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References | PMC10844074 |
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Key Points | PMC10245194 |
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Question | multiple cardiovascular disease, CVD | CVD | Is a home visit from a peer health coach effective at improving systolic blood pressure (SBP) and other clinical outcomes for veterans with multiple cardiovascular disease (CVD) risks? | PMC10245194 |
Findings | In this randomized clinical trial of 264 US veterans, there was no significant improvement in SBP in participants who received the peer health coaching intervention. However, a significant improvement in the mental health–related quality of life was reported in the intervention group compared with the control group. | PMC10245194 |
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Meaning | Findings from this trial indicate that a peer health coaching intervention can create opportunities for well-being improvements beyond blood pressure control. | PMC10245194 |
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Importance | death, CVD | CVD, CARDIOVASCULAR DISEASE | Although cardiovascular disease (CVD) is the leading cause of death in the US, CVD risk factors remain suboptimally controlled. | PMC10245194 |
Objective | CVD | To test the effectiveness of a home-visit, peer health coaching intervention to improve health outcomes for veterans with multiple CVD risks. | PMC10245194 |
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Design, Setting, and Participants | obesity, hypertension, overweight | OBESITY, HYPERLIPIDEMIA, CVD, MAY, HYPERTENSION | This 2-group, unblinded randomized clinical trial, called Vet-COACH (Veteran Peer Coaches Optimizing and Advancing Cardiac Health), used a novel geographic-based method to recruit a racially diverse population of veterans with low income. These veterans were enrolled at the Seattle or American Lake Veterans Health Affairs primary care clinics in Washington state. Veterans with a diagnosis of hypertension with at least 1 blood pressure reading of 150/90 mm Hg or higher in the past year, and 1 other CVD risk factor (current smoker, overweight or obesity, and/or hyperlipidemia), who resided in Census tracts with the highest prevalence of hypertension were eligible to participate. Participants were randomized to the intervention group (n = 134) or control group (n = 130). An intention-to-treat analysis was performed from May 2017 to October 2021. | PMC10245194 |
Intervention | Participants in the intervention group received peer health coaching for 12 months with mandatory and optional educational materials, an automatic blood pressure monitor, a scale, a pill organizer, and healthy nutrition tools. Participants in the control group received usual care plus educational materials. | PMC10245194 |
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Main Outcomes and Measures | CVD | The primary outcome was a change in systolic blood pressure (SBP) from baseline to 12-month follow-up. Secondary outcomes included change in health-related quality of life (HRQOL; measured using the 12-item Short Form survey’s Mental Component Summary and Physical Component Summary scores), Framingham Risk Score, and overall CVD risk and health care use (hospitalizations, emergency department visits, and outpatient visits). | PMC10245194 |
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Results | The 264 participants who were randomized (mean [SD] age of 60.6 [9.7] years) were predominantly male (229 [87%]) and 73 (28%) were Black individuals and 103 (44%) reported low annual income (<$40 000 per year). Seven peer health coaches were recruited. No difference was found in change in SBP between the intervention and control groups (−3.32 [95% CI, −6.88 to 0.23] mm Hg vs −0.40 [95% CI, −4.20 to 3.39] mm Hg; adjusted difference in differences, −2.05 [95% CI, −7.00 to 2.55] mm Hg; | PMC10245194 |
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Conclusions and Relevance | This trial found that, although the peer health coaching program did not significantly decrease SBP, participants who received the intervention reported better mental HRQOL compared with the control group. The results suggest that a peer-support model that is integrated into primary care can create opportunities for well-being improvements beyond blood pressure control. | PMC10245194 |
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Trial Registration | ClinicalTrials.gov Identifier: | PMC10245194 |
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Introduction | death, CVD | CVD, RECRUITMENT, CARDIOVASCULAR DISEASE | Cardiovascular disease (CVD) is the leading cause of death in the US, and non-Hispanic Black Americans have a higher burden of CVD than other groups.Successful management of cardiovascular risks is a complex process that requires self-monitoring, using medications, adjusting diet and physical activity, and working effectively with health care clinicians.The goal of this randomized clinical trial, Veteran Peer Coaches Optimizing and Advancing Cardiac Health (Vet-COACH), was to test the effectiveness of a home-visit, peer health coaching intervention to improve health outcomes for veterans with multiple CVD risks. We used a neighborhood-based recruitment strategy for both the coaches and participants, targeting areas with a disproportionate number of people with cardiovascular risks. | PMC10245194 |
Methods | PMC10245194 |
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Study Design, Setting, and Participants | hypertension | HYPERTENSION, RECRUITMENT | A description of the trial design, intervention components, and peer health coach training has been previously published.Veterans were eligible to participate if they had a diagnosis of hypertension (with an We sent recruitment letters to 2921 potentially eligible veterans. Of the 1419 veterans we were able to contact, 425 agreed to complete an additional screening to determine eligibility, of whom 264 were randomized ( | PMC10245194 |
Participant Flow Diagram | CPRS indicates Computerized Patient Record System; HV, home visit; TV, telephone visit.After completing baseline data collection, participants were randomized to receive either a home-based peer-support intervention for 12 months or usual care. Block randomization with varying blocks of 4 or 6 was used to ensure the treatment groups were not imbalanced at any time. Concealment was used to prevent study staff from obtaining information on the sequence of assignment during the baseline assessment. The trial was unblinded; the same staff conducted both the research visits and peer health coach supervision. | PMC10245194 |
