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Methods | PMC10257092 | |||
Data Acquisition | SECONDARY | This quantile treatment effects study is a secondary analysis of pooled participant data. We obtained aggregate data through personal correspondence with the authors of Stone et al, | PMC10257092 | |
Statistical Analysis | PMC10257092 | |||
Data Quality Testing and Processing | depression | To test data completeness, we compared the counts of treatment-assigned and placebo-assigned participants in the aggregate data we received against the values reported by Stone et al.From the data obtained, we calculated 2 candidate measures of depression response since both percentage and absolute depression response are commonly used in studies. | PMC10257092 | |
Testing Rank Similarity | depression | We separately tested for rank similarity using our 2 candidate measures of depression response. We used the rank similarity test of Frandsen and Lefgren | PMC10257092 | |
Quantile Treatment Effects | depression, QTE | We calculated each quantile of percentage depression response separately in the treatment and placebo arms, at quantiles from the 5th percentile to 95th percentile, in increments of 5%. The QTEs were calculated as the difference between percentage depression response in the treatment vs placebo arms at a given quantile. The QTE 95% CIs were calculated by bootstrapping, using 10 000 iterations of the basic algorithm from the ci_quantile_diff function of the Hmisc R package, version 4.7-1. The QTEs were graphically plotted without covariates using the ci_qtet function of the qte R package, version 1.3.1 (R Foundation for Statistical Computing). Significance testing was performed via paired, 2-sided tests, with a significance threshold of | PMC10257092 | |
Results | PMC10257092 | |||
Data Quality | depression | The aggregate data we received implied 71 393 participants, of whom 47 243 were assigned to drug and 24 150 to placebo. These values match the counts reported by Stone et al.There was a slight and statistically significant difference in mean baseline depression severity between drug and placebo arms equivalent to 0.15 points on the HAMD-17 scale ( | PMC10257092 | |
Testing Rank Similarity | depression | Since QTE analysis is most richly interpretable when rank similarity can be assumed, we tested whether our data and intended formulation were consistent with rank similarity. Following the method of Frandsen and Lefgren,Since there is not consensus in the literature about whether to define depression response as a percentage change from baseline as we have done vs an absolute change from baseline, we also tested for rank similarity using absolute change from baseline as the response variable. Under this alternative formulation, the interaction term between baseline depression severity and treatment arm in the model becomes significant ( | PMC10257092 | |
Quantile Treatment Effects | depression | Next, we characterized the estimated distribution of antidepressant response. We calculated the depression response distribution separately in treatment and control conditions ( | PMC10257092 | |
Distribution of Percentage Depression Response | depression | The distribution of percentage change of depression severity from baseline to trial end is depicted for each treatment arm. Error bars represent 95% CIs. | PMC10257092 | |
Quantile Treatment Effects of Antidepressants Compared With Placebo | depression | For each quantile (τ) of depression response, the difference between the treatment arm and placebo arm depression response at that quantile is shown, expressed as a percentage, along with its bootstrapped 95% CI. | PMC10257092 | |
QTEs at Selected Quantiles | QTE | Abbreviation: QTE, quantile treatment effect. | PMC10257092 | |
Discussion | MDD, depression | SECONDARY | We conducted a secondary analysis of pooled IPD from 232 randomized clinical trials submitted to the FDA for antidepressant monotherapy for MDD to characterize the distribution of antidepressant response by depression severity. We observed that the population distribution of depression responses was strictly superior in the treatment arm vs the placebo arm in this filtered data set of participants with severe baseline depression. All studied portions of the depression response distribution were at least as favorable in the treatment arm as in the placebo arm. The participants with the worst response receiving antidepressant treatment responded at least as favorably (in terms of percentage improvement in HAMD-17 scores) as the participants with the worst response receiving placebo. Likewise, the participants with the best response receiving antidepressant treatment responded at least as favorably as the participants with the best response receiving placebo, and similarly for everyone in between. The response was most pronounced in the center of the distribution. These observations do not depend on any special assumptions; they are a simple consequence of the raw quantile distributions of antidepressant treatment response.We did not observe violations of rank similarity in our data when using the percentage definition of depression response. In contrast, when we defined depression response in terms of absolute improvement from baseline, there was a formal violation of rank similarity, although the magnitude of that observed violation was small. Our ability to test for rank similarity was limited. For instance, we only had the data to test for the potentially rank-distorting influence of a single potential moderator of treatment effect and not several other potential moderators that have been reported in the literature, such as brain network and perfusion patterns.How should we interpret the fact that the middle of the quantile distribution is where the drug and placebo curves separate the most? Rank similarity permits the following interpretation: participants who would have had a typical, middling response to placebo (ie. a percentage change of HAMD-17 score from baseline to final response at or near the median of the distribution of placebo responses) stand to gain the most from active drug. In contrast, patients who would have had a robust response with placebo receive little additional benefit from active drug. Perhaps this is because those with a robust response to placebo need no further treatment. Similarly, nonresponders to placebo would have received little additional benefit from active drug. Perhaps this is because individuals who do not respond to placebo experience a particularly entrenched form of depression that also responds poorly to drugs.These findings are exploratory and would need to be confirmed through specialized placebo run-in trials with a prolonged run-in duration (eg, the 6 weeks of placebo tested herein) followed by randomization of all run-in period participants, in contrast to common placebo run-in practices.Our analysis does not directly contradict that of Stone et alAnalyses based on rank similarity tend to estimate response distributions as the broadest possible values that are consistent with the data. If rank similarity is only partly or approximately true, then the true distribution of antidepressant response would be more concentrated than the responses estimated herein. It would take a very large violation of rank similarity to arrive at responses as concentrated as those reported by Stone et al. | PMC10257092 |
Strengths and Limitations | depression | ADVERSE EFFECTS | A strength of this study is its use of FDA data, which include both published and unpublished high-quality randomized clinical trials and their pooled IPD. Another strength is that the population-level findings do not depend on any special assumptions.One limitation of the study is that individual-level findings depend on the rank similarity assumption, which is unproven. Other limitations include lack of associated data and therefore omitted analyses concerning adverse effects, long-term effects, demographic characteristic covariates, and study-specific information. The lack of study-specific information in particular means that we cannot account for between-study heterogeneity, which might otherwise affect the study-adjusted drug and placebo response curves and the magnitude of calculated QTEs. In keeping with other QTE analyses in the literature, we did not attempt an analysis of very finely resolved quantiles, such as the bottom 1% of the population.Moreover, although we do not consider our choice to exclude patients with less severe depression from the analysis as a limitation to the internal validity of our study, this choice potentially limits the generalizability of our results to patients with mild depression. That exclusion further limits direct comparison of our results with those of Stone et al. | PMC10257092 |
