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Participants | Alzheimer’s disease, memory loss, dementia, cognitive impairment | Participants were aged 66 years or older on waiting lists at 3 MOW programs in Florida (1 program) and Texas (2 programs). We included participants who had self-reported or proxy-reported dementia during the programs’ intake assessment—a process completed for all individuals who request meals from these 3 MOW programs. Specifically, we relied on a question in the programs’ intake assessments: “Has a doctor or other health care professional told you that you suffer from memory loss, cognitive impairment, any type of dementia, or Alzheimer’s disease?” Prospective participants who resided outside the program’s daily service area were excluded from participation. | PMC10733798 |
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Randomization | The statistician (R.G.) generated a 1:1 stratified, permuted, block randomization scheme, in which each block comprised 6 participants. | PMC10733798 |
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Interventions | Participants randomized to daily-delivered meals were to receive 5 lunchtime meals delivered to their homes, 2 to 5 times per week, by an MOW program volunteer or a paid driver who interacted with the participant and provided an informal wellness check (all employees/volunteers are asked by programs to report any concerns as part of their program’s standard practice). Programs were not given any specific instructions about how to deliver these meals; rather, given the pragmatic nature of this study, programs were asked to provide meals as they would in usual practice. Participants randomized to drop-shipped meals received 10 frozen meals, mailed via FedEx, to their home every 2 weeks from TRIO Community Meals. Meals in both arms met the same nutritional standards (ie, adhered to current Dietary Guidelines for Americans | PMC10733798 |
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Measures and Primary Study Outcome | To examine feasibility, we tracked enrollment, examined baseline characteristics between the randomized arms, monitored participants’ fidelity to the intervention, measured the proportion of participants who we were able to link with CMS data, and analyzed the primary study outcome. Participants’ demographics (ie, age, race and ethnicity, sex, and living arrangement) were obtained by the programs during the usual intake assessment process and shared with the research team. Racial and ethnic groups were self-reported or proxy-reported and included participants who were Black, Latino or Hispanic, White, and other race and ethnicity, which included Asian, multiracial, and “other,” as reported by the programs. Results for those categorized as other were combined because the small numbers could result in participant identification. Fidelity (eg, received meals for 6 months, discontinued meals, and reasons for discontinuing meals) came from the programs’ administrative data. The primary study outcome was the number of days from randomization to nursing home admission, ascertained using a Minimum Data Set admission assessment (completed for all new nursing home residents regardless of payer or intent of stay), within 6 months of randomization. | PMC10733798 |
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Adverse Events | deaths | BROWN | Participant deaths, while expected and not related to the intervention, were tracked by the research team. All deaths were reported to the safety officer, the Brown University institutional review board, and the National Institute on Aging program officer for review and oversight. | PMC10733798 |
Linking Data | Outcome data were obtained by linking enrolled participants with CMS administrative data, which were obtained through a study-specific data use agreement that included the 2021 to 2022 Medicare Master Beneficiary Summary File (MBSF) and the 2021 to 2022 Minimum Data Set. | PMC10733798 |
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Sample Size and Power | Given that this was a pilot study, the target sample size was not based on power but rather on available funds to provide meals for 6 months to enrolled participants. Assuming that the proportions of participants who would be admitted to nursing homes in 6 months were 11% in the daily-delivered arm and 13% in the drop-shipped frozen meals arm, among 243 participants (115 in the drop-shipped frozen arm and 128 in the daily-delivered arm), we had 80% power to detect a hazard ratio of 0.33. | PMC10733798 |
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Statistical Analysis | death | REGRESSION, EVENT | We used an intention-to-treat analysis; all participants were observed until death, outcome event, or end of the 6-month follow-up. We examined baseline demographic characteristics using data provided by programs. We examined differences in our primary study outcome, time to nursing home admission, between the 2 interventions using a Cox proportional hazards regression model that adjusted for baseline covariates (ie, age, race and ethnicity, sex, living arrangement, and indicator for the program) to address possible imbalances across arms. | PMC10733798 |
Results | Study-specific IDs of 325 prospective enrollees who met inclusion criteria were sent to the research team and were randomized between April and October 2021 ( | PMC10733798 |
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CONSORT Diagram | CONSORT indicates Consolidated Standards of Reporting Trials. | PMC10733798 |
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Demographic Characteristics of Individuals Randomized by Enrollment Status | The difference between individuals who were enrolled and those who were randomized but not enrolled was significant at Other race and ethnicity includes Asian, multiracial, and “other,” as reported by the programs. Results for those categorized as other were combined because the small numbers could result in participant identification.For the total participants enrolled, 227 (93.4%) were linked deterministically to their CMS data; 16 participants (6.6%) could not be deterministically linked to the CMS data (6 in the daily-delivered meals group and 10 in the drop-shipped frozen meals group). There were no statistically significant differences in baseline characteristics between linked and nonlinked participants.Comparing participants by study arm, the majority of participants were female (78 [67.8%] for drop-shipped frozen meals and 74 [57.8%] for daily-delivered meals) and White (64 [55.7%] for drop-shipped frozen meals and 64 [50.0%] for daily-delivered meals) ( | PMC10733798 |
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Time From Randomization to Nursing Home Placement by Study Arm | Survival probability for mortality and nursing home placement were derived from Centers for Medicare & Medicaid Services data and observed 6 months from randomization (hazard ratio, −0.67; 95% CI, −1.52 to 0.19). The number at risk represents the average across linkage imputations. Not all 16 individuals were linked in every imputation, resulting in fewer than 241 participants overall. Shaded areas indicate 95% CIs. Daily indicates daily-delivered meals; frozen, drop-shipped frozen meals. | PMC10733798 |