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Vet-COACH Intervention | ELEVATED BLOOD PRESSURE | Of the 7 peer health coaches, 1 was assigned to a participant in each intervention arm and made 5 home visits and 5 telephone visits over 12 months. Telephone visits were used between in-home visits as check-ins on goal setting and progress. The protocol was modified to telephone-only visits after the start of the COVID-19 pandemic in March 2020.Peer health coaches assessed blood pressure control, provided social support, targeted health education, assisted participants with health goal setting, and linked participants to clinic and community-based resources. Five required modules were completed during health coaching sessions: blood pressure, physical activity, nutrition, medication adherence, and communication with medical team or physician. Participants could review nonmandatory modules, such as weight management, smoking cessation, limiting alcohol intake, and managing stress, according to their personal interests and needs. Participants received a manual of educational materials, an automatic blood pressure monitor, a scale, a pill organizer, and healthy nutrition tools.To monitor intervention fidelity, peer health coaches completed an encounter form at each visit to document the educational content, progress toward previously set goals, and referrals. Ongoing assessments were used to ensure that the content delivered by the peer health coach adhered to 80% or more of the intervention components. Each peer health coach audio recorded the first home visit for each participant until the study team ensured fidelity. A 5% random sample of visits were audio recorded and transcribed for continued fidelity assessment and peer health coach training.The intervention was linked to VHA primary care in several ways. All participants were required to be enrolled in and active users of VHA primary care. We used VHA criteria to define study eligibility criteria for veterans with out-of-range blood pressure levels. Peer health coaches communicated with the study team regarding urgent issues in addition to attending meetings every other week to present cases. The peer health coaches encouraged participants to follow-up with their primary care clinic for routine care and when their blood pressure was elevated beyond the normal range. The study team communicated elevated blood pressure readings and other clinical needs (eg, appointment requests, medication refills, or other referrals) to primary care clinical staff via the electronic health record or direct contact.Participants in the control group received usual medical care plus the same educational materials provided to the intervention group. Elevated blood pressure readings at study enrollment and exit visits were reported to their primary care team. | PMC10245194 |
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Outcomes and Measures | CVD, BLOOD, SECONDARY | The primary outcome was a change in systolic blood pressure (SBP) from baseline to the 12-month follow-up. Blood pressure readings were obtained using standard procedures with a blood pressure monitor (UA-767F Multi-User Blood Pressure Monitor; A&D Medical). The mean of 3 blood pressure measurements was used. If a participant did not complete an exit visit, blood pressure readings were extracted from the medical record for a 3-month period around the date of the missed exit visit (using the lowest value for the selected day at an outpatient visit, excluding inpatient and emergency department [ED] values). Mean blood pressure readings were categorized using standard criteria.A dichotomous secondary outcome was defined as the percentage of respondents meeting prespecified normal blood pressure goal (≤120/80 mm Hg).Self-reported demographic characteristics included age, sex, marital status, educational level, annual income, and race and ethnicity. Race and ethnicity were studied due to the distribution of CVD risk factors in the US. Participants were asked to identify their race from 1 or more of the following categories: American Indian or Alaska Native, Asian and Pacific Islander, Black, White, or multiracial. | PMC10245194 |
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Statistical Analysis | We projected a sample size of 400 veterans to detect a clinically significant difference between intervention and control groups in SBP change of 5 mm Hg between baseline and 12-month follow-up.We examined distributions of demographic and clinical variables of participants in the intervention and control arms and reported summary statistics for all baseline covariates and outcomes (means [SDs] for continuous variables; frequencies [percents] for categorical variables) by randomized group. We examined the association between baseline measures and outcome variables by randomized group for the linearity and equality of slopes necessary for use in subsequent statistical models. All analyses were performed with R, version 4.3.0 (R Foundation for Statistical Computing), and SAS, version 9.4 (SAS Institute Inc).Primary intent-to-treat analyses compared changes in SBP from baseline to 12 months between the intervention and control groups using a mixed-effects model adjusted for baseline SBP values and treatment group. We included a physician-level and peer health coach–level (for intervention group only) random effect to account for the correlation of multiple patients per physician with multiple patients per peer health coach.We performed prespecified sensitivity analyses to examine whether number of coach visits influenced the effect of the intervention on the primary outcome. We also conducted a post hoc stratified analysis before and after the start of the COVID-19 pandemic since trial activities were conducted remotely after March 2020. Participants with 12-month outcomes that were captured before March 5, 2020, were defined as the pre–COVID-19 subgroup, and the remaining participants were defined as the post–COVID-19 subgroup. The post–COVID-19 subgroup had 128 participants (64 control participants; 64 intervention participants). Because the SF-12 had 15% missing values, we analyzed patient and clinical factors that were associated with missingness. We performed multiple imputation using mice package in R to impute results to allow analysis for all participants and to reduce any bias associated with the missing data (eMethods and eTables 1 and 2 in | PMC10245194 |
