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3.1. Safety | nausea, vomiting, anemia, abdominal pain | ADVERSE EVENTS, ADVERSE EVENT, ADVERSE EVENT, ANEMIA | Most of the study patients received 8 or more doses of nimotuzumab and at least 2 cycles of chemotherapy. Adverse events were reported in 49 patients (73.11%). A total of 319 adverse events of 83 different types were recorded. Treatment-related adverse events were recorded in 8.1% of patients. Severe AEs related to the treatment were registered in 1.5% of the patients, of these only four AEs (1.2%) related to the monoclonal (5.9% of the patients had treatment-related adverse events, and the proportion of patients with at least one serious adverse event related to the treatment was 1.5%. Most of the related AEs were mild and moderate and progressed towards recovery or improvement. No patient died from any adverse event associated with the use of the monoclonal antibody. The most frequent AEs were nausea (10%), anemia (8%), abdominal pain (8%), weakness (5%), and vomiting (5%). The frequency of related AE was 8.1%, and the proportion of serious AE related (very probable, probable, or possible) with the use of nimotuzumab was 1.2%. | PMC10162878 |
3.2. Survival Analysis | DISEASE, METASTATIC DISEASE | In the front-line setting, median overall survival of 9.0 months (95% CI; 8.36-15.11) was reached, and 1- and 2-year survival rates reached values of 38.8 and 7.6, respectively, while the overall mPFS was 8.03 ± 0.99 (6.08-9.90) months.In patients with locally advanced disease, a global median OS of 16.36 months (95% CI; 14.35-18.38) was reached, and 1- and 2-year survival rates reached values of 72.2 and 29.2, respectively. In patients with metastatic disease, a global median OS of 6.23 months (95% CI; 4.32-8.13) was reached, and 1- and 2-year survival rates reached values of 18.1 and 3.0, respectively (
In patients with locally advanced disease, a median PFS of 9.6 months (95% CI; 4.91-14.20) was reached, and the PFS rate at one year was 39%. No patient achieved the 2-year PFS rate. In 20 patients with locally advanced disease who received 8 or more doses of nimotuzumab, the mOS increased to 17.4 months (IC95% 15.56-19.17), and 1- and 2-year survival rates reached values of 78.7 and 31.9, respectively (In patients with metastatic disease, a median PFS of 7.6 months was reached (95% CI; 6.08-9.90), and the PFS rates at one year and two years reached values of 20.5 and 5.1, respectively. | PMC10162878 | |
3.3. Clinical Response | DISEASE, REMISSION, METASTATIC DISEASE, RECURRENT DISEASE | The study obtained a 3.1% of complete remission and 15.4% of partial remission, which contributed to an objective response rate of 18.5%, and the disease control rate was achieved in 43.1% of the study patients (In patients who received 8 or more doses of nimotuzumab, the objective response increased to 26.1% and the disease control to 60.9%. In the stratum of patients with locally advanced disease, a 39.1% of objective response was obtained, and disease control was achieved in 60.9% of the patients. Those patients who received 8 or more doses of nimotuzumab reached a 45.0% of objective response and a 70.0% of disease control.In patients with metastatic disease, a 7.14% of objective response was obtained (only partial remission), achieving control of the disease in 33.3% of the patients in this stratum. Patients who received 8 or more doses of nimotuzumab reached an 11.5% of objective response, and the disease control increased by 20%.Of the four patients with recurrent disease upon inclusion, 3 achieved a partial response and one stable disease; thus, the control of the disease was achieved in all four. | PMC10162878 | |
4. Discussion | tumor, neutropenia, neuropathy, toxicity, thrombocytopenia, rash, pancreatic cancer, unresectable pancreatic cancer, tumors, pancreatic adenocarcinoma | ADVERSE REACTIONS, TUMOR, NEUTROPENIA, FOLLICULITIS, METASTATIC PANCREATIC CANCER, ADVERSE EVENTS, NEUROPATHY, THROMBOCYTOPENIA, DISEASE, METASTATIC DISEASE, PANCREATIC CANCER, INFILTRATING, TUMORS, PANCREATIC ADENOCARCINOMA, INFILTRATED | In the present study, with a mean follow-up time of 11.4 months, the very low toxicity profile of nimotuzumab was confirmed when administered in combination with gemcitabine in conditions of real-world practice.The fundamental problem in terms of toxicity of the therapies that target the EGFR is the appearance of severe rash, infiltrated lymphocytes, folliculitis, and other adverse reactions that can cause in kidney cells and gastrointestinal mucosa. These reactions are caused by the interaction of these therapies with receptors found in other tissues of the body than the tumor [
In the phase III randomized clinical trial comparing the anti-EGFR monoclonal antibody cetuximab+gemcitabine versus gemcitabine as monotherapy, toxicity was significant to detriment of the monoclonal antibody. There was no significant difference between the groups when assessing overall survival, and the combination was less effective than gemcitabine alone; therefore, its use was not approved for the treatment of these patients [Ko et al. studied patients with previously untreated locally advanced or metastatic pancreatic adenocarcinoma that were randomized to bevacizumab (10 mg/kg q2w) plus cetuximab (400/250 mg/mThe anti-EGFR tyrosine kinase inhibitor erlotinib was the first to show a slight increase in survival in combination with gemcitabine in the Phase III NCIC CTG PA.3 clinical trial that included 569 patients with advanced or metastatic pancreatic cancer, randomized to receive erlotinib+gemcitabine, or gemcitabine alone. A statistically significant benefit was obtained in favor of patients treated with the combination: in terms of global OS (HR, 0.82; The OSAG Phase III study that compared the combination of nimotuzumab and gemcitabine versus gemcitabine in patients with locally advanced or metastatic pancreatic cancer obtained a statistically significant clinical improvement in global OS and PFS with the combination of nimotuzumab and gemcitabine. In this study, data from 186 patients were analyzed: 93 in the nimotuzumab+gemcitabine group and 93 in the placebo+gemcitabine group. In patients treated with nimotuzumab, a 2-month advantage in overall survival was achieved, with a median overall survival of 8.6 months; survival rates at 12 and 18 months of 34% and 17%, respectively, in this group; and a statistically significant difference when compared with the control group (In another phase III clinical trial, a total of 92 Chinese patients were randomly assigned to the nimotuzumab-gemcitabine (The safety and survival results for the nimotuzumab+gemcitabine combination also reflected in the abovementioned German and Chinese studies could be considered together with other clinical-demographic variables such as ECOG and age when thinking about a personalized therapy in a real-world condition.Lima et al. evaluated the response to treatment and overall survival of 118 patients with advanced pancreatic adenocarcinoma in an observational and retrospective Cuban study. Patients were treated with nimotuzumab but combined with a GEMOX (gemcitabine+oxaliplatin) chemotherapy regimen. The median survival was 13.8 months (95% CI: 11.7-15.8). The second line of chemotherapy was administered to 42 patients, obtaining a median survival of 17.4 months (95% CI: 13.5-21.4). 51 grade 3-4 adverse events were reported, presented in 27 patients (22.9%). The most frequent adverse events were neuropathy (14.4%), neutropenia (10.2%), and thrombocytopenia (9.3%) [The combination of leucovorin, gemcitabine, cisplatin, and 5FU (LGCF) combined with bevacizumab and cetuximab versus LGCF was compared in a phase III study in patients with locally advanced or metastatic pancreatic adenocarcinoma. The benefit was achieved to the detriment of immunotherapy, in mPFS (3.0 versus 9.0 months) and mOS (7.0 vs. 10.0 months) [The phase III clinical trial of Imaoka et al. compared the combination of gemcitabine and S-1 (tegafur/gimeracil/oteracil), versus S-1 alone, and in a third group, gemcitabine alone, in patients older than 70 years with unresectable pancreatic cancer. It was found that there was no statistically significant benefit for the combination, superior to that of gemcitabine monotherapy. Median OS values of 10.2 months, 8.0 months, and 8.5 months, respectively, were reached [When analyzing specifically survival results in locally advanced disease, the mOS of 16.4 months and the 1-year survival rate (72.2%) obtained in our study in this patients were higher than the value obtained by the patients in the Phase III OSAG study with the same disease status and treatment [In a 2016 randomized study that again compared gemcitabine alone versus gemcitabine and erlotinib, but only in patients with locally advanced disease, the median OS in the combination group was lower than that achieved in those treated with gemcitabine alone (11.9 versus 13.6 months, respectively) [The mOS obtained in patients with metastatic disease in the present study was five months lower than the value obtained by the FOLFIRINOX subgroup in the PRODIGE study and two months lower than the result obtained in the nab-paclitaxel+gemcitabine subgroup in the MPACT study. Also, the mOS obtained in the present study is one month higher than that achieved by the subgroup of 69 patients with metastatic disease treated with nimotuzumab in the OSAG study (17.2%) [The Phase III study “MPACT” compared nab-paclitaxel+gemcitabine (431 patients) versus gemcitabine (430 patients) in metastatic patients. It obtained a median OS of 8.7 months in the group treated with the combination, OS rate of 35% at 12 months, and a median PFS of 5.5 months. An increase of 1.8 months in OS was obtained in the combination group compared to monotherapy [In the Phase II-III trial “PRODIGE 4,” which compared gemcitabine with FOLFIRINOX versus gemcitabine in patients with metastatic pancreatic cancer and good performance status, an increase of 4.3 months in median survival was obtained in favor of the combination (11.1 vs. 6.8 months; In our study, the overall objective response was lower than that achieved in other published studies. The overall disease control rate obtained in the present study was lower than that achieved in the group of patients treated with the same treatment scheme in the OSAG Phase III study [The primary limitation of this study is that the number of subjects required to estimate the proportion of patients with serious adverse events related to the use of the product was not reached, and the sample size was small. Another limitation deals with the impossibility to perform any biomarker determination to identify subgroups of patients that could receive greater survival benefits. Nevertheless, there are evidence that pancreatic cancer cells with EGFR high expression were sensitive to nimotuzumab treatment in vivo [Immunotherapy and targeted therapy did not yield significative changes in pancreatic cancer, due to PDAC tumor immune microenvironment with lack of infiltrating T cells and low tumor mutational burden. Also, the biomarkers commonly used to predict immunotherapy efficacy in other tumors seem to be useless in PC [With the exception of erlotinib and nimotuzumab, all EGFR inhibitors failed in clinical trials in PDAC, indicating the presence of underlying molecular mechanisms that bestow intrinsic and acquired resistance to this group [ | PMC10162878 |
