Avelumab in Patients With Metastatic Colorectal Cancer.

BACKGROUND: Metastatic colorectal cancer (mCRC) is incurable, and median overall survival is less than 2½ years. Although monoclonal antibodies that block PD-1/PD-L1 interactions are active in microsatellite unstable/mismatch repair deficient tumors, a growing dataset shows that most patients with microsatellite stable/mismatch repair proficient tumors will not benefit from the blockade of PD-1/PD-L1 interactions. Here we present results from patients with mCRC (n = 22) treated with the anti-PD-L1 monoclonal antibody avelumab. METHODS: Patients received treatment on a phase I, open-label, dose-escalation trial via a consecutive parallel-group expansion in colorectal cancer. Patients aged 18 years and older with mCRC measurable by RECIST v1.1 who had received at least 1 line of systemic therapy for metastatic disease enrolled. Patients with prior immune checkpoint inhibitor treatment were excluded. Patients received avelumab 10 mg/kg intravenously every 2 weeks. The primary endpoint was the objective response rate. RESULTS: Twenty-two participants received treatment from July 2013 to August 2014. There were no objective responses and median progression-free survival was 2.1 months (95% CI: 1.4-5.5 months). There were 5 grade 3 treatment-related adverse events: GGT elevation (n = 2), PRESS (n = 1), lymphopenia (n = 1), and asymptomatic amylase/lipase elevation (n = 1). CONCLUSION: As demonstrated with other anti-PD-1/PD-L1 monoclonal antibodies, avelumab is not active in unselected patients with mCRC (ClinicalTrials.gov Identifier: NCT01772004).

Rate of thrombosis in children and adolescents hospitalized with COVID-19 or MIS-C.

Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is associated with thrombotic complications in adults, but the incidence of COVID-19-related thrombosis in children and adolescents is unclear. Most children with acute COVID-19 have mild disease, but coagulopathy has been associated with multisystem inflammatory syndrome in children (MIS-C), a postinfectious complication. We conducted a multicenter retrospective cohort study to determine the incidence of thrombosis in children hospitalized with COVID-19 or MIS-C and evaluate associated risk factors. We classified patients into 1 of 3 groups for analysis: COVID-19, MIS-C, or asymptomatic SARS-CoV-2. Among a total of 853 admissions (COVID-19, n = 426; MIS-C, n = 138; and asymptomatic SARS-CoV-2, n = 289) in 814 patients, there were 20 patients with thrombotic events (TEs; including 1 stroke). Patients with MIS-C had the highest incidence (9 [6.5%] of 138) vs COVID-19 (9 [2.1%] of 426) or asymptomatic SARS-CoV-2 (2 [0.7%] of 289). In patients with COVID-19 or MIS-C, a majority of TEs (89%) occurred in patients age ≥12 years. Patients age ≥12 years with MIS-C had the highest rate of thrombosis at 19% (9 of 48). Notably, 71% of TEs that were not present on admission occurred despite thromboprophylaxis. Multivariable analysis identified the following as significantly associated with thrombosis: age ≥12 years, cancer, presence of a central venous catheter, and MIS-C. In patients with COVID-19 or MIS-C, hospital mortality was 2.3% (13 of 564), but it was 28% (5 of 18) in patients with TEs. Our findings may help inform pediatric thromboprophylaxis strategies.

Initial von Willebrand factor antigen values in adolescent females predict future values.