Conclusions | MDD, depression | Among participants with baseline HAMD-17 scores of 20 or higher from 232 FDA trials for antidepressant monotherapy for MDD, all segments of the distribution of depression responses were more favorable with active treatment vs control. These findings suggest that if our statistical assumptions hold, then there is the possibility that nearly all patients with MDD with baseline HAMD-17 scores of 20 or greater experience at least some benefit from antidepressant therapy, although the magnitude of the response is more clinically meaningful in some patients than others. If our assumptions are not met, it is also possible that the same aggregate benefit is concentrated in substantially fewer patients. Regardless, estimating the percentage of patients who benefit from antidepressant therapy is a challenging task that depends on the statistical assumptions used. | PMC10257092 | |
Purpose | above-the-knee, fractures | Different studies have shown that weightbearing is safe in stable transsyndesmotic, isolated lateral simple ankle fractures. Despite this evidence, AO guidelines still recommend immobilization with above-the-knee cast for 4–6 weeks for these fractures. The objective of this study was to compare the outcomes of mobilization and weightbearing to those of immobilization and non-weightbearing in patients with stable transsyndesmotic, lateral isolated simple ankle fractures. | PMC10771350 | |
Methods | fracture | Fifty patients were randomly assigned to permissive weightbearing in a walking boot or non-weightbearing immobilization using a below-the-knee cast. Primary outcome was ankle functionality as scored by the Olerud-Molander Ankle Score (OMAS). Secondary outcomes were radiological displacement of fracture, range of motion (ROM), calf circumference, and RAND 36-item health survey. Patients were in follow-up for 24 months. | PMC10771350 | |
Results | Ankle functionality after six and twelve weeks was significantly higher for the intervention group, with respectively 30 points ( | PMC10771350 | ||
Conclusion | fractures | Weightbearing and mobilization using a walking boot may be a safe treatment for patients with stable Weber B fractures. | PMC10771350 | |
Supplementary Information | The online version contains supplementary material available at 10.1007/s00590-023-03651-6. | PMC10771350 | ||
Keywords | PMC10771350 | |||
Introduction | PMC10771350 | |||
Background and objectives | thrombosis, fractures, traumatic injuries | THROMBOSIS, ADVERSE EFFECTS | Ankle fractures are common traumatic injuries requiring adequate management. In the USA, approximately 673.214 ankle fractures occurred between 2012 and 2016, with an incidence of 4.22/10.000 person-years [When patients are restricted to a prolonged period of immobilization, adverse effects regarding recovery, increased physical effort, and risk of thrombosis are observed [This study aims to compare mobilization and weightbearing using a walking boot to immobilization and non-weightbearing in a below-the-knee cast. Patients will be assessed based on functional, anatomical and health state outcomes. | PMC10771350 |
Patients and methods | PMC10771350 | |||
Trial design | ®, trauma | This randomized controlled trial was conducted in a high volume trauma center in [location blinded]. Interventional treatment consisted of six weeks of mobilization and weightbearing using a Rebound® walker, while the control group was designated to six weeks of immobilization and non-weightbearing with a below-the-knee cast. The study was conducted according to the CONSORT guidelines [ | PMC10771350 | |
Sample size calculation | We determined that a total of 46 patients would be required to provide a 80% power. With an effect size of 15 points of difference on the OMAS and a variance of 324 (square of SD in study by Dehghan et al.), 23 patients per group were required [ | PMC10771350 | ||
Participants | fracture, fractures, ankle injuries | HANSEN | From March 2018 to October 2019, patients aged ≥ 16 years old visiting the emergency department with an isolated Weber B fracture (Lauge Hansen supination-eversion stage 2-4A) were screened for eligibility. Patients were eligible for inclusion if non-weightbearing radiographs showed congruent ankle joint on mortise view (medial clear space < 6 mm and ≤ 1 mm wider than the superior clear space). Weightbearing radiographs (weightbearing and non-weightbearing) were acquired after one week. If the ankle was deemed stable after one week, informed consent was signed and patients were randomized. Patients showing a widened medial clear space (> 6 mm) on radiographs were excluded and underwent open reduction and internal fixation. Exclusion criteria were ankle injuries other than isolated Weber B fractures, bilateral fractures, delay in presentation of more than 14 days after injury, and contralateral amputation of upper leg, lower leg or foot. | PMC10771350 |
Randomization | RS | After written consent was obtained, patients were randomly appointed to the control or intervention group (1:1 ratio) by the investigators (SF, RS) using an online randomization tool, provided by ‘Researchmanager’ [ | PMC10771350 | |
Interventions | plaster | A cast below the knee was applied by a trained plaster technician in the non-weightbearing group. The cast was applied from a few centimeters below the tuberositas tibiae to the base of the toes. The ankle was fixed in a plantigrade position. Patients assigned to cast group were specifically instructed not to bear weight on the affected limb. If any cast-related complaints occurred during treatment, a new cast was fitted. The weightbearing group was fitted a walking boot (Rebound® Air Walker, Össur, Reykjavik, Iceland). These patients were instructed on permissive weightbearing and use of the walking boot. Instructions included the removal of the walking boot when not weightbearing to mobilize the affected ankle.Although recent studies suggest thromboprophylaxis is no longer indicated in permissive weightbearing [ | PMC10771350 | |
Outcome measures | Primary outcome measure was the Olerud-Molander Ankle Score (OMAS; ordinal scale 0–100 with intervals of 5 points, whereas lower scores indicate worse outcome) after six weeks to compare ankle functionality in both groups. The OMAS is a frequently used ankle functionality score based on patient-reported measures [ | PMC10771350 | ||
Follow-up | trauma | Physical follow-up was planned at week 0, and 6 and 12 weeks after trauma. After these visits, patients were instructed to contact the primary investigator in case of medical complaints. Patient files were checked both 12 months and 24 months after randomization. Patients were randomized in week 0. Radiological imaging evaluation was conducted in week 0 (weightbearing anteroposterior (AP) and non-weightbearing AP, lateral and mortise radiographs) and after six weeks (non-weightbearing AP, lateral and mortise radiographs). During every follow-up moment, physical examination (ROM, calf circumference) of the ankle was conducted, and patients were required to complete OMAS and RAND SF-36 questionnaire. | PMC10771350 | |
Statistical methods | All statistical analysis were performed using SPSS (IBM Corp. IBM SPSS Statistics for MacOS, Version 25.0, Armonk, NY, USA) and were conducted according to the intention-to-treat principle. In order to prevent type I errors, per-protocol analysis was also conducted. Every outcome measure was compared between the control and intervention arms of the study. If there was equal variance of continuous variables, independent samples T test was used. Mann–Whitney U test was performed for the remainder of continuous variables. Wilcoxon ranked test was used for the analysis of non-normally distributed dependent variables. SF-36 questionnaire results were translated to percental values using the Orthotoolkit SF-36 software [ | PMC10771350 | ||
Results | A total of 147 patients were eligible for inclusion. Fifty patients were randomized. Of these, 24 were randomized in the non-weightbearing group and 26 in the walking boot group. Weightbearing radiographs excluded 23 (15.6%) of 147 patients due to ankle joint instability. Twenty-two (14.9%) of 147 patients were not willing to participate. Other reasons for exclusion can be found in Fig. Flow diagram describing patient enrollment and randomization during this trial. *Different treatment initiated by surgeon: 3 weeks non-mobilization in a below-the-knee cast, followed by 3 weeks of mobilization using a below-the-knee castBaseline characteristics | PMC10771350 | ||
Fracture healing | callus, posttraumatic, fracture, fractures, trauma | Radiologic follow-up after six weeks showed no fracture displacement in any patients. All fractures showed signs of callus bridging of the fracture site after 6 weeks. For illustration: Figure Radiographs taken posttraumatic and after six weeks of permissive weightbearing. Image 1a and b were obtained 2 days after trauma for this patients. Lateral view (image | PMC10771350 | |
