Impact of the Children's Oncology Group's supportive care clinical practice guideline endorsement program: An institutional survey.

BACKGROUND: Supportive care clinical practice guidelines (CPGs) facilitate the incorporation of the best available evidence into pediatric cancer care. We aimed to assess the impact of the work of the Children's Oncology Group (COG) Supportive Care Guideline Task Force on institutional supportive care practices. PROCEDURE: An online survey was distributed to representatives at 209 COG sites to assess the awareness, use, and helpfulness of COG-endorsed supportive care CPGs. Availability of institutional policies regarding 13 topics addressed by current COG-endorsed CPGs was also assessed. Respondents described their institutional processes for developing supportive care policies. RESULTS: Representatives from 92 COG sites responded to the survey, and 78% (72/92) were "very aware" of the COG-endorsed supportive care CPGs. On average, sites had policies that addressed seven COG-endorsed supportive care CPG topics (median = 7, range: 0-12). Only 45% (41/92) of sites reported having institutional processes for developing supportive care policies. Of these, most (76%, 31/41) reported that the COG-endorsed CPGs have a medium or large impact on policy development. Compared with sites without processes for supportive care policy development, sites with established processes had policies on a greater number of topics aligned with current COG-endorsed CPG topics (mean = 6.6, range: 0-12 vs mean = 7.9, range: 2-12; p = 0.027). CONCLUSIONS: Most site respondents were aware of the COG-endorsed supportive care CPGs. Less than half of the COG sites represented in the survey have processes in place to implement supportive care policies. Improvement in local implementation is required to ensure that patients at COG sites receive evidence-based supportive care.

Brochure intervention to manage bothersome taste changes in pediatric patients receiving cancer therapy.

BACKGROUND: Primary objective was to determine if a patient informational brochure describing potentially useful strategies could help manage specific taste changes. Secondary objective was to describe the specific strategies used and whether the strategies were perceived as being helpful. PROCEDURE: This single-center study included pediatric patients with cancer or hematopoietic cell transplant recipients receiving active treatment who experienced bothersome taste changes in the last month. Participants participated in baseline and follow-up interviews conducted 14-21 days apart. A brochure that listed 16 potentially helpful strategies was provided at baseline. At follow-up, we asked about brochure use and whether it helped. At both interviews, we asked about experienced taste changes, strategies used, and whether strategy helped. RESULTS: Of 100 enrolled participants, different (87%) and bad (72%) taste were most common at baseline. Following the brochure intervention, statistically significant reductions were observed in food tasting different, bad, bland, bitter, sour, and metallic. For most strategies, the proportion of patients who used specific strategies or found them helpful was not significantly different between baseline and follow-up. However, "eating foods you like" was considered helpful in significantly more participants who used the strategy in follow-up (72 out of 89, 80.9%) compared with baseline (55 out of 95, 57.9%; p = .008). Between visits, 81.2% looked at the brochure. Among participants, 53.1% found the brochure helpful, very helpful, or extremely helpful. CONCLUSIONS: A brochure that offered strategies to manage changes in taste helped participants cope with them. Further research should evaluate the brochure using randomized and multicenter trials.

Clinical practice guideline-inconsistent management of fever and neutropenia in pediatric oncology: A Children's Oncology Group study.