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Discussion | dementia | This pilot study demonstrated the feasibility of implementing a pragmatic randomized clinical trial among participants with self- or proxy-reported dementia on waiting lists at MOW programs. We also showed the ability to link participants with their CMS data, monitor fidelity, and measure the time to nursing home placement. We observed that participants who received daily-delivered meals had lower rates of nursing home placement within 6 months compared with participants who received drop-shipped frozen meals, although these differences were not statistically significant. While this pilot trial was not adequately powered to detect effects that were as large as the observed differences at a 5% nominal level, the results suggest that there may be lower nursing home placement among individuals with self- or proxy-reported dementia who received daily-delivered meals with socialization and a safety check compared with individuals who received drop-shipped frozen meals.We enrolled 243 of 325 individuals with self- or proxy-reported dementia on waiting lists for MOW. The 243 participants differed by race and ethnicity and program from those not enrolled, suggesting that future work using this approach may need to consider the generalizability of enrollees compared with the eligible population. These findings provide useful estimates for the number of people who meet eligibility criteria we would need to identify on waiting lists at local MOW programs to enroll the required number of participants in a well-powered trial. In addition, the variation by program addressed the importance of understanding practices at each site, which relates to different methods of using waiting lists and contacting people to initiate service. We also found that we were able to link all but 16 participants with their CMS data using the information routinely collected by MOW programs. This information and our approach to linking the unlinked individuals may be helpful to other pragmatic trialists who are collecting identifiable information to link with administrative data.The results from this pilot study, which took place during 2021, must be interpreted considering the COVID-19 pandemic and implications it had on our study. First, MOW programs implemented procedures in response to the pandemic that reduced the frequency and kind of interactions that drivers had with clients, 1 of the key differentiators between the 2 study arms. For example, 1 program implemented social distancing requirements in which a driver could not enter a home but rather had to hang a bag with the food on the door, knock, and step away. Another program reduced delivery of daily-delivered meals to twice per week during the pandemic because of a decline in volunteer drivers. The reduction in the number of daily deliveries meant some meals were delivered chilled and may have needed preparation (eg, reheating). While reheating the chilled meals may have been simpler than preparing the frozen meals, the benefit of the ready-to-eat meal characterized by the daily meal delivery model may have been reduced for some. Given these COVID-19–related changes to the ways in which meals were delivered for the daily-delivered meals arm, it is likely that the effect of daily-delivered meals was attenuated in this pilot study. In addition, our measure of participant fidelity (ie, receiving meals for the full 6-month study period) could have been impacted by the pandemic and may have been specific to the population with self-reported dementia. Based on the National Survey of Older Americans Act Participants, more than 80% of its respondents received meals for 6 or more months. | PMC10733798 |
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Limitations | dementia | Consistent with the pragmatic design, this study relied on self-reported and proxy-reported information to identify individuals with dementia. Using information that programs typically collect, this pilot is more generalizable than a study that requires a confirmed diagnosis. Future research should validate this self-reported information or assess dementia severity more thoroughly to further nuance recommendations of meal-delivery effectiveness. Another possible limitation is that more participants in the arm assigned to drop-shipped frozen meals lived alone compared with those assigned to daily-delivered meals. We adjusted for living arrangements in the survival model to address this imbalance, but there may still be the possibility of bias, particularly given the challenges that participants expressed for transporting, storing, and reheating frozen meals that were likely exacerbated if living alone. | PMC10733798 |
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Conclusions | dementia | The findings of this pilot clinical trial demonstrated the feasibility of conducting an embedded pragmatic trial within MOW programs, enrolling older adults with dementia, monitoring their fidelity, linking data, and measuring participants’ outcomes. Although there was lower nursing home placement among participants receiving daily-delivered meals, this result was not significant; however, it does suggest that proceeding to a full-scale, conclusive, pragmatic randomized clinical trial is warranted to inform decision-making about the provision of home-delivered meals for homebound older adults living with dementia. This information is important as health systems, health care professionals, medical institutions, and health plans are increasingly providing meals to patients, a large and growing number of whom are living with dementia. | PMC10733798 |
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Background | esophageal and gastric cardia cancers | COMPLICATIONS | Chemoradiotherapy complications has always been of great concern to both clinicians and patients during the course of treatment. The purpose of the present study was to examine the effectiveness of oral famotidine on the reduction of hematologic complications of patients with esophageal and gastric cardia cancers undergoing radiotherapy. | PMC10199581 |
Methods | anemia, esophageal and cardia cancers | THROMBOCYTOPENIA, ANEMIA, GRANULOCYTOPENIA, LYMPHOCYTOPENIA | A single-blind controlled trial was conducted on 60 patients with esophageal and cardia cancers, who were undergoing chemoradiotherapy. Patients were randomly assigned to 2 groups with 30 patients to receive either 40 mg of oral famotidine (daily and 4 h before each session) or placebo. Complete blood count with differential, platelet counts, and hemoglobin levels were obtained weekly during treatment. The main outcome variables were lymphocytopenia, granulocytopenia, thrombocytopenia, and anemia. | PMC10199581 |
Results | thrombocytopenia | THROMBOCYTOPENIA | The findings indicated a significant effect of famotidine on reduction of thrombocytopenia among intervention group compared to control group ( | PMC10199581 |
Keywords | PMC10199581 |
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Background | dysphagia, nausea,, Cancer, death, toxicity, cancer, thrombocytopenia, cardia, esophageal cancers, nausea, fatigue, vomiting, anemia, lymphopenia, hypotension, weight loss, cancers, micronuclei, dermatitis | ESOPHAGEAL CANCER, DYSPHAGIA, CANCERS, CARDIOVASCULAR DISEASES, CANCER, THROMBOCYTOPENIA, MINOR, DNA DAMAGE, ESOPHAGITIS, GRANULOCYTOPENIA, LYMPHOPENIA, ANEMIA, CHROMOSOMAL ABERRATIONS, DERMATITIS, COMPLICATIONS, CANCER | According to recent estimates, by 2025 the prevalence of cancer is expected to soar by 45% in developed countries. Cancer is the second cause of death worldwide following cardiovascular diseases. More than one million cases of gastric cardia and 450,000 cases of esophageal cancers are being diagnosed annually, which are the seventh and eighth most prevalent cancers, respectively [Chemo-radiotherapy with or without surgery is an approved and favored treatment strategy in gastric cardia and esophageal cancers. Esophagitis and aggravation of transient dysphagia is witnessed in approximately 75% of patients who undergo chemoradiotherapy. Besides, they may experience early acute complications such as dermatitis, fatigue, weight loss, nausea and vomiting, as well as hematological complications like lymphopenia, granulocytopenia, thrombocytopenia and finally anemia [Irradiation-induced dose-dependent decrease occurs in all hematopoietic cell lineage. Reduction in the number of lymphocytes, granulocytes, and red blood cells occurs in hours, days, and weeks after the initiation of treatment, respectively [The importance of the adverse consequences of radiotherapy particularly the hematological complications becomes more prominent with acknowledging the fact that radiotherapy is widely used all over the world for either palliative or curative purposes. Of nearly 10.9 million people who are diagnosed with cancer annually, radiation therapy is given to about 60%, among them 40% are meant for curative treatment [Effective and timely management of radiotherapy complications should be taken seriously. For radiation oncologists, identifying an efficient and non-toxic radio-protective agent has always been