Elevated plasma levels of glial fibrillary acidic protein (GFAP), ubiquitin c-terminal hydrolase L1 (UCH-L1), and neurofilament light chain (NFL) have been observed in numerous studies of TBI patients. It is reasonable to view traumatic optic neuropathy (TON) as a focal form of TBI. The purpose of this study was to assess if circulating GFAP, UCH-L1, and NFL are also elevated in a porcine model of TON. Serum levels of GFAP, UCH-L1, and NFL were measured immediately before optic nerve crush and 1 h post-injury in 10 Yucatan minipigs. Severity of optic nerve crush was confirmed by visual inspection of the optic nerve at time of injury, loss of visual function as measured by flash visual evoked potential (fVEP) at 7 and 14 days, and histological analysis of axonal transport of cholera toxin-β (CT-β) within the optic nerve. Post-crush concentrations of GFAP, UCH-L1, and NFL were all significantly elevated compared with pre-crush concentrations (p

Background Neoadjuvant yttrium-90 transarterial radioembolization (TARE) is increasingly being used as a strategy to facilitate resection of otherwise unresectable tumors due to its ability to generate both tumor response and remnant liver hypertrophy. Perioperative outcomes after the use of neoadjuvant lobar TARE remain underinvestigated. Methods A single center retrospective review of patients who underwent lobar TARE prior to major hepatectomy for primary or metastatic liver cancer between 2007 and 2018 was conducted. Baseline demographics, radioembolization parameters, pre- and post-radioembolization volumetrics, intra-operative surgical data, adverse events, and post-operative outcomes were analyzed. Results Twenty-six patients underwent major hepatectomy after neoadjuvant lobar TARE. The mean age was 58.3 years (17-88 years). 62% of patients (n=16) had primary liver malignancies while the remainder had metastatic disease. Liver resection included right hepatectomy or trisegmentectomy, left or extended left hepatectomy, and sectorectomy/segmentectomy in 77% (n=20), 8% (n=2), and 15% (n=4) of patients, respectively. The mean length of stay was 8.3 days (range, 3-33 days) and there were no grade IV morbidities or 90-day mortalities. The incidence of post hepatectomy liver failure (PHLF) was 3.8% (n=1). The median time to progression after resection was 4.5 months (range, 3.3-10 months). Twenty-three percent (n=6) of patients had no recurrence. The median survival was 28.9 months (range, 16.9-46.8 months) from major hepatectomy and 37.6 months (range, 25.2-53.1 months) from TARE. Conclusions Major hepatectomy after neoadjuvant lobar radioembolization is safe with a low incidence of PHLF.

Purpose: Report relevance of molecular groups to clinicopathologic features, germline SMARCB1/SMARCA4 alterations (GLA), and survival of children with atypical teratoid rhabdoid tumor (ATRT) treated in two multi-institutional clinical trials. Materials and Methods: Seventy-four participants with newly diagnosed ATRT were treated in two trials: infants (SJYC07: age < 3 years; n = 52) and children (SJMB03: age 3–21 years; n = 22), using surgery, conventional chemotherapy (infants), or dose-dense chemotherapy with autologous stem cell rescue (children), and age- and risk-adapted radiotherapy [focal (infants) and craniospinal (CSI; children)]. Molecular groups ATRT-MYC (MYC), ATRT-SHH (SHH), and ATRT-TYR (TYR) were determined from tumor DNA methylation profiles. Results: Twenty-four participants (32%) were alive at time of analysis at a median follow-up of 8.4 years (range, 3.1–14.1 years). Methylation profiling classified 64 ATRTs as TYR (n = 21), SHH (n = 30), and MYC (n = 13), SHH group being associated with metastatic disease. Among infants, TYR group had the best overall survival (OS; P = 0.02). However, outcomes did not differ by molecular groups among infants with nonmetastatic (M0) disease. Children with M0 disease and Conclusions: Among infants, those with ATRT-TYR had the best OS. ATRT-SHH was associated with metastases and consequently with inferior outcomes. Children with nonmetastatic ATRT benefit from postoperative CSI and adjuvant chemotherapy.

Background There is considerable interest in improving the education and care of women with inflammatory bowel disease (IBD) to improve pregnancy outcomes. Despite increased awareness, not all women with IBD have access to pregnancy-related education and the quality of counseling is variable. We aimed to assess the effectiveness of a simple educational intervention for improving pregnancy-related knowledge and to evaluate the effect of education on patient outcomes including anxiety, depression, and quality of life in women with IBD. Methods This prospective study of women with IBD who were pregnant or planning a pregnancy evaluated the effectiveness of a single gastroenterologist-led educational intervention in improving pregnancy-related knowledge, measured using the Crohn’s and Colitis Pregnancy Knowledge score 1 month postintervention. Secondary outcomes included the effect on anxiety and depression, quality of life, medication adherence, and patient satisfaction. Results One hundred women with IBD were recruited. Fifty percent were pregnant at the time of the intervention. Baseline knowledge scores were similar independent of the patients’ pregnancy status or whether they had previously received counseling from their gastroenterologist. Median Crohn’s and Colitis Pregnancy Knowledge scores postintervention (n = 82) were higher than preintervention scores (14/17 vs 10/17; P < 0.001). In addition, 32% of patients had poor knowledge at baseline (score ≤7/17), compared to only 5% after the intervention (P < 0.001). There was a significant improvement in total anxiety and depression and quality of life scores postintervention. Medication adherence and patient satisfaction were excellent. Conclusions Uptake of this gastroenterologist-led educational intervention has the potential to improve pregnancy knowledge, promote medication adherence, and enhance quality of life for women with IBD globally.