BACKGROUND: The primary objective was to measure the proportion of episodes where care delivery was inconsistent with selected recommendations of a clinical practice guideline (CPG) on fever and neutropenia (FN) management. The influence of site size on CPG-inconsistent care delivery, and association between patient outcomes and CPG-inconsistent care were described. METHODS: This retrospective, multicenter study included patients less than 21 years old with cancer who were at high risk of poor FN outcomes and were previously enrolled to a Children's Oncology Group (COG) study at participating National Cancer Institute Community Oncology Research Program (NCORP) institutions from January 2014 through December 2015. Patients were randomly selected for chart review by participating sites from a COG-generated list. Care delivered in each episode was adjudicated (CPG-consistent or CPG-inconsistent) against each of five selected recommendations. RESULTS: A total of 107 patients from 22 sites, representing 157 FN episodes, were included. The most common CPG-inconsistent care delivered was omission of pulmonary computerized tomography in patients with persistent FN (60.3%). Of 74 episodes where assessment of four (episodes without persistent FN) or five (episodes with persistent FN) recommendations was possible, CPG-inconsistent care was delivered with respect to at least one recommendation in 63 (85%) episodes. Site size was not associated with CPG-inconsistent care delivery. No statistically significant association between CPG-inconsistent care and fever recurrence was observed. CONCLUSIONS: In this cohort of pediatric patients at high risk of poor FN outcomes, CPG-inconsistent care was common. Opportunities to optimize resource stewardship by boosting supportive care CPG implementation are highlighted.

Outcomes of chemotherapy-induced nausea and vomiting guideline adherence in pediatric and adult patients: a systematic review.

PURPOSE: This study describes chemotherapy-induced nausea and vomiting (CINV) control rates in pediatric and adult patients who did or did not receive guideline-consistent CINV prophylaxis. METHODS: We conducted a systematic literature review of studies published in 2000 or later that evaluated CINV control in patients receiving guideline-consistent vs. guideline-inconsistent CINV prophylaxis and reported at least one CINV-related patient outcome. Studies were excluded if the guideline evaluated was not publicly available or not developed by a professional organization. Over-prophylaxis was defined as antiemetic use recommended for a higher level of chemotherapy emetogenicity than a patient was receiving. RESULTS: We identified 7060 citations and retrieved 141 publications for full-text evaluation. Of these, 21 publications (14 prospective and seven retrospective studies) evaluating guidelines developed by six organizations were included. The terms used to describe CINV endpoints and definition of guideline-consistent CINV prophylaxis varied among studies. Included studies either did not address over-prophylaxis in their definition of guideline-consistent CINV prophylaxis (48%; 10/21) or defined it as guideline-inconsistent (38%; 8/21) or guideline-consistent (3/21; 14%). Eleven included studies (52%; 11/21) reported a clinically meaningful improvement in at least one CINV endpoint in patients receiving guideline-consistent CINV prophylaxis. Ten reported a statistically significant improvement. CONCLUSIONS: This evidence supports the use of guideline-consistent prophylaxis to optimize CINV control. Institutions caring for patients with cancer should systematically adapt CINV CPGs for local implementation and routinely evaluate CINV outcomes.

Impact of dexamethasone on transplant-related mortality in pediatric patients: a multi-site, propensity score-weighted, retrospective assessment.

Dexamethasone use during hematopoietic cell transplant (HCT) conditioning varies between pediatric centers. This study aimed to estimate the difference in 1-year treatment-related mortality (TRM) between patients who did or did not receive dexamethasone during HCT conditioning. Secondary objectives were to estimate the difference between dexamethasone-exposed and dexamethasone-unexposed groups in 1-year event-free survival (EFS), time to neutrophil engraftment, acute graft-versus-host disease (aGVHD), and invasive fungal disease (IFD) at day + 100. This was a seven-site, international, retrospective cohort study. Patients < 18 years old undergoing their first allogeneic or autologous myeloablative HCT for hematologic malignancy or aplastic anemia between January 1, 2012, and July 31, 2017, were included. To control for potential confounders, propensity score weighting was used to calculate the standardized mean difference for all endpoints. Among 242 patients, 140 received dexamethasone during HCT conditioning and 102 did not. TRM was unaffected by dexamethasone exposure (1.7%; 95% CI - 7.4, 10.2%). Between-group differences in secondary outcomes were small. However, dexamethasone exposure significantly increased possible, probable, and proven IFD incidence (9.0%, 95% CI 0.8, 17.3%). TRM is not increased in pediatric patients who receive dexamethasone during HCT conditioning. Clinicians should consider potential IFD risk when selecting chemotherapy-induced vomiting prophylaxis for pediatric HCT patients.