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Results | PMC10245194 |
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Trial Participants | HIGH BLOOD PRESSURE | Of the 264 randomized participants (130 to control group; 134 to intervention group), 225 completed the 12-month follow-up (85% completion rate). Eighty participants (60%) in the intervention group received at least 8 of the 10 total number of required visits. From the optional modules, weight management was selected by most participants (72 [43%]), followed by managing stress (29 [17%]). Clinical teams were alerted to high blood pressure readings (from 68 participants) and other medical needs (from 64 participants). Participants received care from 75 unique VHA physicians at a given time. Some participants were assigned to 2 peer health coaches (23 [17%]), and the remaining participants were assigned to a single peer health coach (111 [83%]). There were 7 peer health coaches.The trial participants had a mean (SD) age of 60.6 (9.7) years; included 229 males (87%) and 35 females (13%); self-identified as Hispanic (17 [6%]), non-Hispanic Black (73 [28%]), non-Hispanic White (123 [47%]), or multiracial (30 [11%]) individuals; and reported low annual income (103 [44%]). Participants across treatment groups were similar in age, race and ethnicity, annual income, and other demographic variables ( | PMC10245194 |
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Baseline Characteristics of Vet-COACH Trial Participants | CVD | Abbreviations: BMI, body mass index (calculated as weight in kilograms divided by height in meters squared); DBP, diastolic blood pressure; ED, emergency department; FRS, Framingham Risk Score (10-year estimate of CVD risk, ranging from 0% to >30%); HRQOL, health-related quality of life; LDL-C, low-density lipoprotein cholesterol; MCS, SF-12 Mental Component Summary (range: 0-100 points, with lower scores indicating poorer mental HRQOL); PCS, Short Form 12 Item Physical Component Summary (range: 0-100 points, with lower scores indicating poorer physical HRQOL); SBP, systolic blood pressure; Vet-COACH, Veteran Peer Coaches Optimizing and Advancing Cardiac Health.SI conversion factor: To convert LDL-C to millimoles per liter, multiply by 0.0259.Race and ethnicity were self-identified by participants from the following categories: American Indian or Alaska Native; Asian and Pacific Islander; Black; Hispanic, Latino, or Spanish origin; non-Hispanic; White; or multiracial. | PMC10245194 |
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Outcomes | We found no significant difference in change in SBP between the intervention and control groups (−3.32 [95% CI, −6.88 to 0.23] mm Hg vs −0.40 [95% CI, −4.20 to 3.39] mm Hg; adjusted difference in differences, −2.05 [95% CI, −7.00 to 2.55] mm Hg; | PMC10245194 |
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Differences in Primary and Secondary Outcomes Between Intervention and Control Groups | CVD, REGRESSION | Abbreviations: BMI, body mass index (calculated as weight in kilograms divided by height in meters squared); BP, blood pressure; DBP, diastolic blood pressure; FRS, Framingham Risk Score (10-year estimate of CVD risk, ranging from 0% to >30%); HRQOL, health-related quality of life; LDL-C, low-density lipoprotein cholesterol; MCS, Mental Component Summary (range: 0-100 points, with lower scores indicating poorer mental HRQOL); NA, not applicable; OR, odds ratio; PCS, Physical Component Summary (range: 0-100 points, with lower scores indicating poorer physical HRQOL); SBP, systolic blood pressure.SI conversion factor: To convert LDL-C to millimoles per liter, multiply by 0.0259.Smoker results are logistic regression.The PCS score had more than 15% missing data; results were based on multiple imputation analysis.We did not find a significant difference in number of hospitalizations, ED visits, or primary care visits in the 12 months after randomization among the intervention vs control participants ( | PMC10245194 |
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Previous Year Health Care Use at Baseline and 12 Months Between Intervention and Control Groups | Abbreviation: ED, emergency department. | PMC10245194 |
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Discussion | calmness, depression, pain | CVD, HYPERTENSION | The goal of the Vet-COACH trial was to test a peer-support intervention aimed at improving cardiovascular health and quality of life among veterans who resided in areas with a high prevalence of hypertension. We used a novel neighborhood-based strategy and recruited a racially diverse population with low annual income. We found that the peer health coaching intervention did not improve blood pressure levels but led to improvements in mental HRQOL, as measured by the SF-12 MCS score, which included questions about impact on emotions, ability to function, pain interfering with work, energy level, calmness, and depression. The difference of 3.64 points exceeded the minimally important difference (ie, smallest change in an outcome that a patient would identify as important) of 3 for the SF-12 MCS score,Although disproportionately affected by CVD, Black adults remain underrepresented in clinical trials. | PMC10245194 |
Strengths and Limitations | The Vet-COACH trial has several strengths. First, intervention protocols were designed to be practical and feasible, thus allowing replication in other clinic settings. Second, we accounted for clustering by peer health coach. Largely ignored in peer health coaching studies is the peer health coach’s contribution to the intervention effect.This study also has several limitations. First, due to a variety of challenges, including the COVID-19 pandemic, the trial was underpowered to detect a difference in the primary outcome due to lower-than-projected sample size. | PMC10245194 |
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Conclusions | The Vet-COACH randomized clinical trial adds to the literature on the effectiveness of peer support, which has shown mixed results, | PMC10245194 |