How much do traits of aquatic macrophytes affect rates of ecosystem metabolism in a shallow riparian pond? The factors that drive patterns of primary production and ecosystem respiration (E...

OBJECTIVE To estimate the incidence of failed induction of labor and the associated patient risk factors. METHODS We performed a case-control study from a cohort of nulliparous women who delivered between 39 and 41 weeks of gestation after an induction of labor in one of seven hospitals. Cases of failed induction were defined using the Obstetric Care Consensus criteria (ie, cesarean delivery performed in early labor [less than 6 cm dilatation] after at least 12 hours of oxytocin administration from membrane rupture). For each case of failed induction, the next four women who did not meet the criteria for failed induction of labor were selected for the control group, matched by hospital. We identified characteristics associated with failed induction of labor using a multivariable conditional logistic regression that was constructed with backward stepwise method for variable selection. RESULTS Across the hospitals, 4,123 of 10,175 nulliparous women were induced (40.5%), of whom 82 had a failed induction of labor (2.0%). A total of 328 women were selected for the matched control group. Baseline characteristics were similar between the groups. Compared with women in the control group, women with a failed induction were more likely to have a delivery body mass index (BMI) of 40 or higher (28.0 vs 8.2%, P

We previously demonstrated the safety of doses up to 48 Gy in 4 fractions with stereotactic body radiotherapy (SBRT) in poor surgical candidates with localized renal cell carcinoma (RCC). In an additional expansion cohort, we aimed to assess the safety of further dose escalation to 48-60 Gy in 3 fractions.Patients were required to have localized RCC and be poor surgical candidates due to medical comorbidities. Dose-limiting toxicity (DLT) was defined as acute (180 days) grade ≥3 gastrointestinal/genitourinary toxicity by CTCAEv4. Tumor response was assessed using RECIST 1.1 criteria measurements every 6 months for 3 years and optional percutaneous biopsy.Groups of 4, 4, and 3 patients received 48, 54, and 60 Gy in 3 fractions, respectively from 2012 to 2016. Median follow-up was 34.3 months. Zero DLTs were observed. Acute toxicities were limited to grade 1 fatigue and nausea in 45.5% and 18.1%. Late grade 2+ and grade 3+ possibly treatment-related events occurred in 18.1% and 9.1%, respectively. Three-year local control was 90% by RECIST 1.1 criteria. Five of 5 post-treatment biopsies in the expansion cohort were positive by Hematoxylin and Eosin staining. Three of the 5 patients with positive biopsies have been observed for 1.2-3.9 years without evidence of progression.Dose escalation to 60 Gy in 3 fractions was achieved without DLTs. Favorable local control rates were observed, and the interpretation of post-SBRT biopsies remains uncertain. Further studies comparing SBRT to percutaneous ablation for poor surgical candidates with RCC are warranted.

Here we use the ALSUntangled methodology to review Tamoxifen as an ALS treatment. We show that it has plausible mechanisms, a positive preclinical study, a case report and 2 small trials suggesting benefits. We show that it appears reasonably safe, though there is a small risk of developing cancer with long term use. While we cannot yet endorse this as an ALS treatment, there is enough evidence to warrant another larger ALS trial.

CONTEXT: This scoping review examines the current research on the effect of cannabis upon pain intensity in spinal cord injury (SCI) pain. Chronic pain is a significant secondary condition following SCI, and traditional treatments (e.g. opioids, NSAIDs) are often criticized for providing inadequate relief. As a result, there is increasing interest in and use of cannabis and cannabinoid-based medications as an alternative means of pain control. OBJECTIVE: The purpose of this review was to examine the scientific evidence on the effect of cannabis/cannabinoids upon pain intensity in SCI by mapping the current literature. METHODS: Two hundred and fifty-two studies were identified by searching electronic databases for articles published through February 2020. In addition, reviewers scanned the reference lists of identified articles and examined clinicaltrials.gov for unpublished data in this area. Title, abstract, and full-text reviews were completed by two independent reviewers. Data extraction was performed by a single reviewer and verified by a second reviewer. RESULTS: Six articles covering five treatment studies were included. Studies yielded mixed findings likely due to large variability in methodology, including lack of standardized dosing paradigms, modes of use, and duration of trial. CONCLUSIONS: The current quality and level of evidence is insufficient to draw reliable conclusions of the efficacy of cannabis upon SCI-related pain itensity. We identify specific limitations of past studies and present guidelines for future research. Trial registration: ClinicalTrials.gov identifier: Nct01606202..