INTRODUCTION: Diagnosing von Willebrand Disease (VWD) in adolescent females is challenging as menstruation and physiologic stress elevate von Willebrand factor (VWF) laboratory values. AIM: To develop a VWF prediction model for adolescent females based on initial VWF results. METHODS: We identified female patients aged 9 to 21 years with any VWF laboratory test over a 5-year period (2017-2021) at any Texas Children's Hospital facility. Patient demographics, VWF testing, haemoglobin concentration, serum ferritin and site of clinical testing were collected (initial and subsequent laboratory evaluations). A Bayesian linear regression model was developed. Prediction intervals were analysed to identify thresholds for patients in whom repeat testing was unlikely to identify low VWF levels (< 50%), consistent with VWD. RESULTS: A total of 6125 adolescent females underwent VWF testing; 1204 (19.7%) had repeat testing. Based on the prediction model, initial VWF antigen values of 80%, 90% and ≥100% carried a 92.6%, 96.6% and ≥98.0% probability of having repeat normal repeat VWF values, respectively. Subjects assessed in outpatient adolescent medicine or gynaecology clinics were more likely to have low VWF values compared to those assessed in the acute care setting (p < .001). Median presenting haemoglobin and serum ferritin were 12.4 g/dL and 13 ng/mL, respectively and were similar in those with normal versus low VWF antigen values. CONCLUSION: Repeat testing in adolescent females whose initial VWF antigen values are ≥90% is unlikely to identify additional patients with VWD. Iron deficiency screening should be performed in all adolescent females.

Pulmonary embolism in pediatric and adolescent patients with COVID-19 infection during the SARS-CoV-2 delta wave.

Coronavirus disease 2019 (COVID-19) infection in children has been associated with thrombosis, though few cases of COVID-associated pulmonary embolism (PE) have been described. We performed a retrospective review of the nine cases of COVID-19-associated PE during the B.1617.2 variant surge at Texas Children's Hospital. The patient cohort largely contained unvaccinated obese adolescents. All patients were critically ill with two requiring catheter-directed thrombolysis in addition to anticoagulation. Eight of the nine patients had COVID pneumonia along with PE. This report stresses the importance of maintaining a high index of suspicion for PE in pediatric COVID-19 infection and vaccinating obese adolescent patients.

COVID-19 vaccine (mRNA BNT162b2) and COVID-19 infection-induced thrombotic thrombocytopenic purpura in adolescents.

The mRNA COVID-19 vaccine and COVID-19 infection caused by the SARS-CoV-2 virus may be immunologic triggers for the development of thrombotic thrombocytopenic purpura (TTP). There is not yet literature that discusses TTP induced by COVID-19 vaccination or infection in pediatric or adolescent patients. We describe three adolescents presenting with TTP (both de novo and relapsed disease) following administration of the Pfizer COVID-19 vaccine or after COVID-19 infection. Our observations demonstrate that the Pfizer-BioNTech mRNA vaccine and COVID-19 infection can act as triggers for the development/relapse of both congenital and acquired TTP.

Patient Characteristics and Treatment Outcomes of Symptomatic Catheter-Related Arterial Thrombosis in Infants: A Retrospective Cohort Study.

OBJECTIVE: To describe the clinical characteristics, outcomes, and adverse events of treatment for symptomatic infant catheter-related arterial thrombosis. STUDY DESIGN: Single-center retrospective medical record review of 99 infants (age <365 days) with catheter-related arterial thrombosis, either following indwelling arterial catheter placement or cardiac catheterization, who were treated with anticoagulation over an 8-year span at a pediatric tertiary care center. Outcomes measured include thrombosis progression, bleeding events, and thrombus resolution following the treatment period. RESULTS: Thromboses were secondary to indwelling arterial catheter placement in 51 (51.5%) and cardiac catheterization in 48 (48.5%). The median age at diagnosis of catheter-related arterial thrombosis was 52 days. All patients received therapeutic anticoagulation with either unfractionated heparin or low molecular weight heparin for a maximum of 28 days. Progression of catheter-related arterial thrombosis occurred in 8 (8.1%) patients. One (1%) major and 3 (3%) minor bleeding events occurred within the cohort. Complete thrombus resolution was observed in 60 (60.6%), partial resolution in 33 (33.3%), and no resolution in 6 (6.1%) following the treatment period. Factors associated with complete thrombus resolution included time from intervention to catheter-related arterial thrombosis diagnosis (median of 1 day vs 5 days in those who experienced thrombus resolution vs those who did not, P = .035), and iliac and/or femoral artery involvement (P = .015). CONCLUSIONS: Our treatment approach to infant catheter-related arterial thrombosis is safe and effective. Limitations of the study are its retrospective nature with a limited number of patients from a single institution. Additional prospective studies are needed to determine the optimal treatment approach to catheter-related arterial thrombosis in infants.