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Introduction | sleep disordered breathing complaints | BACTERIAL DISEASES, CHRONIC ADENOIDITIS, MIDDLE EAR INFECTION, RHINOSINUSITIS, INFLAMMATIONS, MIDDLE EAR | Chronic adenoiditis (CA) is a common condition in pediatric otorhinolaryngological clinical practice, frequently associated with chronic or recurrent middle ear infections, rhinosinusitis, and sleep disordered breathing complaints; these situations often require specialist consultations, antibiotic prescriptions and, in some cases, surgical treatment [Chronic or recurrent inflammations of the nasopharyngeal and middle ear district are generally bacterial diseases, mainly sustained by an infectious focus located within the nasopharynx or in the deep adenoidal pads; it is characterized by a complex interplay between different bacterial species, sometimes within the setting of a resistant bacterial biofilm [Based on this, current therapeutic management of children with CA should overcome the emerging issue of increasing resistance of bacterial biofilm to traditional antibiotic treatment (which is up to 10–1000 higher than the one reported for the corresponding planktonic species), and be modulated to target the individual respiratory microbiome. Under these circumstances, some studies have suggested the effectiveness of topic probiotic treatment by means of The aim of this study was to assess the efficacy and safety of the topical nasal administration of a probiotic compound based on | PMC10857951 |
Materials and methods | PMC10857951 |
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Study design and setting | This prospective, double-blind, randomized controlled study was carried out at the University of Milan’s Department of Clinical Sciences and Community Health between January 2019 and January 2021. The protocol was approved BY the Ethics Committee “Milano Area 2” (protocol number AC-TAR-2018, September 10 | PMC10857951 |
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Study subjects | choanal atresia, adenoidal hypertrophy, acute febrile illness, upper respiratory tract infection | ACUTE ADENOIDITIS, ADENOIDAL HYPERTROPHY, SYSTEMIC DISEASE, UPPER RESPIRATORY TRACT INFECTIONS | The study involved children aged 2–18 years with CA defined as adenoidal hypertrophy detected by means of nasopharyngeal flexible video-endoscopy and recurrent infectious exacerbations (i.e., ≥ 3 episodes of acute adenoiditis requiring antibiotic treatment in the former 6 months or ≥ 4 episodes in the former 12 months) in the presence of persistent mucous secretion at the adenoidal surface [The exclusion criteria were the following: previous ear surgery or adenoidectomy; previous tonsillar surgery; concomitant systemic diseases; craniofacial, neuromuscular, immunological, syndromic, or defined genetic abnormalities; choanal atresia; chronic eardrum perforation; immunomodulatory treatment, vitamin D supplementation or complementary and alternative medicine assumption in the previous 30 days; acute febrile illness; upper respiratory tract infection or antibiotic therapy in the previous 14 days. | PMC10857951 |
Interventions | DMD, acute adenoidal infections, hypertrophic adenoids, choanal space occlusion | RECRUITMENT | Upon enrolment (T0), a complete clinical history (including the number of documented acute adenoidal infections occurring in the previous 3 months) was taken, and the child’s gender and age were recorded; all the children underwent a detailed otorhinolaryngological clinical examination including nasopharyngeal flexible video-endoscopy (performed by the same trained examiner) aimed at grading the blockage of nasopharynx space by hypertrophic adenoids expressed as the percentage of choanal space occlusion.Upon enrolment, the patients were double-blindly randomized 1:1 via a random number generator to:the control group, which received a placebo nasal spray, 1 puff each nostril twice a day for 90 days;the study group, which received the administration of Rinogermina spray (DMD ITALIA s.r.l, Rome), 1 puff each nostril twice a day for 90 days:The compliance to the assigned treatment was evaluated by counting the number of dispensed and returned devices.Clinical assessment was repeated at the end of the treatment (90 days after recruitment, T1), and 90 days later (90 days after treatment suspension, T2). | PMC10857951 |
Statistical analysis | acute adenoidal infections | The sample size was determined on the basis of the primary endpoint, which was to evaluate the impact of the topical administration of Rinogermina nasal spray on the reduction of the number of acute adenoidal infections, and was computed using published data reporting a 15% reduction of acute exacerbation in children receiving topic probiotic treatment [The results are given as absolute numbers and percentages, or as arithmetical mean values ± standard deviation. The dichotomous outcomes were analyzed using contingency table analysis, and continuous variables using non-parametric tests.A | PMC10857951 |
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Acknowledgements | Publication was granted by The Italian Ministry of Health-Ricerca Corrente 2023. | PMC10857951 |
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Authors' contributions | ST designed the study and drafted the manuscript; DDP, FF: data collection and helping in drafting the manuscript: SB, LG, LB: data collection; LP, PM, and PC reviewed the paper for important intellectual considerations. | PMC10857951 |
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Funding | Open access funding provided by Università degli Studi di Milano within the CRUI-CARE Agreement. This study was sponsored by DMG ITALIA S.r.l. | PMC10857951 |
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Data availability | Data available on request due to privacy/ethical restrictions. | PMC10857951 |
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Declarations | PMC10857951 |
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Ethical approval | The protocol was approved by the Ethics Committee “Milano Area 2” (protocol number AC-TAR-2018) on September 10, 2018, and the research was carried out in line with standard directives from the Ethics Committee “Milano Area 2.” | PMC10857951 |
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Competing interests | ST: advisor for Sanofi and GSK. All other authors declare no competing interests. | PMC10857951 |
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References | PMC10857951 |
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Key Points | PMC10238946 |
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Question | NASOPHARYNGEAL CANCER | Can bevacizumab be safely combined with chemoradiation in the treatment of nasopharyngeal cancer? | PMC10238946 |