Effective data sharing is key to accelerating research to improve diagnostic precision, treatment efficacy, and long-term survival in pediatric cancer and other childhood catastrophic diseases. We present St. Jude Cloud (https://www.stjude.cloud), a cloud-based data-sharing ecosystem for accessing, analyzing, and visualizing genomic data from >10,000 pediatric patients with cancer and long-term survivors, and >800 pediatric sickle cell patients. Harmonized genomic data totaling 1.25 petabytes are freely available, including 12,104 whole genomes, 7,697 whole exomes, and 2,202 transcriptomes. The resource is expanding rapidly, with regular data uploads from St. Jude's prospective clinical genomics programs. Three interconnected apps within the ecosystem—Genomics Platform, Pediatric Cancer Knowledgebase, and Visualization Community—enable simultaneously performing advanced data analysis in the cloud and enhancing the Pediatric Cancer knowledgebase. We demonstrate the value of the ecosystem through use cases that classify 135 pediatric cancer subtypes by gene expression profiling and map mutational signatures across 35 pediatric cancer subtypes. Significance: To advance research and treatment of pediatric cancer, we developed St. Jude Cloud, a data-sharing ecosystem for accessing >1.2 petabytes of raw genomic data from >10,000 pediatric patients and survivors, innovative analysis workflows, integrative multiomics visualizations, and a knowledgebase of published data contributed by the global pediatric cancer community. This article is highlighted in the In This Issue feature, p. 995

In both truncus arteriosus communis (TAC) and tetralogy of Fallot (TOF), there is a rare phenotype that includes a single branch pulmonary artery (PA) arising from a solitary great artery and major aortopulmonary collaterals (MAPCAs) supplying the contralateral lung. We describe the intracardiac and great vessel anatomy of infants with this phenotype, consider rationale for classifying patients as TOF vs. TAC, and describe surgical outcomes. Our institution's surgical database was reviewed for patients with a single branch PA from a solitary arterial trunk and contralateral MAPCAs from 2007 to 2019. Demographic, imaging, and surgical data were collected and described. All 11 patients underwent complete repair with a median right ventricular to aortic pressure ratio of 0.36 (range 0.26-0.50). At 0.1-9.1 years after repair (median 0.8 years) there was approximately balanced left-right lung perfusion (median 52% to the right lung, range 34-74%). The MAPCA lungs exemplified the full spectrum of PA and MAPCA anatomy, from absent intrapericardial PAs with all single supply MAPCAs to a normally arborizing PA with all dual supply MAPCAs and present pulmonary valve leaflet tissue. All patients had a systemic semilunar valve with 3 thin and similarly sized leaflets and fibrous continuity with the tricuspid valve, and all had coronary origins and outflow tract morphology more consistent with TOF. It is appropriate to classify all patients with a single anomalous PA from a solitary arterial trunk and MAPCAs to the contralateral lung as TOF rather than TAC Type A3. All variants were amenable to surgical repair.

Background: Survivors of childhood cancer have an increased risk of therapy-related cardiovascular disease. It is not known whether family history of cardiovascular disease further increases risk of adverse cardiovascular outcomes among survivors. Methods: Family history of cardiovascular disease was collected from 1,260 survivors [median age at diagnosis, 8 years (range, 0–23); age at last follow-up, 35 years (range, 18–66)] of childhood cancer in the St. Jude Lifetime Cohort Study. Multivariable risk models evaluated associations with cardiovascular disease (Common Terminology Criteria for Adverse Events grade 2–4 events) and cardiovascular risk factors. Results: Among survivors exposed to chest-directed radiation and/or anthracycline chemotherapy (n = 824), 7% reported a first-degree family history of heart failure, 19% myocardial infarction, 11% stroke, 26% atherosclerotic disease (myocardial infarction and/or stroke), 62% hypertension, and 31% diabetes mellitus. Eighteen percent of exposed survivors developed heart failure, 9% myocardial infarction, 3% stroke, 11% atherosclerotic disease, 30% hypertension, and 9% diabetes mellitus. Having a first-degree family history of atherosclerotic disease was independently associated with development of treatment-related heart failure [RR, 1.38; 95% confidence interval (CI), 1.01–1.88; P = 0.04] among exposed survivors. Risk for hypertension was increased among exposed survivors with a first-degree family history of hypertension (RR, 1.55; 95% CI, 1.26–1.92; P < 0.0001) or of any cardiovascular disease [myocardial infarction, stroke, or heart failure (RR, 1.30; 95% CI, 1.06–1.59; P = 0.01)]. Conclusions: Family history of cardiovascular disease and cardiovascular risk factors independently increased risk of heart failure and hypertension among survivors of childhood cancer exposed to cardiotoxic therapies. Impact: These data show the importance of cardiovascular family history as a risk factor for cardiovascular disease in survivors of childhood cancer.