essential. Radio-protective agents are utilized in order to prevent or reduce cellular damage due to ionizing radiation. They are often antioxidants that must be administered concomitantly or prior to the treatment [Sulfur compounds such as amifostine are the first compounds that have been evaluated as radio-protective agents. Evidence suggests that amifostine is a potent and systemically effective radioprotector when it is administered in high doses. However, it shows toxicity at the high doses required for radioprotection that pertains to survival benefits. Its severe side effects (e.g. nausea, vomiting, and hypotension), along with the non-oral route, and the need for blood pressure monitoring during injection have hindered its use. Therefore, there is still a considerable need for an effective agent with minor side effects [It has been shown that H2 receptor antagonists such as cimetidine and famotidine have radioprotective effects. Famotidine has been known as a strong agent to reduce radiation-induced apoptosis, as well as lipid peroxidation, DNA damage, chromosomal aberrations, micronuclei formation, and lethality [Existing evidence confirms that famotidine has been a promising agent in protecting leukocytes from radiation-induced apoptosis [ | PMC10199581 |
Methods and materials | PMC10199581 |
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Trial design and participants | esophageal and gastric cardia cancers | This was a single center, parallel designed (1:1), single-blind randomized placebo-controlled trial performed on patients with esophageal and gastric cardia cancers who were referred to the radiation oncology clinic of the Vali-E-asr Hospital, Zanjan, Iran, from September 2020 to December 2021. | PMC10199581 |
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Ethical considerations | The present study was approved by the Ethics Committee of Zanjan University of Medical Sciences [IR.ZUMS.REC.1399.158]. Written informed consent was obtained from all participant. Patients entered the study with their full awareness and willingness. Patients could withdraw from the study at any time. The medicine used in the present study has potentially no serious side effects. No prescription charges were obtained from patients. | PMC10199581 |
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Eligibility criteria | cardia cancers, Death, non-metastatic esophageal | TREATMENT COMPLICATIONS, RENAL IMPAIRMENT | The inclusion criteria were considered the patients aged ≥ 18 years with non-metastatic esophageal and cardia cancers who were candidates for chemo-radiotherapy and did not receive Proton pump inhibitors (PPIs) and other H2-blockers.Death during the study, being unable to continue treatment due to the severity of treatment complications, having renal impairment, being hypersensitive to H2-blockers, using any other H2-blockers (e.g. cimetidine) simultaneously and need to use PPI family medicines during the treatment process, caused an exclusion from the study. | PMC10199581 |
Interventions | esophageal and cardia cancers | COMPLICATIONS | This trial was designed to determine the effectiveness of oral famotidine on reducing the acute hematological complications of radiotherapy among patients with esophageal and cardia cancers. All patients received a fixed therapeutic dose of external beam radiation therapy. 15MV high-energy photon from linear accelerator (Siemens Primus, Siemens Medical Systems, Concord, CA, USA) was used for treatment. Patients were treated with 3 fields per day with a dose rate of 180 cGy/day, five days/week. Planning target volume (PTV) was 5 mm from clinical target volume (CTV). Dose-volume histogram (DVH) was considered mean dose of 30 Gy and mean dose of 15 Gy for liver and spleen, respectively. Moreover, patients received the chemotherapy regimen of paclitaxel 80 mg/m | PMC10199581 |
Outcomes | cancer, anemia | LYMPHOCYTOPENIA, CANCER, THROMBOCYTOPENIA, ANEMIA, GRANULOCYTOPENIA, COMPLICATIONS | Acute hematological complications of radiotherapy including lymphocytopenia, granulocytopenia, thrombocytopenia, and anemia were the outcome variables of the study that were assessed once at baseline and then weekly at the end of each week using complete blood count (CBC) with differential at the laboratory of Vali-e-Asr hospital by blinded laboratory staff using KX-21N hematology analyzer (Sysmex Corporation, Kobe, Hyogo, Japan). The results of lab tests were then collected and evaluated by an assessor blinded to random allocation of study groups. The variables of age, gender, the week in which lab tests were done and the type of cancer were also collected using a checklist. | PMC10199581 |
Sample size | The sample size was determined based on the study of Razzaghdoust et al. [ | PMC10199581 |
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Randomization and blinding | Participants, laboratory staff, data collectors, outcome assessors were blinded by not informing them of the group allocations. Data analysts were blinded by providing them with a blinded version of the data. The principal Investigator was aware of treatment assignments. Random sequence of participants was made using Blocked randomization (blocks of 4) by Microsoft Excel, using the RAND function. Sequentially numbered, opaque, sealed envelopes were used to conceal the allocation sequence from the researchers who were enrolling and assessing the participants. Outcome assessment was done by the same assessor for two groups. | PMC10199581 |
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Statistical analyses | Shapiro–Wilk test was used to test the normality of the numeric data. Mean ± standard deviation (SD), median (IQR) and frequency (%) were used to report descriptive statistics, as applicable. Between-group comparisons were examined using Mann–Whitney U test and independent samples t-test with mean difference (MD) and 95% confidence interval (95%CI). Within-group comparisons were investigated through Friedman test with a post-hoc analysis using Wilcoxon signed-rank test with Bonferroni correction. The CONSORT flow diagram | PMC10199581 |
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Results | PMC10199581 |
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Basic characteristics of the participants | esophageal cancer, gastric cardia adenocarcinomas, SD, squamous cell carcinoma and, adenocarcinoma | OESOPHAGEAL CANCER | A total of 60 patients (32 male, 28 female) with stage I–III esophageal cancer including squamous cell carcinoma and adenocarcinoma, in addition to stage I–III Siewert type I esophagogastric junction (EGJ) and gastric cardia adenocarcinomas were included in the study.With regard to the gender ratio of the participants, in both groups there was 16 (53.3%) males and 14 (46.7%) females.Mean ± SD age of total participants was 66.55 ± 11.57. Mean age of participants in control group was 67.17 ± 12.73 and in intervention group was 65.93 ± 10.46. We found that there was no significant difference between the two groups in terms of age (t(58) = 0.410, | PMC10199581 |