SF-36 | No statistical differences between both treatment groups were observed at baseline. There was however a statistical significant difference after six week in the intervention group compared to the control group (Table | PMC10771350 | ||
Harms | fracture, posttraumatic complex regional pain, pain | ADVERSE EVENTS, EVENTS | No serious adverse events where observed. In five patients, unintended events were registered. Four events were related to contingency hospitalization due to pre-existent medical conditions. In one case, a patient randomized to the cast group developed posttraumatic complex regional pain syndrome. No delay of fracture union was observed in this patient. This patient was referred to our specialized pain clinic and treated with amitriptyline after which she reached a pain-free state approximately one month after completion of follow-up. | PMC10771350 |
Discussion | fracture, dislocation, pain, fractures, atrophy | ATROPHY | Permissive weightbearing using a walking boot resulted in both better ankle function and health-related quality of life after six weeks when compared to non-weightbearing immobilization using a below-the-knee cast.This study is not the first to compare mobilization and weightbearing to immobilization and non-weightbearing [The comparison of calf circumference measurements between treatment groups did not yield any statistically significant differences at any of the follow-up intervals. It should be acknowledged that this study was not designed with sufficient statistical power to accurately determine the significance of any differences in calf circumference between groups. Therefore, it would be premature to draw definitive conclusions regarding the significance of any observed differences in calf circumference. However, when comparing the baseline and 6-week follow-up, a significant decrease in calf circumference was observed in the control group. After 12 weeks, patients in the control group no longer showed a difference in calf circumference when compared to baseline. These changes of the calf as observed during the follow-up were according to the expected outcome, as long-term immobilization causes adaptive changes including atrophy and loss of strength, which are reversible after physical training [At the time of the initiation of this study, the weightbearing radiograph was not standard practice in [location blinded]. Ankle joint stability was assessed in a non-weightbearing radiograph by measuring medial clear space and was deemed unstable if this was > 6 mm. With the intervention group mobilizing within 10 days after fracture, there was need for elimination of possible false positive stable fractures because of the possibility of dislocation after weightbearing. In this study, assessment of the stability of the ankle joint was performed through physical and radiological examination. Notably, a total of 23 patients (comprising 16% of the total screened patients) who had been deemed eligible for conservative treatment based on the non-weightbearing mortise assessment were subsequently excluded due to the detection of medial clear space widening on the weightbearing Mortise assessment. Images depicting the ankle of a patient were added as supplementary material. These images demonstrate the transition from a stable ankle joint, as observed in non-weightbearing radiographs, to an unstable joint, as evident in weightbearing radiographs.This study explores different aspects of fracture care in a randomized design, not only does it investigate ankle functionality after fracture, but it also aimed to explore quality of life differences between the intervention and control group. By using standardized outcome measures, we aimed to reduce the risk for detection bias.Unfortunately, the study encountered difficulties with regard to patient inclusion, as several patients declined to participate due to various reasons. These reasons included apprehension about mobilization and weightbearing, concerns about joint instability during mobilization, and general fears of pain. Furthermore, some patients who were deemed fit for inclusion by the study's supervising surgeon were ultimately excluded due to pre-existing immobility. Another limitation pertains to the measurement of ankle functionality after 6 weeks: while patients in both the control and intervention group were asked to complete the OMAS approximately 30 min after removal of the cast or walker, patients in the control group were immobilized for 6 weeks and those in the intervention group were allowed to remove the walker from time to time at home and engage in physical exercise. Although a direct comparison between the two groups may not be appropriate at this time as the intervention group has been mobilizing for 6 weeks, while the control group has not had this opportunity yet, the study was designed to assess the differences in outcomes after 6 weeks. Cast-related stiffness is a well-known consequence of immobilization as previous research has shown that functional recovery after casting may take up to 10 weeks after immobilization [ | PMC10771350 |
Conclusion | fractures | Permissive weightbearing using a walking boot seems a safe and viable treatment for patients with stable Weber B fractures with regard to ankle functionality. This study highlights the potential advantages of using a walking boot such as increased patient satisfaction, improved self-care, and faster return to work. | PMC10771350 | |
Author contributions | RVV | Conceptualization was done by SF and RVV; data curation was done by RCS, SF, and RVV; formal analysis was carried out by RCS, SF, and RVV; methodology was done by RCS and SF; supervision was done by RVV, EDL, BB, and BM; writing—original draft were done by RCS; writing—review and editing were done by RVV, BB, BM, and EDL. All authors have read and agreed to the published version of the manuscript. | PMC10771350 | |
Funding | No funding was acquired for this study. | PMC10771350 | ||
Data availability | Available upon request. | PMC10771350 | ||
Declarations | PMC10771350 | |||
Conflict of interest | The authors have no potential conflicts of interest. | PMC10771350 | ||
Ethical approval | This study was approved by the local medical ethical committee. | PMC10771350 | ||
Consent for publication | Consent for publication was given by the local medical ethical committee. | PMC10771350 | ||
References | PMC10771350 | |||
Abstract | advanced/metastatic, gastric/gastroesophageal junction cancer, GC/GEJC/esophageal adenocarcinoma | DISEASE | First‐line chemotherapy for advanced/metastatic human epidermal growth factor receptor 2 (HER2)‐negative gastric/gastroesophageal junction cancer (GC/GEJC) has poor median overall survival (OS; <1 year). We report efficacy and safety results from Chinese patients in the phase III global CheckMate 649 study of nivolumab plus chemotherapy vs chemotherapy for the first‐line treatment of GC/GEJC/esophageal adenocarcinoma (EAC). Chinese patients with previously untreated advanced or metastatic GC/GEJC/EAC were randomized to receive nivolumab (360 mg Q3W or 240 mg Q2W) plus chemotherapy (XELOX [capecitabine and oxaliplatin] Q3W or FOLFOX [oxaliplatin, leucovorin and 5‐fluorouracil] Q2W), nivolumab plus ipilimumab (not reported) or chemotherapy alone. OS, blinded independent central review‐assessed progression‐free survival (PFS), objective response rate (ORR), duration of response (DOR) and safety are reported. Of 1581 patients enrolled and randomized, 208 were Chinese. In these patients, nivolumab plus chemotherapy resulted in clinically meaningful improvement in median OS (14.3 vs 10.2 months; HR 0.61 [95% CI: 0.44‐0.85]), median PFS (8.3 vs 5.6 months; HR 0.57 [95% CI: 0.40‐0.80]), ORR (66% vs 45%) and median DOR (12.2 vs 5.6 months) vs chemotherapy, respectively. The safety profile was acceptable, with no new safety signals observed. Consistent with results from the global primary analysis of CheckMate 649, nivolumab plus chemotherapy demonstrated a clinically meaningful improvement in OS and PFS and higher response rate vs chemotherapy and an acceptable safety profile in Chinese patients. Nivolumab plus chemotherapy represents a new standard first‐line treatment for Chinese patients with non‐HER2‐positive advanced GC/GEJC/EAC.
What's new?
First‐line nivolumab plus chemotherapy demonstrated superior overall survival versus chemotherapy and an acceptable safety profile in advanced gastric/gastroesophageal junction/esophageal adenocarcinoma in the global CheckMate 649 trial. Chinese patients have high unmet need in this disease setting, and in this analysis, nivolumab plus chemotherapy demonstrated clinically meaningful improvement in efficacy versus chemotherapy with an acceptable safety profile in Chinese patients from CheckMate 649.
Nicole Bao: Affiliation at the time the study was conducted.