Phytophthora species cause crown, root, and aerial canker diseases in diverse horticultural crops, resulting in a loss of yield, loss of quality, and plant death. Breeding programs are interested in developing genotypes resistant to these and other pathogens, but current screening methods for tree crops are time-consuming, potentially spanning many years. Here we present a rapid in vitro assay in which walnut shoots obtained from tissue culture can be challenged with Phytophthora zoospores and monitored for symptom development within a week. As a proof of concept, two cultivars, scion variety ‘Chandler’ and clonal rootstock ‘RX1’, with known different degrees of crown rot susceptibility, were inoculated in vitro with P. pini (formerly included in P. citricola complex), and results of the assay reproducibly matched the differences in disease susceptibility generally observed for these two walnut selections under greenhouse and orchard conditions. In addition, when the in vitro assay was used for inoculations with P. capsici, which is not pathogenic on walnut, no disease development was observable, indicating that the assay can discriminate between species of Phytophthora that are aggressive on walnut and those not known as walnut pathogens. Our results suggest that this in vitro shoot inoculation procedure may provide rapid assessments useful for prescreening resistance to Phytophthora in walnuts. Further testing of the assay is justified to determine whether it can resolve more subtle differences in resistance and whether it can be useful with other perennial hosts of Phytophthora.

With the emergence of multi-drug-resistant strains of Mycobacterium tuberculosis, there is a pressing need for new oral drugs with novel mechanisms of action. A number of scaffolds with potent anti-tubercular in vitro activity have been identified from phenotypic screening that appear to target MmpL3. However, the scaffolds are typically lipophilic, which facilitates partitioning into hydrophobic membranes, and several contain basic amine groups. Highly lipophilic basic amines are typically cytotoxic against mammalian cell lines and have associated off-target risks, such as inhibition of human ether-a-go-go related gene (hERG) and IKr potassium current modulation. The spirocycle compound 3 was reported to target MmpL3 and displayed promising efficacy in a murine model of acute tuberculosis (TB) infection. However, this highly lipophilic monobasic amine was cytotoxic and inhibited the hERG ion channel. Herein, the related spirocycles (1-2) are described, which were identified following phenotypic screening of the Eli Lilly corporate library against M. tuberculosis. The novel N-alkylated pyrazole portion offered improved physicochemical properties, and optimization led to identification of a zwitterion series, exemplified by lead 29, with decreased HepG2 cytotoxicity as well as limited hERG ion channel inhibition. Strains with mutations in MmpL3 were resistant to 29, and under replicating conditions, 29 demonstrated bactericidal activity against M. tuberculosis. Unfortunately, compound 29 had no efficacy in an acute model of TB infection; this was most likely due to the in vivo exposure remaining above the minimal inhibitory concentration for only a limited time.

Childhood cancer survivors treated with radiation therapy (RT) and osteotoxic chemotherapies are at increased risk for fractures. However, understanding of how genetic and clinical susceptibility factors jointly contribute to fracture risk among survivors is limited. To address this gap, we conducted genome-wide association studies of fracture risk after cancer diagnosis in 2,453 participants of European ancestry from the Childhood Cancer Survivor Study (CCSS) with 930 incident fractures using Cox regression models (i.e., time-to-event analysis) and prioritized sex- and treatment-stratified genetic associations. We performed replication analyses in 1,417 survivors of European ancestry with 652 incident fractures from the St. Jude Lifetime Cohort Study (SJLIFE). In discovery, we identified a genome-wide significant (P36 Gray only: HR=3.79, 95% CI: 1.95–7.34, P=8.2×10(−5)). These head/neck RT-specific HAGHL SNP effects were replicated in female SJLIFE survivors. In silico bioinformatics analyses suggest these fracture risk alleles regulate HAGHL gene expression and related bone resorption pathways. Genetic risk profiles integrating this locus may help identify female survivors who would benefit from targeted interventions to reduce fracture risk.

As treatment evolves and the population who survive childhood cancer ages and increases in number, researchers must use novel approaches to prevent, identify and mitigate adverse effects of treatment. Future priorities include collaborative efforts to pool large cohort data to improve detection of late effects, identify late effects of novel therapies, and determine the contribution of genetic factors along with physiologic and accelerated aging among survivors. This knowledge should translate to individual risk prediction and prevention strategies. Finally, we must utilize health services research and implementation science to improve adoption of survivorship care recommendations outside of specialized pediatric oncology centers.

PURPOSE Survivors of childhood cancer treated with anthracyclines and/or chest-directed radiation are at increased risk for heart failure (HF). The International Late Effects of Childhood Cancer Guideline Harmonization Group (IGHG) recommends risk-based screening echocardiograms, but evidence supporting its frequency and cost-effectiveness is limited. PATIENTS AND METHODS Using the Childhood Cancer Survivor Study and St Jude Lifetime Cohort, we developed a microsimulation model of the clinical course of HF. We estimated long-term health outcomes and economic impact of screening according to IGHG-defined risk groups (low [doxorubicin-equivalent anthracycline dose of 1-99 mg/m2 and/or radiotherapy < 15 Gy], moderate [100 to < 250 mg/m2 or 15 to < 35 Gy], or high [≥ 250 mg/m2 or ≥ 35 Gy or both ≥ 100 mg/m2 and ≥ 15 Gy]). We compared 1-, 2-, 5-, and 10-year interval-based screening with no screening. Screening performance and treatment effectiveness were estimated based on published studies. Costs and quality-of-life weights were based on national averages and published reports. Outcomes included lifetime HF risk, quality-adjusted life-years (QALYs), lifetime costs, and incremental cost-effectiveness ratios (ICERs). Strategies with ICERs < $100,000 per QALY gained were considered cost-effective. RESULTS Among the IGHG risk groups, cumulative lifetime risks of HF without screening were 36.7% (high risk), 24.7% (moderate risk), and 16.9% (low risk). Routine screening reduced this risk by 4% to 11%, depending on frequency. Screening every 2, 5, and 10 years was cost-effective for high-risk survivors, and every 5 and 10 years for moderate-risk survivors. In contrast, ICERs were > $175,000 per QALY gained for all strategies for low-risk survivors, representing approximately 40% of those for whom screening is currently recommended. CONCLUSION Our findings suggest that refinement of recommended screening strategies for IGHG high- and low-risk survivors is needed, including careful reconsideration of discontinuing asymptomatic left ventricular dysfunction and HF screening in low-risk survivors.