Discussion | tumor, micronucleus, lymphocytopenia, thrombocytopenia, micronuclei, esophageal cancers, spermatogenesis, gastric cardia, prostate cancer, radiation-induced micronucleus | ESOPHAGEAL CANCER, TUMOR, ASPERMATOGENESIS, LYMPHOCYTOPENIA, THROMBOCYTOPENIA, DNA DAMAGE, CHROMOSOMAL ABNORMALITIES, PROSTATE CANCER, COMPLICATIONS | In the current study we assessed the effectiveness of oral famotidine as a redioprotective agent in reducing hematological complications of radiotherapy among a population of patients with gastric cardia and esophageal cancers. Our findings revealed that there was a significant reduction in thrombocytopenia in the famotidine group compared to placebo group. Moreover, the lymphocyte and platelet counts were also significantly different between famotidine and placebo groups after four weeks.In a study conducted by Razzaghdoust et al., the effect of famotidine (80 mg/day) as a radioprotective agent on rectal mucosa was evaluated in a group of prostate cancer patients treated with radiotherapy [Consistent with the results of our study, it was previously shown that among a population of prostate cancer patients undergoing radiation therapy, famotidine had a significant impact on reducing lymphocytopenia caused by radiation therapy [Also in murine models, the significant role of famotidine as a radioprotector has been observed [In another murine study, radioprotective effect of vitamin C and famotidine has been indicated, as they could significantly decrease cytotoxic effect of radiation on spermatogenesis in mice by probable mechanism of radical scavenging [With regard to the reduction in the number of hematological cells as a result of irradiation therapy, apoptosis has been revealed to be the main culprit. Being a strong scavenger of In another study antioxidation and immunomodulation have been proposed as influential mechanisms of cimetidine radioprotective effects [One of the consequences of DNA damage and repair is micronucleus formation. The number of micronucleated cells represents the cytogenetic damage caused by X-irradiation. Cimetidine was found to have a dose-dependent protective significant effect against radiation-induced micronucleus formation in human peripheral blood lymphocytes [In an experimental study to assess a combination of melatonin and famotidine as radioprotectors, Samei et al. has concluded that the radioprotective effect of combined famotidine and melatonin was the same as famotidine alone. However, famotidine has been shown to be a good radioprotective agent for normal tissue, its accretion in tumor tissues may cause a reduction in the efficacy of radiotherapy. What’s more, the results of the 2,2-diphenylpicrylhydrazyl (DPPH) assay, has demonstrated that famotidine did not have any antioxidant capacity and the 20 µg/ml and 40 µg/ml concentrations did not differ significantly. Even so, the 80 µg/ml dose of famotidine was significantly different from other doses [A dose of 5 mg/kg for famotidine was suggested to be significantly effective before 4 Gy irradiation, resulting in approximately 50% reduction in DNA damage in vivo in mouse leukocytes [It has been shown in another study that with regard to radioprotective role, famotidine alone can be as effective as it is in combination with other drugs [A DRF of 1.5–2 has been previously reported for cimetidine, ranitidine and famotidine. All three drugs were revealed to significantly decrease the frequency of radiation-induced micronuclei and chromosomal abnormalities at different doses. However, famotidine was shown to be significantly more effective compared to either cimetidine or ranitidine [ | PMC10199581 |
Conclusion | cancer, thrombocytopenia | CANCER, THROMBOCYTOPENIA | Our findings proved that famotidine was an effective radioprotector in terms of the lymphocyte and platelet counts, so that at the end of the study patients in famotidine group showed significantly higher frequencies of lymphocytes and platelets. Besides, in the famotidine group, a significant reduction in thrombocytopenia was observed. To the best of the author’s knowledge, there is a small number of studies to assess famotidine as a radioprotector, most of which are in vivo. Therefore, drawing a favorable comparison between the existing evidence and the results we secured in this study is somewhat difficult. We recommend conducting further research studies and clinical trials in various cancer patient populations using different doses of famotidine or a combination of radioprotective agents to suggest an optimum dose and provide more information about the possible side effects of such drugs in different populations and conditions. | PMC10199581 |
Acknowledgements | Not applicable. | PMC10199581 |
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Author contributions | ZKM, OY, AZ, and AS designed the study. ZKM, OY and MR provided the data and performed data analyses and quality control. ZKM supervised the study. MR conducted the statistical analysis. MR wrote the main manuscript text. MR prepared all figures. ZKM takes responsibility for the paper as a whole. All authors reviewed the manuscript. | PMC10199581 |
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Funding | This study was performed without funding. | PMC10199581 |
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Availability of data and materials | The datasets used and analyzed during the current study are available from the corresponding author on reasonable request. | PMC10199581 |
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Declarations | PMC10199581 |
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Ethics approval and consent to participate | This study was conducted in compliance with the Declaration of Helsinki and guidelines on Good Clinical Practice and was conducted with the approval of the Ethics Committee of Zanjan University of Medical Sciences [IR.ZUMS.REC.1399.158], and a written informed consent was obtained from all participants. | PMC10199581 |
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Consent for publication | Not applicable. | PMC10199581 |
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Competing interests | The authors declare that they have no competing interests. | PMC10199581 |
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References | PMC10199581 |
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Key Points | PMC10698621 |
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Question | colorectal cancer | COLORECTAL CANCER, LIVER METASTASES | Is microsatellite-stable or mismatch repair–proficient advanced colorectal cancer with liver metastases (LM) resistant to immune checkpoint inhibitors? | PMC10698621 |
Findings | DISEASE, SECONDARY | In this secondary analysis of a randomized clinical trial of 180 patients, those without LM had significantly improved progression-free and overall survival. In patients without LM, durvalumab and tremelimumab treatment was associated with improved progression-free survival and disease control rate, not overall survival. | PMC10698621 |
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Meaning | colorectal cancer | LIVER METASTASIS, COLORECTAL CANCER, SECONDARY | Future clinical trials of immune checkpoint inhibitors in microsatellite-stable or mismatch repair–proficient advanced colorectal cancer should stratify patients according to the presence of LM and focus on understanding the mechanism of resistance by LM.This secondary analysis of a randomized clinical trial investigates whether the presence of liver metastasis is an indicator of treatment resistance to immune checkpoint inhibitors (ICIs) in patients with advanced colorectal cancer. | PMC10698621 |
Importance | COLORECTAL CANCER, LIVER METASTASES | Immune checkpoint inhibitors (ICIs) have limited activity in microsatellite-stable (MSS) or mismatch repair–proficient (pMMR) colorectal cancer. Recent findings suggest the efficacy of ICIs may be modulated by the presence of liver metastases (LM). | PMC10698621 |
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Objective | COLORECTAL CANCER | To investigate the association between the presence of LM and ICI activity in advanced MSS colorectal cancer. | PMC10698621 |
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Design, Setting, and Participants | treatment-refractory colorectal cancer, Cancer | SECONDARY, CANCER | In this secondary analysis of the Canadian Cancer Trials Group CO26 (CCTG CO.26) randomized clinical trial, patients with treatment-refractory colorectal cancer were randomized in a 2:1 fashion to durvalumab plus tremelimumab or best supportive care alone between August 10, 2016, and June 15, 2017. The primary end point was overall survival (OS) with 80% power and 2-sided α = .10. The median follow-up was 15.2 (0.2-22.0) months. In this post hoc analysis performed from February 11 to 14, 2022, subgroups were defined based on the presence or absence of LM and study treatments. | PMC10698621 |
Intervention | Durvalumab plus tremelimumab or best supportive care. | PMC10698621 |
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Main Outcomes and Measures | tumor, death | REGRESSION, TUMOR, SECONDARY, DISEASE | Hazard ratios (HRs) and 90% CIs were calculated based on a stratified Cox proportional hazards regression model. Plasma tumor mutation burden at study entry was determined using a circulating tumor DNA assay. The primary end point of the study was OS, defined as the time from randomization to death due to any cause; secondary end points included progression-free survival (PFS) and disease control rate (DCR). | PMC10698621 |