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Findings | NASOPHARYNGEAL CANCER | In this nonrandomized controlled trial of 44 patients with locoregionally advanced nasopharyngeal cancer, the addition of bevacizumab to standard chemoradiation was not associated with excessive or unwarranted toxic effects. | PMC10238946 |
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Meaning | nasopharyngeal cancer | NASOPHARYNGEAL CANCER | These findings suggest that the addition of bevacizumab to chemoradiation for nasopharyngeal cancer may be safe and tolerable. | PMC10238946 |
Importance | NPC | NASOPHARYNGEAL CARCINOMA | The long-term outcomes associated with adding bevacizumab, a vascular endothelial growth factor inhibitor, to standard chemoradiation have continued to be favorable for a group of patients with locoregionally advanced nasopharyngeal carcinoma (NPC). | PMC10238946 |
Objective | To assess long-term toxic effects and clinical outcomes associated with chemotherapy, radiation therapy (RT), and bevacizumab for NPC. | PMC10238946 |
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Design, Setting, and Participants | cancer, Cancer | ONCOLOGY, CANCER, CANCER | This single-arm phase II nonrandomized controlled trial was conducted by the National Cancer Trials Network group and NRG Oncology (formerly Radiation Therapy Oncology Group), with accrual from December 13, 2006, to February 5, 2009, and data analysis from June 26 to July 1, 2019. The study was conducted at 19 cancer centers with a median (IQR) follow-up of 9.0 (7.7-9.3) years. Included patients were adults (aged ≥18 years) with NPC that was World Health Organization (WHO) histologic grade I to IIb or III, American Joint Committee on Cancer stage IIB or greater, and with or without lymph node involvement. | PMC10238946 |
Interventions | Patients received 3 cycles of bevacizumab (15 mg/kg) concurrently with standard cisplatin (100 mg/m | PMC10238946 |
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Main Outcomes and Measures | hemorrhage | ADVERSE EVENTS, HEMORRHAGE, METASTASIS | The primary end point was grade 4 hemorrhage or grade 5 adverse events in the first year. Secondary end points were locoregional progression–free (LRPF) interval, distant metastasis–free (DMF) interval, progression-free survival (PFS), overall survival (OS), and other adverse events. Long-term toxic effects and clinical outcomes were reported due to the limited follow-up in the initial report for this trial and the importance of long-term outcomes when combining bevacizumab with chemoradiation. | PMC10238946 |
Results | dysphagia, death, hearing impairment, hemorrhage, dry mouth | DYSPHAGIA, DISEASE PROGRESSION, DISEASE, HEARING IMPAIRMENT, HEMORRHAGE, DRY MOUTH | Among 46 patients with NPC who were enrolled, 44 patients were analyzed (29 males [65.9%]; 23 Asian [52.3%], 2 Black [4.5%], and 16 White [36.4%]; 38 not Hispanic [86.4%]; median [IQR] age, 48.5 [39.0-56.0] years). There were 33 patients with a Zubrod performance status of 0, indicating that they were fully functional and asymptomatic (75.0%); 32 patients with a WHO histologic grade of IIb or III (72.7%); and 39 patients with stage III or IVB disease (88.6%). Among analyzed patients, 42 individuals received radiation therapy of 69.96 Gy or greater (95.5%; dose range, 65.72-70.00 Gy); 30 patients received 3 cycles of cisplatin (68.2%) with RT, and 31 patients received 3 cycles of bevacizumab with RT (70.5%); this was followed by 3 cycles of adjuvant cisplatin in 21 patients (47.7%), fluorouracil in 24 patients (54.5%), and bevacizumab in 23 patients (52.3%). No grade 4 hemorrhage or grade 5 AEs were reported in the first year or thereafter. Late grade 3 AEs occurred in 16 patients (36.4%), including 7 patients with dysphagia (15.9%), 6 patients with hearing impairment (13.6%), and 2 patients with dry mouth (4.5%). The 1- and 5-year rates of feeding tube use were 5 of 41 patients (12.2%) and 0 of 27 patients, respectively. There were 19 patients (43.2%) who progressed or died without disease progression (6 patients with locoregional progression [13.6%], 8 patients with distant progression [18.2%], and 5 patients who died without progression [11.4%]). The 5- and 7-year rates were 79.5% (95% CI, 67.6%-91.5%) and 69.7% (95% CI, 55.9%-83.5%) for OS, 61.2% (95% CI, 46.8%-75.6%) and 56.3% (95% CI, 41.5%-71.1%) for PFS, 74.9% (95% CI, 61.4%-86.6%) and 72.3% (95% CI, 58.4%-84.7%) for LRPF interval, and 79.5% (95% CI,66.4%-90.0%) for both times for DMF interval. Among 13 patients who died, death was due to disease in 8 patients (61.5%). | PMC10238946 |
Conclusions and Relevance | hemorrhage | HEMORRHAGE, DISEASE, METASTASIS | In this nonrandomized controlled trial, no grade 4 hemorrhage or grade 5 AEs were reported in the first year or thereafter among patients with NPC receiving bevacizumab combined with chemoradiation. The rate of distant metastasis was low although 89% of patients had stage III to IVB disease, suggesting that further investigation may be warranted. | PMC10238946 |
Trial Registration | ClinicalTrials.gov Identifier: | PMC10238946 |
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Introduction | NASOPHARYNGEAL CANCER | There are currently 2 standard treatment options for locoregionally advanced nasopharyngeal cancer (LA-NPC). Patients can be treated with induction chemotherapy followed by concurrent chemoradiotherapy (CCRT) or CCRT followed by adjuvant chemotherapy.Overexpression of vascular endothelial growth factor (VEGF) A has been associated with a poor prognosis for NPC. | PMC10238946 |
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Methods | Cancer | CANCER | Patients signed written informed consent for this nonrandomized controlled study. The study was approved by the National Cancer Institute and participating centers’ institutional review boards; it is registered at ClinicalTrials.gov ( | PMC10238946 |