Healthcare professional perspectives following implementation of an infection management care pathway for pediatric patients with cancer: a qualitative study.

PURPOSE: The Pediatric Oncology Group of Ontario (POGO) supported an effort to implement infection management care pathways based on clinical practice guidelines, to improve the consistency of infection management in pediatric cancer patients. The objective of this qualitative study was to describe the perspective of healthcare professionals (HCPs) following implementation. METHODS: Four tertiary pediatric oncology centers in Ontario, Canada, implemented the pathways. We randomly identified three HCPs per group (clinical pharmacists; nurse case managers, educators or practitioners and physician assistants; pediatric oncology fellows; or pediatric oncology staff physicians) per site and invited them to participate in a qualitative interview. One-on-one interviews were conducted remotely, followed by thematic analysis of interview transcripts. RESULTS: A total of 66 invitations were extended and 42 HCPs participated. Identified themes were: (1) implementation approach, (2) access and navigation, (3) engagement, (4) concerns, (5) workplace benefits, (6) reception, and (7) provincial harmonization. HCPs preferred in-person implementation strategies over e-mail communication. They identified teaching/educational utility and benefits to non-oncology departments and non-tertiary centers participating in shared care of patients. Other positive aspects related to evidence-based practice, safety, supporting oncology HCPs, and benefits to patients and families. Concerns included need to ensure users applied clinical judgement and loss of autonomy. Provincial harmonization of practice was viewed positively, although potential logistical and institutional cultural barriers were raised. CONCLUSIONS: Following infection management care pathway implementation, HCPs described educational utility and benefits to non-oncology departments, oncology HCPs, patients, and families. Our findings may facilitate future infection management care pathway provincial harmonization.

Palonosetron in pediatric patients: A single-center, retrospective evaluation of policy and clinical practice guideline discordance.

INTRODUCTION: Clinical practice guidelines (CPGs) recommending palonosetron for the prevention and management of chemotherapy-induced nausea and vomiting (CINV) were adapted for use at our institution. Palonosetron was restricted for use in patients experiencing breakthrough CINV and receiving highly emetogenic chemotherapy (HEC) or undergoing stem cell transplant conditioning and in patients with refractory CINV receiving HEC. Given the significant cost of palonosetron, we aimed to determine the proportion of chemotherapy blocks where palonosetron use was discordant with the institutional policy or source CPG. METHODS: A retrospective review of the health records of patients who received palonosetron between 1 July 2019 and 30 June 2020 was undertaken. Details of palonosetron use, antiemetic regimen and the date and time of each vomit during the acute and delayed phases were collected for each chemotherapy block where palonosetron was given. Discordance with the institutional policy and the source CPG was determined by assessing the indication for palonosetron and the dose. In the subset of chemotherapy blocks where information regarding vomiting episodes was available, the extent of acute phase chemotherapy-induced vomiting (CIV) control was reported. RESULTS: Four hundred thirty-eight chemotherapy blocks, representing 122 patients (mean age 9 years), receiving 595 palonosetron doses were included. Palonosetron use was discordant with institutional policy during most (72%; 314/438) of the chemotherapy blocks analyzed. However, palonosetron use was concordant with the source CPG during most chemotherapy blocks (74%; 326/438). Complete CIV control during the acute phase was observed in 66% (195/295) of chemotherapy blocks where palonosetron was given, irrespective of concomitant antiemetics administered. CONCLUSION: The majority of palonosetron use at our institution was discordant with institutional policy, but concordant with the source CPG. Our institutional policy has since been updated to be more aligned with the source CPG.

Vomiting in children and adolescents receiving intravenous pegaspargase: a retrospective study.

Due to an evidence gap, the emetogenicity of intravenous (IV) pegaspargase was unable to be included in the clinical practice guideline classifying chemotherapy emetogenicity in pediatric patients. This single-center, retrospective chart review describes the proportion of pediatric patients who did not vomit during the acute phase (complete response; CR) after receiving IV pegaspargase and provides an emetogenicity classification using a preexisting framework. Of 44 patients who received IV pegaspargase between 2011 and 2020, 13 received a serotonin receptor antagonist plus dexamethasone or palonosetron alone and all experienced a CR. We, therefore, recommend classifying IV pegaspargase as moderately emetogenic.

