Mapping the Evidence for Opioid-Mediated Changes in Malignancy and Chemotherapeutic Efficacy: Protocol for a Scoping Review.

BACKGROUND: Numerous reports contend opioids can augment or inhibit malignancy. At present, there is no consensus on the risk or benefit posed by opioids on malignancy or chemotherapeutic activity. Distinguishing the consequences of opioid use from pain and its management is challenging. Additionally, opioid concentration data is often lacking in clinical studies. A scoping review approach inclusive of preclinical and clinical data will improve our understanding of the risk-benefit relationship concerning commonly prescribed opioids and cancer and cancer treatment. OBJECTIVE: The aim of the study is to map diverse studies spanning from preclinical to clinical regarding opioids with malignancy and its treatment. METHODS: This scoping review will use the Arksey six stages framework to (1) identify the research question; (2) identify relevant studies; (3) select studies meeting criteria; (4) extract and chart data; (5) collate, summarize, and report results; and (6) conduct expert consultation. An initial pilot study was undertaken to (1) parameterize the extent and scale of existing data for an evidence review, (2) identify key factors to be extracted in systematic charting efforts, and (3) assess opioid concentration as a variable for its relevance to the central hypothesis. Six databases will be searched with no filters: MEDLINE, Embase, CINAHL Complete, Cochrane Library, Biological Sciences Collection, and International Pharmaceutical Abstracts. Trial registries will include ClinicalTrials.gov, Cochrane CENTRAL, International Standard Randomised Controlled Trial Number Registry, European Union Clinical Trials Register, and World Health Organization International Clinical Trials Registry. Eligibility criteria will include preclinical and clinical study data on opioids effects on tumor growth or survival, or alteration on the antineoplastic activity of chemotherapeutics. We will chart data on (1) opioid concentration from human subjects with cancer, yielding a "physiologic range" to better interpret available preclinical data; (2) patterns of opioid exposure with disease and treatment-related patient outcomes; and (3) the influence of opioids on cancer cell survival, as well as opioid-related changes to cancer cell susceptibility for chemotherapeutics. RESULTS: This scoping review will present results in narrative forms as well as with the use of tables and diagrams. Initiated in February 2021 at the University of Utah, this protocol is anticipated to generate a scoping review by August 2023. The results of the scoping review will be disseminated through scientific conference proceedings and presentations, stakeholder meetings, and by publication in a peer-reviewed journal. CONCLUSIONS: The findings of this scoping review will provide a comprehensive description of the consequences of prescription opioids on malignancy and its treatment. By incorporating preclinical and clinical data, this scoping review will invite novel comparisons across study types that could inform new basic, translational, and clinical studies regarding risks and benefits of opioid use among patients with cancer. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/38167.

Oral Step-Down Therapy With Levofloxacin for Febrile Neutropenia in Children With Cancer.

BACKGROUND: Although febrile neutropenia (FN) is a frequent complication in children with cancer receiving chemotherapy, there remains significant variability in selection of route (intravenous [IV] vs oral) and length of therapy. We implemented a guideline with a goal to change practice from using IV antibiotics after hospital discharge to the use of step-down oral therapy with levofloxacin for most children with FN until absolute neutrophil count > 500. The objectives of this study were to determine the impact of this guideline on home IV antibiotic use, and to evaluate the safety of implementation of this guideline. METHODS: We performed a quasi-experimental, pre-post study of discharge FN treatment at a stand-alone children's hospital in patients without bacteremia discharged between January 2013 and October 2018. In January 2015, a multidisciplinary team created a guideline to switch most children with FN to oral levofloxacin, which was formally implemented as of September 2017. Discharges during the postintervention period (after September 2017) were compared to discharges in the preintervention period (between January 2013 and December 2014). RESULTS: In adjusted multivariable regression analyses, the postimplementation period was associated with a decrease in home IV antibiotics (adjusted risk ratio [aRR], 0.07 [95% confidence interval {CI}, .03-.13]) and fewer IV antibiotic initiations within 24 hours of a new healthcare encounter up to 7 days after discharge (aRR, 0.39 [95% CI, .17-.93]) compared to the preintervention time period. CONCLUSIONS: Step-down oral levofloxacin for children with FN who are afebrile with an ANC ≤ 500 at discharge is feasible and resulted in similar clinical outcomes compared to home IV antibiotics.

Dronabinol Prescribing and Exposure Among Children and Young Adults Diagnosed with Cancer.