OBJECTIVES To determine whether utilisation of a serum microRNA (miRNA) test could improve treatment appropriateness and cost-effectiveness for patients with Stage I non-seminomatous germ cell tumours (NSGCTs). PATIENTS AND METHODS A decision tree model was built to investigate treatment course, clinical and cost outcomes for patients with Stage IA (T1N0M0S0) and IB (T2-4N0M0S0) NSGCT. The model compared outcomes and cost of standard approach using histopathology, conventional serum tumour markers and radiographic staging (standard model) to a miRNA-based approach using the standard model + post-orchidectomy serum miR-371a-3p (marker model). Probabilities of expected treatment and outcomes were based on presence/absence of cancer upon entering into the model. Overtreatment was defined as adjuvant chemotherapy or primary retroperitoneal lymph node dissection in a patient without cancer. Undertreatment was defined as initial surveillance for a patient with cancer. RESULTS Utilising the miRNA marker-based approach, 26% of patients avoid overtreatment and 8% avoid undertreatment in Stage IA NSGCT; 27% avoid overtreatment and 23% avoid undertreatment in Stage IB disease. Appropriate treatment decision-making increased from 65% to 94% and 50% to 92% for Stage IA and IB, respectively. The miRNA-based approach remained cost-effective over a wide range of performance characteristics with savings of ~$1400 (American dollars)/patient for both Stage IA and IB disease. CONCLUSION A miRNA-based approach may potentially select patients with Stage I NSGCT for correct treatment in a cost-effective manner. Identification of residual teratoma-only remains an issue. Prospective studies are necessary to validate these findings.

INTRODUCTION: Patients with hormone receptor-positive/HER2-negative (HR+/HER2−) metastatic breast cancer have benefitted from treatment with palbociclib, a cyclin-dependent kinase (CDK) 4/6 inhibitor capable of selectively targeting mechanisms of cell cycle progression that contribute to tumor cell proliferation. Palbociclib use in this setting demonstrates improved progression-free survival when given in combination with aromatase inhibitors or fulvestrant. AREAS COVERED: The authors describe the current state of research surrounding palbociclib use in breast cancer, present evidence supporting a role for palbociclib in additional subtypes of metastatic breast cancer such as HER2-positive (HER2+) and triple-negative, report ongoing clinical trials aimed at expanding the scope of use for palbociclib, and discuss expected clinical results that will better inform decisions on including palbociclib as a part of breast cancer treatment strategies. EXPERT OPINION: Preclinical and clinical studies have shown promising evidence for palbociclib use in metastatic HER2+ and androgen receptor-expressing triple-negative breast cancer but mixed results in the adjuvant/neoadjuvant setting, where differences may only be detectable in high-risk disease. Palbociclib combinations may constitute viable replacements for chemotherapy in the neoadjuvant setting as part of de-escalation strategies. Investigation into synergy of palbociclib with immunotherapies is also ongoing based on non-canonical effects of CDK4/6 inhibition on the tumor immune microenvironment.

Background To review long-term outcomes and saphenous vein (SV) occlusion rate after endovenous ablation (EVA) for symptomatic varicose veins. Methods A review of our EVA database (1998–2018) with at least 3-years of clinical and sonographic follow-up. The primary end point was SV closure rate. Results 542 limbs were evaluated. 358 limbs had radiofrequency and 323 limbs had laser ablations; 542 great saphenous veins (GSV), 106 small saphenous veins (SSV) and 33 anterior accessory saphenous veins (AASV) were treated. Follow-up was 5.6 ± 2.3 years; 508 (74.6%) veins were occluded, 53 (7.8%) partially occluded and 120 (17.6%) were patent. On multivariable Cox regression analysis, male sex (HR 1.6, 95% CI [0.46–018], p = 0.012) and use anticoagulation (HR 2.0, 95% CI [0.69–0.34], p = 0.044) were predictors of long-term failure. On Kaplan-Meier curve, we had an 86.3% occlusion rate. Conclusion Our experience revealed a 5-year closure rate of 86.3%. Ablations have satisfactory occlusion rate.