Results | Of 180 patients enrolled (median age, 65 [IQR, 36-87] years; 121 [67.2%] men; 19 [10.6%] Asian, 151 [83.9%] White, and 10 [5.6%] other race or ethnicity), LM were present in 127 (70.6%). For patients with LM, there was a higher proportion of male patients (94 of 127 [74.0%] vs 27 of 53 [50.9%]; | PMC10698621 |
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Conclusions and Relevance | colorectal cancer | SECONDARY, LIVER METASTASES, COLORECTAL CANCER | In this secondary analysis of the CCTG CO.26 study, the presence of LM was associated with worse outcomes for patients with advanced colorectal cancer. Patients without LM had improved PFS and higher DCR with durvalumab plus tremelimumab. Liver metastases may be associated with poor outcomes of ICI treatment in advanced colorectal cancer and should be considered in the design and interpretation of future clinical studies evaluating this therapy. | PMC10698621 |
Introduction | cancer, deaths, Colorectal cancer, colorectal cancer | CANCER, COLORECTAL CANCER, COLORECTAL CANCER, METASTATIC DISEASE | Colorectal cancer is the third most commonly diagnosed cancer and the second leading cause of cancer-related mortality worldwide. In 2020, approximately 1.93 million patients were diagnosed with colorectal cancer, resulting in 935 000 deaths.Recent findings suggest that advanced colorectal cancer with metastatic disease in the liver may be resistant to ICI treatment. For example, Fakih et al | PMC10698621 |
Methods | treatment-refractory, colorectal cancer, death, Cancer | COLORECTAL CANCER, CANCER | The Canadian Cancer Trials Group (CCTG) CO.26 study is a phase 2 study that randomized 180 patients with treatment-refractory advanced colorectal cancer unselected for MSI status to durvalumab, an antibody against programmed death ligand 1, plus tremelimumab, an antibody against the cytotoxic T-cell lymphocyte antigen-4 or best supportive care (BSC) in a 2:1 fashion between August 10, 2016, and June 15, 2017. | PMC10698621 |
Statistical Analysis | tumor | REGRESSION, SECONDARY, TUMOR | For this retrospective secondary analysis performed from February 11 to 14, 2022, patients were divided into groups based on the presence or absence of LM and study treatments. Cohorts with and without LM were based on radiological findings at the time of study entry. Plasma tumor mutation burden (pTMB) was determined from blood samples collected prior to study therapy using a circulating tumor DNA assay (GuardantOMNI next-generation sequencing panel; Guardant Health Inc) and reported as mutations per megabase (Mb). Overall survival and PFS were analyzed according to intention to treat. Hazard ratios (HRs) and 90% CIs were calculated based on a stratified Cox proportional hazards regression model. A Cochran-Mantel-Haenszel test was used for the interaction in DCR among study groups. The presence of LM was assessed as a potential factor associated with OS, PFS, and DCR benefits using a test of interaction between treatment groups and the presence or absence of LM. Proportions between groups were compared with χ | PMC10698621 |
Results | A total of 180 patients were enrolled and randomized, with 119 patients in the durvalumab plus tremelimumab group and 61 in the BSC group. The median age was 65 years (range, 36-87 years); there were 121 men (67.2%) and 59 women (32.8%). In terms of race and ethnicity, 19 patients (10.6%) were Asian, 151 (83.9%) were White, and 10 (5.6%) were of other race or ethnicity. At the time of study entry, LM were present in 127 patients (70.6%), including 80 of 119 (67.2%) in the durvalumab plus tremelimumab group and 47 of 61 (77.0%) in the BSC group ( | PMC10698621 |
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Study Flow Diagram | PMC10698621 |
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Baseline Characteristics of the Intention-to-Treat Population | tumor | ONCOLOGY, TUMOR, LIVER METASTASES | Abbreviations: ECOG, Eastern Cooperative Oncology Group; EGFR, epidermal growth factor receptor; LM, liver metastases.Unless otherwise indicated, data are expressed as No. (%) of patients.Includes American Indian or Alaska Native, Black, Native Hawaiian or Other Pacific Islander, and unknown race or ethnicity.Scores range from 0 to 5, with lower scores indicating fewer restrictions in daily activity.Plasma tumor mutation burden was higher in patients with LM than in those without LM (median, 19.2 [IQR, 11.5-30.6] vs 12.3 [IQR, 7.7-20.6] mutations/Mb; Among patients randomized to BSC, the median OS was 3.61 (90% CI, 3.15-4.47) months for patients with LM and 4.98 (90% CI, 1.91-9.00) for patients without LM. For patients in the durvalumab plus tremelimumab group, the median OS was 5.39 (90% CI, 3.81-6.24) months for patients with LM and 9.43 (90% CI, 7.39-10.18) months for patients without LM ( | PMC10698621 |
Univariate Analysis of OS and PFS by Treatment and Presence of LM | DISEASE, LIVER METASTASES | Abbreviations: DCR, disease control rate; HR, hazard ratio; LM, liver metastases; NA, not applicable; OR, odds ratio; OS, overall survival; PFS, progression-free survival. | PMC10698621 |
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Survival by Treatment Groups and Presence of Liver Metastases | Error bars indicate 90% CIs. BSC indicates best supportive care.On univariable analysis, there were no differences in OS between the durvalumab plus tremelimumab and BSC groups, regardless of LM, and a test of interaction was negative. Progression-free survival was improved with in the durvalumab plus tremelimumab group among patients without LM (HR, 0.54 [90% CI, 0.35-0.96]; | PMC10698621 |
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Subgroup Analysis of Overall Survival (OS) and Progression-Free Survival (PFS) in Multivariable Analysis | tumor | TUMOR | BSC indicates best supportive care; HR, hazard ratio; pTMB, plasma tumor mutation burden. | PMC10698621 |
Discussion | colorectal cancer, small-cell lung cancer, melanoma | COLORECTAL CANCER, MELANOMA, MULTIPLE CANCER, MALIGNANT NEOPLASM, MALIGNANT NEOPLASMS, METASTATIC DISEASE, HEPATOCELLULAR CARCINOMA AND CHOLANGIOCARCINOMA, METASTATIC DISEASE | Metastatic disease involving the liver is common in advanced solid malignant neoplasms. The proportion of patients with LM is particularly high in advanced colorectal cancer, with approximately 70% having liver involvement either alone or in combination with other sites of metastatic disease.The presence of LM is associated with unfavorable outcomes in multiple cancers.In addition to ICIs, the presence of LM may confer resistance to other immune-modulating agents. El-Khoueiry et alPatients with LM have been reported to respond poorly to ICIs in other solid malignant neoplasms such as melanoma and non–small-cell lung cancer,Although pTMB was significantly higher in patients with LM, there were no significant differences in alterations of genes commonly found in advanced colorectal cancer other than Recently, ICIs have shown significant efficacy and changed the treatment landscapes in hepatocellular carcinoma and cholangiocarcinoma.Previous reports of the lack of efficacy of ICIs in patients with LM and advanced colorectal cancer are from single-arm phases 1 and 2 studies | PMC10698621 |
Limitations | This study has some limitations. Our analysis was unplanned and exploratory in nature. Additionally, it had limited statistical power because there were only 53 patients without LM. Studies reporting differential impact with regard to the presence of LM are heterogeneous. It is possible that different ICIs may have different activity levels and our findings may be specific to durvalumab plus tremelimumab. | PMC10698621 |
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Conclusions | LMs | SECONDARY, LIVER METASTASES, COLORECTAL CANCER | In this secondary analysis of the CCTG CO.26 trial, LMs were associated with worse survival outcomes among patients with advanced colorectal cancer. Liver metastases should be considered in the design and interpretation of future clinical studies evaluating ICI therapy. | PMC10698621 |