| PMC10092493 |
Abbreviations | death, Tumorstreatment‐related | ONCOLOGY | adverse eventblinded independent central reviewconfidence intervalcombined positive scoreduration of responseesophageal adenocarcinomaEastern Cooperative Oncology Group performance statusoxaliplatin, leucovorin and 5‐fluorouracilgastric cancergastroesophageal junction cancerhuman epidermal growth factor receptor 2hazard ratiolower limit of normalmicrosatellite instability‐highmicrosatellite stableobjective response rateoverall survivalprogrammed death‐1programmed death ligand 1progression‐free survivalevery 2 weeksevery 3 weeksResponse Evaluation Criteria in Solid Tumorstreatment‐related adverse eventcapecitabine and oxaliplatin | PMC10092493 |
INTRODUCTION | Gastric cancer, death, tumor, cancer, PD, tumors | GASTRIC CANCER, TUMOR, CANCER, CPS, TUMORS | Gastric cancer (GC) is the fifth most commonly diagnosed cancer and the fourth leading cause of cancer‐related death worldwide.CheckMate 649 is the largest, randomized phase III study of first‐line PD‐1 inhibitor‐based therapies in patients with unresectable advanced or metastatic, nonHER2‐positive GC/GEJC/EAC. In the primary analysis, nivolumab plus chemotherapy showed superior OS benefit vs chemotherapy alone in patients whose tumors expressed programmed death (PD) ligand 1 (L1) combined positive score (CPS) ≥5 (hazard ratio [HR] 0.71, A meta‐analysis of immune checkpoint inhibitor monotherapy for the treatment of GC/GEJC indicated that Asian patients as a subgroup had greater OS benefit than non‐Asian patients; this benefit has also been observed in other tumor types. | PMC10092493 |
METHODS | PMC10092493 | |||
Study design | cancer, tumor, PD‐L1 | ONCOLOGY, CANCER, TUMOR, CPS | This multicenter, open‐label, randomized phase III study enrolled patients at 175 hospitals and cancer centers in 29 countries, including 22 centers in China. Patients were initially randomized to receive nivolumab plus ipilimumab or chemotherapy alone at a 1:1 ratio. Amendments to the protocol resulted in randomization at a 1:1:1 ratio to nivolumab plus chemotherapy (XELOX [capecitabine and oxaliplatin] or FOLFOX [oxaliplatin, leucovorin and 5‐fluorouracil]), nivolumab plus ipilimumab or chemotherapy alone; subsequently, the nivolumab plus ipilimumab treatment group was closed, and patients were randomized in a 1:1 manner to treatment with nivolumab plus chemotherapy or chemotherapy alone. Patients were randomized with interactive web response technology in block sizes of six. Once informed consent was obtained from the patient, they were enrolled and assigned to treatment. A treatment allocation list was generated by the sponsor. Web registration was implemented by a third party, and the sequence of assignment was concealed until treatment allocation was complete. Investigators were not blinded to treatment allocation since the trial was open label.Stratification factors were tumor cell PD‐L1 expression (≥1% vs <1% including indeterminate), Eastern Cooperative Oncology Group performance status (ECOG PS; 0 vs 1), chemotherapy type (XELOX vs FOLFOX) and region (Asia vs United States and Canada vs rest of world). All patients in the Chinese subgroup analysis were Asian. Additional amendments to the protocol resulted in patients with PD‐L1 CPS ≥5 being the primary population although patients continued to be enrolled regardless of PD‐L1 expression. | PMC10092493 |
Patients | Detailed methods were previously described. | PMC10092493 | ||
Treatments | Patients received nivolumab plus investigator's choice of XELOX (360 mg nivolumab day 1, 130 mg/m | PMC10092493 | ||
Endpoints | OS, PD‐L1 | CPS, SECONDARY | The dual primary endpoints for nivolumab plus chemotherapy vs chemotherapy in the global population were OS and PFS per blinded independent central review (BICR) in patients with PD‐L1 CPS ≥5. Hierarchically tested secondary endpoints included OS in patients with PD‐L1 CPS ≥1 and in all randomized patients. Other secondary endpoints that were not formally tested included PFS and ORR per BICR at different PD‐L1 CPS cutoffs and in all randomized patients. Prespecified exploratory endpoints included DOR per BICR, landmark survival rates, biomarkers that were potentially associated with efficacy and safety and tolerability. The Chinese subgroup analysis includes data from the primary, secondary and key exploratory endpoints, but the endpoint analyses are descriptive. | PMC10092493 |
Assessments | PD‐L1, death, tumor, Tumor, Treatment‐relatedness, Tumors, TRAEs, Cancer | ADVERSE EVENT, DISEASE PROGRESSION, TUMOR, TUMOR, ADVERSE EVENTS, TUMORS, CPS, EVENTS, CANCER | Incidence of death, treatment‐related adverse events (TRAEs), serious adverse events, TRAEs leading to discontinuation and TRAEs with potential immunologic etiology were assessed using the Medical Dictionary for Regulatory Activities version 23.0, and adverse events (AEs) were graded in severity using the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0. AEs included events reported between the first dose and 30 days after the last dose of study therapy. Treatment‐relatedness could refer to nivolumab, at least one chemotherapy component or both in the nivolumab plus chemotherapy group. Tumors were assessed by computed tomography or magnetic resonance imaging at baseline, then every 6 weeks from first dose for 48 weeks, then every 12 weeks until disease progression.Tumor cell PD‐L1 expression and PD‐L1 CPS were assessed using the Dako PD‐L1 IHC 28‐8 pharmDx assay (Dako, an Agilent Technologies Inc. company, Santa Clara, CA) at two central laboratories. Tumor cell PD‐L1 expression was defined as the percentage of viable tumor cells with partial or complete membrane staining in at least 100 viable tumor cells. CPS was generated by re‐scoring PD‐L1 stained slides and was defined as the number of PD‐L1‐positive tumor cells with partial or complete membrane staining, plus lymphocytes and macrophages with membrane staining, intracellular staining or both, divided by the total viable tumor cells multiplied by 100.The all randomized patient population included all patients that were concurrently randomized to receive nivolumab plus chemotherapy or chemotherapy. The primary population included all randomized patients with PD‐L1 CPS ≥5. ORR was evaluated for all randomized patients with at least one measurable or target lesion at baseline. The safety population included all patients that received at least one dose of assigned study treatment. | PMC10092493 |
Statistical analyses | Statistical analyses were performed using SAS version 9.4 (Cary, NC). For the Chinese subgroup patient population, a two‐sided stratified log‐rank test was not performed for OS and PFS as described for the global population. | PMC10092493 | ||
RESULTS | PMC10092493 | |||
Patients | PD‐L1, death, esophageal adenocarcinoma, tumor | TUMOR, GASTROESOPHAGEAL JUNCTION CANCER, ESOPHAGEAL ADENOCARCINOMA, MAY, ONCOLOGY, CPS, GASTRIC CANCER | From April 2017 to May 2019, 357 Chinese patients were assessed for eligibility in CheckMate 649. Among these, 208 patients were randomized to receive nivolumab plus chemotherapy (n = 99) or chemotherapy alone (n = 109); 99 patients in the nivolumab plus chemotherapy group and 106 patients in the chemotherapy group received at least one dose of the assigned treatment (Figure Trial profile for Chinese patients. OS, overall survival; PFS, progression‐free survival. Baseline demographics and clinical characteristics
Abbreviations: CPS, combined positive score; ECOG PS, Eastern Cooperative Oncology Group performance status; FOLFOX, oxaliplatin, leucovorin and 5‐fluorouracil; GC, gastric cancer; GEJC, gastroesophageal junction cancer; LLN, lower limit of normal; PD‐L1, programmed death ligand 1; XELOX, capecitabine and oxaliplatin.Based on case report form. All randomized patients had an ECOG PS of 0 or 1 based on interactive response technology.No Chinese patients with esophageal adenocarcinoma were enrolled.Includes indeterminate tumor cell PD‐L1 expression.Per World Health Organization histological classification.Patients who received at least one dose of the assigned treatment. | PMC10092493 |
