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BCR/TCR repertoire metrics can predict pCR and EFS | To assess whether baseline BCR and TCR measures could predict pCR (Supplementary Figs. | PMC10624889 |
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Development and validation of an integrated prognostic model | REGRESSION | Considering the previous results, we tested whether a model including baseline clinicopathological, immune-related features, and treatment-related information including response could predict EFS in NeoALTTO. BCR and TCR measures (details in METHODS) were included in the variable selection process, together with pCR information, clinicopathological variables and a set of gene signatures. The model was developed on a training cohort of 221 patients from the NeoALTTO trial with all included data available, using a forward stepwise approach with Akaike Information Criteria (AIC) to select the best model (Supplementary data The variables selected in the final model included BCR evenness, TIL levels, pCR status (ypT0/is), clinical nodal status and hormone receptor status (the final Cox regression model is shown in Supplementary data In NeoALTTO, the C-index calculated on the training cohort (The score was then divided into tertiles (cutoffs at −1.3763 and −0.8143), and Kaplan–Meier analysis was performed to estimate EFS in the groups identified (Supplementary Fig. | PMC10624889 |
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Tumor microenvironment characteristics are associated with BCR/TCR repertoire metrics and the prognostic score | tumor | TUMOR | To explore the relationship of BCR/TCR characteristics, TILs and prognosis with the tumor microenvironment composition in the NeoALTTO and CALGB 40601 cohorts, we applied the microenvironment cell populations (MCP)-counter toolWe first evaluated the correlations of the abundance scores for each cell type were with the BCR/TCR measures, TIL levels and the HER2-EveNT score (Supplementary Fig. We next compared cell subtypes according to both pCR (ypT0/is ypN0) status and prognostic group (Supplementary Fig. | PMC10624889 |
Gene expression profiling highlights biological differences in the prognostic groups | We next aimed to better characterize the gene expression features associated with the HER2-EveNT score by evaluating correlations with known signatures and performing comparisons between the prognostic groups. This in-depth characterization allowed us to identify the most relevant features captured by the score, including mostly processes associated to immune activation and suppression.First, we evaluated the correlation between the HER2-EveNT score as a continuous variable and hallmark biological processes | PMC10624889 |
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Discussion | tumor, TILs, breast cancer, cancer, already-discussed, tumors | TUMOR, INFILTRATION, HER2-POSITIVE BREAST CANCER, BREAST CANCER, ADVERSE EVENTS, CANCER, DISEASE, RESIDUAL CANCER, TUMORS | HER2-positive breast cancer represents a heterogeneous entity, as shown by PAM50 molecular subtypesWhile pCR achievement is a strong prognostic factor in HER2-positive breast cancers after neoadjuvant therapyOther predictive/prognostic models have been developed in early-stage HER2-positive breast cancer. For example, a combined score of TILs and tumor cellularity (CelTIL) measured at week 2 after starting neoadjuvant anti-HER2 therapy (without chemotherapy) provided predictive information in the PAMELA studyBy characterizing the gene expression profiles of the prognostic groups, we showed an enrichment for immune-related processes in the group presenting good prognosis after either pCR or RD, leading us to hypothesize that tumors presenting an active immune response at baseline present biological similarities beyond HER2/estrogen receptor pathways activation.As we are moving toward optimizing treatment strategies, we may argue that the lack of pCR in patients with baseline favorable clinical/immune features may not necessarily require treatment escalation approaches in all patients. In the seminal trial KATHERINE, post-operative trastuzumab emtansine (T-DM1) showed remarkable benefit compared to trastuzumab in patients with RD at surgery; however, more adverse events were also observedThe role of B cell infiltration and clonal diversity in modulating the immune response in cancer has been described by several worksIn light of all these aspects, our model could be prospectively tested in studies designed to evaluate approaches involving the use of immunotherapy-based regimens and/or de-escalation/shorter duration of post-operative treatments in low risk patients with an excellent prognosis, as well as alternative therapeutic strategies in those with poor outcome.Our study presented several challenges and limitations. In addition to the already-discussed differences in terms of patient populations, the NeoALTTO and the CALGB 40601 trials had some differences in study design, namely in the timing of the start of neoadjuvant paclitaxel and in the post-operative treatments (details in the METHODS). We standardized the survival outcome measure (EFS) used for our analyses across the two trials; however, neither NeoALTTO nor CALGB 40601 were powered to detect survival benefits. Moreover, these trials evaluated lapatinib, which is not currently adopted in early-stage HER2-positive breast cancer. Therefore, validating these findings in cohorts receiving standard treatment regimens (e.g., pertuzumab in combination with trastuzumab) would be extremely valuable.Characterizing the BCR and TCR repertoires from bulk RNA sequencing data represents a challenge in itselfIn addition, more reliable cutoffs may need to be defined for the HER2-EveNT score. Moreover, the inclusion of the residual cancer burden, given its prognostic value in patients with RDDespite these considerations, findings from NeoALTTO were confirmed in CALGB 40601, suggesting the robustness of the results, which first and foremost provide the rationale for interrogating more extensively the role of B cells in this disease.In conclusion, we demonstrated the heterogeneity of BCR repertoire measures and immune response within HER2-positive breast cancer and the potential of BCR diversity as a prognostic biomarker. Our model identified a group of patients with immune-enriched tumors who may be eligible for treatment de-escalation approaches, even after RD, and highlighted the importance of integrating clinicopathological characteristics, treatment response information, and immune-related features to define the clinical risk in the neoadjuvant setting. Further validation of our findings and exploration of the role of BCR/TCR repertoire measures in HER2-positive as well as other breast cancer subtypes is warranted. | PMC10624889 |
Methods | PMC10624889 |
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NeoALTTO and CALGB 40601 study designs and patient populations | tumor, death, primary malignant neoplasm, breast cancer | TUMOR, RECURRENCE, BREAST CANCER, EVENT, DISEASE, MAY, SECONDARY, BREAST, PRIMARY MALIGNANT NEOPLASM | The NeoALTTO phase III trial randomized 455 HER2-positive early-stage BC patients to receive neoadjuvant trastuzumab (T), lapatinib (L) or T + LThe primary endpoint of the trial was pCR defined as either absence of invasive tumor cells in the breast (ypT0/is) as defined by the National Surgical Adjuvant Breast and Bowel Project criteria, later amended to the absence of invasive tumor cells in the breast and in the axillary lymph nodes (ypT0/is ypN0) according to the Food and Drug Administration criteria. The main secondary endpoint was EFS, defined as the time from randomization to first event, i.e., breast cancer relapse after surgery, second primary malignant neoplasm, or death without recurrence for women who received surgery for breast cancer, or, for those who did not undergo surgery, death during clinical follow-up or non-completion of any neoadjuvant investigational drugs due to progressive disease. OS was defined as the time from randomization to death from any cause.In the phase III CALGB 40601 trial, 305 eligible patients with newly diagnosed, histologically confirmed, untreated clinical stage II to III HER2-positive disease were randomized to receive neoadjuvant weekly paclitaxel in combination with either T, L, or T + L for 16 weeksEthics committee and relevant health authorities at each participating site approved the NeoALTTO and CALGB 40601 studies and all patients provided written informed consent including future biomarker research. For NeoALTTO, the sites which run the trial are listed in Supplementary data The NeoALTTO trial is registered at In NeoALTTO, clinical data were collected at Institut Jules Bordet and Frontier Science Scotland; analyses are based on the on the clinical study database frozen on May 26, 2016. In CALGB 40601, clinical data were collected at the CALGB (Alliance) Statistics and Data Center; analyses are based on the on the clinical study database frozen on October 06, 2021. | PMC10624889 |
Samples collection and processing, TILs evaluation | tumor | TUMOR | Out of the 455 patients enrolled in the NeoALTTO trial, baseline frozen tumor biopsies were available for 423 patients. RNA was successfully sequenced from frozen tumor samples in 254 patients as previously describedIn the CALGB 40601 trial, RNA sequencing data from baseline frozen tumor samples were available for 264 patients, as previously reportedStromal TILs were scored as % following the International TILs Working Group guidelines | PMC10624889 |
RNA sequencing data processing | RNA sequencing processing for baseline frozen biopsy samples in the two trials has been previously describedWhen evaluating the potential technical differences between NeoALTTO and CALGB 40601 in terms of number of normalized BCR and TCR reads and clones, we considered the difference in read length as potential cause of such differences, and explored whether and how BCR/TCR read/clone counts would be impacted in NeoALTTO by trimming reads from 100-bp to 50-bp (Supplementary data The “tximport” R package (v1.16.1)Intrinsic subtypes were obtained from RNAseq gene expression data in both studies by applying a HER2/estrogen receptor subgroup-specific gene normalization method | PMC10624889 |