Study Objectives and Patient Eligibility | cancer, Anderson Cancer, RTOG, Cancer | CANCER, DISEASE, CANCER | RTOG 0615 is a nonrandomized multicenter phase II trial at 19 cancer centers that included patients with previously untreated stage IIB through IVB NPC (according to the American Joint Committee on Cancer Staging Manual, 6th Edition [AJCC 6]). Participating centers were the Beth Israel Medical Center, Memorial Sloan Kettering Cancer Center, Stanford University Medical Center, City of Hope Medical Center, Chinese University of Hong Kong, University Of Texas MD Anderson Cancer Center, MD Anderson Cancer Center-Orlando, McGill University, Thomas Jefferson University Hospital, University of Medicine and Dentistry of New Jersey-New Jersey Medical School, Princess Margaret Hospital, University of Wisconsin Hospital, Schiffler Cancer Center, Medical College of Wisconsin, Radiological Associates of Sacramento, University Of Western Ontario, University of Pittsburgh Medical Center-Shadyside Hospital, St. John’s Hospital Cancer Institute, and Christiana Care Health Services, Inc. Patients with Zubrod performance status of 0 (indicating fully functioning and asymptomatic) to 1 (indicating symptomatic but completely ambulatory) who met criteria for blood counts and other tests (eg, white blood cell [WBC] count ≥4000/μl; platelet count ≥100 ×10Standard of care pretreatment evaluations consisted of history collection and physical, dental, nutritional, audiogram, and laboratory studies. Magnetic resonance imaging (MRI) of the nasopharynx or neck was required unless there was a contraindication (ie, use of a pacemaker), in which case a computed tomography (CT) scan of the nasopharynx or neck was required. Additional tests to evaluate the extent of disease included chest x-ray; tests of alkaline phosphatase level, liver function, and lactate dehydrogenase level; and liver and bone scans when indicated. Positron emission tomography (PET) was optional at the time of this protocol. | PMC10238946 |
Radiation, Chemotherapy, and Bevacizumab Guidelines | primary disease, tumor, necrotic | DISEASE, TUMOR, CAVITY, NECROTIC | For radiation planning, fusion of MRI or PET/CT scans with treatment-planning CT images was encouraged to accurately define the gross tumor volume, which consisted of the primary disease in the nasopharynx and nodes greater than 1 cm in diameter or nodes with necrotic centers. Areas at risk for subclinical spread of disease included the entire nasopharynx, retropharyngeal nodal regions, clivus, skull base, pterygoid fossae parapharyngeal fat (coverage of trigeminal nerve V3), sphenoid sinus, and posterior third of the nasal cavity or maxillary sinuses, including the pterygopalatine fossae (coverage of trigeminal nerve V2) and bilateral neck I through V lymph nodal regions. Level I nodal regions were not included in the N0 neck. IMRT was delivered in 33 fractions using a simultaneous integrated boost technique in which the planning target volume (PTV) of the gross disease received radiation doses as follows: PTVBevacizumab (15 mg/kg) was given concurrently with cisplatin (100 mg/m | PMC10238946 |
Follow-up and End Points | Cancer | ADVERSE EVENT, ADVERSE EVENT, CANCER | Patients underwent weekly examinations during CCRT. Follow-up evaluations occurred every 3 months during the first 2 years, every 6 months during years 3 to 5, and then annually. Adverse events were graded per National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0. Adverse events scored as definitely, probably, or possibly associated with protocol treatment (or with unknown association) were considered treatment associated. | PMC10238946 |
Primary End Point and Sample Size Derivation | hemorrhage | ADVERSE EVENTS, HEMORRHAGE | The primary end point was treatment-associated grade 4 hemorrhage or treatment-associated grade 5 adverse events in the first year after the start of treatment. The trial used a Fleming 2-stage design with 14 and 42 patients in the first and second stage (0.14 one-sided α and 83% power; acceptable and unacceptable rates of 5% and 15%, respectively); more details were given in the initial publication. | PMC10238946 |
Secondary End Points | hemorrhage, death | ADVERSE EVENTS, HEMORRHAGE | Secondary end points were treatment-associated grade 4 hemorrhage or treatment-associated grade 5 adverse events after the first year, death during treatment or within 30 days of treatment completion (regardless of the cause of death), other grade 3 to 5 adverse events, feeding tube use rates, treatment tolerability (for each treatment component, concurrent and adjuvant), locoregional progression–free (LRPF) interval, DMF interval, PFS, and OS. Long-term treatment–associated AEs and clinical outcomes (OS, PFS, LRPF interval, and DMF interval), including 5- and 7-year rates, that were not specified in the protocol are reported for this study. | PMC10238946 |
Statistical Analysis | cancer, tumor, death | TUMOR, METASTASIS, RECURRENCE, CANCER, MINOR | For the concurrent phase, tolerability was measured by the percentage of patients receiving 2 or more cycles of cisplatin and bevacizumab with RT; it was scored by study chairs (N.Y.L., J.K., and D.G.P.) as no variation or minor variation for tumor volume contouring score and organs at risk contouring score. For the adjuvant phase, tolerability was measured by the percentage of patients receiving 2 or more cycles of cisplatin, fluorouracil, and bevacizumab. If either component had a tolerability rate of less than 50%, that component would not be recommended for further study without modification. Failure for LRPF rate was local or regional progression or recurrence or death due to study cancer or unknown causes with an undocumented site of failure. Failure for DMF rate was distant metastasis. Failure for PFS was local, regional, or distant recurrence or progression, or death due to any cause. Failure for OS was death due to any cause. All time-to-event end points were defined from the time of registration to failure; patients without failure were censored at the last follow-up. LRPF and DMF rates were estimated by subtracting cumulative incidence estimates from 100%; death without failure was considered a competing risk for both end points. PFS and OS rates were estimated by the Kaplan-Meier method. CIs for 5- and 7-year OS and PFS rates were calculated using Greenwood variance and normal approximation; LRPF and DMF interval rates were computed using a log-log transformation and normal approximation. Acute and late toxic effect periods were defined as 90 days or less vs greater than 90 days, respectively, after the end of treatment. CIs for treatment-associated AE rates across time were computed using the Wald method. Eligible patients who started protocol treatment were included in the analysis. DMF survival rates (with failure as distant metastasis or death) at 5 and 7 years are also presented as an unplanned sensitivity analysis to allow comparison with other published trials. Data were analyzed using SAS statistical software version 9.4 (SAS Institute), with analysis from June 26 to July 1, 2019. | PMC10238946 |
Results | PMC10238946 |