5. Conclusions | PDAC | Nimotuzumab combined with gemcitabine as first-line treatment option represents a safe and useful alternative for the treatment of PDAC under real-world conditions. The administration of nimotuzumab as part of possible multimodal combination of agents that target a subset of cancer-associated fibroblasts or their secreted products (e.g., TGF- | PMC10162878 | |
Acknowledgments | Carvajal | The authors thank Rider Isaac Verdecia, Bachelor in English Language, Associate Professor, and Master in Higher Education Communicative Competence, who help with the language edition. Also, the authors would like to acknowledge the Cuban Network of Clinical Research Coordinators (Yusleidy Blanco González, Mileydis Sotolongo Pérez, Yindra Hernández Díaz, Yaisa Mileidy Parés Ojeda, Belkys María López, Anairis Herrera Suarez, Karelia Cortina Nápoles, Herminia Rodríguez Castañeda, Judith Ojeda de Pedro, Yaneydis Lores Méndez, María de los Angeles Pabón Bello, Damicelis González Martínez, Yaquelin Naranjo, Ahimara Rosado Rosado, Yadisleydis Elías Oquendo, and Cecilia Sayoux). Also, we thank the clinical research assistants of the Cuba's National Clinical Trials Coordinating Center (Neri Georgina Campañá Cobas, Yoan Sotero Armenteros, Anabel Amador González, Nadia Aguilera, Yoryana Ramírez Sánchez, Yurka Prieto Ferro, José R Cabrera Cepero, Teresa Cepero Quiñones, Diana Rosa Fernández Ruiz, Iralys Benítez Guzmán, Thayde Trujillo Tirado, Giselle Veguilla Alomar, Mayler Ramírez Sosa, Alicia Rodríguez Bernabé, Zaima Rodríguez Feria, Clara Carvajal Mena, Dianne Griñan Semaná, and Dayamí Soler Cano) and the technical support provided by Clinical Monitors from the Center of Molecular Immunology: Annia Gortes Quiñones, Leticia Cabrera Benítez, Meylan Cepeda Portales, Jose J. Hernández, Delmis M. Batista Calzado, and Milagros Domecq Salmon. | PMC10162878 | |
Data Availability | The data sets used and/or analyzed during the current study are available from the corresponding author upon reasonable request. | PMC10162878 | ||
Conflicts of Interest | Three authors currently work at the Center of Molecular Immunology, the institution that generated and originally patented nimotuzumab. The other authors do not have any commercial or financial relationships that could be taken as a potential conflict of interest. | PMC10162878 | ||
Authors' Contributions | B. Martorell, P. | ADVERSE EVENTS, DISEASE, ADENOCARCINOMA OF THE PANCREAS | Study concepts and design were carried out by Y. Sánchez, Y. Saumell, A. R. Valls, and P. P. Guerra. Literature research was carried out by Y. Sánchez, Y. Saumell, A. R. Valls, and P. P. Guerra. Clinical data collection was carried out by Y. Sánchez, M. L. Concepción, Y. Amador, A. Piriz, R. Rabassa, A. Leyva, O. Arguelles, L. Leblanch, S. Moret, G. Rivero, A. L. Vasallo, and B. Martorell. Data analysis was carried out by Y. Sánchez, Y. Saumell, and L. Sánchez. Statistical analyses were carried out by L. Sánchez and Y. Saumell. Manuscript preparation was carried out by Y. Saumell. Manuscript editing was carried out by all authors. All authors revised and approved the final manuscript.Distribution of patients evaluated in the study.The Kaplan-Meier curves for overall survival in first-line treatment patients and according to disease status at inclusion. SD: standard deviation; CI: confidence interval.The Kaplan-Meier curves for overall survival in treatment patients with 8 or more doses of nimotuzumab and according to disease status at inclusion. SD: standard deviation; CI: confidence interval.The Kaplan-Meier curves for progression-free survival in first-line treatment patients and according to disease status at inclusion. SD: standard deviation; CI: confidence interval.Distribution of patients according to demographic and clinical variables.SD: standard deviation; QR: quartile range.General information on adverse events.
List of treatment-related adverse events according to CTCAE
Clinical response for the first-line treatment stratum.
Summary of the main results of clinical trials with anti-EGFR+chemotherapy as first-line treatment in patients with locally advanced or metastatic adenocarcinoma of the pancreas.CI: confidence interval; HR: hazard ratio; N/A: not available; ORR: objective response rate; OS: overall survival; PFS: progression-free survival; Gem: gemcitabine; LGCF: leucovorin, gemcitabine, cisplatin, and 5FU. | PMC10162878 |
Background | anhedonia | CHRONIC PAIN | Neuropsychopharmacologic effects of long-term opioid therapy (LTOT) in the context of chronic pain may result in subjective anhedonia coupled with decreased attention to natural rewards. Yet, there are no known efficacious treatments for anhedonia and reward deficits associated with chronic opioid use. Mindfulness-Oriented Recovery Enhancement (MORE), a novel behavioral intervention combining training in mindfulness with savoring of natural rewards, may hold promise for treating anhedonia in LTOT. | PMC10106294 |
Methods | Veterans receiving LTOT ( | PMC10106294 | ||
Results | anhedonia | Patients treated with MORE demonstrated significantly increased LPP and SCL to natural reward cues and greater decreases in subjective anhedonia relative to those in the SG. The effect of MORE on reducing anhedonia was statistically mediated by increases in LPP response during savoring. | PMC10106294 | |
Conclusions | chronic pain, anhedonia | DISORDER, CHRONIC PAIN | MORE enhances motivated attention to natural reward cues among chronic pain patients on LTOT, as evidenced by increased electrocortical and sympathetic nervous system responses. Given neurophysiological evidence of clinical target engagement, MORE may be an efficacious treatment for anhedonia among chronic opioid users, people with chronic pain, and those at risk for opioid use disorder. | PMC10106294 |
Key words | PMC10106294 | |||
Materials and methods | PMC10106294 | |||
Participants | chronic pain | CHRONIC PAIN | In this ancillary mechanistic study, we added a neurophysiological assessment protocol to an ongoing clinical trial (NCT02935621) where EEG outcomes were not proposed as part of the original clinical trial design. This mechanistic study evaluated neurophysiological (EEG and SCL) data from a sample of Veterans with chronic pain receiving LTOT (Baseline demographic and clinical characteristics (Subjects were allowed to enter more than one opioid type. SHAPS, Snaith Hamilton Anhedonia and Pleasure Scale. | PMC10106294 |
Procedures | Following screening, participants who gave written informed consent completed demographic and clinical assessments, including the Snaith Hamilton Anhedonia and Pleasure Scale (SHAPS) (Snaith et al., | PMC10106294 | ||
Interventions | pain | EVENTS, CHRONIC PAIN | The manualized MORE intervention program provided training in mindfulness, reappraisal, and savoring skills as techniques to cope with opioid craving, pain, and negative affect. Group sessions were 2 h long and led by a psychologist. Sessions included training in mindful breathing and body scan techniques to help patients self-regulate pain and opioid craving, reappraisal training to decrease negative emotions, and savoring training to amplify natural reward processing. With respect to savoring, specifically, participants were trained to mindfully focus attention on the sensory features of a pleasant object presented in the session (e.g. a rose), and then to appreciate and enjoy any positive emotions or pleasurable body sensations arising during the encounter with the pleasant stimulus. Then, participants were asked to engage in daily 15 min home practice of mindfulness as well as practicing savoring with naturally-occurring pleasant objects and events in everyday life.To control for non-specific factors including attention by a caring professional, therapeutic expectancy, and social support, we employed a manualized active SG control in this study. The SG consisted of 8 weekly, 2 h, process-oriented, Rogerian group psychotherapy sessions, in which a psychologist facilitated emotional expression and discussion of topics pertinent to chronic pain and opioid use/misuse. This client-centered SG format was validated in prior RCTs of MORE (Garland et al., | PMC10106294 |