Emicizumab in pediatric hemophilia: Bleeding and surgical outcomes from a single-center retrospective study.

Real-world data describing emicizumab prophylaxis in pediatric hemophilia A is limited with current literature providing a heterogenous approach to procedural management. We performed a retrospective review on the 28 patients who have been treated with emicizumab prophylaxis at Texas Children's Hospital from 2018 to 2021. After starting emicizumab, the mean annualized bleeding rate reduced from 3.61 to 0.44. Seven surgical procedures were performed in the cohort, and all treated with pre- and postoperative factor replacement resulting in one minor bleeding event. We demonstrate a successful experience with emicizumab prophylaxis and safe perioperative approach with a focus on minimizing postoperative bleeding.

Diagnosis, Clinical Characteristics, and Treatment Modalities of Adolescent May-Thurner Syndrome-associated Deep Venous Thrombosis.

May-Thurner syndrome (MTS) predisposes individuals to develop lower extremity deep venous thrombosis (DVT) because of compression of the left common iliac vein. Diagnosis of the anatomic obstruction is critical for effective therapy, as treatment by interventional radiology is often required in addition to anticoagulation to prevent thrombus progression and recurrence. The authors performed a retrospective review of adolescent patients who presented with MTS-associated DVT at a pediatric tertiary care center from 2009 to 2018 to assess for delays in MTS diagnosis after the presentation. Fourteen patients (median age 16.5 y, range, 13.8 to 17.9 y) were included, no DVTs were provoked by a central venous catheter. The median time from DVT to MTS diagnosis was 0.65 months (range, 0 to 21.5 mo). The initial imaging modalities used for DVT diagnosis were not able to diagnosis MTS. All patients were treated with anticoagulation and 13 underwent interventional therapy. Four patients had thrombus progression or recurrence, whereas 6 had complete thrombus resolution on follow-up imaging. Three patients who had a delayed MTS diagnosis had clinical worsening despite therapeutic anticoagulation requiring rehospitalization. Adolescent patients with "unprovoked" left lower extremity DVT should undergo appropriate imaging to diagnose MTS to allow for adequate medical and interventional therapy.

Clinical characteristics and outcomes of combined thrombolysis and anticoagulation for pediatric and young adult lower extremity and inferior vena cava thrombosis.

Effective treatment for acute, extensive, symptomatic lower extremity (LE) thrombosis involves thrombolysis in addition to anticoagulation. There is limited available data on the outcomes and safety of thrombolysis to help guide its use in pediatrics and young adults. A retrospective study of children and young adults (<21 years of age) that received catheter directed thrombolysis (CDT) for LE and inferior vena cava (IVC) thrombosis was performed over a 5-year span at a pediatric tertiary care center. A total of 29 patients were identified for inclusion in the study, 76% (n = 22) received overnight CDT while 24% (n = 7) received tissue plasminogen activator as a bolus dose during a single interventional procedure. The median age of the cohort was 15.8 years (range 0-19.1). All patients were treated with a course of therapeutic anticoagulation. The thromboses represented were extensive, with 93% (n = 27) being occlusive and affecting multiple venous segments. Thrombus resolution occurred in 35% (n = 10) of patients. Rivaroxaban use (p < 0.01) during the course of anticoagulation and estrogen-containing hormonal therapy (p = 0.01) use prior to diagnosis were associated with thrombus resolution, while Hispanic ethnicity (p = 0.06) had a trend toward thrombus persistence. There were one major and 3 minor bleeding events that occurred as complications of thrombolysis and no treatment related deaths. This study provides baseline information that can be used to help guide clinicians treating similar patients and suggests the need to develop an improved, uniform treatment approach for superior resolution rates.

Comparison of published guidelines for management of coagulopathy and thrombosis in critically ill patients with COVID 19: implications for clinical practice and future investigations.