OBJECTIVE To delineate the impact of treatment exposures and chronic health conditions on psychological, educational, and social outcomes in adolescent survivors of Wilms tumor. METHODS Parent reports from the Childhood Cancer Survivor Study were analyzed for 666 adolescent survivors of Wilms tumor and 698 adolescent siblings. Adjusting for race and household income, survivors were compared to siblings on the Behavior Problems Index and educational outcomes. Multivariable modified Poisson regression estimated relative risks (RR) for therapeutic exposures and chronic health conditions (CTCAE 4.03 graded) among survivors, adjusting for sex, race, income, and age at diagnosis. RESULTS Compared to siblings, adolescent survivors of Wilms tumor were more likely to take psychoactive medication (9.4% vs. 5.1%, p < 0.001) and utilize special education services (25.5% vs. 12.6%, p < 0.001) but did not differ significantly in emotional and behavioral problems. Survivors were less likely to be friendless (7.2% vs. 10.1%, p = 0.04) but were more likely to have difficulty getting along with friends (14.5% vs. 7.8%, p < 0.001). Among survivors, use of special education services was associated with abdomen plus chest radiation (RR = 1.98, CI:1.18-3.34). Those with grade 2-4 cardiovascular conditions had higher risk for anxiety/depression (RR = 1.95, CI:1.19-3.19), headstrong behaviors (RR = 1.91, CI:1.26-2.89), and inattention (RR = 1.56, CI:1.02-2.40). CONCLUSIONS Adolescent survivors of Wilms tumor were similar to siblings with respect to mental health concerns overall but were more likely to require special education. Monitoring of psychosocial and academic problems through adolescence is warranted, especially among those treated with radiation to the abdomen plus chest or with cardiac conditions.

Background The goals of this study were to determine whether serum concentrations of endocannabinoids (eCB) and related lipids predict disease status in patients with amyotrophic lateral sclerosis (ALS) relative to healthy controls, and whether concentrations correlate with disease duration and severity. Methods Serum concentrations of the eCBs 2-arachidonoylglycerol (2-AG) and N-arachidonoylethanolamine (AEA), and related lipids palmitoylethanolamine (PEA), oleoylethanolamine (OEA), and 2-oleoylglycerol (2-OG), were measured in samples from 47 patients with ALS and 19 healthy adults. Hierarchical binary logistic and linear regression analyses assessed whether lipid concentrations predicted disease status (ALS or healthy control), duration, or severity. Results Binary logistic regression revealed that, after controlling for age and gender, 2-AG, 2-OG and AEA concentrations were unique predictors of the presence of ALS, demonstrating odds ratios of 0.86 (P = .039), 1.03 (P = .023), and 42.17 (P = .026), respectively. When all five lipids and covariates (age, sex, race, ethnicity, body mass index, presence of a feeding tube) were included, the resulting model had an overall classification accuracy of 92.9%. Hierarchical linear regression analyses indicated that in patients with ALS, AEA and OEA inversely correlated with disease duration (P = .030 and .031 respectively), while PEA demonstrated a positive relationship with disease duration (P = .013). None of the lipids examined predicted disease severity. Conclusions These findings support previous studies indicating significant alterations in concentrations of circulating lipids in patients with ALS. They suggest that arachidonic and oleic acid containing small lipids may serve as biomarkers for identifying the presence and duration of this disease.

Objectives This study compares outcomes for patients with displaced femoral neck fractures undergoing hemiarthroplasty (HA) or total hip arthroplasty (THA) by surgeons of different fellowship training. Design Retrospective review of HEALTH trial data. Setting Eighty clinical sites across 10 countries. Patients/participants One thousand four hundred forty-one patients ≥50 years with low-energy hip fractures requiring surgical intervention. Intervention Patients were randomized to either HA or THA groups in the initial data set. Surgeons' fellowship training was ascertained retrospectively, and outcomes were compared. Main outcome measurements The main outcome was an unplanned secondary procedure at 24 months. Secondary outcomes included death, serious adverse events, prosthetic joint infection (PJI), dislocation, discharge disposition, and use of ambulatory devices postoperatively. Results There was a significantly higher risk of PJI in patients treated by surgeons without fellowship training in arthroplasty (P = 0.01), surgeons with unknown fellowship training (P = 0.03), and surgeons with no fellowship training (P = 0.02) than those treated by an arthroplasty-trained surgeon. There were significantly higher odds of being discharged to a facility rather than home in patients who underwent surgery by a surgeon with no fellowship training compared with arthroplasty-fellowship-trained surgeons (P = 0.03). Conclusions Arthroplasty for hip fracture can be performed by all orthopaedic surgeons with equivalent reoperation rates. Infection prevention strategies and use of "care pathways" by arthroplasty-fellowship-trained surgeons may account for the lower risk of PJI and higher rate of discharge to home. The authors advocate for the use of evidence-based infection prevention initiatives and standardized care pathways in this patient population. Level of evidence Prognostic Level II. See Instructions for Authors for a complete description of levels of evidence.