Assessment of natural reward responsiveness | In an experimental laboratory session, participants were presented with images representing natural rewards or neutral cues. On each trial, participants were first shown a fixation cross for 500 ms, followed by 250–500 ms jittered blank screen and then an image and instruction label for 5000 ms. Across 64 trials, cues were presented in a randomized, event-related design.Participants were instructed to View or Regulate responses to natural reward stimuli. On View trials, participants were instructed to simply attend to images of naturally rewarding stimuli (e.g. social affiliation, natural beauty, athletic victories, etc.) validated in prior studies (Garland, Bryan, Nakamura, Froeliger, & Howard, | PMC10106294 | ||
EEG | BRAIN | EEG was continuously recorded from 10 midline scalp sites (Fz, F3, F4, FC1, FC2, FCz, Cz, CP1, CP2, PZ) using an active sensor cap with Ag/AgCl electrodes (actiCap GmbH, Herrsching, Germany). All recordings were collected by an actiCHamp amplifier (Brain Products GmbH, Gilching, Germany). Data were acquired at a sampling rate of 500 Hz, a resolution of 0.489 EEG data preprocessing was conducted using a custom MATLAB (MATLAB version 9.3.0,.713579 (R2017b), | PMC10106294 | |
Skin conductance | SKIN | Skin conductance sensors were placed on the middle phalanx of the index and middle fingers of the non-dominant hand. A BIOPAC MP160 amplifier provided a constant voltage (0.5 V) across the two electrodes. Change relative to a 500 ms pre-stimulus baseline was computed in half-second epochs. | PMC10106294 | |
Anhedonia | The SHAPS (Snaith et al., | PMC10106294 | ||
Positive affect | POSITIVE | The Positive and Negative Affect Schedule-short form (PANAS-SF) was used to assess positive affect with 10 items rated on a Likert-type scale (1 = | PMC10106294 | |
Reward experience | One item from the Applied Mindfulness Process Scale (AMPS; Li, Black, & Garland, | PMC10106294 | ||
Statistical analysis | anhedonia | This mechanistic study was powered to detect the effects of MORE on neurophysiological processes. Power analysis conducted with G*power 3.1 indicated that 60 subjects were required to detect a statistically significant (Given the canonical time window of the LPP and our Next, to perform an intention-to-treat analysis of the effects of treatment on SHAPS scores over time, we used linear mixed modeling (LMM) in SPSS 27 with maximum likelihood estimation and fixed effects consisting of a time factor and between-subjects treatment factor (MORE Finally, we examined correlations between neurophysiological responses (LPP and SCL) and anhedonia scores in the follow-up period. In an exploratory post-hoc analysis, we also examined neurophysiological correlates of positive affect and reward experience. We then conducted a path analysis in the R version 4.0.3 Lavaan package using maximum likelihood estimation with robust (Huber–White) standard errors to evaluate neurophysiological responses as a mediator of treatment effects (MORE | PMC10106294 | |
Results | PMC10106294 | |||
Baseline equivalence | There was no significant between-groups difference by Treatment condition on the LPP ( | PMC10106294 | ||
Treatment effects on LPP response | Effects of treatment on the LPP (Changes in parietal (Pz) late positive potential (LPP) during (Difference waves (post-treatment minus pre-treatment) depicting effects of Mindfulness-Oriented Recovery Enhancement (MORE) | PMC10106294 | ||
Treatment effects on SCL response | Effects of treatment on SCL (Difference waves (post-treatment minus pre-treatment) depicting effects of Mindfulness-Oriented Recovery Enhancement (MORE) | PMC10106294 | ||
Treatment effects on anhedonia, positive affect, and reward experience | In LMM of SHAPS scores, the Treatment × Time interaction was significant, With regard to PANAS positive affect, although the main effect of Time was significant | PMC10106294 | ||
Association between neurophysiological mechanisms and anhedonia, positive affect, and reward experience | Across the entire sample, pre-post increases in LPP during the regulate strategy correlated with lower SHAPS scores throughout the follow-up, Path model indicating that the effect of Mindfulness-Oriented Recovery Enhancement (MORE) | PMC10106294 | ||
Discussion | anhedonia, OUD, chronic pain, decreased anhedonia, depression | CHRONIC PAIN, BRADLEY, SKIN | Here we obtained neurophysiological evidence in support of the hypothesis that MORE increases motivated attention to natural reward cues in chronic pain patients on LTOT – effects that were associated with decreased anhedonia. Relative to an active SG psychotherapy control condition, participants in the MORE group exhibited heightened LPP and SCL responses to natural reward stimuli. In individual difference analyses, increases in LPP activity during savoring predicted reductions in anhedonia symptoms through a 4-month follow-up.Findings suggest that training in attention allocation to the positive exteroceptive and interoceptive features of a stimulus context (i.e. savoring) through MORE can amplify LPP markers of motivated attention to natural reward stimuli. MORE's effects were similar on View and Regulate trials; though MORE provides training in proactive up-regulation of reward via savoring, it seems to enhance motivated attention to natural reward cues in a bottom-up fashion even when no conscious attempts to savor are made. Hypothetically, repeated practice of savoring may restructure the reward value of non-drug rewards, such that over time, no proactive efforts to up-regulate reward are needed; indeed, automatic (implicit) emotion regulation has been observed and indexed by the LPP (Zhang & Zhou, SCL during attention to natural reward cues also increased following 8 weeks of treatment with MORE, with no difference between the View and Regulate conditions. In contrast, SCL and the LPP decreased among participants in the SG – likely a function of habituation. Skin conductance habituation has been reliably demonstrated during viewing of positive affective images (Codispoti, Ferrari, & Bradley, Further, based on a recent systematic review (Kiluk et al., The current study had several other important limitations. First, because that the present analysis did not examine MORE's effects during attention to negative emotional stimuli, it is possible that MORE might increase attentional responses to emotionally salient stimuli of any valence. Yet, prior studies have indicated that MORE decreases attention to both negatively valenced stimuli (Garland et al., In summary, following 8 weeks of treatment with MORE, patients receiving LTOT for chronic pain exhibited increased electrocortical and sympathetic nervous system responses during attention to natural reward cues that predicted decreases in anhedonia 4 months after treatment ended. In light of neurophysiological evidence of clinical target engagement, adequately powered, full-scale clinical trials are now needed to test the efficacy of MORE as a means of treating anhedonia and reward deficits among chronic opioid users, people with chronic pain, and those at risk for OUD. Given that anhedonia is the hallmark of depression, and depression may exacerbate the risk for opioid misuse and OUD among chronic pain patients (Emery & Akil, | PMC10106294 |
Supplementary material | For supplementary material accompanying this paper visit https://doi.org/10.1017/S0033291721003834.click here to view supplementary material | PMC10106294 | ||
Author contributions | SPENCER | Eric L. Garland: conceptualization, methodology, formal analysis, funding acquisition, project administration, investigation, resources, data curation, writing – original and editing. Spencer Fix: software, methodology, formal analysis, data curation, writing-original and editing, visualization, investigation. Justin Hudak: software, methodology, formal analysis, data curation, writing-editing, visualization, investigation. Edward Bernat: software, methodology, formal analysis, data curation, writing-editing, visualization. Yoshio Nakamura | PMC10106294 | |
Financial support | ABUSE | This work was supported by W81XWH-16-1-0522 from the Department of Defense (PI: Garland), R01DA042033 from the National Institute on Drug Abuse (PI: Garland), and R61AT009296 from the National Center for Complementary and Integrative Health (PI: Garland). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The content is solely the responsibility of the author and does not necessarily represent the official views of the Department of Defense or National Institutes of Health. | PMC10106294 | |
Conflict of interest | Eric Garland, Ph.D., LCSW is the Director of the Center on Mindfulness and Integrative Health Intervention Development. The Center provides Mindfulness-Oriented Recovery Enhancement (MORE), mindfulness-based therapy, and cognitive behavioral therapy in the context of research trials for no cost to research participants; however, Dr Garland has received honoraria and payment for delivering seminars, lectures, and teaching engagements (related to training clinicians in mindfulness) sponsored by institutions of higher education, government agencies, academic teaching hospitals, and medical centers. Dr Garland also receives royalties from the sale of books related to MORE, and is a consultant of and licensor to BehaVR, LLC. The remaining authors have nothing to disclose. | PMC10106294 | ||
References | PMC10106294 | |||