Efficacy | death, PD‐L1 | CPS, MAY | After a minimum follow‐up (time from concurrent randomization of the last patient to data cutoff [May 27, 2020]) of 12.1 months, Chinese patients with PD‐L1 CPS ≥5 in the nivolumab plus chemotherapy group had a 46% reduction in risk of death and a 5.9‐month improvement in median OS (15.5 months [95% CI: 11.9‐25.5] vs 9.6 months [95% CI: 8.0‐12.1]; HR 0.54 [95% CI: 0.36‐0.79]) vs the chemotherapy group, respectively. Patients with PD‐L1 CPS ≥1 had a 38% reduction in risk of death (HR 0.62 [95% CI: 0.43‐0.87]) and a 4.4‐month improvement in median OS (14.3 months [95% CI: 11.5‐17.5] vs 9.9 months [95% CI: 8.1‐12.1]) vs the chemotherapy group. OS was also improved for all randomized patients in the nivolumab plus chemotherapy group, with a 4.0‐month improvement of median OS (14.3 months [95% CI: 11.5‐17.5] vs 10.3 months [95% CI: 8.1‐12.1]) as well as a 39% reduction in risk of death (HR 0.61 [95% CI: 0.44‐0.85]) vs the chemotherapy group. The 12‐month OS rates were numerically higher in the nivolumab plus chemotherapy group vs the chemotherapy group in all patient populations, at 61% (95% CI: 49‐71) vs 41% (95% CI: 30‐52) for PD‐L1 CPS ≥5, 57% (95% CI: 46‐67) vs 42% (95% CI: 32‐52) for PD‐L1 CPS ≥1 and 57% (95% CI: 46‐66) vs 43% (95% CI: 33‐52) for all randomized patients, respectively (Figure Overall survival in Chinese patients. Overall survival in patients with PD‐L1 CPS ≥5 (A), PD‐L1 CPS ≥1 (B) and in all randomized patients (C). Chemo, chemotherapy; CI, confidence interval; CPS, combined positive score; HR, hazard ratio; mo, months; NIVO, nivolumab; OS, overall survival; PD‐L1, programmed death ligand 1The median PFS per BICR for patients with PD‐L1 CPS ≥5 treated with nivolumab plus chemotherapy vs chemotherapy was improved by 4.2 months (8.5 months [95% CI: 5.9‐12.4] vs 4.3 months [95% CI: 4.1‐6.5]; HR 0.52 [95% CI: 0.34‐0.77]) with a 48% reduction in risk of progression or death. The median PFS for patients with PD‐L1 CPS ≥1 was improved in the nivolumab plus chemotherapy group by 3.4 months (8.3 months [95% CI: 6.0‐12.3] vs 4.9 months [95% CI: 4.1‐6.8]; HR 0.57 [95% CI: 0.40‐0.82]) with a 43% reduction in risk of progression or death vs the chemotherapy group, respectively. Similarly, all randomized patients had a 2.7‐month improvement in median PFS with nivolumab plus chemotherapy (8.3 months [95% CI: 6.2‐12.3]) vs chemotherapy (5.6 months [95% CI: 4.2‐6.8]; HR 0.57 [95% CI: 0.40‐0.80]) with a 43% reduction in risk of progression or death. PFS rates at 12 months were numerically higher in the nivolumab plus chemotherapy group, at 42% (95% CI: 30‐53) vs 16% (95% CI: 9‐26) for PD‐L1 CPS ≥5, 40% (95% CI: 29‐50) vs 16% (95% CI: 9‐25) for PD‐L1 CPS ≥1 and 40% (95% CI: 30‐50) vs 16% (95% CI: 9‐25) for all randomized patients, respectively (Figure Progression‐free survival in Chinese patients. Progression‐free survival per BICR in patients with PD‐L1 CPS ≥5 (A) and PD‐L1 CPS ≥1 (B) and in all randomized patients (C). BICR, blinded independent central review; chemo, chemotherapy; CI, confidence interval; CPS, combined positive score; HR, hazard ratio; mo, months; NIVO, nivolumab; PD‐L1, programmed death ligand 1; PFS, progression‐free survivalAn objective response per BICR occurred in 47 patients (68% [95% CI: 56‐79]) treated with nivolumab plus chemotherapy and in 34 patients (48% [95% CI: 36‐60]) treated with chemotherapy in the PD‐L1 CPS ≥5 subgroup with 12 (17%) vs 9 patients (13%) experiencing a complete response, respectively. In all randomized patients, an objective response occurred in 58 patients (66% [95% CI: 55‐76]) treated with nivolumab plus chemotherapy and in 44 patients (45% [95% CI: 35‐56]) treated with chemotherapy, and complete responses occurred in 13 (15%) and 9 patients (9%), respectively (Supplementary Table The HRs for OS consistently favored the nivolumab plus chemotherapy group over the chemotherapy alone group across multiple prespecified subgroups (Supplementary Figure Among all randomized patients, 47% in the nivolumab plus chemotherapy group and 59% in the chemotherapy group received subsequent therapy; 3% and 10% received subsequent immunotherapy, respectively (Supplementary Table | PMC10092493 |
Exposure and safety | Treatment‐relatedness, Cancer | ADVERSE EVENT, ADVERSE EVENTS, ADVERSE EVENT, EVENTS, CANCER | Among all treated Chinese patients, the median (range) duration of treatment in the nivolumab plus chemotherapy group was 6.3 months (0.1‐32.6) for patients receiving nivolumab plus XELOX and 6.5 months (1.0‐30.0) for patients receiving nivolumab plus FOLFOX, while the median duration of treatment was 4.0 months (0.0‐29.2) and 3.9 months (0.8‐30.3) for patients receiving XELOX or FOLFOX alone, respectively. The duration of chemotherapy treatment was similar when comparing nivolumab plus chemotherapy to chemotherapy with the same backbone (Supplementary Table Summary of treatment‐related adverse events in all patients
Patients who received at least one dose of study drug. Includes events reported between first dose and 30 days after last dose of trial therapy. Treatment‐relatedness in the nivolumab plus chemotherapy group refers to nivolumab at least one chemotherapy component or both. Adverse events were assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 and Medical Dictionary for Regulatory Activities version 23.0. There were no grade 5 events in either treatment group. | PMC10092493 |
DISCUSSION | death, TRAEs, PD‐L1 | PRIMARY TUMOR, ADVERSE EVENTS, CPS, SEPARATION, DISEASE CHARACTERISTIC | Chinese patients who received nivolumab plus chemotherapy experienced clinically meaningful improvements in OS and PFS per BICR vs chemotherapy alone in the PD‐L1 CPS ≥5 and PD‐L1 CPS ≥1 groups and in the all randomized population. There was early and sustained separation of OS and PFS curves and a higher percentage of patients alive at 12 months in the nivolumab plus chemotherapy group vs the chemotherapy group, suggesting rapid and durable clinical benefit with nivolumab plus chemotherapy. OS consistently favored nivolumab plus chemotherapy vs chemotherapy across multiple prespecified subgroups, including by PD‐L1 CPS subgroups. Objective response rates were higher and responses were more durable in the nivolumab plus chemotherapy group compared with those in the chemotherapy group for patients with PD‐L1 CPS ≥5 and for all randomized patients. Nivolumab plus chemotherapy had an acceptable safety profile and was consistent with the known safety profiles of the individual treatment components with no new safety signals identified.In the global study population (n = 1581), nivolumab plus chemotherapy demonstrated superior OS vs chemotherapy with a 29% reduction in the risk of death and 3.3‐month improvement in median OS for patients with PD‐L1 CPS ≥5, and a 20% reduction in the risk of death and 2.2‐month improvement in median OS for all randomized patients. Clinically meaningful OS benefit with nivolumab plus chemotherapy vs chemotherapy was also observed in the Chinese subgroup (n = 208) with a 46% reduction in risk of death and 5.9‐month improvement in median OS in patients with PD‐L1 CPS ≥5 and a 39% reduction in risk of death and 4.0‐month improvement in median OS in all randomized patients. While median OS and PFS in the chemotherapy group were shorter in Chinese patients compared with the global study population these were consistent with reports in other global trialsSafety was comparable between the Chinese subgroup and global study population with grade 3 to 4 TRAEs reported for 65% of Chinese patients and 59% of the global study population treated with nivolumab plus chemotherapy. However, rates of any‐grade TRAEs leading to discontinuation from nivolumab plus chemotherapy were higher in Chinese patients than the global study population (51% and 36% of patients, respectively). The type and severity of TRAEs observed in Chinese patients were similar to those observed in the global study population. Despite the increased incidence of TRAEs leading to discontinuation, median duration of treatment was comparable between the global study population and the Chinese subgroup, indicating that TRAEs leading to discontinuation likely did not have a substantial effect on treatment duration in this subgroup.While it is important to note that this analysis was not designed as a formal comparison with the global study population, differences in baseline disease characteristics and practice patterns, including subsequent therapies, were observed. Chinese patients, when compared with the global study population, respectively, had numerically higher rates of ECOG PS 1 (75% vs 58%) and GC as the primary tumor location at initial diagnosis (89% vs 70%). In the nivolumab plus chemotherapy group, a higher percentage of Chinese patients received XELOX compared with the global study population (81% vs 46%, respectively). The rate of subsequent therapy in the Chinese subgroup was also higher than the overall population in both the nivolumab plus chemotherapy (47% vs 38%, respectively) and chemotherapy (59% vs 41%) groups.The randomized phase III trial ORIENT‐16 evaluated the PD‐1 inhibitor sintilimab plus chemotherapy vs chemotherapy in Chinese patients with previously untreated, unresectable advanced, recurrent or metastatic GC/GEJC.It is important to consider the potential limitations of this study and the Chinese subgroup analysis. CheckMate 649 was an open‐label trial. A lack of blinding may result in differences in assessments such as causality of adverse events. The open‐label design was determined to be appropriate due to the use of multiple treatments and dosing regimens. It was not expected that the management of TRAEs (with standard treatment algorithms) or centrally assessed primary endpoints (eg, PFS) would be affected by bias. The Chinese subgroup was relatively small in comparison to the global population (n = 208 vs n = 1581, respectively). | PMC10092493 |