PURPOSE Radiotherapy for childhood cancer is associated with elevated subsequent neoplasm (SN) risk, but the contribution of rare variants in DNA damage response and radiation sensitivity genes to SN risk is unknown. PATIENTS AND METHODS We conducted whole-exome sequencing in a cohort of childhood cancer survivors originally diagnosed during 1970 to 1986 (mean follow-up, 32.7 years), with reconstruction of doses to body regions from radiotherapy records. We identified patients who developed SN types previously reported to be related to radiotherapy (RT-SNs; eg, basal cell carcinoma [BCC], breast cancer, meningioma, thyroid cancer, sarcoma) and matched controls (sex, childhood cancer type/diagnosis, age, SN location, radiation dose, survival). Conditional logistic regression assessed SN risk associated with potentially protein-damaging rare variants (SnpEff, ClinVar) in 476 DNA damage response or radiation sensitivity genes with exact permutation-based P values using a Bonferroni-corrected significance threshold of P < 8.06 × 10−5. RESULTS Among 5,105 childhood cancer survivors of European descent, 1,108 (21.7%) developed at least 1 RT-SN. Out-of-field RT-SN risk, excluding BCC, was associated with homologous recombination repair (HRR) gene variants (patient cases, 23.2%; controls, 10.8%; odds ratio [OR], 2.6; 95% CI, 1.7 to 3.9; P = 4.79 × 10−5), most notably but nonsignificantly for FANCM (patient cases, 4.0%; matched controls, 0.6%; P = 9.64 × 10−5). HRR variants were not associated with likely in/near-field RT-SNs, excluding BCC (patient cases, 12.7%; matched controls, 12.9%; P = .92). Irrespective of radiation dose, risk for RT-SNs was also associated with EXO1 variants (patient cases, 1.8%; controls, 0.4%; P = 3.31 × 10−5), another gene implicated in DNA double-strand break repair. CONCLUSION In this large-scale discovery study, we identified novel associations between RT-SN risk after childhood cancer and potentially protein-damaging rare variants in genes involved in DNA double-strand break repair, particularly HRR. With replication, these results could affect screening recommendations for childhood cancer survivors and risk-benefit assessments of treatment approaches.

We are presenting a compelling case of a 61-year-old female with a history of appendiceal mucinous adenocarcinoma (AMA) with a new complaint of irritative lower urinary tract symptoms. Magnetic resonance imaging (MRI) showed a semi-circumferential, T2 hyperintense, rim enhancing, and lacking restricted diffusion lesion involving the urethra and infiltrating the right perineal and internal obturator muscles. The suspected differential diagnosis was urethral malignancy, based on her cancer history and MRI findings. After interdisciplinary consensus, the patient underwent excision of the lesion, and pathology was consistent with metastasis from the primary tumor. The urethra is a rare site of primary malignancy and metastatic disease. In particular, a non-contiguous metastatic disease involving the urethra is exceedingly rare. To the best of our knowledge, this is the first report of an AMA metastasizing to the urethra.

BACKGROUND Previous literature demonstrates increased mortality for traumatic brain injury (TBI) with transfer to a Level II versus Level I trauma center. Our objective was to determine the effect of the most recent American College of Surgeons-Committee on Trauma (ACS-COT) "Resources for the Optimal Care of the Injured Patient" resources manual ("The Orange Book") on outcomes after severe TBI after interfacility transfer to Level I versus Level II center. METHODS Utilizing the Trauma Quality Program Participant Use File of the American College of Surgeons admission year 2017, we identified patients with isolated TBI undergoing interfacility transfer to either Level I or Level II trauma center. Logistic regression was performed to determine independent associations with mortality. RESULTS There were 10,268 (71.6%) transferred to a Level I center and 4,025 (28.4%) were transferred to a Level II center. They were mostly male (61.4%) with a mean ± SD age of 61 ± 20.8 years. Mean Injury Severity Score was 16.3 ± 6.3 and most were injured in a single-level fall (51.5%). Patients transferred to a Level I center were less likely to be White (82.3% vs. 84.7%, 0.002) and more likely to have sustained penetrating trauma (2.7% vs. 1.6%

Supplemental Digital Content is available in the text., Background: Abdominal aortic aneurysm (AAA) is an important cause of cardiovascular mortality; however, its genetic determinants remain incompletely defined. In total, 10 previously identified risk loci explain a small fraction of AAA heritability. Methods: We performed a genome-wide association study in the Million Veteran Program testing ≈18 million DNA sequence variants with AAA (7642 cases and 172 172 controls) in veterans of European ancestry with independent replication in up to 4972 cases and 99 858 controls. We then used mendelian randomization to examine the causal effects of blood pressure on AAA. We examined the association of AAA risk variants with aneurysms in the lower extremity, cerebral, and iliac arterial beds, and derived a genome-wide polygenic risk score (PRS) to identify a subset of the population at greater risk for disease. Results: Through a genome-wide association study, we identified 14 novel loci, bringing the total number of known significant AAA loci to 24. In our mendelian randomization analysis, we demonstrate that a genetic increase of 10 mm Hg in diastolic blood pressure (odds ratio, 1.43 [95% CI, 1.24–1.66]; P=1.6×10−6), as opposed to systolic blood pressure (odds ratio, 1.06 [95% CI, 0.97–1.15]; P=0.2), likely has a causal relationship with AAA development. We observed that 19 of 24 AAA risk variants associate with aneurysms in at least 1 other vascular territory. A 29-variant PRS was strongly associated with AAA (odds ratioPRS, 1.26 [95% CI, 1.18–1.36]; PPRS=2.7×10−11 per SD increase in PRS), independent of family history and smoking risk factors (odds ratioPRS+family history+smoking, 1.24 [95% CI, 1.14–1.35]; PPRS=1.27×10−6). Using this PRS, we identified a subset of the population with AAA prevalence greater than that observed in screening trials informing current guidelines. Conclusions: We identify novel AAA genetic associations with therapeutic implications and identify a subset of the population at significantly increased genetic risk of AAA independent of family history. Our data suggest that extending current screening guidelines to include testing to identify those with high polygenic AAA risk, once the cost of genotyping becomes comparable with that of screening ultrasound, would significantly increase the yield of current screening at reasonable cost.