1. Introduction | obesity, OA, osteoarthritis, pain, ColEx, disability, musculoskeletal problems, knee pain, osteoarthritic, injuries | OBESITY, DEGENERATION, OSTEOARTHRITIS, ARTHRITIC CHANGES, OSTEOARTHRITIS, DISEASE | Athletic injuries are commonly implicated in the development of early osteoarthritic (EOA) changes in the knee. These changes have a significant impact on athletic performance, and therefore the early detection of EOA is paramount. The objective of the study is to assess the impact of different interventions on individuals with EOA, particularly focusing on recreational athletes. The study aims to evaluate the effectiveness of three treatment groups in improving various aspects related to knee EOA, including pain, range of motion, strength, and function. A study was undertaken with 48 recreational athletes with EOA who were assigned to one of three groups by the referring orthopedic surgeon: collagen (Col), exercise (Ex), or collagen and exercise (ColEx) groups. All the participants received their respective group-based intervention for 12 weeks. Visual analog scale (VAS), knee flexion range of motion (ROM) knee flexors and extensors strength, and KOOS were assessed at baseline, and after 4 weeks, 8 weeks, and 12 weeks of intervention. VAS for activity improved in all treatment groups, with no difference between groups. The between-group analysis for knee ROM revealed a significant difference (Sports are physical activities that require skill. Sporting activities and their capacity to cause musculoskeletal problems have traditionally been the subject of much discussion [The knee joint is a functional unit that is responsible for transmitting load during both extensive and daily activities. The magnitude of the load can range from exceedingly low to very large. Sporting activities place a large level of repetitive stress on the tibiofemoral joint. Hence, it becomes imperative to detect these arthritic changes within the knee joint early and introduce primary interventions and therapeutic approaches that could prevent further progression of the disease [Osteoarthritis (OA) is a global health problem that affects over 300 million people and is a major cause of disability. In India, the prevalence of knee OA is found to be 28.7% and approximately 80% of Indians who claim to have knee pain show signs of OA, out of which 20% report an incapability to carry out daily activities [Knee OA is important not only due to its high prevalence rate compared to other types of OA, but because it is increasingly being reported in the young and in athletic populations [The identification of risk factors in EOA is crucial to initiate adequate and prompt conservative management and to prevent progression of the condition to the point where surgical intervention becomes necessary [Etiological considerations contributing to EOA can be broadly classified into endogenous and exogenous factors. Genetic factors, especially those coding for the structural proteins in type II collagen, gender, where studies show that females are more prone to developing osteoarthritis because of the anatomical difference that exists between the genders, various ethnic groups, and the age of the individual are the endogenous factors contributing to the disease [External factors like meniscal tears, which may accelerate the process of arthritic changes, obesity, i.e., a BMI > 30, injuries involving the ligaments of the knee, which may lead to decreased joint stability and could cause joint degeneration, and acquired knee axis deviations and various nutritional deficits, are a few factors that could account for the early onset of the disease [The first line of management for knee pain associated with arthritic changes is often pharmacological, followed by therapeutic intervention [A 12-week program of collagen supplementation is known to significantly reduce self-reported pain in young athletes [Management of knee OA can be broadly categorized as pharmacological and non-pharmacological. Therapeutic interventions are targeted to reduce pain, increase strength, and improve knee joint function. Exercise programs implemented for a period of 16 weeks are known to improve muscle strength, reduce pain, and improve the functionality of the knee joint [An agent with a reported positive effect on self-reported knee pain in athletes is hydrolyzed type I and native type II collagen. A 12-week program of collagen supplementation is known to significantly reduce self-reported pain in young athletes [In light of the aforementioned considerations, the present study aims to investigate the effectiveness, superiority, and relative benefits of three distinct treatment paradigms for athletes diagnosed with early arthritic changes in the knee. Specifically, the study will evaluate the impact of collagen supplementation, exercise, and exercise along with collagen supplementation, as modes of intervention, on alleviating knee pain, improving joint function, and potentially slowing the progression of knee OA. Hence, against the above background, the present study is undertaken to understand the effectiveness and superiority, and to review the relative benefits, of three different treatment paradigms in athletes diagnosed with early arthritic changes in the knee. | PMC10706409 |
2. Methods | PMC10706409 | |||
2.1. Design and Participants | knee injury, pain, knee muscle strength and knee muscle, knee pain, trauma | HAND OSTEOARTHRITIS, SECONDARY | A double-blind, quasi-randomized trial was conducted in the hospital settings of Kasturba Medical college, Mangalore, between March 2021 and March 2022. The primary outcomes were measured using the pain scale and assessed using the visual analogue scale (VAS). The functional outcomes were measured using the knee injury and osteoarthritis outcome score (KOOS) and the secondary outcomes were knee muscle strength and knee muscle range of motion (ROM). A total sample size of 48 was included and a standard deviation of 0.74 was acquired from a previous study at a confidence level of 95% and precision d = 0.86 [Participants were randomly allocated by the referring surgeon using a random number table, and subjects were randomly allocated using the non-purposive sampling technique in one of the routinely followed and prescribed treatment groups, i.e., group (1) was the exercise therapy group, group (2) the collagen supplementation group, and group (3) underwent a combined intervention of exercise therapy and collagen supplementation (The inclusion criteria were as follows: (a) athletes above the age of 18 and below 55; (b) knee pain and stiffness that interferes with sports performance; (c) grades I and II on the Kellgren Lawrence scale, as diagnosed and confirmed by an orthopedician. The participants were screened based on the study’s eligibility requirements. The participants were excluded if they had any recent trauma or injury to the knee or any surgery in the past 3 months. | PMC10706409 |
2.2. Instruments | A handheld dynamometer was used to assess the muscle strength, ROM was assessed using the universal goniometer, and the KOOS scale was used to evaluate the patient-reported outcomes. | PMC10706409 | ||
2.3. Intervention | abductors, hip muscle | Group 1—exercise therapy group;Group 2—collagen supplementation;Group 3—combined intervention of exercise therapy and collagen supplementation.The exercises prescribed to both groups were:hip muscle strengthening exercises, including hip flexors, abductors, adductors, and extensors;knee muscle strengthening exercises, including dynamic quadriceps exercise, hamstring curls, gastrocnemius stretching, and squatting;cycling. | PMC10706409 | |
2.4. Data Collection | musculoskeletal injury, knee injury | HAND OSTEOARTHRITIS | The study received ethical approval from the Institutional Ethics Committee, KMC Mangalore, Manipal Academy of Higher Education (IECKMC MLR 02-2021/54). The study was enrolled into India’s clinical trial registry under the identifier CTRI/2021/04/033091. Recreational athletes of either gender, aged from 18 to 52 years, with no current history of musculoskeletal injury, were recruited after providing their written informed consent. Demographic data and baseline data were noted on the day the patient was referred for physiotherapy. The data included a 10 cm visual analogue scale (VAS), the knee injury and osteoarthritis outcome score (KOOS), knee flexion range of motion (ROM), which was measured using a goniometer, and knee flexor and extensor muscle strength, which was quantified using a handheld dynamometer. All of the aforementioned outcome measures were assessed at 4 weeks, 8 weeks, and 12 weeks, respectively. A qualified physiotherapist delivered the exercise programs, following which the clinical endpoints were measured by the primary investigator, who was blinded to the study. | PMC10706409 |
2.5. Statistical Analysis | The collected data were entered into the Statistical Package for Social Sciences (SPSS) version 21.0. A descriptive analysis of the baseline characteristics of the study subjects was carried out. Baseline data were compared between groups, and as the data were normally distributed, an unpaired | PMC10706409 | ||
3. Results | PMC10706409 | |||
3.1. Patient Demographics | ColEx | Patient demographics: The study included 48 participants with a mean age of approximately 29–30 years, divided into three groups: collagen + exercise (ColEx), collagen (Col), and exercise (Ex). | PMC10706409 | |
3.2. Pain Score at Weeks 4, 8 and 12 | Pain | Pain score: Pain levels significantly reduced in all three groups over 12 weeks (At rest, ColEx: | PMC10706409 | |
3.3. Knee Flexion ROM at Weeks 4, 8 and 12 | knee flexion ROM | The knee flexion ROM ( | PMC10706409 | |
3.4. Knee Flexor Strength at Weeks 4, 8 and 12 | The knee flexor strength at baseline was statistically significant in all three groups from baseline to 12 weeks ( | PMC10706409 | ||
3.5. KOOS Score at Weeks 4, 8 and 12 | ColEx, pain | KOOS Score: (All three groups exhibited significant reductions in pain levels over the 12-week study period. The ColEx group experienced a substantial reduction in pain at rest, with a | PMC10706409 | |
