Immunocompromised pediatric patients constitute a growing population that is particularly vulnerable to bacterial infection, necessitating prompt recognition and treatment. This study assessed the ...utility of interleukin-27 (IL-27) and procalcitonin (PCT) as biomarkers of bacterial infection among immunocompromised pediatric subjects.
This is a single-center prospective cohort study conducted from July 2016 through September 2017, drawing subjects from the inpatient units at Cincinnati Children's Hospital Medical Center (CCHMC), a large, tertiary care children's hospital. Patients were included if they fit the definition of immunocompromised and were under clinical suspicion for infection, defined by the acquisition of a blood culture at any point during the admission. The primary analysis assessed the accuracy of IL-27 to diagnose bacterial infection in immunocompromised pediatric patients, using PCT as a comparator.
293 patients were recruited, representing 400 episodes of suspected bacterial infection. The median age was 7.8 years (IQR 3.1-13.8 years). Fifty-three percent (n = 213) of the population had a primary oncologic diagnosis, 24% (n = 95) had received a bone marrow transplant, and 21% (n = 85) had received a solid organ transplant. The overall infection rate was 37%, with 70% of those patients having some form of culture positivity. Twenty-eight-day mortality was 5%, 60-day mortality was 9%, with 87% of patients surviving to hospital discharge. The AUC's of the ROC curve to diagnose bacterial infection were 0.62 (0.5-0.68) for IL-27 and 0.65 (0.6-0.73) for PCT. Using the previously determined cutoff of 5.0 ng/mL, the specificity of IL-27 to diagnose bacterial infection reached 94%, with a negative predictive value of 64%.
Despite prior work demonstrating IL-27 and PCT as possible biomarkers of bacterial infection in immunocompromised pediatric patients, we were unable to validate these findings. This illustrates the challenges associated with developing reliable biomarkers of bacterial infection in this vulnerable population.
Background: Locoregionally advanced, stage IV head and neck cancer has traditionally carried a poor prognosis. We sought to assess changes in patterns of failure, prognostic factors for recurrence, ...and overall outcome, using two different strategies of chemoradiotherapy conducted in prospective, multi-institutional phase II trials. Patients and methods: Three hundred and thirty-seven stage IV patients were treated from 1989 to 1998. We compared locoregional and distant recurrence rates, overall survival and progression-free survival from two different treatment strategies: intensive induction chemotherapy followed by split-course chemoradiotherapy (type 1, n=127), or intensified, split-course, hyperfractionated multiagent chemoradiotherapy alone (type 2, n=210). Univariate and multivariate analyses of 12 chosen covariates were assessed separately for the two study types. Results: The pattern of failure varied greatly between study types 1 and 2 (5-year locoregional failure of 31% and 17% for study types 1 and 2, respectively, P=0.01; 5-year distant failure rate of 13% and 22% for study types 1 and 2, P=0.03). Combined 5-year overall survival was 47% 95% confidence interval (CI) 41% to 53%) and progression-free survival was 60% (95% CI 55% to 66%). Both treatment strategies yielded similar survival rates. Poor overall survival and distant recurrence were best predicted by advanced nodal stage. Locoregional recurrence was extremely rare for patients with T0–T3 tumor stage, regardless of lymph-node stage. Conclusions: This analysis suggests that pattern of failure in primary head and neck cancer may be dependent upon treatment strategy. Randomized clinical trials of induction chemotherapy are warranted as a means to determine if a decrease in distant metastases can lead to an increase in survival rates in the setting of effective chemoradiotherapy for locoregional control. Additionally, this analysis provides impetus for randomized clinical trials of organ preservation chemoradiotherapy in sites outside the larynx and hypopharynx.
Efforts to reduce the late toxicity associated with chemoradiation (CRT) for locally advanced head and neck squamous cell cancer (LA-HNSCC) have focused on radiotherapy (RT) dose de-escalation. In ...this phase I/II protocol investigating the addition of everolimus to induction chemotherapy (IC), we incorporated a novel response-adapted volume de-escalation (RAVD) approach using IC response to guide the extent of RT volume reduction.