Critically ill patients with COVID-19 are at increased risk for thrombotic complications which has led to an intense debate surrounding their anticoagulation management. In the absence of data from randomized controlled clinical trials, a number of consensus guidelines and recommendations have been published to facilitate clinical decision-making on this issue. However, substantive differences exist between these guidelines which can be difficult for clinicians. This review briefly summarizes the major societal guidelines and compares their similarities and differences. A common theme in all of the recommendations is to take an individualized approach to patient management and a call for prospective randomized clinical trials to address important anticoagulation issues in this population.

Sex Differences in Tolerability to Anti-Programmed Cell Death Protein 1 Therapy in Patients with Metastatic Melanoma and Non-Small Cell Lung Cancer: Are We All Equal?

BACKGROUND: Immune-related adverse events (irAEs) have emerged as a serious clinical issue in the use of immune checkpoint inhibitors (ICIs). Risk factors for irAEs remain controversial. Therefore, we studied sex differences in irAEs in patients treated with anti-programmed cell death protein 1 (PD-1) therapy. MATERIALS AND METHODS: All patients with metastatic melanoma and non-small cell lung cancer (NSCLC) treated with anti-PD-1 therapy at Mayo Clinic Rochester and Florida from 2015 to 2018 were reviewed. Kaplan-Meier method and log-rank test was used for time-to-event analysis. RESULTS: In 245 patients with metastatic melanoma, premenopausal women were more likely to experience irAEs (all grades) compared with postmenopausal women and men (67% vs. 60% vs. 46%), primarily because of an increase in endocrinopathies (33% vs. 12% vs. 10%, respectively). In patients with NSCLC (231 patients), women (all ages) were also more likely to develop irAEs of all grades (48% vs. 31%). Women with NSCLC were more likely to develop pneumonitis (11% vs. 4%) and endocrinopathies (14% vs. 5%). No differences in grade ≥3 toxicities were seen across sexes in both cohorts, but women were more likely to receive systemic steroids for the treatment of irAEs compared with men. Better progression-free-survival was observed in women with NSCLC and irAEs (10 months vs. 3.3 months) compared with women without irAEs. CONCLUSION: Women with metastatic melanoma and NSCLC are more likely to experience irAEs compared with men. We also observed differences between sexes in the frequency of certain irAEs. Larger studies are needed to investigate the mechanisms underlying these associations. IMPLICATIONS FOR PRACTICE: The results of this study suggest that women may be at a higher risk for immune-related adverse events (irAEs) compared with men when treated with anti-programmed cell death protein 1 therapy. In addition, women were more likely to develop certain irAEs, including endocrinopathies and pneumonitis. Close follow-up of women undergoing treatment with immune checkpoint inhibitors will allow clinicians to diagnose these treatment-related complications early, potentially reducing their associated morbidity and mortality. In addition, a possible association between irAEs and response to therapy was observed.

Reflectance-Based Vegetation Index Assessment of Four Plant Species Exposed to Lithium Chloride.

This study considers whether a relationship exists between response to lithium (Li) exposure and select vegetation indices (VI) determined from reflectance spectra in each of four plant species: Arabidopsis thaliana, Helianthus annuus (sunflower), Brassica napus (rape), and Zea mays (corn). Reflectance spectra were collected every week for three weeks using an ASD FieldSpec Pro spectroradiometer with both a contact probe (CP) and a field of view probe (FOV) for plants treated twice weekly in a laboratory setting with 0 mM (control) or 15 mM of lithium chloride (LiCl) solution. Plants were harvested each week after spectra collection for determination of relevant physical endpoints such as relative water content and chlorophyll content. Mixed effects analyses were conducted on selected endpoints and vegetation indices (VI) to determine the significance of the effects of treatment level and length of treatment as well as to determine which VI would be appropriate predictors of treatment-dependent endpoints. Of the species considered, A. thaliana exhibited the most significant effects and corresponding shifts in reflectance spectra. Depending on the species and endpoint, the most relevant VIs in this study were NDVI, PSND, YI, R1676/R1933, R750/R550, and R950/R750.