Purpose: The therapeutic utility of Cannabis in cancer is a topic of intense interest. Dronabinol is synthetic Δ9-tetrahydrocannabinol (THC), the primary psychoactive component of Cannabis sativa, and is approved for treating refractory chemotherapy-induced nausea and vomiting. Little is known about dronabinol prescribing in children and young adults, and no published concentration data are available. This study evaluated national level dronabinol use and assessed concentrations of THC and its primary metabolites in patients with cancer <27 years of age prescribed dronabinol. Methods: Observational review of records from the Pediatric Health Information System (PHIS) and a regional network of hospitals in the Intermountain West, including a tertiary care children's hospital, Primary Children's Hospital (PCH), for inpatients <27 years of age prescribed dronabinol. Prospective blood samples were collected from children with cancer at PCH. Results: Across PHIS institutions, overall dronabinol prescribing aligned with the pharmacy records for those with cancer (p < 0.0001), and of these, 10.4% received dronabinol as inpatients. Blood collected within 72 hours of dronabinol administration was available from 10 children with a median age of 12.5 (range 6-17) years. Quantifiable concentrations were found in 4 (13%), 6 (20%), and 1 (3%) samples assayed for THC, 11-nor-9-carboxy-Δ9-tetrahydrocannabinol (COOH-THC), and 11-hydroxy-Δ9-tetrahydrocannabinol (OH-THC), respectively. THC concentrations ranged between 0.100 and 0.128 ng/mL and were not associated with dose. Conclusion: Dronabinol prescribing appears exclusive to patients diagnosed with cancer, and its use has increased steadily in the past decade. In a small sample of children administered dronabinol, THC and metabolite concentrations were consistently low or undetectable.

Supportive care medications coinciding with chemotherapy among children with hematologic malignancy.

Pharmacokinetic (PK) conflicts can arise between supportive care medications (SCM) and chemotherapy in children with hematologic malignancy (HM). In this retrospective study, medical records for children (28 days-18 years) diagnosed with HM and receiving an SCM antimicrobial were collected from a hospital network between 1 May 2000 and 31 December 2014. PK drug-gene associations were obtained from a curated pharmacogenomics database. Among 730 patients (median age of 7.5 (IQR 3.7-13.9) years), primarily diagnosed with lymphoid leukemia (52%), lymphoma (28%), or acute myeloid leukemia (16%), chemotherapy was administered in 2846 hospitalizations. SCM accounted for 90.5% (n = 448) of distinct drugs with 93% (n = 679) of children, receiving ≥5 different SCM/hospitalization. Same-day SCM/chemotherapeutic PK gene overlap occurred in 48.3% of hospitalizations and was associated with age (p = 0.026), number of SCM, HM subtype, surgery, and hematopoietic stem cell transplant (p < 0.0001). A high and variable SCM burden among children with HM receiving chemotherapy poses a risk for unanticipated PK conflicts.

Neonatal nonimmune hemolytic anemia.

PURPOSE OF REVIEW: As in adults and older children, anemia in newborn infants can be the result of erythropoietic failure, hemorrhage, or hemolysis. When hemolysis is the prime consideration, it can be challenging for physicians caring for neonates to choose from the wide variety of available diagnostic tests. This review describes the authors' opinions regarding rational, consistent, and cost-effective means of making an exact diagnosis of a neonatal hemolytic condition. RECENT FINDINGS: Two recent advances in the diagnosis of neonatal nonimmune hemolytic disorders are highlighted in this review: introduction of flow cytometry-based Eosin-5-maleimide (EMA) uptake as a screening test to identify RBC membrane defects and next-generation sequencing (NGS)-based panels to uncover exact mutations causing hemolysis. SUMMARY: The availability of newer tools such as EMA and NGS to diagnose specific hemolytic conditions, which might otherwise remain unknown, enables neonatal practitioners not only to identify the exact cause of hemolysis but also to discover novel mutations that can be implicated in the cause of neonatal hemolytic processes.

Likelihood of bone recurrence in prior sites of metastasis in patients with high-risk neuroblastoma.