Abstract | PMC9991501 |
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Objective | advanced/unresectable, cancer, death | CANCER | First-line pembrolizumab with/without chemotherapy versus chemotherapy was evaluated in programmed death ligand 1 combined positive score ≥1, locally advanced/unresectable or metastatic gastric cancer/gastrooesophageal junction cancer in the KEYNOTE-062 study. We present results for patients enrolled in Asia. | PMC9991501 |
Methods | SECONDARY | Eligible patients were randomly assigned 1:1:1 to pembrolizumab 200 mg, pembrolizumab plus chemotherapy (cisplatin + 5-fluorouracil or capecitabine) or placebo plus chemotherapy Q3W. End points included overall survival (primary) in combined positive score ≥1 and combined positive score ≥10 populations and safety and tolerability (secondary). | PMC9991501 |
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Results | A total of 187 patients were enrolled in Asia (pembrolizumab, | PMC9991501 |
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Conclusions | death, cancer/gastrooesophageal junction cancer | This post hoc analysis showed pembrolizumab monotherapy was associated with numerically improved overall survival and a favourable tolerability profile versus chemotherapy in Asians with programmed death ligand 1–positive advanced gastric cancer/gastrooesophageal junction cancer.This study is registered with Subgroup analysis of patients enrolled in Asia in the KEYNOTE-062 study showed first-line pembrolizumab versus chemotherapy improved overall survival and had a favourable tolerability profile in programmed death ligand 1–positive advanced gastric cancer/gastrooesophageal junction cancer. | PMC9991501 |
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Introduction | Gastric cancer, death, gastrooesophageal junction cancer, cancer, cancer death, advanced/metastatic, GEJC | GASTRIC CANCER, GASTROOESOPHAGEAL JUNCTION CANCER, CANCER | Gastric cancer (GC) and gastrooesophageal junction cancer (GEJC) is the fifth most frequently diagnosed cancer and the third leading cause of cancer death globally (The standard of care for the 85% of patients with unresectable, locally advanced/metastatic GC/GEJC in Asia is doublet or triplet fluoropyrimidine- and platinum-based chemotherapy in the first-line treatment setting (The anti–programmed death 1 (PD-1) monoclonal antibody pembrolizumab first demonstrated antitumour activity in previously untreated and treated patients with GC/GEJC in the multicohort phase 2 KEYNOTE-059 study (Given the differences in median OS and in regional use of second-line chemotherapy, we conducted a post hoc subgroup analysis to further describe the efficacy and safety of pembrolizumab (with or without chemotherapy) compared with chemotherapy alone in patients with GC/GEJC who were enrolled in Asia in the KEYNOTE-062 study. | PMC9991501 |
Material and methods | PMC9991501 |
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Trial design, patients and treatment | Full details of the phase 3 KEYNOTE-062 study (All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1964 and later versions. The study protocol and all amendments were approved by the appropriate ethics committee at each centre. The study was conducted in accordance with the protocol, its amendments, and standards of Good Clinical Practice. All patients provided written informed consent. | PMC9991501 |
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Assessments and outcomes | Tumour, tumour, Cancer | ADVERSE EVENT, TUMOUR, ADVERSE EVENT, TUMOUR, INFUSION REACTION, CPS, CANCER | Tumour responses were assessed using Response Evaluation Criteria in Solid Tumours, version 1.1 (RECIST v1.1), by blinded independent central review (BICR) every 6 weeks. Adverse events were assessed throughout the study and at 30 days after treatment discontinuation (90 days for serious AEs and immune-mediated AEs and infusion reactions) and were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (version 4.0). PD-L1 expression was centrally assessed during screening using PD-L1 IHC 22C3 pharmDx (Agilent) and was scored using CPS (the number of PD-L1–staining cells [tumour cells, lymphocytes, macrophages] divided by the total number of viable tumour cells, multiplied by 100).The current analysis evaluated OS, progression-free survival (PFS), objective response rate (ORR) and duration of response (DOR) based on BICR assessment per RECIST v1.1 in patients with PD-L1 CPS ≥1 (intention-to-treat population) and in patients with PD-L1 CPS ≥10. Safety and tolerability were also evaluated. | PMC9991501 |
Statistical analysis | Efficacy was evaluated in all randomly assigned patients in Asia and safety was evaluated in all randomly assigned patients in Asia who received ≥1 dose of study treatment. OS, PFS and DOR were estimated using the nonparametric Kaplan–Meier method and rules for censoring, and between-arm differences in OS and PFS were assessed using a log-rank test. A Cox proportional hazards model with the Efron method of handling ties was used to estimate hazard ratios (HRs) and associated 95% confidence intervals (CIs). Statistical comparisons for efficacy were not performed. The data cut-off date for this analysis was 26 March 2019. | PMC9991501 |
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Results | PMC9991501 |
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Patients | MAY | Between 18 September 2015, and 26 May 2017, 763 patients (pembrolizumab, Baseline characteristics of patients enrolled in Asia in the KEYNOTE-062 study
| PMC9991501 |
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Efficacy—pembrolizumab monotherapy versus chemotherapy | death | CPS | In the PD-L1 CPS ≥1 population, median OS was 22.7 months (95% CI, 14.3–28.5) with pembrolizumab versus 13.8 months (95% CI, 10.5–16.9) with chemotherapy (HR, 0.54; 95% CI, 0.35–0.82) (Kaplan–Meier estimates of overall survival for patients enrolled in Asia in the KEYNOTE-062 study. Pembrolizumab monotherapy versus chemotherapy in the (A) programmed death ligand 1 (PD-L1) combined positive score (CPS) ≥1 population and the (B) PD-L1 CPS ≥10 population. Pembrolizumab plus chemotherapy versus chemotherapy in the (C) PD-L1 CPS ≥1 population and the (D) PD-L1 CPS ≥10 population. HR, hazard ratio and NE, not estimable.In the PD-L1 CPS ≥1 population, median PFS was 4.1 months (95% CI, 2.2–7.2) with pembrolizumab versus 6.5 months (95% CI, 4.2–7.1) with chemotherapy (HR, 1.11; 95% CI, 0.76–1.64) (Kaplan–Meier estimates of progression-free survival for patients enrolled in Asia in the KEYNOTE-062 study. Pembrolizumab monotherapy versus chemotherapy in the (A) PD-L1 CPS ≥1 population and the (B) PD-L1 CPS ≥10 population. Pembrolizumab plus chemotherapy versus chemotherapy in the (C) PD-L1 CPS ≥1 population and the (D) PD-L1 CPS ≥10 population.In the PD-L1 CPS ≥1 population, 14 of 62 patients (22.6%) who received pembrolizumab versus 23 of 61 (37.7%) who received chemotherapy had an objective response, with complete responses in 4 of 62 patients (6.5%) versus 3 of 61 (4.9%), respectively (Response summary for patients enrolled in Asia in the KEYNOTE-062 study by PD-L1 CPS cut-off | PMC9991501 |
Efficacy—pembrolizumab plus chemotherapy versus chemotherapy | CPS | In the PD-L1 CPS ≥1 population, median OS was 16.5 months (95% CI, 12.8–19.6) with pembrolizumab plus chemotherapy versus 13.8 months (95% CI, 10.5–16.9) with chemotherapy (HR, 0.78; 95% CI, 0.53–1.16) (In the PD-L1 CPS ≥1 population, median PFS was 8.5 months (95% CI, 7.0–10.3) with pembrolizumab plus chemotherapy versus 6.5 months (95% CI, 4.2–7.1) with chemotherapy (HR, 0.64; 95% CI, 0.44–0.94) ( | PMC9991501 |
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Safety—all treatment arms | ADVERSE EVENTS | Treatment-related AEs occurred in 35 of 62 (56.5%), 62 of 62 (100%), and 53 of 57 patients (93.0%) receiving pembrolizumab, pembrolizumab plus chemotherapy and chemotherapy, respectively (Treatment-related adverse events
| PMC9991501 |