C9ORF72 hexanucleotide repeat expansion: From ALS and FTD to a broader pathogenic role?

The major gene underlying monogenic forms of amyotrophic lateral sclerosis (ALS) and fronto-temporal dementia (FTD) is C9ORF72. The causative mutation in C9ORF72 is an abnormal hexanucleotide (G4C2) repeat expansion (HRE) located in the first intron of the gene. The aim of this review is to propose a comprehensive update on recent developments on clinical, biological and therapeutics aspects related to C9ORF72 in order to highlight the current understanding of genotype-phenotype correlations, and also on biological machinery leading to neuronal death. We will particularly focus on the broad phenotypic presentation of C9ORF72-related diseases, that goes well beyond the classical phenotypes observed in ALS and FTD patients. Last, we will comment the possible therapeutical hopes for patients carrying a C9ORF72 HRE.

Feasibility of three times weekly symptom screening in pediatric cancer patients.

OBJECTIVE: Primary objective was to determine the feasibility of three times weekly symptom reporting by pediatric cancer patients for eight weeks. METHODS: We included English-speaking patients 8-18 years of age with cancer. Patients were sent reminders by text or email to complete Symptom Screening in Pediatrics Tool (SSPedi) three times weekly for eight weeks. When patients reported at least one severely bothersome symptom, the symptom report was emailed to the primary healthcare team. Patient-reported outcomes were obtained at baseline, week 4 ± 1 and week 8 ± 1. Symptom documentation, intervention provision for symptoms and unplanned healthcare encounters were determined by chart review at weeks 4 and 8. The primary endpoint was feasibility, defined as at least 75% patients achieving adherence with at least 60% of SSPedi evaluations. We planned to enroll successive cohorts until this threshold was met. RESULTS: Two cohorts consisting of 30 patients (cohort 1 (n = 20) and cohort 2 (n = 10)) were required to meet the feasibility threshold. In cohort 1, 11/20 (55%) met the SSPedi completion threshold. Interventions applied after cohort 1 included engaging parents to facilitate pediatric patient self-report, offering mechanisms to remember username and password and highlighting potential benefits of symptom feedback to clinicians. In cohort 2, 9/10 (90%) met the SSPedi completion threshold and thus feasibility was met. Patient-reported outcomes and chart review outcomes were obtained for all participants in cohort 2. CONCLUSIONS: Three times weekly symptom reporting by pediatric patients with cancer for eight weeks was feasible. Mechanisms to enhance three times weekly symptom reporting were identified and implemented. Future studies of longitudinal symptom screening can now be planned.

Symptom management care pathway adaptation process and specific adaptation decisions.

BACKGROUND: There is substantial heterogeneity in symptom management provided to pediatric patients with cancer. The primary objective was to describe the adaptation process and specific adaptation decisions related to symptom management care pathways based on clinical practice guidelines. The secondary objective evaluated if institutional factors were associated with adaptation decisions. METHODS: Fourteen previously developed symptom management care pathway templates were reviewed by an institutional adaptation team composed of two clinicians at each of 10 institutions. They worked through each statement for all care pathway templates sequentially. The institutional adaptation team made the decision to adopt, adapt or reject each statement, resulting in institution-specific symptom management care pathway drafts. Institutional adaption teams distributed the 14 care pathway drafts to their respective teams; their feedback led to care pathway modifications. RESULTS: Initial care pathway adaptation decision making was completed over a median of 4.2 (interquartile range 2.0-5.3) weeks per institution. Across all institutions and among 1350 statements, 551 (40.8%) were adopted, 657 (48.7%) were adapted, 86 (6.4%) were rejected and 56 (4.1%) were no longer applicable because of a previous decision. Most commonly, the reason for rejection was not agreeing with the statement (70/86, 81.4%). Institutional-level factors were not significantly associated with statement rejection. CONCLUSIONS: Acceptability of the 14 care pathways was evident by most statements being adopted or adapted. The adaptation process was accomplished over a relatively short timeframe. Future work should focus on evaluation of care pathway compliance and determination of the impact of care pathway-consistent care on patient outcomes. TRIAL REGISTRATION: clinicaltrials.gov, NCT04614662. Registered 04/11/2020, https://clinicaltrials.gov/ct2/show/NCT04614662?term=NCT04614662&draw=2&rank=1 .