Patients with measurable LA-HNSCC received two cycles of IC (cisplatin, paclitaxel, cetuximab ± everolimus). Patients with ≥50% reduction in the sum of tumor diameters good response (GR) received TFHX (paclitaxel, fluorouracil, hydroxyurea, and 1.5 Gy twice daily RT every other week) to a dose of 75 Gy with the single planning target volume (PTV1) encompassing exclusively gross disease. Patients with <50% response non-response (NR) were treated with TFHX encompassing PTV1 and the next nodal station at risk (PTV2) to a dose of 45 Gy followed by a sequential boost to PTV1 to a dose of 75 Gy.
Ninety-four patients were enrolled. Randomization to everolimus was discontinued on interim analysis after 50 patients due to futility. IC response was evaluable in 89 patients. Thirty-seven patients (41.6%) had GR and 52 (58.4%) had NR. There was a trend for improved progression-free (P = 0.086) but not overall survival (P = 0.94) for GR versus NR. The 2-year PFS and OS were 86.0% and 83.5% for GR and 68.7% and 85.4% for NR, respectively. NR were significantly more likely to undergo G-tube placement during treatment (50.0% GR versus 73.5% NR, P = 0.040) and be G-tube dependent at 6-month follow-up (5.7% GR versus 32.6% NR, P = 0.005).
The addition of everolimus to IC was not beneficial. The elimination of elective nodal coverage in patients with GR to IC did not appear to compromise outcomes and resulted in significantly decreased late toxicity. Further investigation of RAVD is warranted.
NCT01133678
Adult studies have demonstrated potential harm from resuscitation with 0.9% sodium chloride (0.9%NaCl), resulting in increased utilization of balanced crystalloids like lactated ringers (LR). The ...sodium and potassium content of LR has resulted in theoretical safety concerns, although limited data exists in pediatrics. We hypothesized that use of LR for resuscitation would not be associated with increased electrolyte derangements compared to 0.9%NaCl.
A prospective, observational cohort study of critically ill children who received ≥ 20 ml/kg of fluid resuscitation and were admitted to two pediatric intensive care units from November 2017 to February 2020. Fluid groups included patients who received > 75% of fluids from 0.9%NaCl, > 75% of fluids from LR, and a mixed group. The primary outcome was incidence of electrolyte derangements (sodium, chloride, potassium) and acidosis.
Among 559 patients, 297 (53%) received predominantly 0.9%NaCl, 74 (13%) received predominantly LR, and 188 (34%) received a mixture. Extreme hyperkalemia (potassium ≥ 6 mmol/L) was more common in 0.9%NaCl group (5.8%) compared to LR group (0%), p 0.05. Extreme acidosis (pH > 7.1) was more common in 0.9%NaCl group (11%) compared to LR group (1.6%), p 0.016.
LR is associated with fewer electrolyte derangements compared to 0.9%NaCl. Prospective interventional trials are needed to validate these findings.
We conducted a randomized phase II study to evaluate the impact of adding bevacizumab (B) to 5-fluorouracil (5-FU), hydroxyurea (HU), and radiotherapy (FHX) for intermediate-stage and select T4 head ...and neck squamous cell cancers (HNSCC).
Eligible patients had newly diagnosed HNSCC. Randomization was 2:1 in favor of BFHX. All patients received 500 mg HU p.o. b.i.d., 600 mg/m2/day continuous infusion 5-FU, and b.i.d. radiotherapy with or without bevacizumab 10 mg/kg administered on day 1 of each 14-day cycle. Patients received five cycles consisting of chemoradiotherapy for 5 days followed by 9 days without therapy.
Twenty-six patients were enrolled (19 BFHX and 7 FHX). The study was halted following unexpected locoregional progression. Two-year survival was 68%; 89% treated with FHX and 58% (95% confidence interval 33% to 78%) treated with BFHX. Two-year locoregional control was 80% after chemoradiotherapy and 85% after surgical salvage. All locoregional progression occurred in T4 tumors randomized to BFHX. Two patients receiving BFHX died during therapy, and one died shortly after therapy. No catastrophic bleeding events were seen.
Locoregional progression seen in T4N0-1 tumors treated with BFHX was unexpected and led to study termination. The addition of bevacuzimab to chemoradiotherapy for HNSCC should be limited clinical trials.