PURPOSE/OBJECTIVES: Despite recent improvements in outcomes, 40% of children with high-risk neuroblastoma will experience relapse, facing a guarded prognosis for long-term cure. Whether recurrences are at new sites or sites of original disease may guide decision making during initial therapy. METHODS AND MATERIALS: Eligible patients were retrospectively identified from institutional databases at first metastatic relapse of high-risk neuroblastoma. Included patients had disease involving metaiodobenzylguanidine (MIBG)-avid metastatic sites at diagnosis and first relapse, achieved a complete or partial response with no more than one residual MIBG-avid site before first relapse, and received no total body irradiation or therapy with (131)I-MIBG before first relapse. Anatomically defined metastatic sites were tracked from diagnosis through first relapse to determine tendency of disease to recur at previously involved versus uninvolved sites and to assess whether this pattern was influenced by site irradiation. RESULTS: Of 159 MIBG-avid metastatic sites identified among 43 patients at first relapse, 131 (82.4%) overlapped anatomically with the set of 525 sites present at diagnosis. This distribution was similar for bone sites, but patterns of relapse were more varied for the smaller subset of soft tissue metastases. Among all metastatic sites at diagnosis in our subsequently relapsed patient cohort, only 3 of 19 irradiated sites (15.8%) recurred as compared with 128 of 506 (25.3%) unirradiated sites. CONCLUSIONS: Metastatic bone relapse in neuroblastoma usually occurs at anatomic sites of previous disease. Metastatic sites identified at diagnosis that did not receive radiation during frontline therapy appeared to have a higher risk of involvement at first relapse relative to previously irradiated metastatic sites. These observations support the current paradigm of irradiating metastases that persist after induction chemotherapy in high-risk patients. Furthermore, they raise the hypothesis that metastatic sites appearing to clear with induction chemotherapy may also benefit from radiotherapeutic treatment modalities (external beam radiation or (131)I-MIBG).

Neonatal hemolytic jaundice: morphologic features of erythrocytes that will help you diagnose the underlying condition.

BACKGROUND: Many cases of severe neonatal hyperbilirubinemia never have the underlying cause of the jaundice clearly identified. Thus they are said to have 'idiopathic' severe neonatal jaundice. However, finding the exact cause, if it is a genetic condition, can enable informed anticipatory guidance regarding future episodes of hemolysis, anemia, or bilirubin cholelithiasis. OBJECTIVE: 'Next generation' gene sequencing can often reveal the mutations responsible for severe neonatal hyperbilirubinemia, but wisely using this new technology involves selective application, employing this testing only if inexpensive technology fails to reveal the diagnosis. METHODS: In this review, we display and discuss five types of red blood cell morphological abnormalities that have helped us categorize cases of neonatal hemolytic jaundice. RESULTS: As an aid to applying inexpensive technology, we review morphological abnormalities of erythrocytes that are easily identified on a blood film. When found, these abnormalities can be important clues to the underlying hemolytic condition giving rise to neonatal jaundice. CONCLUSIONS: Applying these simple and inexpensive methods can assist neonatologists in caring for neonates who have hemolytic jaundice. We predict that by using these principals the term 'idiopathic' neonatal jaundice will become less common as the underlying causes are identified.

Safety, dose, and timing of reteplase in treating occluded central venous catheters in children with cancer.

OBJECTIVES: Recombinant tissue plasminogen activator, alteplase, began to be commonly used to restore the patency of occluded central venous catheters (CVCs) as urokinase production was halted in the late 1990s. However, alteplase often requires an extended dwell time to restore patency to occluded CVCs. In adults, reteplase, a newer thrombolytic agent, has been reported to restore patency to CVCs in 30 minutes. The authors prospectively evaluated the safety and efficacy of reteplase in restoring patency to occluded CVCs in children with cancer. METHODS: This was a dose escalation trial. The dose of reteplase was initiated at 0.1 units and increased by increments of 0.1 units to a maximum dose of 0.4 units. Each dose was tested on at least three participants. Time to patency after reteplase administration was recorded by nurses caring for the patients. Attempts to access the line occurred every 15 minutes for 1 hour. CVCs that remained occluded after 1 hour were treated with alteplase. RESULTS: Reteplase was administered to 15 clotted CVCs. Twelve of the 15 were cleared with an average dwell time of 38 minutes. The time to patency did not appear to correlate with the dose. No adverse events were reported. CONCLUSIONS: Reteplase can restore patency to occluded CVCs in a pediatric population. Reteplase appears to have comparable efficacy with alteplase, but reteplase may require shorter dwell times. A prospective, randomized, clinical trial is warranted to determine whether reteplase is as effective as alteplase in restoring patency to occluded CVCs.