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BCR and TCR repertoire diversity measures | BCR/TCR repertoires were extracted from bulk RNA sequencing data using the MiXCR toolIsotypes (IgG, IgA, IgM, IgD, IgE) for the BCR heavy chain were determined based on the constant region (C region) information, whenever present. In particular, the isotype could not be determined in 23% of the IGH clones in NeoALTTO and 19% in CALGB 40601. For the remaining IGH clones, isotype proportions are shown in Supplementary Fig The following BCR and TCR repertoire metrics were calculated: read counts, number of clones, length of the CDR3, top and second top clone proportions. Diversity indices including Gini index, Gini-Simpson index and species evenness were calculated as well. Those measures were computed for each BCR/TCR chain separately, as well as “global” measures considering all clones belonging to either BCR or TCR (Supplementary data Evenness and second top clone were calculated if at least two different clones were present. Gini and Gini-Simpson indices were calculated when at least 1 clone was present, assigning a value of 0 when only one clone was present. CDR3 length was calculated when at least one clone was present. We defined BCR/TCR metrics (illustrative examples in Supplementary Fig. From the MiXCR output, we calculated these measures for each chain forming BCR and TCR (IGH/K/L and TRA/B/D/G, respectively), as well as global values from the total reads mapping to BCR and TCR, thus representing the whole BCR and TCR repertoires.For univariable and multivariable analyses, the Shapiro-Francia test was used to evaluate normality of the BCR and TCR measures separately in NeoALTTO and CALGB 40601. In details, when a BCR/TCR feature had no values equal to 0 in the cohort, a log transformation (log | PMC10624889 |
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Development of the prognostic model | ypN0 | A forward stepwise approach was used to build the prognostic model. In particular, starting from a null Cox model for EFS, variables selected from a pool were added following the AIC method [function “steps” from the “stats” R package (v4.0.5)Before calculating the signature scores, genes with a total read count across all samples < 20 were excluded, and normalization was performed by dividing gene counts by the sample mean gene count followed by logWith regards to BCR and TCR measures, the same procedure followed for uni- and multi-variate analysis was applied in NeoALTTO (i.e., transformation according to the Shapiro-Francia test, then centering and scaling).The model was developed on a cohort of 221 patients from the NeoALTTO trial with all data available. Subsequent analysis regarding the prognostic score in NeoALTTO were then performed in a cohort of 233 patients with all the variables selected for the model available, except for the analyses including pCR in breast + axilla (ypT0/is ypN0), which were performed on 224 patients.A prognostic score (HER2-EveNT) was computed multiplying the coefficient obtained for each variable in the final Cox model (Supplementary data The score was therefore calculated as:BCR evenness (standardized value) × 0.300436587 + TILs (%) × −0.024107504 + pCR (0 or 1) × −0.568111234 + HR status (0 or 1) × −0.525011259 + nodal status (0 or 1) × −0.504914127.As the coefficients are the natural logarithm of the HRs for each variable, the score represents a measure of the relative risk of relapse calculated based on the values of each variable in the single patient, with a lower score being associated with a better prognosis. Variables with a negative coefficient were associated with improved EFS, while a positive coefficient was associated with worse prognosis.This score was then divided into tertiles. As EFS > 90% was reached for the first tertile in NeoALTTO, the cutoff between the first and the intermediate tertiles was used to define the two final prognostic groups. An external independent validation was performed testing the model in 230 patients from the CALGB 40601 trial with pCR, hormone receptor, clinical nodal status, TILs, and BCR evenness data available. As BCR evenness was not log transformed in NeoALTTO, the BCR evenness values in CALGB 40601 were only centered by removing the mean of NeoALTTO BCR evenness (0.7917893) and scaled dividing the obtained values by the NeoALTTO BCR evenness standard deviation (0.1004482) before computing the HER2-EveNT score.The concordance index (Harrel’s C-index) was assessed to estimate the predictive performance of the model. Cutoffs derived from NeoALTTO were applied on the score calculated in CALGB 40601 to identify correspondent prognostic groups. | PMC10624889 |
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Immune-deconvolution, gene set enrichment analysis, differential expression analysis, gene ontology analysis | The MCP-counter tool (v1.2.0)In order to evaluate biological pathways at the single-sample level and their correlation with the prognostic score as a continuous variable, we applied GSVA (v1.36.3)The differential gene expression analysis between good and poor prognosis groups was performed using DEseq2 on gene-level abundance estimates from Salmon (functions “DESeqDataSetFromTximport” and “DESeq”). These analyses were performed on the NeoALTTO and CALGB 40601 data separately. Genes with low expression levels (sum of the reads across all samples < 10) were removed before the analysis. In order to identify genes and pathways/biological processes associated to prognosis according to our model, prognostic groups in the whole population (Gene set enrichment analysis comparing the prognostic groups was performed applying the “fgsea” R package (v1.14.0)Gene ontology analysis on the “biological process” domain was performed on all the identified differentially expressed genes with FDR < 0.05 and log | PMC10624889 |