Children's Oncology Group's 2023 blueprint for research: Cancer control and supportive care.

The objective of the Cancer Control and Supportive Care (CCL) Committee in the Children's Oncology Group (COG) is to reduce the overall morbidity and mortality of therapy-related toxicities in children, adolescents, and young adults with cancer. We have targeted five major domains that cause clinically important toxicity: (i) infections and inflammation; (ii) malnutrition and metabolic dysfunction; (iii) chemotherapy-induced nausea and vomiting; (iv) neuro- and oto-toxicty; and (v) patient-reported outcomes and health-related quality of life. Subcommittees for each domain prioritize randomized controlled trials and biology aims to determine which strategies best mitigate the toxicities. The findings of these trials are impactful, informing clinical practice guidelines (CPGs) and directly leading to changes in the standard of care for oncology practice. With the development of new therapies, there will be new toxicities, and the COG CCL Committee is dedicated to developing interventions to minimize acute and delayed toxicities, lessen morbidity and mortality, and improve quality of life in pediatric and young adult patients with cancer.

Children's Oncology Group's 2023 blueprint for research: Pharmacy.

Children's Oncology Group (COG) pharmacists and pharmacy technicians from more than 200 COG-member institutions comprise the COG Pharmacy Discipline. Discipline members serve an essential role in the design and execution of COG clinical trials. Core activities include study drug management, study drug access, clinical trial operations, protocol harmonization, and direct patient care. Discipline members are also actively involved in continuing education, membership engagement, and research across other COG committees/domains. Future areas of committed growth for the discipline include pharmacogenomics, pharmacokinetics, pharmacoeconomics, pharmaceutics, and implementation science.

Treatment of breakthrough and prevention of refractory chemotherapy-induced nausea and vomiting in pediatric cancer patients: Clinical practice guideline update.

This clinical practice guideline update provides recommendations for treating breakthrough chemotherapy-induced nausea and vomiting (CINV) and preventing refractory CINV in pediatric patients. Two systematic reviews of randomized controlled trials in adult and pediatric patients informed the recommendations. In patients with breakthrough CINV, escalation of antiemetic agents to those recommended for chemotherapy of the next higher level of emetogenic risk is strongly recommended. A similar recommendation to escalate therapy is made to prevent refractory CINV in patients who did not experience complete breakthrough CINV control and are receiving minimally or low emetogenic chemotherapy. A strong recommendation to use antiemetic agents that controlled breakthrough CINV for the prevention of refractory CINV is also made.

Reliability and validity of proxy-SSPedi and mini-SSPedi in pediatric patients 2-7 years receiving cancer treatments.