Sepsis‐associated acute kidney injury (AKI) is a significant problem in critically ill children and adults resulting in increased morbidity and mortality. Fundamental mechanisms contributing to ...sepsis‐associated AKI are poorly understood. Previous research has demonstrated that peroxisome proliferator‐activated receptor α (PPARα) expression is associated with reduced organ system failure in sepsis. Using an experimental model of polymicrobial sepsis, we demonstrate that mice deficient in PPARα have worse kidney function, which is likely related to reduced fatty acid oxidation and increased inflammation. Ultrastructural evaluation with electron microscopy reveals that the proximal convoluted tubule is specifically injured in septic PPARα deficient mice. In this experimental group, serum metabolomic analysis reveals unanticipated metabolic derangements in tryptophan‐kynurenine‐NAD+ and pantothenate pathways. We also show that a subgroup of children with sepsis whose genome‐wide expression profiles are characterized by repression of the PPARα signaling pathway has increased incidence of severe AKI. These findings point toward interesting associations between sepsis‐associated AKI and PPARα‐driven fatty acid metabolism that merit further investigation.
Sepsis‐associated acute kidney injury (SA‐AKI) is a significant problem in the critically ill children. Using a mouse model of sepsis, we show that expression of PPARα, a nuclear hormone receptor transcription factor that regulates fatty acid oxidation and inflammation, protects against the development of SA‐AKI and other metabolic derangements. We also show that children with septic shock whose genome‐wide expression profiles are characterized by decreased PPARα expression have greater incidence of SA‐AKI, which points toward the exciting possibility of treating this condition with clinically available PPARα agonists.
An Apple a Day Keeps Dialysis Away Stenson, Erin K; Kendrick, Jessica
Clinical journal of the American Society of Nephrology,
09/2021, Volume:
16, Issue:
9
Journal Article
We hypothesized induction chemotherapy (IndCT) would improve distant control (DC) without compromising locoregional control (LRC) for locoregionally advanced head and neck cancer patients. ...Additionally, we systematically lowered radiotherapy (RT) doses attempting to maintain LRC while decreasing toxicity.
Stages III–IV (M0) locoregionally advanced head and neck cancer patients received carboplatin/paclitaxel (Taxol) IndCT followed by four or five cycles consisting of 5 days of paclitaxel, fluorouracil, hydroxyurea, and BID RT followed by a nine day break. RT dose to gross disease (high risk), intermediate, and low-risk volumes were reduced from cohort A (n = 68): 75, 60, and 45 Gy; to cohort B (n = 64): 75, 54, and 39 Gy; then cohort C (n = 90): 72, 51, and 36 Gy.
A total of 222 patients accrued from November 1998 to September 2002. Median follow-up is 56 months. In all, 93/96/76% achieved a complete response to concurrent chemoradiotherapy (CRT) in cohort A/B/C. Three- and 5-year overall survivals (OSs) are 68% and 62%, respectively. Five-year LRC and DC are 91% and 87%, respectively. Response to IndCT predicted for OS, LRC, and time to progression (TTP). Cohort C patients had similar OS (P = 0.95), LRC, and DC, but worse (TTP) (P = 0.027).
IndCT before CRT reduces distant progression while maintaining high LRC. The cohort B schedule provides the best therapeutic ratio. A randomized trial investigating IndCT before CRT has been initiated.
The complement cascade is an important part of the innate immune system. In addition to helping the body to eliminate pathogens, however, complement activation also contributes to the pathogenesis of ...a wide range of kidney diseases. Recent work has revealed that uncontrolled complement activation is the key driver of several rare kidney diseases in children, including atypical hemolytic uremic syndrome and C3 glomerulopathy. In addition, a growing body of literature has implicated complement in the pathogenesis of more common kidney diseases, including acute kidney injury (AKI). Complement-targeted therapeutics are in use for a variety of diseases, and an increasing number of therapeutic agents are under development. With the implication of complement in the pathogenesis of AKI, complement-targeted therapeutics could be trialed to prevent or treat this condition. In this review, we discuss the evidence that the complement system is activated in pediatric patients with AKI, and we review the role of complement proteins as biomarkers and therapeutic targets in patients with AKI.
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