4. Discussion | muscle weakness, functional disability, pain, reduced pain, trauma | DISEASE PROGRESSION, MUSCLE WEAKNESS, EVENTS | The objective of this study was to determine the efficacy, superiority, and relative benefits of three different paradigms of treatment, i.e., exercise therapy, collagen supplementation, and a combination of collage supplementation with exercise therapy, in alleviating pain, and improving muscle strength, range of motion, and functional scores in athletes diagnosed with EOA.VAS on activity (In our study, athletes diagnosed with EOA were managed conservatively using either exercise therapy (routine exercises + proprioceptive exercises), oral collagen supplements, or both. The implications for exercise and pain reduction in an arthritic joint include Interleukin 1 beta [The findings of our study are in line with another 12-week study of participants with knee OA, which concluded that strengthening and coordination exercises conducted three times a week reduced pain in 63% of sessions [In the present study, it was also observed that the collagen group did not demonstrate a statistically significant difference in pain relief when compared to the other groups (Differences in joint mobility were measured using the ROM method and isometric muscle strength was quantified with a hand-held dynamometer. We observed a moderate to strong improvement in the ROM and knee muscle strength in individuals with EOA in the Ex-group. The ROM of the arthritic knee joint is thought to be a crucial determinant in the development of muscle weakness during isokinetic activity [In the present study, active knee flexion ROM increased significantly in the Ex-group as compared to the other groups (In our present study, the KOOS scores showed a statistically significant difference for the ColEx and the Ex-group at the end of 12 weeks (EOA is a constellation of anatomical abnormalities that cause functional disability and pain. There are various risk factors associated with disease progression; however, it appears that early joint damage or trauma during sporting events is a more common cause in the athletic population. The assessment and effective management of EOA in an athlete is frequently difficult due to his or her increased exercise demands and requirement for an accelerated return to sport. Athletes who participate in sports that require quick acceleration and instant deceleration, who engage in continuous training with an impact on joints, or who compete at an elite level for extended periods are at a higher risk of developing EOA [EOA management should always include a variety of therapeutic options targeted at alleviating pain and improving function. The recommended management framework should prioritize nonpharmacological techniques, followed by nutritional supplements and analgesics. In the present study, the ColEx group displayed significant changes in all the investigated parameters; however, exercise therapy is a standalone treatment.Considerably significant changes were seen in the results when compared to individuals treated with collagen supplementation alone. Therefore, the authors highly recommend using oral collagen supplementation along with exercise as the treatment of choice in EOA.We accept that our study had several limitations. As subject randomization was achieved through allocation and not concealment, a possible selection bias could have occurred. Second, because this study was conducted on recreational athletes, the capacity to extend these findings to a larger population is limited, and lastly, the sample size within the included groups is relatively small. | PMC10706409 |
5. Conclusions and Future Directions | OA | DISEASE PROGRESSION | The influence of sports practice on the development of EOA is a cause for concern. The ability to treat OA in its early stages may be largely linked to alterations in specific extrinsic or intrinsic factors associated with the patient to spare the joint from further disease progression; these factors include sports practice, equipment, and load. Nonpharmacological management such as muscle strengthening, and training plays an important role in the care of athletes with EOA. The present study concluded that exercise therapy as a standalone treatment exhibited considerably significant changes; however, exercise therapy combined with oral collagen supplementation was effective and superior to the other interventions in improving the VAS scores, strength, and KOOS scores in people with EOA. Further studies need to be conducted, wherein the effect of exercise and collagen supplementation on cartilage health should be correlated with the radiological findings and clinical biomarkers for EOA. | PMC10706409 |
Author Contributions | A.J.P. and C.E.—conceptualization of the topics. D.T.T.—data collection and writing of the manuscript. S.R. and M.C.D.—reviewing of the manuscript. Y.D.K., V.D.P., V.P.—final manuscript editing and supervision of the study. All authors have read and agreed to the published version of the manuscript. | PMC10706409 | ||
Institutional Review Board Statement | The study received ethical approval from the Institutional Ethics Committee, KMC Mangalore, Manipal Academy of Higher Education (IECKMC MLR 02-2021/54). | PMC10706409 | ||
Informed Consent Statement | Informed consent was obtained from all subjects involved in the study. | PMC10706409 | ||
Data Availability Statement | Available on OSF–DOI 10.17605/OSF.IO/V6Y9P. | PMC10706409 | ||
Conflicts of Interest | The authors declare no competing conflict of interest. | PMC10706409 | ||
References | knee flexion ROM, pain, ColEx, extensors, knee flexion | RECRUITMENT | Patient recruitment and study design flowchart. * collagen + exercise ** collagen *** exercise.Changes in the range of motion (ROM) of knee flexion among the three treatment groups (collagen + exercise—ColEx, collagen—Col, and exercise—Ex) at different time intervals (4 weeks, 8 weeks, and 12 weeks) during the study period.((Within-group difference comparison of pain outcomes using the VAS scale and KOOS—functional outcomes among the three groups over time, i.e., baseline, 4 weeks, 8 weeks, and 12 weeks, along with corresponding Within-group difference comparison of outcomes of knee flexion ROM and muscle strength of knee flexors and extensors among the three groups over time, i.e., baseline, 4 weeks, 8 weeks, and 12 weeks, along with corresponding Analyses of the between-group analysis.* | PMC10706409 |
Background | EXPOSURE TO ALCOHOL | Exposure to alcohol advertising and sponsorship through elite sport is associated with harmful use of alcohol. Owing to strong financial and cultural ties between alcohol and sport in Australia, policy action to restrict alcohol sport sponsorship is unlikely to occur without strong public support for change. This study tested whether exposure to counter-advertising exposing industry marketing of harmful products—a technique shown to be effective in tobacco control—promotes higher support for policy change and less favourable beliefs about the alcohol industry among sport spectators. | PMC9969365 | |
Methods | A sample of 1,075 Australian adults aged 18–49 years who planned to watch an National Rugby League (NRL) State of Origin series game, featuring prominent alcohol sponsorship, was recruited through an online panel and randomly assigned to one of three conditions: control (neutral advertisement); counter-advertisement exposing alcohol harms; counter-advertisement exposing alcohol sponsorship and harms. Participants completed a pre-test questionnaire and viewed their assigned counter-advertisement multiple times in the 5–7 days before the NRL game. Within four days of watching the game, participants completed post-test measures. | PMC9969365 | ||
Results | sports-related alcohol | Compared to both the control advertisement and the counter-advertisement exposing alcohol harms, participants who viewed the counter-advertisement exposing alcohol sponsorship and harms were significantly more likely to indicate support for each of four policies aimed at restricting sports-related alcohol marketing, including the complete removal of alcohol sponsorship from sport (51% vs. 32% and 37%). They were also significantly less likely to agree with statements such as “alcohol companies should be allowed to sponsor sport since their products are legal” (39% vs. 63% and 60%) and significantly less likely to report liking alcohol companies in general (38% vs. 59% and 54%). There were no significant differences in policy support or industry beliefs between participants who saw the counter-advertisement exposing alcohol harms and those who saw the control advertisement. | PMC9969365 | |
Conclusion | Counter-advertising employing messages that expose and critique the intent and impact of pervasive alcohol sponsorship in sport has potential to bolster public support for policies targeting alcohol sport sponsorship, diminish beliefs supportive of alcohol industry marketing strategies and enhance negative views of alcohol companies and their marketing practices. | PMC9969365 | ||
Supplementary Information | The online version contains supplementary material available at 10.1186/s12889-023-15250-5. | PMC9969365 | ||
Keywords | PMC9969365 | |||
Background | sports-related alcohol | EVENTS, EVENT, HOLIDAYS | Alcohol companies invest heavily in sponsorship of elite sport, with 30 of the leading alcoholic beverage brands globally spending a combined $764.5 million on sport sponsorship in 2018 [While spectator participation levels at sporting events have been impacted by the COVID-19 pandemic, around one in five Australians aged 15 and over was projected to attend at least one sporting event in 2022 [At present, there are very few restrictions on alcohol advertising, and no restriction of alcohol brand sponsorship of sport, under current legislation and regulatory codes in Australia. For example, while the Commercial Television Industry Code of Practice limits the broadcast of advertisements (ads) for alcoholic products on television to mature and adult viewing classification periods, alcohol brand sponsorship and alcohol product advertising during live sporting events and sports programs on weekends and public holidays are notable exemptions to these time-based controls [Given the embedded financial and cultural association between alcohol and sport in Australia, government implementation of controls of alcohol sponsorship of sport is unlikely to occur without strong public support, a known driver of advocacy success and policy action [The present study aimed to address this gap by testing whether spectators who are shown a counter-ad exposing alcohol sponsorship and harms before viewing an alcohol-sponsored sporting event report (i) higher post-event support for policy restricting sports-related alcohol marketing and (ii) less favourable beliefs about the alcohol industry, compared to spectators shown a control ad. We also tested the counter-ad exposing alcohol sponsorship and harms against a traditional alcohol counter-ad (exposing harms associated with alcohol use) to assess the relative effectiveness of each style of counter-ad on spectators’ level of policy support and beliefs about the alcohol industry. | PMC9969365 |