CONCLUSIONS | In this preplanned analysis of Chinese patients enrolled in CheckMate 649, nivolumab plus chemotherapy resulted in clinically meaningful improvements in OS, PFS, ORR and DOR compared with chemotherapy alone, and the safety profile was acceptable and showed no new safety signals, consistent with results from the global study population. | PMC10092493 | ||
AUTHOR CONTRIBUTIONS | The work reported in the paper has been performed by the authors unless clearly specified in the text. Kohei Shitara, Mingshun Li and Ming Lei contributed to the conception and design of the study. Tianshu Liu, Yuxian Bai, Xiaoyan Lin, Wei Li, Jufeng Wang, Xiaochun Zhang, Hongming Pan, Chunmei Bai, Li Bai, Ying Cheng, Jingdong Zhang, Haijun Zhong, Yi Ba, Wenwei Hu, Ruihua Xu, Weijian Guo, Shukui Qin, Nong Yang, Jianwei Lu and Lin Shen recruited and/or treated patients and gathered clinical data on efficacy and safety. Mingshun Li analyzed the clinical data, Ming Lei performed biomarker analyses and Tian Chen conducted statistical analyses. Ming Lei, Mingshun Li, Nicole Bao and Tian Chen verified the data. All authors interpreted the data. All authors had access to all the data in the study, participated in developing or reviewing the manuscript and provided final approval to submit the manuscript for publication. The work reported in the paper has been performed by the authors unless clearly specified in the text. | PMC10092493 | ||
CONFLICT OF INTEREST | cancer | CANCER | Kohei Shitara reports grants and personal fees from Astellas Pharma, Eli Lilly and Company, Ono Pharmaceutical, Daiichi Sankyo, Taiho Pharmaceutical and Merck Pharmaceutical; grants from Dainippon Sumitomo Pharma, Chugai Pharma, Medi Science and Eisai; and personal fees from Bristol Myers Squibb, Takeda Pharmaceuticals, Pfizer, Novartis, AbbVie, Yakult, GlaxoSmithKline, Amgen and Boehringer Ingelheim. Ming Lei reports employment with Bristol Myers Squibb and ownership of stock in Bristol Myers Squibb. Mingshun Li reports employment with Bristol Myers Squibb. Tian Chen reports holding a patent to combination therapy with anti‐IL‐8 antibodies and anti‐PD‐1 antibodies for treating cancer. Lin Shen reports grants from Beijing Xiantong Biomedical Technology Co. Ltd, Qilu Pharmaceutical Co. Ltd, Zaiding Pharmaceutical (Shanghai) Co. Ltd, Jacobio Pharmaceuticals Co. Ltd, Beihai Kangcheng (Beijing) Medical Technology Co. Ltd and Boehringer Ingelheim; and consulting fees from Harbor BioMed and Merck. All other authors declare no competing interests. | PMC10092493 |
ETHICS STATEMENT | This study was conducted in accordance with the trial protocol and with Good Clinical Practice guidelines developed by the International Council for Harmonisation. Written informed consent was obtained from all patients per the Declaration of Helsinki principles. The study is registered at | PMC10092493 | ||
Supporting information |
Click here for additional data file. | PMC10092493 | ||
ACKNOWLEDGEMENTS | This study was supported by Bristol Myers Squibb and Ono Pharmaceutical Co. Ltd. We thank the patients and their families who made this study possible, the investigators and the clinical study teams at Bristol Myers Squibb (Princeton, NJ) and Ono Pharmaceutical Co. Ltd. (Osaka, Japan) and Dako (an Agilent Technologies Inc. company, Santa Clara, CA) for collaborative development of the PD‐L1 IHC 28‐8 pharmDx assay. Professional medical writing assistance was provided by Ben Labbe, PhD of Parexel, funded by Bristol Myers Squibb. | PMC10092493 | ||
DATA AVAILABILITY STATEMENT | Bristol Myers Squibb will honor legitimate requests for clinical trial data from qualified researchers. Data will be shared with external researchers whose proposed use of the data has been approved. Complete de‐identified patient data sets will be eligible for sharing 2 years after completion of the CheckMate 649 study. Before data are released the researcher(s) must sign a Data Sharing Agreement after which the de‐identified and anonymized datasets can be accessed within a secured portal. Bristol Myers Squibb policy on data sharing may be found at | PMC10092493 | ||
REFERENCES | PMC10092493 | |||
Background | end-expiratory occlusion | SEPTIC SHOCK | An increase in cardiac index (CI) during an end-expiratory occlusion test (EEOt) predicts fluid responsiveness in ventilated patients. However, if CI monitoring is unavailable or the echocardiographic window is difficult, using the carotid Doppler (CD) could be a feasible alternative to track CI changes. This study investigates whether changes in CD peak velocity (CDPV) and corrected flow time (cFT) during an EEOt were correlated with CI changes and if CDPV and cFT changes predicted fluid responsiveness in patients with septic shock. | PMC10116770 |
Methods | HEMODYNAMIC INSTABILITY | Prospective, single-center study in adults with hemodynamic instability. The CDPV and cFT on carotid artery Doppler and hemodynamic variables from the pulse contour analysis EV1000™ were recorded at baseline, during a 20-s EEOt, and after fluid challenge (500 mL). We defined responders as those who increased CI ≥ 15% after a fluid challenge. | PMC10116770 | |
Results | arrhythmias, septic shock | ARRHYTHMIAS, SEPTIC SHOCK | We performed 44 measurements in 18 mechanically ventilated patients with septic shock and without arrhythmias. The fluid responsiveness rate was 43.2%. The changes in CDPV were significantly correlated with changes in CI during EEOt ( | PMC10116770 |
Conclusions | arrhythmias, septic shock | ARRHYTHMIAS, SEPTIC SHOCK | In septic shock patients without arrhythmias, an increase in CDPV greater than 10.5% during a 20-s EEOt predicted fluid responsiveness with > 95% specificity. Carotid Doppler combined with EEOt may help optimize preload when invasive hemodynamic monitoring is unavailable. However, the 61% gray zone is a major limitation (retrospectively registered on Clinicaltrials.gov NCT04470856 on July 14, 2020). | PMC10116770 |
Supplementary Information | The online version contains supplementary material available at 10.1186/s13054-023-04422-9. | PMC10116770 | ||
Keywords | PMC10116770 | |||
Background | preload-responsive, stroke, EEOt, increases cardiac preload | STROKE, SEPTIC SHOCK | Fluid responsiveness is defined as an increase in cardiac index (CI) in response to an increase in preload [Several functional hemodynamic tests for assessing fluid responsiveness have been introduced in clinical practice in the last few years [The EEOt is based on an interruption of mechanical ventilation at the end of expiration for 15–30 s. This maneuver increases cardiac preload, venous return, and stroke volume (SV) in preload-responsive patients. In one study [We conducted this study to assess (1) if there was a correlation between the changes in carotid Doppler peak velocity (CDPV) or in corrected flow time (cFT) and the changes in CI induced by a 20-s EEOt; (2) if EEOt-induced changes in CDPV and cFT predict fluid responsiveness in patients admitted to intensive care unit (ICU) with septic shock. | PMC10116770 |
Methods | PMC10116770 | |||