Outcomes of augmented allograft figure-of-eight sternoclavicular joint reconstruction.

BACKGROUND: Sternoclavicular joint (SCJ) instability is a rare condition resulting in impaired function and shoulder girdle pain. Various methods for stabilizing the SCJ have been proposed, with biomechanical analysis demonstrating superior stiffness and peak load properties with a figure-of-8 tendon graft technique. The purpose of this study was to evaluate the clinical outcomes of SCJ reconstruction with an interference screw figure-of-8 allograft tendon technique. METHODS: A retrospective analysis of a consecutive cohort of patients from 2007 to 2011 was performed for all patients undergoing SCJ reconstruction for instability. All patients were treated for SCJ instability with a figure-of-8 allograft reconstruction augmented by 2 tenodesis screws. Outcomes were performed with the American Shoulder and Elbow Surgeons (ASES) score, the shortened Disabilities of the Arm, Shoulder, and Hand (QuickDASH) score, and the visual analog scale (VAS) for pain score for all patients. Intraoperative and postoperative complications were recorded. RESULTS: A total of 10 patients were included in the study, with an average follow-up of 38 months (range, 11.6-66.8 months). Preoperatively, the mean ASES score was 35.3 points (range, 21.7-55 points), whereas the postoperative mean ASES score increased to 84.7 points (range, 66.6-95 points). The mean VAS score improved from 7.0 (range, 5-10) before surgery to 1.15 (range, 0-3) at follow-up, and the QuickDASH score average was 17.0 points (range, 0 to 38.6 points). Minor postoperative complications were noted in 2 patients. CONCLUSION: Patients who underwent repair of SCJ instability by an augmented figure-of-8 allograft tendon reconstruction report marked improvements in both shoulder function and pain relief.

Nutritional Strategies for Managing Iron Deficiency in Adolescents: Approaches to a Challenging but Common Problem.

Iron deficiency (ID) is a common and challenging problem in adolescence. In order to prevent, recognize, and treat ID in this age range, it is critical to understand the recommended daily intake of iron in relation to an adolescent's activity, dietary habits, and basal iron losses. Adolescents following vegetarian or vegan diets exclusively rely on plant-based, nonheme iron, which has decreased bioavailability compared with heme iron and requires increased total iron intake. Individuals with disordered eating habits, excessive menstrual blood loss, and certain chronic health conditions (including inflammatory bowel disease and heart failure) are at high risk of ID and the development of symptomatic iron deficiency anemia (IDA). Adolescent athletes and those with sleep and movement disorders may also be more sensitive to changes in iron status. Iron deficiency is typically treated with oral iron supplementation. To maximize iron absorption, oral iron should be administered no more than once daily, ideally in the morning, while avoiding foods and drinks that inhibit iron absorption. Oral iron therapy should be provided for ≥3 mo in the setting of ID to reach a ferritin of 20 ng/mL before discontinuation. Intravenous iron is being increasingly used in this population and has demonstrated efficacy and safety in adolescents. It should be considered in those with persistent ID despite a course of oral iron, severe and/or symptomatic IDA, and chronic inflammatory conditions characterized by decreased gastrointestinal iron absorption.

Traumatic intracranial hemorrhage in pediatrics: Implications of factor XIII deficiency and consumptive coagulopathy in abusive head trauma evaluation.

For infants that present with intracranial hemorrhage in the setting of suspected abusive head trauma (AHT), the standard recommendation is to perform an evaluation for a bleeding disorder. Factor XIII (FXIII) deficiency is a rare congenital bleeding disorder associated with intracranial hemorrhages in infancy, though testing for FXIII is not commonly included in the initial hemostatic evaluation. The current pediatric literature recognizes that trauma, especially traumatic brain injury, may induce coagulopathy in children, though FXIII is often overlooked as having a role in pediatric trauma-induced coagulopathy. We report an infant that presented with suspected AHT in whom laboratory workup revealed a decreased FXIII level, which was later determined to be caused by consumption in the setting of trauma induced coagulopathy, rather than a congenital disorder. Within the Child Abuse Pediatrics Research Network (CAPNET) database, 85 out of 569 (15 %) children had FXIII testing, 3 of those tested (3.5 %) had absent FXIII activity on qualitative testing, and 2 (2.4 %) children had activity levels below 30 % on quantitative testing. In this article we review the literature on the pathophysiology and treatment of low FXIII in the setting of trauma. This case and literature review demonstrate that FXIII consumption should be considered in the setting of pediatric AHT.