Method | PMC9969365 | |||
Design and participants | sports-related alcohol | EVENT | The study design was a pre-post, between-subjects experiment comprising three counter-advertising conditions: (A) control (neutral ad); (B) counter-ad exposing alcohol harms; (C) counter-ad exposing alcohol sponsorship and harms. A sample of Australian adults was recruited by Ipsos from their non-probability online panel (and panel partners). Panel members were eligible to participate if they were aged 18–49 years and planned to watch an upcoming 2021 NRL State of Origin game. The NRL State of Origin series is an elite sporting event in Australia that features extensive alcohol marketing [Following confirmation of their study eligibility, participants completed a pre-test (baseline) questionnaire, viewed a 30-second version of their assigned counter-ad twice and then reported their cognitive and emotional responses to the ad. Participants were randomly allocated to counter-advertising condition using a least-filled quota pre-programmed procedure set up in the backend of the baseline survey by Ipsos. For each condition, gender (male/female) and age (18–34/35–49 years) quotas were applied to achieve a relatively even distribution of participant characteristics in each condition at baseline. An alcohol consumption screening question was also asked of participants at the start of the baseline survey to obtain an approximate 80/20 split of at least monthly drinkers (cf. irregular/non-drinkers). Participants were invited to complete a short exposure task on each of the intervening days between the baseline survey and the game, which was intended to increase their dose of exposure to the assigned ad. Each day, the task rotated between exposing participants to either a 15- or 30-second version of their assigned counter-ad before asking them to answer a single rating question. To test for effects of the counter-ads on support for policies restricting sports-related alcohol marketing and beliefs about the alcohol industry, participants completed a post-test (follow-up) survey within four days of watching the game. Based on previous experimental studies testing audience responses to sport sponsorship [ | PMC9969365 |
Counter-advertising intervention | The counter-ad The counter-ad The | PMC9969365 | ||
Measures | The set of outcomes that form the basis of this paper are described below. Other domains measured in the baseline and/or follow-up surveys (e.g., brand awareness; sponsorship recall and recognition; image-based similarity; event-sponsor fit; brand attitudes, preferences and purchase intentions; alcohol harm beliefs; alcohol attitudes; next week drinking intentions) are the focus of a separate paper (manuscript under review). | PMC9969365 | ||
Responses to counter-advertisement | confusion | Immediately following counter-ad exposure at baseline, participants rated their cognitive (e.g., believability, relevance to them), motivational (i.e., felt motivated to reduce the amount of alcohol I drink) and emotional (e.g., confusion, surprise) responses to their assigned counter-ad using questions adapted from previous studies [ | PMC9969365 | |
Policy support | sports-related alcohol, neutral/oppose’ | At follow-up, participants indicated their level of support (1 = ‘strongly oppose’ to 7 = ‘strongly support’) for four proposed policies aimed at restricting sports-related alcohol marketing. Responses were collapsed into ‘support’ (5–7) and ‘neutral/oppose’ (1–4) categories. | PMC9969365 | |
Beliefs about the alcohol industry | ’ | At follow-up, participants indicated the extent to which they agreed or disagreed (1 = ‘strongly disagree’ to 7 = ‘strongly agree’) with three positively framed and two negatively framed statements about alcohol companies. Responses were collapsed into ‘agree’ (5–7) or ‘neutral/disagree’ (1–4) categories. Participants also provided a rating of how they feel about alcohol companies in general on a scale ranging from 1 = ‘I don’t like them at all’ to 7 = ‘I like them a lot’, with responses collapsed into ‘like’ (5–7) and ‘neutral/dislike’ (1–4) categories. | PMC9969365 | |
Baseline characteristics | Participants recorded their gender, age, residential postcode, highest level of educational attainment, parental status and frequency of drinking alcohol over the last 12 months. Socio-economic status (SES) was determined according to the Australian Bureau of Statistic’s Index of Relative Socio-Economic Disadvantage ranking for Australia using participants’ residential postcodes [ | PMC9969365 | ||
Statistical analysis | ’ cognitive, motivational and emotional responses | SENSITIVITY, REGRESSIONS | Data were analysed using Stata/MP V.16.1 (StataCorp, College Station, Texas). One-way analyses of variance with Bonferroni-adjusted post hoc pairwise comparisons were used to test for differences in participants’ cognitive, motivational and emotional responses to the counter-ad (measured at baseline) by condition. Overall differences in participants’ level of support for each policy proposal were assessed using McNemar’s test. Separate logistic regressions were conducted to test for differences by condition in the proportion of participants who were in support of each policy proposal, agreed with each alcohol industry belief statement and reported liking alcohol companies in general (all outcomes measured at follow-up). Where a significant (p < 0.05) omnibus test for condition was found, pairwise differences were assessed with a Bonferroni correction applied for multiple comparisons. All models controlled for days elapsed between surveys, dose of advertising exposure and game number. Sensitivity analyses were conducted using the original, continuous versions of the policy support and industry belief variables (see Supplementary Material 1). As the pattern of results was generally comparable to those found when using the dichotomous versions of these variables, for ease of interpretation, only the latter are presented in text. | PMC9969365 |
Results | PMC9969365 | |||
Sample characteristics | The final sample comprised n = 1,075 eligible adults who were recruited and completed data collection (baseline survey, short exposure tasks, follow-up survey) between 2 June and 18 July 2021 (see Fig.
Sample characteristics by counter-advertising condition (n = 1075)Notes: Percentages are rounded so may not sum to 100%. All sample characteristics were assessed at baseline
CONSORT flow diagram | PMC9969365 | ||
Responses to counter-advertisement at baseline | As shown in Table
Participants’ cognitive, motivational and emotional responses to counter-advertisement at baseline (n = 1075)oxy_comment_start comment="The footnotes have gotten mixed up in your reordering of the tables. Thus, we have fixed these to match how the tables are currently being shown in the proof. However, please note that our requested changes to the proof in the methods section will mean that the order of the tables in text will revert to how it was in our submitted manuscript. After you have made our requested changes, can you please double-check that the footnotes to each table are correctly matching? If possible, it would be great if we could be sent an updated proof to confirm this for ourselves."Notesoxy_comment_end: Boldfaced figures highlight the counter-advertisement that produced the strongest response among participants. Pairwise differences were assessed using one-way analysis of variance with Bonferroni correction. a Significantly higher than control ad at p < 0.05; b Significantly higher than counter-ad exposing alcohol harms at p < 0.05; c Significantly higher than counter-ad exposing alcohol sponsorship at p < 0.05Compared to seeing the control ad (M = 2.13), viewing either counter-ad made participants feel more motivated to reduce the amount of alcohol they consume, although these scores were only around the mid-point of the scale (i.e., M = 4.28–4.45). In general, participants’ emotional responses to the counter-ads were moderate (means ranged from 1.97 (‘confused’) to 4.40 (‘encouraged’) on the 7-point scale). However, the counter-ad exposing alcohol sponsorship and harms elicited stronger feelings of surprise (M = 4.28 vs. M = 3.15, | PMC9969365 | ||
Policy support at follow-up | REGRESSION | Across all conditions, participants showed stronger support for a ban on alcohol during sporting broadcasts at times when children watch TV (63%) than a ban on alcohol advertising at sports grounds (47%; McNemar’s χ
Effects of counter-advertising condition on policy support and beliefs about alcohol industry marketing at follow-up (n = 1075)oxy_comment_start comment="As noted above, the footnotes have gotten mixed up in your reordering of the tables. Thus, we have fixed these to match how the tables are currently being shown in the proof. However, please note that our requested changes to the proof in the methods section will mean that the order of the tables in text will revert to how it was in our submitted manuscript. After you have made our requested changes, can you please double-check that the footnotes to each table are correctly matching? If possible, it would be great if we could be sent an updated proof to confirm this for ourselves."Notesoxy_comment_end: Boldfaced figures highlight the counter-advertisement that produced the highest (policy support, beliefs opposing alcohol industry marketing) or lowest (beliefs supportive of alcohol industry marketing, overall belief about alcohol companies) percentage among participants. Logistic regression models controlled for days elapsed between surveys, dose of advertising exposure and game number. Where the omnibus test for counter-advertising condition was significant (p < 0.05), pairwise differences were assessed with a Bonferroni correction applied. a Significant difference compared to control ad at p < 0.05; b Significant difference compared to counter-ad exposing alcohol harms at p < 0.05 | PMC9969365 | |