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Patient Characteristics and Treatment Compliance | Among 46 patients with NPC enrolled in the study from December 13, 2006, to February 5, 2009, 44 patients (29 males [65.9%]; 23 Asian [52.3%], 2 Black [4.5%], and 16 White [36.4%]; 38 not Hispanic [86.4%]; median [IQR] age, 48.5 [39.0-56.0] years) were eligible for analysis (1 patient did not start protocol therapy, and 1 patient was ineligible due to low WBC count; see patient flowchart in | PMC10238946 |
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Study Flowchart | PMC10238946 |
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Pretreatment Patient Characteristics | Cancer | CANCER | Abbreviations: AJCC, American Joint Committee on Cancer; WHO, World Health Organization.There was an option for more than 1 self-reported race in the patient clinical record. | PMC10238946 |
Treatment Outcome Data | cancer, deaths, death, failure | EVENTS, METASTASIS, CANCER | Median (IQR) follow-up for surviving patients was 9.0 (7.7-9.3) years compared with 2.5 (2.1-2.9) years for the initial report. After the initial report, 7 additional deaths were reported, for a total of 13 deaths (29.5%). Estimated 5- and 7-year OS rates were 79.5% (95% CI, 67.6%-91.5%) and 69.7% (95% CI, 55.9%-83.5%), respectively. After the initial report, 7 additional PFS events were reported, for a total of 19 events (43.2%; 6 patients with locoregional progression [13.6%], 8 patients with distant progression [18.2%], and 5 patients who died without progression [11.4%]). The first failure among new events was locoregional progression in 2 patients, distant metastasis in 3 patients, death due to other causes in 1 patient, and death due to unknown causes in 1 patient. Estimated 5- and 7-year PFS rates were 61.2% (95% CI, 46.8%-75.6%) and 56.3% (95% CI, 41.5%-71.1%), respectively. After the initial report, 5 additional LRPF events (4 locoregional progressions and 1 death due to unknown causes) were reported, for a total of 12 events (27.3%; 8 locoregional progressions, 2 deaths due to study cancer, and 2 deaths due to unknown causes). Estimated 5- and 7-year LRPF interval rates were 74.9% (95% CI, 61.4%-86.6%) and 72.3% (95% CI, 58.4%-84.7%), respectively. After the initial report, 4 additional DMF events were reported, for a total of 9 events (20.5%). Estimated 5- and 7-year DMF interval rates were both 79.5% (95% CI, 66.4%-90.0%). Estimated 5- and 7-year DMF survival rates were 65.8% (95% CI, 51.8%-79.9%) and 60.9% (95% CI, 46.4%-75.5%). | PMC10238946 |
Estimates of Survival Rates | Shaded areas indicate pointwise 95% CIs. | PMC10238946 |
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Toxic Effects Data | dysphagia, hearing impairment, hemorrhages, neuralgia, dry mouth | DYSPHAGIA, ADVERSE EVENTS, HEARING IMPAIRMENT, ADVERSE EVENT, HEMORRHAGES, DRY MOUTH | No grade 4 hemorrhages or grade 5 adverse events in the first year were reported in the prior publication,The most frequently reported late adverse event grades were grade 3, occurring in 16 patients (36.4%); grade 2, occurring in 16 patients (36.4%); and grade 1, occurring in 9 patients (20.5%). There were late grade 3 reports of dysphagia in 7 patients (15.9%), hearing impairment in 6 patients (13.6%), dry mouth in 2 patients (4.5%), and neuralgia not otherwise specified in 2 patients (4.5%). No other late grade 3 adverse event was reported in more than 1 patient. Late adverse event rates over time are summarized in | PMC10238946 |
Grade 3 Treatment-Associated Late Adverse Event Rates by Category and Term | Cancer | ADVERSE EVENT, ADVERSE EVENT, CANCER | Abbreviation: NOS, not otherwise specified.Treatment associated is defined as definitely, probably, or possibly associated with the protocol treatment. The late period is defined as more than 90 days after the end of treatment. Time points were measured from the end of treatment, with a window of 3 months before or after the given time. Adverse events were graded with National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0. | PMC10238946 |
Discussion | head and neck squamous cell carcinoma, death, tumors, kidney cell cancer, lung cancer | HEPATOCELLULAR CARCINOMA, INFILTRATION, TUMORS, METASTASIS | Findings from our initial reportImmunotherapy (ie, programmed cell death 1 protein [PD1] inhibitors), has shown activity and promise for recurrent and metastatic NPC. Several phase II nonrandomized controlled trialsPhase III randomized clinical trialsCombining anti-VEGF with anti–PD1 and PDL1 therapies may be associated with further improvement in efficacy by reversing VEGF-mediated immunosuppression and promoting T cell infiltration in tumors. This combination strategy was found to be effective in hepatocellular carcinoma, kidney cell cancer, lung cancer, and head and neck squamous cell carcinoma.A systemic reviewApproximately 20% of patients developed distant metastasis for NPC despite aggressive chemoradiation, and the key may be to determine who these patients are. | PMC10238946 |
Limitations | tumors | TUMORS | A limitation of this study was the small, nonrandomized sample size of 44 patients with locoregionally advanced NPC. Nonetheless, our findings suggest that VEGF inhibition may be combined safely with standard chemoradiation. We did not observe excessive rates of toxic effects with this combination even when tumors were close to major blood vessels, which is almost always the case for locoregionally advanced NPC. Another limitation was that the staging system for NPC has changed since the completion of this study. Given that our primary end point was safety and toxic effects, we do not believe that the change in the staging system would be associated with changes in our end point. Furthermore, 10 patients in the entire cohort may possibly be downstaged given the change in the staging system since the completion of this study, and therefore, we do not feel that excellent treatment outcomes were purely outcomes associated with staging migration from T4 (AJCC Staging Manual, 7th Edition) to T2 (AJCC Staging Manual, 8th Edition). | PMC10238946 |
Conclusions | hemorrhage | HEMORRHAGE, DISEASE, METASTASIS | In this phase II nonrandomized controlled trial, no grade 4 hemorrhage or grade 5 AEs were reported with the addition of bevacizumab to CCRT for locally or regionally advanced NPC. The relatively low rate of distant metastasis despite nearly 90% of patients presenting with stage III to IVB disease is intriguing and may warrant further investigation. Given that 20% of patients died from disease, | PMC10238946 |
References |
Trial Protocol
Click here for additional data file.