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Discussion | tumours, cancers, death | CPS, CANCERS, TUMOURS | In this subpopulation analysis of the phase 3 KEYNOTE-062 trial, first-line pembrolizumab monotherapy was associated with numerically improved OS compared with chemotherapy for patients enrolled in Asia with PD-L1–positive GC/GEJC. A greater benefit was observed with pembrolizumab monotherapy in this subgroup analysis compared with the overall KEYNOTE-062 study population, where OS with pembrolizumab monotherapy was found to be noninferior to chemotherapy in patients with PD-L1 CPS ≥1 but associated with longer OS in patients with PD-L1 CPS ≥10 (Longer survival times were expected in this analysis because Asian ethnicity, and residing in Asia, are favourable prognostic factors for patients with GC (PFS outcomes for patients enrolled in Asia were also similar to the overall study population for patients receiving chemotherapy, but the median PFS for patients receiving pembrolizumab plus chemotherapy was better for patients enrolled in Asia than the overall study population, especially amongst patients with PD-L1 CPS ≥10. Furthermore, no difference was apparent between treatment arms. However, more objective responses were achieved with pembrolizumab plus chemotherapy. Objective response rate amongst patients randomly assigned to receive pembrolizumab also appeared to be higher in the PD-L1 CPS ≥10 population, which is consistent with the overall population in KEYNOTE-062, as well as observations made in the KEYNOTE-061 study of second-line pembrolizumab monotherapy (The incidence of treatment-related AEs was also similar in this analysis compared to the overall study population analysis, with substantially lower rates observed in the pembrolizumab monotherapy arm. This finding suggests a treatment option for previously untreated patients who may be suitable candidates for chemotherapy; there is concern, however, regarding potential AEs, especially given that AEs occurring with chemotherapy may be more likely to occur in individuals from East Asian countries compared with individuals from Western countries (The role of pembrolizumab in the treatment of advanced GC remains to be determined; however, the current analysis adds to the existing body of evidence and is especially informative because GC is one of the most commonly diagnosed cancers and is a leading cause of death in Asia (Ongoing studies in the first-line treatment setting are evaluating pembrolizumab plus chemotherapy (KEYNOTE-859; NCT03675737) and pembrolizumab plus trastuzumab and chemotherapy (KEYNOTE-811; NCT03615326) and will provide additional support for the efficacy and safety of pembrolizumab in patients with GC/GEJC, including patients enrolled in Asia.In conclusion, although statistical comparisons were not conducted, this subpopulation analysis of data for patients enrolled in Asia in the KEYNOTE-062 study indicates that pembrolizumab monotherapy was associated with numerically improved OS outcomes compared with chemotherapy alone for patients with advanced GC/GEJC with PD-L1 CPS ≥1 and CPS ≥10 tumours. Pembrolizumab monotherapy was also associated with a favourable tolerability profile compared with chemotherapy, which is consistent with observations from the overall KEYNOTE-062 study population. | PMC9991501 |
Abbreviations | PD, death, MSI-H | VIRUS, DISEASE, MICROSATELLITE INSTABILITY, EPSTEIN, ADVERSE EVENT, ONCOLOGY, CPS, GASTROOESOPHAGEAL JUNCTION CANCER, GASTRIC CANCER | BICR, blinded independent central review; CPS, combined positive score; CR, complete response; DOR, duration of response; EBV, Epstein–Barr virus; ECOG PS, Eastern Cooperative Oncology Group performance status; ERBB2, Erb-B2 receptor tyrosine kinase 2; GC, gastric cancer; GEJC, gastrooesophageal junction cancer; HER2, human epidermal growth factor receptor 2; ITT, intention to treat; MSI, microsatellite instability; MSI-H, high microsatellite instability; ORR, objective response rate; OS, overall survival; PD, progressive disease; PD-1, programmed death 1; PD-L1, programmed death ligand 1; PFS, progression-free survival; PR, partial response; Q3W, every 3 weeks; SD, stable disease; SOC, standard of care; TRAE, treatment-related adverse event | PMC9991501 |
Authors’ contribution | Shinichi, Jen-Shi | Conception, design or planning of the study: Yee Chao, Shi Rong Han, Shinichi Shiratori, Sukrut Shah and Kohei ShitaraAcquisition of data: Hironaga Satake, Keun-Wook Lee, Hyun Cheol Chung, Jeeyun Lee, Jen-Shi Chen, Takaki Yoshikawa, Kenji Amagai, Kun-Huei Yeh, Masahiro Goto, Yee Chao, Ka-On Lam and Kohei ShitaraAnalysis of data: Kensei Yamaguchi, Ka-On Lam and Shi Rong HanInterpretation of the results: Hironaga Satake, Keun-Wook Lee, Hyun Cheol Chung, Jen-Shi Chen, Takaki Yoshikawa, Yee Chao, Ka-On Lam, Sukrut Shah and Kohei ShitaraDrafting of the manuscript: Hironaga Satake and Kohei ShitaraCritically reviewing or revising of the manuscript for important intellectual content: Hironaga Satake, Keun-Wook Lee, Hyun Cheol Chung, Jeeyun Lee, Kensei Yamaguchi, Jen-Shi Chen, Takaki Yoshikawa, Kenji Amagai, Kun-Huei Yeh, Masahiro Goto, Yee Chao, Ka-On Lam, Shi Rong Han, Shinichi Shiratori, Sukrut Shah and Kohei ShitaraFinal approval of the version to be published: All authors. | PMC9991501 |
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Disclosures | Jen-Shi | ONCOLOGY, EVENTS, CROSS | Hironaga Satake reports research funding paid to his institution from Ono Pharmaceutical Co Ltd, Daiichi Sankyo and Taiho Pharmaceutical Co Ltd, and honoraria for lectures from Bristol Myers Squibb Co., Ltd., Bayer Co., Ltd., Chugai Pharmaceutical Co., Ltd, Daiichi Sankyo Co., Ltd., Eli Lilly Japan Co., Ltd., MSD Co., Ltd., Ono Pharmaceutical Co., Ltd., Sanofi Co., Ltd., Taiho Pharmaceutical Co., Ltd., Takeda Co., Ltd. and Yakult Honsha Co., Ltd.Keun-Wook Lee reports grants paid to his institution for conducting clinical trials from Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, AstraZeneca, Ono Pharmaceutical Co., Ltd., Merck KGaA, Pfizer, BeiGene, Astellas Pharma, ALX Oncology, Zymeworks, Macrogenics, Five Prime Therapeutics, Seagen, Bolt Therapeutics, Trishula Therapeutics, Oncologie, Pharmacyclics, LSK BioPharma, MedPacto, Green Cross Corp, ABLBIO, Y-BIOLOGICS, Genexine, Daiichi Sankyo, Taiho Pharmaceutical, InventisBio, Leap Therapeutics and Solasia; and personal fees from ISU ABXIS, Bayer, Daiichi Sankyo, Merck Sharp and Dohme, Bristol Myers Squibb, Vifor Pharma for consultation and Ono Pharmaceutical Co., Ltd., and Boryung for honoraria.Hyun Cheol Chung reports consulting fees from Taiho, Celltrion, MSD, Eli Lilly, Bristol Myers Squibb, Merck Serono, Gloria, Beigene, Amgen and Zymework; honoraria from Merck-Serono and Eli Lilly; and that his institution received grants from Eli Lilly, GSK, MSD, Merck Serono, Bristol Myers Squibb, Ono Pharmaceutical Co., Ltd., Taiho, Amgen, Beigene, Incyte and Zymework.Jeeyun Lee reports no conflicts of interest.Kensei Yamaguchi reports receiving payment or honoraria from Taiho Pharm, Daiichi Sankyo, Eli Lilly Japan, Ono Pharmaceutical Co., Ltd., and Bristol Myers Squibb.Jen-Shi Chen reports no conflicts of interest.Takaki Yoshikawa reports lecture fees from Bristol Myers Squibb, MSD, Ono Pharmaceutical Co., Ltd., Taiho, Daiichi Sankyo, Lilly, Otsuka, Terumo, Covidien, EA Pharma, and AstraZeneca.Kenji Amagai reports research funding from MSD, Taiho Pharmaceutical, Daiichi Sankyo, Nippon Zoki Pharmaceutical and Hisamitsu Pharmaceutical.Kun-Huei Yeh reports no conflicts of interest.Masahiro Goto reports receiving grants or contracts from Chugai Pharma, Nippon Kayaku and Taiho Pharmaceutical; and fees or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Daiichi Sankyo Company, Limited, Ono Pharmaceutical Co., Ltd., Taiho Pharmaceutical, MSD K.K., Takeda Pharmaceutical Company Limited, Sumitomo Dainippon Pharma Co., Ltd., Yakult Pharmaceutical Industry Co., Ltd. and Eli Lilly Japan K.K.Yee Chao reports no conflicts of interest.Ka-On Lam reports receiving support from MSD; honoraria for lecturing and speaker bureaus from MSD, Bristol Myers Squib, Eli Lilly, Novartis, Bayer, Daiichi Sankyo, AstraZeneca, Merck, Amgen, Taiho, Sanofi; and serving as an advisory board member for MSD, Bristol Myers Squibb, Eli Lilly, Novartis, Bayer, Daiichi, Sankyo, AstraZeneca, Merck and Amgen.Shi Rong Han is an employee of MSD K.K., Tokyo, Japan.Shinichi Shiratori is an employee of and a stockholder in MSD K.K., Tokyo, Japan.Sukrut Shah is an employee of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA and has stock in Merck & Co., Inc., Rahway, NJ, USA.Kohei Shitara reports employment/leadership position/advisory roles with Takeda, Pfizer, Ono Pharmaceutical Co., Ltd., MSD, Taiho Pharmaceutical, Novartis, AbbVie, GlaxoSmithKline, Daiichi Sankyo, Amgen, Boehringer Ingelheim; honoraria from Takeda and Bristol Myers Squibb; and research funding from Astellas, Ono Pharmaceutical Co., Ltd., Daiichi Sankyo, Taiho Pharmaceutical, Chugai, MSD, Medi Science, Eisai and Amgen. | PMC9991501 |