Beliefs about the alcohol industry at follow-up | As shown in Table | PMC9969365 | ||
Discussion | cancer, sports-related alcohol, SD, Cancer | CANCER, SECONDARY, EVENT, CANCER | Findings from the present study indicate that counter-advertising exposing alcohol sponsorship and harms has potential to bolster public support for policies to restrict sports-related alcohol marketing, diminish beliefs supportive of alcohol industry marketing and enhance negative views of alcohol companies and their marketing practices. These effects were observed in comparison to both a control ad and a counter-ad highlighting the social harms of excessive alcohol consumption, indicating that it was the specific emphasis on exposing the questionable logic of allowing alcohol companies to promote their product to children during sport that made the counter-ad exposing alcohol sponsorship and harms impactful.For the four assessed policies to restrict sports-related alcohol marketing, the counter-ad exposing alcohol sponsorship and harms succeeded in boosting support by at least 16% points compared to the control ad and at least 12% points compared to the alcohol harms counter-ad. This is notable given that a previous study gauging public support for 14 alcohol control initiatives across seven countries (Australia, Canada, China, India, New Zealand, United Kingdom, United States) found that support for policies restricting alcohol advertising and sponsorship was typically lower than support for policies related to product labelling and consumer education [Across the whole sample, the highest level of support among participants was for the policy framed around protecting children (i.e., a ban on alcohol advertising during sporting broadcasts at times when children watch TV), a finding that aligns with past research showing that proposed alcohol control measures that aim to protect young people are better supported by adults than measures targeting the general population [The counter-ad exposing alcohol sponsorship and harms was effective at dampening specific beliefs supportive of alcohol industry marketing practices, heightening specific beliefs opposing alcohol industry marketing and making participants view alcohol companies less favourably overall. The effect size for this counter-ad detracting from the belief that alcohol companies should be allowed to sponsor sport because their products are legal was particularly large, with percentage point differences of over 20% compared to both the control ad and the counter-ad exposing alcohol harms. These observed shifts in participants’ alcohol industry beliefs in response to seeing counter-advertising exposing and critiquing industry marketing practices are in line with results from a naturalistic experiment where exposure to a movie denormalising the tobacco industry (Assessment of participants’ cognitive and emotional responses to their assigned counter-ad indicated that the counter-ad exposing alcohol sponsorship and harms was perceived as more relevant, thought-provoking and educational (i.e., teaching them something new) than the counter-ad exposing alcohol harms, and also tended to elicit greater surprise and worry. This may reflect participants having had minimal to no prior exposure to public health messages highlighting alcohol industry manipulation tactics, with (to our knowledge) only one previous Australian campaign having used this approach (i.e., Foundation for Alcohol Research and Education’s “Alcohol Truth” social media campaign) [Some study limitations should be acknowledged. First, we only tested a single example of a counter-ad exposing industry marketing practices that in addition to drawing attention to the alcohol industry’s use of sport sponsorship to promote alcohol to children also included mention of a long-term alcohol harm (i.e., cancer) that did not feature in the counter-ad exposing alcohol harms. While this was done to provide context as to why Cancer Council was advocating for the removal of alcohol sponsorship from elite sport, it is not possible to disentangle to what extent the primary (i.e., industry targeting alcohol marketing to youth through sport sponsorship) and secondary (i.e., link between alcohol and cancer) messages of the counter-ad each contributed to the effects we observed. Experimental studies testing multiple examples of counter-advertising exposing alcohol industry practices (including ones without secondary messages) in comparison to other styles of counter-advertising (including ones that focus solely on cancer as a long-term alcohol harm) could provide insight into the features of alcohol counter-ads that most contribute to effectiveness in garnering support for policy change. Second, as this was a naturalistic experiment based around the NRL State of Origin series, our sample was restricted to sport spectators who intended to, and then did watch an event where alcohol sponsorship is typically prominent. An average of 66.29 min (SD = 7.62) of alcohol marketing (including sponsorship) was observed during the two hours of televised coverage of each State of Origin game in 2012 [Key strengths of the current study include the addition of short exposure tasks that ensured participants received a minimum of four exposures to their assigned counter-ad over a week (i.e., two during the baseline survey and at least two subsequent tasks) to better mimic an actual mass media campaign, and the use of a professionally produced, broadcast-quality counter-ad exposing alcohol sponsorship and harms developed following formative research with the target audience. | PMC9969365 |
Conclusion | These study findings suggest that counter-advertising exposing industry marketing of harmful products offers a promising avenue for increasing public support for regulatory change in relation to alcohol sponsorship of elite sport and shifting beliefs about the alcohol industry and the acceptability of its marketing practices. Scaling up such counter-advertising to gain wider population exposure would be relatively inexpensive to implement per capita, when compared to the huge social and economic costs of alcohol use in Australia [ | PMC9969365 | ||
Acknowledgements | The authors thank the advertising agency, | PMC9969365 | ||
Author Contribution | HD, MS and MW designed the experiment. MS oversaw data collection and conducted data analysis in consultation with HD. MS and HD wrote the initial draft of the paper. All authors were involved in refining study protocols, interpretation of data, critically revising the paper and approving the final version. | PMC9969365 | ||
Funding | This research was funded by an Australian National Health and Medical Research Council Project Grant (GNT1159262). | PMC9969365 | ||
Data Availability | The data used and analysed in the current study are available from the corresponding author on reasonable request. | PMC9969365 | ||
Declarations | PMC9969365 | |||
Ethical approval and consent to participate | Cancer | CANCER | Ethical approval to conduct the study was obtained from Cancer Council Victoria’s Human Research Ethics Committee (IER 2002). All methods were carried out in accordance with the relevant guidelines and regulations laid down in the Declaration of Helsinki. All participants provided electronic informed consent at the start of the baseline survey. Additional electronic informed consent was collected at the end of the baseline survey regarding participation in the short exposure tasks and follow-up survey. | PMC9969365 |
Consent for publication | Not applicable. | PMC9969365 | ||
Competing Interests | cancer | CANCER | Authors (MS, HD, EB and MW) are employed by a non-profit organisation that conducts research, public health interventions and advocacy aimed at reducing alcohol-related health harms in the community, especially pertaining to cancer. EB and SP sit on government and/or non-government organisation advisory committees overseeing alcohol control campaigns. | PMC9969365 |
List of abbreviations | National Rugby LeagueSocio-economic status | PMC9969365 | ||
References | PMC9969365 | |||
Subject terms | REFRACTORY MULTIPLE MYELOMA | Elranatamab is a humanized B-cell maturation antigen (BCMA)-CD3 bispecific antibody. In the ongoing phase 2 MagnetisMM-3 trial, patients with relapsed or refractory multiple myeloma received subcutaneous elranatamab once weekly after two step-up priming doses. After six cycles, persistent responders switched to biweekly dosing. Results from cohort A, which enrolled patients without prior BCMA-directed therapy (In a pivotal phase 2 trial, elranatamab, a bispecific antibody targeting B-cell maturation antigen (BCMA) and CD3, had a confirmed objective response rate of 61% in patients with relapsed or refractory multiple myeloma who had not previously received BCMA-directed therapy. | PMC10504075 | |
Main | tumor necrosis | MULTIPLE MYELOMA, DISEASE PROGRESSION, TUMOR NECROSIS, MYELOMA, REFRACTORY MULTIPLE MYELOMA | The introduction of immunomodulatory drugs, proteasome inhibitors and anti-CD38 monoclonal antibodies has transformed the treatment landscape in multiple myeloma. The addition of these agents has substantially improved patient survival; however, outcomes for patients with disease progression after these agents remain poor with a median progression-free survival (PFS) of 4.6 months and median overall survival (OS) of 12.4 months with a standard of care therapy, highlighting an unmet medical need in the relapsed or refractory multiple myeloma populationB-cell maturation antigen (BCMA), a member of the tumor necrosis factor receptor superfamily, is highly expressed on malignant plasma cells, making it an ideal target for the treatment of multiple myelomaElranatamab (PF-06863135) is a humanized bispecific antibody that targets both BCMA (on myeloma cells) and CD3 (on T cells)The registrational phase 2 MagnetisMM-3 study ( | PMC10504075 |