Patient population | tachycardia, hypotension, septic shock, carotid artery stenosis, heart failure | PERIPHERAL ARTERIAL DISEASE, VALVULAR HEART DISEASE, CARDIAC ARRHYTHMIA, SEPTIC SHOCK, CAROTID ARTERY STENOSIS, HEART FAILURE | The institutional review board of Policlinico Agostino Gemelli University Hospital approved the present study (Prot. N. 0048329/18 ID 1677) retrospectively registered on ClinicalTrials.gov NCT04470856 on July 14, 2020. All patients or their legal representatives gave their written informed consent to participate.All adult patients (≥ 18 y) admitted to the general ICU of Policlinico Agostino Gemelli University Hospital with a diagnosis of septic shock who were sedated and mechanically ventilated were considered for inclusion. Patients were eligible if they needed a fluid challenge according to predefined clinical criteria: (1) hypotension (defined as a systolic arterial pressure ≤ 90 mmHg) and/or (2) tachycardia (i.e., ≥ 100 beats/min) and/or (3) urinary flow ≤ 0.5 mL/kg/min for 2 h. Those with significant valvular heart disease, cardiac arrhythmia, heart failure, peripheral arterial disease, or common carotid artery stenosis narrower than 50% were excluded from the study. | PMC10116770 |
Carotid Doppler | One investigator (SD'A) with previous formal training in critical care ultrasound insonated the common carotid artery in a longitudinal view approximately 1–2 cm before the bifurcation using a 5–10-MHz linear array transducer (Vivid™ iq, General Electric Healthcare, Chicago, Illinois, USA) and performed a pulse-wave Doppler analysis. The sample volume was in the vessel’s middle, with the caliper positioned parallel to flow, angled at no more than 60°. We averaged five consecutive measurements to limit the effects of respiratory-induced changes in CDPV and cFT.The ΔCDPV was expressed as a percentage and was calculated with the following formula:The FT was measured from the beginning of the flow tracing’s upstroke to the nadir of its dicrotic notch on a pulse waveform analysis. We used the Wodey’s formula: cFT = FT + 1.29*(HR-60) to correct measurements for the heart rate [ | PMC10116770 | ||
Study endpoints | The primary endpoint of this study was the correlation between changes in CDPV and CI during an EEOt. Secondary endpoints were the correlations between changes in CDPV and CI after the fluid challenge and between changes in cFT and CI during EEOt and after fluid challenge. We also explored the ability of changes in CDPV and cFT during EEOt to predict fluid responsiveness. Differences between responders and non-responders were studied during all three phases of our observation (baseline, EEOt, and fluid challenge). | PMC10116770 | ||
Statistical analysis | BROWN | The distribution of continuous variables was assessed with the Kolmogorov–Smirnov test. Data are expressed as mean ± standard deviation (SD) or median (interquartile range), as appropriate. Categorical variables are reported as fractions and percentages (%). Differences between parametric variables were evaluated with the Student’s t test for unpaired and paired measures or with the Mann–Whitney and Wilcoxon tests, as appropriate. Fisher’s exact test was adopted for categorical variables. LSD and Scheffé’s test were used to correct for multiple comparisons.We used two-way ANOVA to detect significant variable changes across time points between two groups. We calculated a receiving-operator characteristic (ROC) curve using the Wilson–Brown method to summarize the ability of each measure to predict fluid responsiveness across the various thresholds. For all predictors, we identified the optimal threshold based on the Youden index J (Sample size calculation for the primary outcome was made considering a correlation between CDPV changes and CI changes during EEOt of 0.8 with a null hypothesis of correlation set at 0.5. With beta error at 0.8 and a two-sided alfa error of 0.05, 38 measurements were needed to test the study hypothesis. For the area under the ROC curve (AUROC), we considered an AUROC of 0.75, a null hypothesis of 0.5, and beta and alpha error as above. The total required sample was 40 measurements.For the carotid Doppler variables, we calculated how many measurements fell within the gray zone, i.e., the number of cases with a sensitivity < 90% and/or a specificity < 90%.We also estimated the precision and the least significant change (LSC) [Precision was estimated asThe LSC was calculated asWe used SPSS® 28 software (IBM Chicago IL), MedCalc® Statistical Software version 20.210 (MedCalc Software Ltd, Ostend, Belgium; | PMC10116770 | |
Results | We performed 44 measurements on 18 patients. Their characteristics are shown in Table Patient characteristicsData are expressed as median [IQR], mean ± standard deviation, or n (%)PEEP, positive end-expiratory pressure; SAPS, Simplified Acute Physiology Score; and SOFA, Sequential Organ Failure AssessmentThe overall rate of fluid responsiveness was 43.2% (19 out of 44 measures). | PMC10116770 | ||
Hemodynamic effects of EEOt | During the EEOt, the CI increased by 10.9% (from 2.2 ± 0.6 to 2.5 ± 0.8 L/min/mChanges in cardiac index in responders (FR) and non-responders (NFR) during EEOt and after fluid challengeChanges in carotid Doppler peak velocity (CDPV) in responders (FR) and non-responders (NFR) during EEOt and after fluid challenge | PMC10116770 | ||
Hemodynamic effects of fluid challenge | After the 500-mL fluid challenge, in fluid responders, the CI increased by 22.2% (from 2.2 ± 0.6 to 2.8 ± 0.9 L/min/mThe mean values of MAP, HR, SVV, CVP, and SVRI did not change significantly during EEOt and after the fluid challenge. | PMC10116770 | ||
Correlation between changes in carotid Doppler and in cardiac output measurements | The linear correlation coefficient r between the percentage changes in CDPV and CI during EEOt was 0.52 [0.26–0.71]. A significant but lower correlation was found for cFT (On rmcorr, the percentage changes in CDPV vs. the percentage changes in CI were significantly correlated across EEOt and fluid challenge in responders (The clinical concordance plot showed that the overall fraction of concordant changes (CDPV or cFT vs. CI) was greater for cFT than for CDPV at EEOt (Additional file | PMC10116770 | ||
Discussion | critically ill, end-inspiratory occlusion maneuver, EEOt, septic shock, arrhythmias | CARDIAC FAILURE, CRITICALLY ILL, FLUID OVERLOAD, FRANK, SEPTIC SHOCK, ATRIAL FIBRILLATION, ARRHYTHMIAS | Our results showed a significant correlation between changes in CPDV during EEOt and changes in CI during the subsequent fluid challenge. An increase in CDPV greater than 10.5% during an EEOt predicted fluid responsiveness in ICU patients with septic shock with high specificity. This may allow clinicians to non-invasively identify about 40% of fluid responders and safely administer them fluids without risking a fluid overload.The carotid artery Doppler assessment of fluid responsiveness coupled with an EEOt can be performed in mechanically ventilated patients in whom continuous cardiac monitoring is unavailable or the transthoracic echocardiographic windows are technically impaired. These conditions may be common not only in the ICU, but also in the operating room in patients undergoing major surgery whose chest wall is inaccessible to echocardiography. In this setting, the carotid artery might be the only accessible large-size arterial vessel for performing arterial Doppler. The position of the carotid artery, which is located just distally to the aortic outflow tract, makes its flow a good approximation of the aortic flow [To the best of our knowledge, this is the first study assessing fluid responsiveness using the carotid Doppler variations in association with an EEOt in critically ill patients. The potential usefulness of the changes in carotid Doppler during EEOt has been previously investigated in healthy volunteers [Two studies [EEOt and fluid challenge were not consistently associated with increased Doppler velocity. Namely, CDPV decreased in a minority of responders (3/19 measurements during the EEOt and 2/19 measurements after the fluid challenge) and almost half of the non-responders (11/25 measurements at either time point; Additional file Results of the repeated measures correlation clearly showed that the changes in CDPV and cFT both during EEOt and after fluid challenge were correlated with the parallel changes in CI or SVI in responders. This is consistent with the ability of EEOt-induced changes in CPDV to predict fluid responsiveness in our study. However, the accuracy of CDPV was lower than that of other indices, such as PLR. In fact, the gray zone of CPDV was 61%, meaning that only the CDPV values included in the remaining 39% range were sufficiently accurate to make a clinical decision. A possible explanation for this finding may be that the EEOt causes smaller changes in venous return compared to the PLR. The PLR in fact causes a rapid displacement of a high volume (about 300 mL) of venous blood from the lower body toward the right heart, mimicking an entire fluid challenge [The clinical concordance analysis of the percentage changes in Doppler