BACKGROUND: Symptom Screening in Pediatrics Tool (SSPedi) was developed for symptom screening by children 8-18 years. Objectives were to evaluate the reliability and validity of proxy-SSPedi and self-report mini-SSPedi for younger children. METHODS: This multi-center study enrolled guardians of children 2-7 years receiving cancer treatments (proxy-SSPedi) and their children 4-7 years (mini-SSPedi). The two populations were: (1) More symptomatic group where children were receiving active cancer treatment and were in hospital or clinic for four consecutive days; and (2) Less symptomatic group where children were receiving maintenance therapy for acute lymphoblastic leukemia or had completed cancer therapy. Proxy-SSPedi or mini-SSPedi were completed with measures of mucositis, nausea, pain, quality of life and overall symptoms. Respondents in the more symptomatic group repeated proxy-SSPedi/mini-SSPedi and a global symptom change scale 3 days later. RESULTS: There were 402 guardians and 326 children included in the analysis. Test re-test reliability of proxy-SSPedi showed intraclass correlation coefficient (ICC) 0.83 (95% confidence interval (CI) 0.72-0.90). Mean difference in proxy-SSPedi between more and less symptomatic groups was 9.7 (95% CI 8.3-11.1). Proxy-SSPedi was responsive to change and hypothesized relationships between measures were observed. With a priori threshold ≥0.6, inter-rater ICC among all dyads and those 6-7 years were 0.54 (95% CI 0.45-0.62) and 0.62 (95% CI 0.50-0.71) respectively. Among participating children, other hypothesized reliability and validity thresholds were generally met. CONCLUSIONS: Proxy-SSPedi is reliable, valid and responsive in children 2-7 years old receiving cancer treatments. Mini-SSPedi can be used for children 6-7 years of age.

Perceptions of parents of pediatric patients with acute lymphoblastic leukemia on oral chemotherapy administration: A qualitative analysis.

OBJECTIVE: To describe the experiences and perspectives of parents of pediatric patients with acute lymphoblastic leukemia (ALL) regarding oral chemotherapy administration during maintenance therapy. METHODS: English-speaking parents of patients 4 to <18 years who were receiving ALL maintenance oral chemotherapy were eligible to participate in this mixed methods study. Using semi-structured interviews, we asked participants how difficult they found oral chemotherapy administration. We also probed regarding barriers and facilitators of oral chemotherapy administration and strategies used to overcome challenges. Lastly, we asked participants for their advice to future parents giving oral chemotherapy to their children. RESULTS: Twenty-three participants were interviewed. One-fifth of participants stated that oral chemotherapy administration at home was hard or very hard. Common factors influencing oral chemotherapy administration were product-related (e.g., formulation) and treatment-related adverse effects (e.g., nausea), lifestyle adjustment (e.g., fitting in with family schedule), and attitudes (e.g., onus of medication administration). Strategies to address oral chemotherapy administration included several administration techniques, scheduling of medication administration, and normalization of medication taking. CONCLUSIONS: Oral chemotherapy administration during ALL maintenance therapy was hard for some parents. Identification of these parents and discussion of strategies to facilitate adherence to oral chemotherapy regimens may optimize patient outcomes.

Prevention of acute and delayed chemotherapy-induced nausea and vomiting in pediatric cancer patients: A clinical practice guideline.

This clinical practice guideline provides recommendations for preventing acute and delayed phase chemotherapy-induced nausea and vomiting (CINV) in pediatric patients. The recommendations are based on two systematic reviews of randomized controlled trials evaluating interventions to prevent (1) acute phase CINV and (2) delayed phase CINV. Recommendations for acute phase and delayed phase CINV prophylaxis are made for patients receiving chemotherapy of varying emetogenicity, as well as for patients not able to receive dexamethasone or a neurokinin-1 receptor antagonist. Evidence gaps, including antiemetic safety and optimal dosing, were identified.

Creating and adapting an infection management care pathway in pediatric oncology.

PURPOSE: While care pathways based upon clinical practice guidelines (CPGs) are important, little is known about optimal approaches to development and adaptation in pediatric oncology. Objectives were to develop care pathway templates for pediatric cancer supportive care that are based upon CPGs and to adapt an infection management care pathway for use at a single institution. METHODS: Study phases were as follows: (1) creation of care pathway templates across multiple supportive care topics; (2) refinement of the infection management care pathway template by interviewing pediatric oncology clinicians at a single institution; and (3) adaptation of the infection management care pathway template for use at a different institution. RESULTS: Informed by seven CPGs, an initial iteration of the infection management care pathway template was created. This template was then refined based upon 20 interviews with pediatric oncology clinicians. Adaptation of the infection management care pathway template for use at a different institution required many changes to improve its clinical usability. Specificity and additional information not considered by the source CPGs were incorporated. CONCLUSION: We developed a process to create care pathway templates across multiple supportive care topics in pediatric oncology and to refine and adapt the infection management care pathway. While we found that the process was feasible, we also identified the need to substantially modify the care pathway during the adaptation process to consider scenarios not addressed by the source CPGs. Future work should measure implementation success.