Results | PMC10504075 | |||
Primary and secondary efficacy endpoints | After a median follow-up of 14.7 months (range: 0.2–25.1 months), the primary endpoint was met with 61.0% (95% confidence interval (CI): 51.8–69.6) of patients having a confirmed objective response per BICR. The best overall response is summarized in Fig. | PMC10504075 | ||
CRS profile of patients who received the 12/32-mg two-step-up priming regimen. | CRS | CRS experienced by each of the 119 patients who received the 12/32-mg two step-up priming regimen is shown by grade after each dose received. Grade 0 denotes no CRS.A total of 55 (44.7%) patients died while on study, the majority ( | PMC10504075 | |
Efficacy and safety with Q2W dosing | Among responders per BICR who switched to Q2W dosing at least 6 months before the data cutoff date ( | PMC10504075 | ||
Discussion | multiple myeloma, neutropenia, neuropathy, toxicity, toxicities, extramedullary disease, infections, CRS, TEAEs, anemia, penta-refractory disease | MULTIPLE MYELOMA, NEUTROPENIA, NEUROPATHY, DISEASE, EVENT, INFECTIONS, COMPLICATIONS, COMPLICATION, ANEMIA, EVENTS, REFRACTORY MULTIPLE MYELOMA | In this phase 2 study in patients with relapsed or refractory multiple myeloma, subcutaneous elranatamab at a dose of 76 mg weekly following a two step-up priming dose regimen of 12 mg and 32 mg during the first week of treatment induced early, deep and durable responses with a manageable safety profileA consistent benefit was observed across clinically relevant subgroups, including in patients with an ECOG performance status of 1 or 2, at least 50% bone marrow plasma cells at baseline and high-risk cytogenetics. Although lower ORRs were observed in patients with extramedullary disease at baseline, R-ISS stage III disease and penta-refractory disease, the response rate in these subgroups was clinically meaningful in these typically poor prognosis subgroups. In responders with extramedullary disease and penta-refractory disease, the benefit of elranatamab was maintained over time as DOR was generally consistent compared to the corresponding better prognosis subgroup. The lower response rate observed in patients with extramedullary disease reflects the historically poor prognosis in this subgroup and has also been observed with other anti-BCMA-targeted agents such as belantamab mafodotin and teclistamabThe results of this study are consistent with results reported from the phase 1 MagnetisMM-1 study in which a response rate of 64% and a median DOR of 17.1 months were observed in patients receiving elranatamab at the efficacious dose range (≥215 to 1,000 µg kgThe most common TEAEs reported in MagnetisMM-3 were CRS, hematologic-related events and infections. Patients who switched to Q2W dosing experienced fewer grade 3 or 4 TEAEs compared to the same time period before switching. However, the interpretation of these findings is limited as no QW comparator group is available to understand the change in AE incidence over time.With premedication and a two step-up priming dose regimen during the first week of treatment, CRS occurred in 56.3% of patients. All CRS events were grade 1 or 2, with no events grade 3 or higher. CRS events generally occurred early in treatment, with 90.6% limited to the step-up doses. Only one patient had a CRS event after the fourth or later dose, and few patients had more than one CRS event. ICANS was infrequent (occurring in 3.4% of patients) and limited to grade 1 or 2 events. Although the study protocol required hospitalization for the step-up priming doses (48 h after the first dose, 24 h after the second dose), the predictable and manageable profile of CRS and ICANS supports the potential for outpatient administration.Although the toxicities associated with BCMA-targeted T-cell-redirecting therapies are similar due to their mechanisms of action, the frequency and severity may vary between agents. CRS is the most frequent AE observed with T-cell-redirecting therapies; however, the incidence and severity are lower with bispecific antibodiesPeripheral neuropathy is a common complication of multiple myeloma and its treatment, especially with early-generation proteasome inhibitors and immunomodulatory drugs such as bortezomib and thalidomide, respectivelyHematologic AEs were frequent, with the most common AEs being neutropenia and anemia. In comparison to other BCMA-targeted T-cell-redirecting therapies, the rate of hematologic AEs with elranatamab was similar or lower after a similar follow-upBCMA-targeted T-cell-redirecting therapies have been linked to a heightened susceptibility to infectious complications due to their mechanism of actionThe interpretation of the results in this study is limited by its single-arm design and lack of direct comparison with other treatment options, as well as by the small sample size in some subgroups. Longer-term follow-up is required to confirm benefits in DOR, PFS and OS. However, current results support further investigation of elranatamab. An ongoing open-label, randomized phase 3 study is evaluating elranatamab monotherapy versus elranatamab + daratumumab versus standard of care daratumumab + pomalidomide + dexamethasone in patients with relapsed or refractory multiple myeloma who have received lenalidomide and a proteasome inhibitor (In this phase 2 study in heavily pretreated patients with relapsed or refractory multiple myeloma, elranatamab demonstrated a high rate of deep and durable responses, including in patients achieving ≥CR, with a manageable safety profile. Administration of a two step-up priming dose regimen successfully mitigated the rate and severity of CRS with a predictable profile supporting the potential for outpatient administration. Although additional follow-up is needed, maintenance or deepening of response was observed with elranatamab following the switch to a biweekly schedule. Biweekly administration may provide greater patient convenience with potentially less toxicity. Elranatamab is also a readily accessible, off-the-shelf therapy, which provides an option for patients unable to access CAR T-cell therapy. These results support the continued development of elranatamab as monotherapy and its further investigation in combination with standard or new therapies for patients with multiple myeloma. | PMC10504075 |
Methods | PMC10504075 | |||
Study design and patients | multiple myeloma, Guillain–Barré syndrome, squamous cell skin cancer or carcinoma, organomegaly, thromboembolic, malignancy, viral infection, impaired cardiovascular function, psychiatric, amyloidosis, skin changes syndrome, human immunodeficiency virus, prolonged QT syndrome, peripheral sensory or motor neuropathy, including active hepatitis B, peripheral motor polyneuropathy, hypersensitivity, POEMS | CARDIOVASCULAR DISEASE, PLASMA CELL DISORDER, VIRAL INFECTION, AMYLOIDOSIS, EVENTS, REFRACTORY MULTIPLE MYELOMA, ACUTE MYOCARDIAL INFARCTION, INFECTIONS, POLYNEUROPATHY, SMOLDERING MULTIPLE MYELOMA, MULTIPLE MYELOMA, ENDOCRINOPATHY, GRAFT VERSUS HOST DISEASE, MOTOR NEUROPATHY, PLASMA CELL LEUKEMIA, HEPATITIS C, HYPERSENSITIVITY, VIRUS, CARDIAC ARRHYTHMIAS, HUMAN IMMUNODEFICIENCY VIRUS, DISEASE, ACUTE CORONARY SYNDROMES | MagnetisMM-3 is an ongoing, multicenter, open-label, single-arm, phase 2 study to evaluate the efficacy and safety of elranatamab monotherapy in patients with relapsed or refractory multiple myeloma.Eligible patients were male or female (if not pregnant or breastfeeding), 18 years of age or older, willing to follow protocol-specified requirements and complete scheduled visits, with a prior diagnosis of multiple myeloma and measurable disease as defined by IMWG criteriaPatients were excluded if they had smoldering multiple myeloma, active plasma cell leukemia, amyloidosis or polyneuropathy, organomegaly, endocrinopathy, monoclonal plasma cell disorder, skin changes syndrome (POEMS), a stem cell transplant ≤12 weeks before enrollment or active graft versus host disease, or any active, uncontrolled bacterial, fungal or viral infection (including active hepatitis B virus, hepatitis C virus, SARS-CoV-2 or human immunodeficiency virus). Active infections had to be resolved at least 14 d before enrollment. Patients were also excluded if they had impaired cardiovascular function or clinically meaningful cardiovascular disease (defined as acute myocardial infarction, acute coronary syndromes, clinically meaningful cardiac arrhythmias, thromboembolic or cerebrovascular events or prolonged QT syndrome) ≤6 months before enrollment, ongoing grade ≥2 peripheral sensory or motor neuropathy, history of Guillain–Barré syndrome or variants or history of any grade ≥3 peripheral motor polyneuropathy, or for cohort B, history of any grade peripheral sensory or motor neuropathy with prior BCMA-directed therapy. Patients with another active malignancy within 3 years before enrollment (except for adequately treated basal cell or squamous cell skin cancer or carcinoma in situ), known or suspected hypersensitivity to elranatamab, previous administration of an investigational drug within 30 d or five half-lives preceding the first dose of elranatamab (whichever was longer), previous treatment with an anti-BCMA bispecific antibody or who received a live attenuated vaccine within 4 weeks of the first dose of treatment were also excluded. Patients were also ineligible if they had surgical, medical or psychiatric conditions or laboratory abnormalities that may increase the risk of study participation or (per investigator’s judgment) make the patient inappropriate for the study.Patients were assigned to 1 of 2 independent, parallel cohorts. Efficacy and safety results in patients naïve to BCMA-directed therapies are reported here (Fig. | PMC10504075 |
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