variables vs. the percentage changes in CI showed that many of the concordant changes in cFT were ± 5% or less. Compared to cFT, CDPV had a greater proportion of clinically significant concordant changes (5–15% or > 15%; categories 2 and 3 in Additional file Despite a clear correlation between cFT and CI changes at EEOt and fluid challenge, cFT did not show a significant predictive ability for fluid responsiveness in our study. The reasons for this are unclear and deserve further investigation. Since the LSC of cFT was only about half the percentage increase in cFT during EEOt or after the fluid challenge in fluid responders, this result does not seem to be due to an insufficient precision of the Doppler technique. Because of the small AUROC of cFT, our study was not powered enough to assess its predictive ability with confidence.In our study, we defined fluid responsiveness as a ≥ 15% increase in CI. This choice was based on previous literature on EEOt. However, an SVI increase could have been an equally valuable target [We may have considered adding an end-inspiratory to the end-inspiratory occlusion maneuver for predicting fluid responsiveness. In a study by Jozwiak et al. [Fluid responsiveness depends on the slope of the Frank–Starling curve, which is critically affected by cardiac contractility. In our study, we excluded patients with cardiac failure, so that the role of cardiac contractility was not specifically assessed. However, previous observations made using aortic Doppler [Some limitations of our study must be acknowledged. Firstly, this study was conducted on adult patients with septic shock in controlled ventilation with 6 mL/kg of PBW with absent or minimal spontaneous breathing, and its findings are not necessarily generalizable to other patient populations. Secondly, this technique is based on manual detection and—as such—is prone to intra-observer variation. In our study, all carotid Doppler measurements were made by a single experienced operator. While this was essential to ensure the reproducibility of our measurements, it may have overestimated their precision and reduced the external validity of our findings. Thirdly, we used the EV1000™/Volume View device, which calculates SVI and CI on the average pulse contour recorded over 20 s. Inevitably, this time window only partially overlapped with those of the EEOt, which may have affected the accuracy of our findings. Fourthly, as specified in our Methods, we compared both the hemodynamic measurements made during EEOt and those made after the fluid challenge with the first baseline (T1), since on T3 the return to the baseline after the EEOt was assessed only visually. Although the effect of the EEOt is assumed to be transient, we cannot exclude that some residual effects may have persisted after the end of EEOt and have reduced the accuracy of the subsequent measurements. Fifthly, the 61% gray zone we found in our study suggests caution when using Doppler results to make clinical decisions. Lastly, carotid Doppler might be less accurate in patients affected by arrhythmias, such as atrial fibrillation, which are common in septic shock patients [ | PMC10116770 |
Conclusions | arrhythmias | ARRHYTHMIAS, SEPTIC SHOCK | Our study showed that in adult patients with septic shock, the changes in CPDV and cFT during EEOt on carotid Doppler are correlated with the changes in CI that occur after a fluid challenge, and that an increase in CDPV greater than 10.5% during a 20-s EEOt predicted fluid responsiveness with > 95% specificity. Carotid Doppler can be used to assess fluid responsiveness in patients who are sedated and mechanically ventilated and without arrhythmias, when invasive hemodynamic monitoring is not immediately available. However, its large gray zone is an important limitation. | PMC10116770 |
Author contributions | AMD | SD'A, AMD, and CS contributed to conception and design of the work. SD'A, AMD, SC, and CP were involved in enrollment and data acquisition. CS, SD'A, AMD, and AM contributed to interpretation of data. SD'A, CS, AMD, and AM were involved in manuscript writing. CS and MA contributed to revision and senior contribution. All authors read and approved the final manuscript. | PMC10116770 | |
Funding | DEL | This study was funded by a finalized grant from Università Cattolica del Sacro Cuore Linea D1/2018. | PMC10116770 | |
Availability of data and materials | All data generated or analyzed during this study are included in this article. The dataset used and/or analyzed during the study is available from the corresponding author on request. | PMC10116770 | ||
Declarations | PMC10116770 | |||
Ethics approval and consent to participate | This study was approved by the institutional review board (Prot. N. 0048329/18 ID 1677) of the Fondazione Policlinico Universitario A. Gemelli- IRCCS and carried out in accordance with the principles outlined in the Declaration of Helsinki. All patients or their legal representatives gave their written informed consent to participate. | PMC10116770 | ||
Consent to publication | Not applicable. | PMC10116770 | ||
Competing interests | On behalf of all authors, the corresponding author states that there is no conflict of interest. | PMC10116770 | ||
References | PMC10116770 | |||
Subject terms | Nasopharyngeal Carcinoma | SOLID TUMOUR, DISEASE, SOLID TUMORS, NASOPHARYNGEAL CARCINOMA, SECONDARY, NASOPHARYNGEAL CARCINOMA | Immunotherapy combined with antiangiogenic targeted therapy has improved the treatment of certain solid tumors, but effective regimens remain elusive for refractory recurrent/metastatic nasopharyngeal carcinoma (RM-NPC). We conducted a phase 2 trial to evaluate the safety and activity of camrelizumab plus apatinib in platinum-resistant (cohort 1, NCT04547088) and PD-1 inhibitor resistant NPC (cohort 2, NCT04548271). Here we report on the primary outcome of objective response rate (ORR) and secondary endpoints of safety, duration of response, disease control rate, progression-free survival, and overall survival. The primary endpoint of ORR was met for cohort 1 (65%, 95% CI, 49.6–80.4, Combination of immune checkpoint inhibitors with anti-angiogenic targeted therapy has shown efficacy in some solid tumours. Here the authors report the results of a phase 2 trial of camrelizumab (anti-PD1) plus apatinib as a second-line or later-line treatment regimen in platinum-resistant (cohort 1) or PD-1 inhibitor-resistant (cohort 2) Recurrent/Metastatic Nasopharyngeal Carcinoma patients. | PMC10425437 |
Introduction | NPC | NASOPHARYNGEAL CARCINOMA, DISEASE | Nasopharyngeal carcinoma (NPC) has unique geographical, etiological and biological characteristics that set it apart from other head and neck tumorsThe combination of a PD-1/PD-L1 inhibitor with an anti-angiogenesis antibody has shown efficacy in many malignanciesIn this phase 2 trial presented here, we report the results of camrelizumab plus apatinib as a second-line or later-line treatment regimen in platinum-resistant (cohort 1) and PD-1 inhibitor-resistant (cohort 2) RM-NPC patients. Both cohort 1 and 2 meets primary end point. In exploratory molecular analyses, B cell marker and tertiary lymphoid structure shows a positive associated with higher ORR in cohort 1, while a higher expression of PD-L1, VEGF Receptor 2 (KDR) and angiogenesis gene expression signatures are related with the higher efficiency in cohort 2. Overall, our study highlights the promising efficacy of the camrelizumab plus apatinib regimen as a viable treatment option for patients with platinum-resistant and PD-1 inhibitor-resistant RM-NPC. Moreover, our molecular analyses offer insights into potential biomarkers and mechanisms that could be targeted for further optimization of treatment strategies in this challenging disease setting. | PMC10425437 |
Results | PMC10425437 | |||
Patients | Between 8 September 2020, and 7 January 2021, 66 patients were screened, of whom 52 were enrolled in the study, with 27 in cohort 1 and 25 in cohort 2, all of whom were included in the full and safety analysis set. On Jan. 31, 2021, the protocol was amended to include 13 additional patients in the cohort 1 and 7 in the cohort 2, giving a total of 40 patients in cohort 1, 32 patients in cohort 2. One of the reasons for the protocol amendment was that too many patients had the desire to participate to this trial and that some of the patients consented before enrollment was halted because of encouraging results of previous enrolled patients in cohort 1 and cohort 2 (Supplementary Table | PMC10425437 |
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