Interventions for the prevention of acute phase chemotherapy-induced nausea and vomiting in adult and pediatric patients: a systematic review and meta-analysis.

PURPOSE: To identify effective and safe interventions to prevent acute phase chemotherapy-induced nausea and vomiting (CINV) in adult and pediatric patients. METHODS: We conducted a systematic review of randomized trials evaluating interventions to prevent acute CINV. Outcomes assessed were complete chemotherapy-induced vomiting (CIV) control, complete chemotherapy-induced nausea (CIN) control, complete CINV control, and discontinuation of antiemetics due to adverse effects. RESULTS: The search identified 65,172 citations; 744 were evaluated at full-text, and 295 (25 pediatric) met eligibility criteria. In patients receiving highly emetogenic chemotherapy (HEC), complete CIV (risk ratio (RR) 1.23, 95% confidence interval (CI) 1.05-1.44) and CIN (RR 1.34, 95% CI 1.10-1.62) control improved when olanzapine was added. The addition of a neurokinin-1 receptor antagonist (NK1RA) to a corticosteroid plus a serotonin-3 receptor antagonist (5HT3RA) also improved complete CIV (RR 1.11, 95% CI 1.08-1.14) and CIN (RR 1.05, 95% CI 1.01-1.08) control. Compared to granisetron/ondansetron, palonosetron provided improved complete CIV control when the 5HT3RA was given alone or when combined with dexamethasone. In patients receiving moderately emetogenic chemotherapy (MEC), dexamethasone plus a 5HT3RA improved complete CIV control compared to a 5HT3RA alone (RR 1.29, 95% CI 1.21-1.39). Only a single meta-analysis evaluating the safety outcome was possible. CONCLUSIONS: For patients receiving HEC, various antiemetic regimens improved CIV and CIN control. For patients receiving MEC, administration of a 5HT3RA plus dexamethasone improved CIV control. Analysis of antiemetic safety was constrained by lack of data.

ADAMTS5 is required for normal trabeculated bone development in the mandibular condyle.

OBJECTIVE: Determine the role of the extracellular matrix protease ADAMTS5 in development of the trabeculated bone of the mandibular condyle. METHODS: The mandibular condyles of wild type and mice deficient in the protease ADAMTS5 were examined for histopathology with Safranin O staining. Microcomputed tomography was performed to analyze the developing bone of the mandibular condyle. RNAscope and immunohistochemistry were utilized to investigate cell type and extracellular matrix expression. RESULTS: Mice deficient in Adamts5, (Adamts5tm1Dgen/J) exhibit an increase in trabecular separation (n = 37 wild type; n = 27: P < 0.0001) and reduction of trabecular thickness P = 0.0116 and bone volume fraction P = 0.0869 in the mandibular condylar head compared to wild type littermates. The altered bone parameters were more pronounced in male Adamts5-/- mice compared to female Adamts5-/- mice (TbSp; P = 0.03). Adamts5 was co-expressed with versican and Gli1 in mesenchymal, stem-like cells in the transition zone where the trabeculated bone is adjacent to mature hypertrophic chondrocytes. Loss of Adamts5 caused a reduction of Bglap expressing osteoblasts throughout mandibular condylar development and in young adult mice. The protease Mmp13, that is involved in mineralization and is expressed by hypertrophic chondrocytes and osteoblasts, was reduced in the mandibular condyle of Adamts5 deficient mice. CONCLUSION: This is the first report of a novel and critical role for Adamts5 in bone formation within the mandibular condyle of the temporomandibular joint. These data indicate Adamts5 may be required in the transdifferentiation of hypertrophic chondrocytes to osteoblasts during trabecular bone formation in development of the mandibular condyle.