Data sharing | Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA (MSD) is obligated to protect the rights and privacy of trial participants. To fulfil the company’s obligation, MSD has a procedure in place for evaluating and fulfilling requests for sharing company clinical trial data with qualified external scientific researchers. As outlined on the MSD data sharing website (available at: | PMC9991501 |
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Funding | Funding for this study was provided by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA. Grant number not applicable. | PMC9991501 |
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Supplementary Material | Click here for additional data file.Click here for additional data file. | PMC9991501 |
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Acknowledgements | The authors thank the patients and their families and caregivers as well as the primary investigators and site personnel for participating in the study. Medical writing and/or editorial assistance was provided by Holly C. Cappelli, PhD, CMPP, of ApotheCom (Yardley, PA, USA). This assistance was funded by MSD K.K., Tokyo, Japan. | PMC9991501 |
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References | PMC9991501 |
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Background | strabismus | STRABISMUS, INTRAOCULAR PRESSURE | It is well-established that maintaining stable intraocular pressure (IOP) within the normal range during ophthalmic surgery is important. Esketamine is a commonly used drug in pediatric general anesthesia due to its good analgesic and sedative effects. However, its application in ophthalmic surgery is limited because it can increase IOP. The effect of esketamine combined with other common anesthetics on IOP has been underinvestigated. This study aimed to investigate the effect of different doses of esketamine combined with propofol and sufentanil on IOP during intravenous induction of general anesthesia for pediatric strabismus surgery. | PMC10426143 |
Methods | strabismus | STRABISMUS | A total of 181 children with strabismus undergoing unilateral eye surgery under general anesthesia were recruited. Intravenous induction included the use of sufentanil 0.1 µg/kg, propofol 3 mg/kg, and esketamine. Base on the dosage of esketamine, the patients were randomly allocated into three groups: esketamine low (EL) group with 0.25 mg/kg (n = 62), esketamine high (EH) group with 0.5 mg/kg (n = 60), and normal saline (NS) group (n = 59). Hemodynamic parameters, respiratory parameters, and IOP of the non-surgical eye were recorded and compared among the three groups at different time points: before induction (T | PMC10426143 |
Results | There were no significant differences in age, gender, body mass index (BMI), and respiratory parameters among the three groups at T | PMC10426143 |
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Conclusion | strabismus | STRABISMUS | Propofol combined with sufentanil significantly decreased IOP during the induction of general anesthesia. Although a dose of 0.5 mg/kg esketamine elevated IOP compared to the low-dose and control groups after induction, the IOP remained lower than baseline. 0.25 mg/kg esketamine combined with propofol and sufentanil had little effect on IOP. Therefore, we advocate that a maximum dose of 0.5 mg/kg esketamine combined with propofol and sufentanil will not elevate IOP compared to baseline in pediatric strabismus surgery. | PMC10426143 |
Trial registration | The registration number is ChiCTR2200066586 at Chictr.org.cn. Registry on 09/12/2022. | PMC10426143 |
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Keywords | PMC10426143 |
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Introduction | sudden increase, Strabismus, retinal detachment, choroidal edema, nausea, vomiting | STRABISMUS, PROLAPSE, CENTRAL RETINAL ARTERY OCCLUSION, LOW INTRAOCULAR PRESSURE, COMPLICATIONS, RETINAL DETACHMENT, DISEASES, INTRAOCULAR PRESSURE | Stable intraocular pressure is beneficial for maintaining the shape and function of the eyeball, essential for the prognosis of patients undergoing ophthalmic surgery or those with ophthalmic diseases. The sudden increase in intraocular pressure during the induction period can lead to nausea, vomiting, central retinal artery occlusion, and even prolapse of intraocular contents. Conversely, excessively low intraocular pressure can induce complications such as retinal detachment and choroidal edema [Strabismus surgery in children is often performed under general anesthesia, and the choice of induction medication can have different impacts on intraocular pressure [In clinical practice, esketamine is often used in combination with other anesthetic drugs (e.g., opioids, propofol, etc.) rather than being used alone [ | PMC10426143 |
Materials and methods | PMC10426143 |
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Study population | retinopathy, allergic, keratopathy, upper respiratory tract infection, strabismus, glaucoma | RETINOPATHY, UPPER RESPIRATORY TRACT INFECTIONS, KERATOPATHY, STRABISMUS, NEUROMUSCULAR DISEASE, GLAUCOMA, EYE | The institutional review board of Tianjin Eye Hospital approved this prospective, randomized, double-blind study, registered in the Chinese Clinical Trial Registry on 09/12/2022 (ChiCTR2200066586). Guardians of all participants signed informed consent after obtaining a detailed understanding of the study objectives, procedures, and potential risks.A total of 181 children with strabismus undergoing monocular surgery under general anesthesia were recruited at our hospital from December 2022 to February 2023. The inclusion criteria were as follows: (1) aged 7 to 12 years; (2) grade I or II in the American Society of Anesthesiologists (ASA) physical status classification. Patients were excluded if they (1) had a history of glaucoma, keratopathy, retinopathy, neuromuscular disease, difficult airway, or upper respiratory tract infection within 2 weeks before surgery; (2) were allergic to related general anesthesia or local anesthesia drugs, or had received medication affecting IOP within 2 days before surgery; (3) were unable to cooperate with IOP measurement under topical anesthesia before the induction of general anesthesia. More details are provided in Fig. | PMC10426143 |
Study methods | Using a random number table created by statisticians using SPSS statistical software, 181 patients were allocated into three groups: esketamine low (EL) group, esketamine high (EH) group, and normal saline (NS) group. All patients had routine fasting for 8 h and liquid fasting for 2 h before surgery. Penehyclidine hydrochloride 0.01 mg/kg was injected intramuscularly 30 min before anesthesia. After admission to the operating room, venous access was established, and noninvasive blood pressure (BP), electrocardiogram (ECG), and pulse oxygen saturation (SpO | PMC10426143 |
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Data collection | INTRAOCULAR PRESSURE | Preoperative general indicators included age, gender, weight, body mass index (BMI), and ASA classification. Systolic blood pressure (SBP), diastolic blood pressure (DBP), heart rate (HR), tidal volume (VT), PETCOThe primary outcome of this study is IOP. IOP at each time point was measured by a skilled ophthalmologist blinded to the group allocation. Before the induction of anesthesia, the patient’s eye was topically anesthetized with 2 drops of 2% lidocaine. The IOP was measured three times by Tono-Pen AVIA intraocular pressure meter (Tono-Pen AVIA, Reichert Technologies, Depew, NY, USA), and the mean values were taken. | PMC10426143 |
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