Targeting of CYP2E1 by miRNAs in alcohol-induced intestine injury.

Although binge alcohol-induced gut leakage has been studied extensively in the context of reactive oxygen species-mediated signaling, it was recently revealed that post-transcriptional regulation plays an essential role as well. Ethanol (EtOH)-inducible cytochrome P450-2E1 (CYP2E1), a key enzyme in EtOH metabolism, promotes alcohol-induced hepatic steatosis and inflammatory liver disease, at least in part by mediating changes in intestinal permeability. For instance, gut leakage and elevated intestinal permeability to endotoxins have been shown to be regulated by enhancing CYP2E1 mRNA and CYP2E1 protein levels. Although it is understood that EtOH promotes CYP2E1 induction and activation, the mechanisms that regulate CYP2E1 expression in the context of intestinal damage remain poorly defined. Specific miRNAs, including miR-132, miR-212, miR-378, and miR-552, have been shown to repress the expression of CYP2E1, suggesting that these miRNAs contribute to EtOH-induced intestinal injury. Here, we have shown that CYP2E1 expression is regulated post-transcriptionally through miRNA-mediated degradation, as follows: (1) the RNA-binding protein AU-binding factor 1 (AUF1) binds mature miRNAs, including CYP2E1-targeting miRNAs, and this binding modulates the degradation of corresponding target mRNAs upon EtOH treatment; (2) the serine/threonine kinase mammalian Ste20-like kinase 1 (MST1) mediates oxidative stress-induced phosphorylation of AUF1. Those findings suggest that reactive oxygen species-mediated signaling modulates AUF1/miRNA interaction through MST1-mediated phosphorylation. Thus, our study demonstrates the critical functions of AUF1 phosphorylation by MST1 in the decay of miRNAs targeting CYP2E1, the stabilization of CYP2E1 mRNA in the presence of EtOH, and the relationship of this pathway to subsequent intestinal injury.

ETC-1002 regulates immune response, leukocyte homing, and adipose tissue inflammation via LKB1-dependent activation of macrophage AMPK.

ETC-1002 is an investigational drug currently in Phase 2 development for treatment of dyslipidemia and other cardiometabolic risk factors. In dyslipidemic subjects, ETC-1002 not only reduces plasma LDL cholesterol but also significantly attenuates levels of hsCRP, a clinical biomarker of inflammation. Anti-inflammatory properties of ETC-1002 were further investigated in primary human monocyte-derived macrophages and in in vivo models of inflammation. In cells treated with ETC-1002, increased levels of AMP-activated protein kinase (AMPK) phosphorylation coincided with reduced activity of MAP kinases and decreased production of proinflammatory cytokines and chemokines. AMPK phosphorylation and inhibitory effects of ETC-1002 on soluble mediators of inflammation were significantly abrogated by siRNA-mediated silencing of macrophage liver kinase B1 (LKB1), indicating that ETC-1002 activates AMPK and exerts its anti-inflammatory effects via an LKB1-dependent mechanism. In vivo, ETC-1002 suppressed thioglycollate-induced homing of leukocytes into mouse peritoneal cavity. Similarly, in a mouse model of diet-induced obesity, ETC-1002 restored adipose AMPK activity, reduced JNK phosphorylation, and diminished expression of macrophage-specific marker 4F/80. These data were consistent with decreased epididymal fat-pad mass and interleukin (IL)-6 release by inflamed adipose tissue. Thus, ETC-1002 may provide further clinical benefits for patients with cardiometabolic risk factors by reducing systemic inflammation linked to insulin resistance and vascular complications of metabolic syndrome.