Objective Past studies have suggested a potential “J shaped” relationship between infrarenal aortic diameter and both cardiovascular disease (CVD) prevalence and all cause mortality. However, screening programmes have focused primarily on large (aneurysmal) aortas. In addition, aortic diameter is rarely adjusted for body size, which is particularly important for women. This study aimed to investigate specifically the relationship between body size adjusted infrarenal aortic diameter and baseline prevalence of CVD. Methods A retrospective analysis was performed on a total of 4882 elderly (>50 years) participants (mean age 69.4 ± 8.9 years) for whom duplex ultrasound to assess infrarenal abdominal aortic diameters had been performed. History of CVDs, including ischaemic heart disease (IHD), and associated risk factors were collected at the time of assessment. A derivation cohort of 1668 participants was used to select cut offs at the lower and upper 12.5% tails of the aortic size distributions (aortic size index of 1.2, respectively), which was then tested in a separate cohort. Results A significantly elevated prevalence of CVD, and specifically IHD, was observed in participants with both small and large aortas. These associations remained significant following adjustment for age, sex, diabetes, hypertension, dyslipidaemia, obesity (body mass index), and smoking. Conclusion The largest and smallest infrarenal aortic sizes were both associated with prevalence of IHD. In addition to identifying those with aneurysmal disease, it is hypothesised that screening programmes examining infrarenal aortic size may also have the potential to improve global CVD risk prediction by identifying those with small aortas.

Background Quality of care in inflammatory bowel disease (IBD) has received much attention internationally; however, the available surveys focus on health professionals rather than patients. Aims To assess the experiences of healthcare for people living with IBD against established Australian IBD Standards. Methods An online cross-sectional survey was conducted with Australians ≥16 years old recruited via Crohn's & Colitis Australia membership, public and private clinics and the Royal Flying Doctor Service. Participants completed a questionnaire incorporating items addressing the Australian IBD Standards 2016, the Picker Patient Experience Questionnaire, IBD Control Survey and the Manitoba Index. Results Complete data were provided by 731 respondents (71.5% female, median age 46 years, ranging from 16 to 84 years). While the majority (74.8%) were satisfied with their IBD healthcare, the care reported did not meet the Australian IBD Standards. Overall, 32.4% had access to IBD nurses, 30.9% to a dietician and 12% to a psychologist in their treating team. Participants managed by public IBD clinics were most likely to have access to an IBD nurse (83.7%), helpline (80.7%) and research trials (37%). One third of respondents reported waiting >14 days to see a specialist when their IBD flared. Participants received enough information, mostly from medical specialists (88.8%) and IBD nurses (79.4%). However, 51% wanted to be more involved in their healthcare. Conclusions These data show discordance between expectations of patients and national standards with current levels of service provision, which fail to deliver equitable and comprehensive IBD care.

PURPOSE: The study aims were to determine the prevalence of balance impairments in adult survivors of pediatric CNS tumors, and to identify predictors of and limitations associated with balance impairments. METHODS: Participants were adult survivors (N=329) of pediatric CNS tumors. Balance was considered impaired among those with composite scores

Background Surveillance with annual mammography and breast magnetic resonance imaging (MRI) is recommended for female survivors of childhood cancer treated with chest radiation, yet benefits, harms, and costs are uncertain. Objective To compare the benefits, harms, and cost-effectiveness of breast cancer screening strategies in childhood cancer survivors. Design Collaborative simulation modeling using 2 Cancer Intervention and Surveillance Modeling Network breast cancer models. Data sources Childhood Cancer Survivor Study and published data. Target population Women aged 20 years with a history of chest radiotherapy. Time horizon Lifetime. Perspective Payer. Intervention Annual MRI with or without mammography, starting at age 25, 30, or 35 years. Outcome measures Breast cancer deaths averted, false-positive screening results, benign biopsy results, and incremental cost-effectiveness ratios (ICERs). Results of base-case analysis Lifetime breast cancer mortality risk without screening was 10% to 11% across models. Compared with no screening, starting at age 25 years, annual mammography with MRI averted the most deaths (56% to 71%) and annual MRI (without mammography) averted 56% to 62%. Both strategies had the most screening tests, false-positive screening results, and benign biopsy results. For an ICER threshold of less than $100 000 per quality-adjusted life-year gained, screening beginning at age 30 years was preferred. Results of sensitivity analysis Assuming lower screening performance, the benefit of adding mammography to MRI increased in both models, although the conclusions about preferred starting age remained unchanged. Limitation Elevated breast cancer risk was based on survivors diagnosed with childhood cancer between 1970 and 1986. Conclusion Early initiation (at ages 25 to 30 years) of annual breast cancer screening with MRI, with or without mammography, might reduce breast cancer mortality by half or more in survivors of childhood cancer. Primary funding source American Cancer Society and National Institutes of Health.