Data Sharing Statement
Click here for additional data file. | PMC10238946 |
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Background | There is consistent evidence that the COVID-19 pandemic is associated with an increased psychosocial burden on children and adolescents and their parents. Relatively little is known about its particular impact on high-risk groups with chronic physical health conditions (CCs). Therefore, the primary aim of the study is to analyze the multiple impacts on health care and psychosocial well-being on these children and adolescents and their parents. | PMC10031163 |
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Methods | obesity, diabetes | OBESITY, RHEUMATIC DISEASES, DIABETES | We will implement a two-stage approach. In the first step, parents and their underage children from three German patient registries for diabetes, obesity, and rheumatic diseases, are invited to fill out short questionnaires including questions about corona-specific stressors, the health care situation, and psychosocial well-being. In the next step, a more comprehensive, in-depth online survey is carried out in a smaller subsample. | PMC10031163 |
Discussion | The study will provide insights into the multiple longer-term stressors during the COVID-19 pandemic in families with a child with a CC. The simultaneous consideration of medical and psycho-social endpoints will help to gain a deeper understanding of the complex interactions affecting family functioning, psychological well-being, and health care delivery. | PMC10031163 |
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Trial registration | German Clinical Trials Register (DRKS), no. DRKS00027974. Registered on 27th of January 2022. | PMC10031163 |
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Keywords | Open Access funding enabled and organized by Projekt DEAL. | PMC10031163 |
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Background | obesity, anxiety, rheumatic disease, depression, diabetes | OBESITY, RHEUMATIC DISEASE, DIABETES | In Germany, around 10% of children and adolescents are affected by a chronic physical health condition, such as obesity, diabetes, or rheumatic disease [Also in times without a pandemic, children and youth with CCs as well as their parents are at increased risk of developing mental health problems, such as anxiety, depression, and impaired health-related quality of life [With respect to regular medical care, which is essential for children and adolescents with CCs, there were major changes. During the lockdown, in most medical institutions across the country, routine consultations took place alternatively by telephone or video contact. Socially and educationally disadvantaged populations might face more problems using telehealth services [ | PMC10031163 |
Methods | PMC10031163 |
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Objectives | obesity, chronic diseases, COVID-19 infection, diabetes | OBESITY, DISEASE, CHRONIC DISEASES, COVID-19 INFECTION, DIABETES | Based on a comprehensive understanding of the complex interplay between medical condition, health care use, and environmental and specific context factors in CC (see Fig. Conceptual model of the proposal considering the ICF structure (modified according to Cieza and Stucki [Based on the biopsychosocial model, the specific study objectives are to examinethe impact of the COVID-19 pandemic on the care of children and adolescents with a CC by analyzing deficiencies, interruptions and unmet needs in care and treatment,the impact of the COVID-19 pandemic on body function and clinical outcomes (e.g., disease specific medical endpoints, physical and mental health), activities and participation of children and adolescents with different chronic diseases (diabetes, obesity, and rheumatic disease),the psychosocial resources and risk perceptions of children and their parents facing the Corona pandemic and their influence on child’s psychosocial adjustment, mental and physical health,the interplay of the physical and mental health of the children,the course of physical and mental health over time,the impact of a potential COVID-19 infection on these variables, anddisease-specific differences and similarities with respect to the impact of the COVID-19 pandemic. | PMC10031163 |
Study design | RECRUITMENT | The ongoing prospective observational study started recruitment in June 2021. A two-step approach (see Fig. Illustration of the study design and recruitment process | PMC10031163 |
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Study participants | Diabetes, diabetes | DIABETES, DIABETES | Parents and their underage children (aged up to 18 years) who are already taking part in any of the three patient registries for diabetes (German Diabetes Prospective Follow-up Registry, DPV [ | PMC10031163 |
Recruitment | RECRUITMENT | Recruitment takes place during the regular check-ups within the participating clinical facilities. Clinicians ask their adolescent patients and their accompanying parents to fill in a two-page short questionnaire during their waiting time; for children younger than 12 years, the questionnaire is only completed by the accompanying parent. After the completed questionnaires are handed over to the treatment team in the healthcare facility, the next step is to ask whether the relatives would also be willing to take part in a further, more extensive survey. If they agree, the families receive a flyer with information and a barcode that leads directly to the online questionnaire. At the end of the questionnaire, consent is obtained from the parents to be contacted again after 1 year. In addition, the parents are asked for parental consent for the participation of the underage child (from about 9 years of age). If the parents agree, the children also receive an online questionnaire at the e-mail address provided and can then fill out the children’s questionnaire themselves. At the end of the respective questionnaires, parents and their children can download quizzes, an audio-guided relaxation training [Recruitment flow chart | PMC10031163 |
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Study measures | This survey uses several questionnaires and self-constructed items to fulfil the primary study objectives stated above. | PMC10031163 |
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Basic survey: Common measures for parents and children | Several measures are administered for the data collection. While parents are asked to fill out the questionnaire for their children under the age of 12, they answer an additional separate questionnaire when their afflicted child is older than 12. The following assessments are identical for the parents of these two age groups. | PMC10031163 |
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COVID-19 pandemic-specific impact on well-being and everyday life | Based on experience from a previous study [ | PMC10031163 |
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Health-related strain | Two self-constructed items [ | PMC10031163 |
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Disease-specific health care use | A total of 10 self-constructed items are implemented to assess the corona-specific utilization of health services in the past 12 months. Parents are asked to provide information about the frequency of disease-specific health care visits; medical appointment cancellations and their causes; and the provision and quality of alternative virtual office hours. | PMC10031163 |
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Basic survey: Common measures for children and adolescents | For the questionnaires aiming at the data collection in children under the age of 12 and adolescents aged 12 years or older, the following measures are applied. | PMC10031163 |
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Perceived stress | A self-constructed item aims to assess how stressed the child feels because of the COVID-19 pandemic with an 11-point numerical rating scale ranging from 0 “not stressed at all” to 10 “totally stressed”. As described above, for children under the age of 12, the accompanying parent is asked to rate this item for their child. | PMC10031163 |
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Perceived loneliness | To measure how lonely a child feels due to the COVID-19 pandemic, a self-constructed item on a Likert scale ranging from 0 to 10 is applied. Older children are asked to select a response ranging from “not stressed at all” to “totally stressed”, and the parents answer this item for younger children. | PMC10031163 |
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COVID-19-specific well-being in everyday life | A self-constructed 5-item scale based on Warschburger et al. [ | PMC10031163 |
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Basic survey: Measures for adolescents | PMC10031163 |
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School experience | HOLIDAYS | Two items have been constructed for the purpose of assessing the educational experiences of adolescents during the COVID-19 pandemic. One multiple-choice question aims to assess the teaching method that the students encountered during the last 2 weeks, with possible answers comprising home-schooling, classroom teaching and frequency, holidays, or having finished school. The other item asks, if applicable, how students have succeeded in learning at home, with a Likert scale ranging from 0 “totally badly” to 10 “totally well”. | PMC10031163 |
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Perceived risk | The risk perception of adolescents is measured with three self-constructed items [ | PMC10031163 |
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Media usage | A 5-point Likert scale established by another survey [ | PMC10031163 |
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Anxiety | Anxiety | Anxiety symptoms (e.g., not being able to stop or control worrying) during the past 2 weeks are measured with the German version of the General Anxiety Disorder-Scale (GAD-7) [ | PMC10031163 |
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