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Gene expression signature analysis on integrated RNA sequencing data | A collection of 709 gene expression signatures derived from the literature and partially summarized beforeThe signature scores were computed by calculating the median expression of all the genes within a signature. Multiple immune-related biomarkers were included in this gene-signature collection, most of them initially extracted by comparing the gene expression pattern of different immune cell sub-populationsSignature scores were then centered removing their mean and scaled dividing them by their standard deviation in the two studies. We next computed the correlation of the signature scores with the prognostic score as continuous value (considering as significant correlations with | PMC10624889 |
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Statistical analysis | tumor, Tumor, cN+/x | TUMOR, TUMOR, REGRESSIONS | The Reporting Recommendations for Tumor Marker Prognostic Studies criteria were followed for this studyUnivariable and multivariable [controlling for tumor size (≥ cT3 vs. cT2 in NeoALTTO, ≥ cT3 vs. cT1-2 in CALGB 40601), nodal status (cN0 vs. cN+/x), hormone receptor status, age as a continuous variable, treatment arm (T or L vs. T + L), PAM50 subtypes (HER2-E vs. others)] Cox proportional hazard models were used for survival analysis. Logistic regressions were used to compute P values for pCR. In univariable analysis for survival, Wilcoxon rank sum (for comparisons between two groups) and Kruskal-Wallis tests (for comparisons between three or more groups) were used to compare continuous variables according to categorical variables. Fisher’s test was performed to compare categorical variables. All correlations were assessed calculating the Spearman’s rank correlation coefficient (rho) on pairwise complete observations, and considered significant for Kaplan–Meier survival curves were used to represent EFS according to prognostic groups, and All Heatmaps were obtained with the “ComplexHeatmap” R package (v2.4.3)All statistical analyses were performed using the R software (v4.0.5) | PMC10624889 |
Reporting summary | Further information on research design is available in the | PMC10624889 |
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Supplementary information |
Supplementary InformationPeer Review FileReporting SummaryDescription of Additional Supplementary FilesSupplementary Data 1−14Supplementary Data 15−20Supplementary Data 21−31Supplementary Data 32−37Supplementary Data 38−40 | PMC10624889 |
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Supplementary information | The online version contains supplementary material available at 10.1038/s41467-023-42635-2. | PMC10624889 |
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Acknowledgements | Breast Cancer, Cancer | ONCOLOGY, BREAST CANCER, CANCER | NeoALTTO is a BIG and SOLTI led trial. CALGB is now part of the Alliance for Clinical Trials in Oncology. Related to the NeoALTTO trial, research reported in this publication was supported by the Fondation contre le cancer, the Breast Cancer Research Foundation, Association Jules Bordet, and the Belgian Fonds National de la Recherche Scientifique (F.R.S-FNRS). Related to the CALGB 40601 trial, research reported in this publication was supported by the National Cancer Institute of the National Institutes of Health under Award Numbers U10CA180821, U10CA180882, and U24CA196171 (to the Alliance for Clinical Trials in Oncology), UG1CA233180, UG1CA233337, UG1CA233373, R01-CA229409, Breast Cancer Research Foundation. The conduct of the NeoALTTO study was funded by GlaxoSmithKline and later Novartis. The RNA sequencing in NeoALTTO, on which part of the analyses described in this manuscript are based, was funded by GlaxoSmithKline. Both trials received support from GlaxoSmithKline, who provided the study drug. For part of the analysis, computational resources have been provided by the Consortium des Équipements de Calcul Intensif (CÉCI), funded by the Fonds de la Recherche Scientifique de Belgique (F.R.S.-FNRS) under Grant No. 2.5020.11 and by the Walloon Region. M.R. was supported by Télévie and the Belgian Fonds National de la Recherche Scientifique (F.R.S.-FNRS) and by Fondation Rose et Jean Hoguet. R.S. is supported by the Breast Cancer Research Foundation (BCRF, grant nr. 17-194). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. | PMC10624889 |
Author contributions | M.R., D.V., F.R., C.S. conceived and designed the study. M.R., A.F.-M., D.V. contributed to develop the methodology. J.C., K.V.B., D.W.H. provided statistical support. B.S., E.P.W., S.E.-A., M.P., S.DC., W.F.S., I.E.K, R.S., S.L., L.P., C.M.P., L.A.C. contributed to data acquisition and to the design of the study. M.R., A.F.-M., D.V., F.R., C.M.P., L.A.C., C.S. analyzed and interpreted the data. M.R., A.F.-M., D.V., K.A.H., J.S.P. performed the analyses. D.V., K.A.H., J.S.P. provided bioinformatics support. C.M.P., L.A.C., F.R., C.S. supervised the analyses and the study. M.R., A.F.-M., D.V., L.A.C., C.S. prepared the manuscript, which was reviewed and approved by all authors. | PMC10624889 |
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Peer review | PMC10624889 |
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Data availability | For reproducibility purposes, the RNA sequencing data (fastq files) at baseline from NeoALTTO have been deposited to the European Genome-phenome Archive (EGA) database under accession number | PMC10624889 |
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Code availability | The custom script used to generate to BCR/TCR measures from MiXCR output is available at | PMC10624889 |
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Competing interests | ONCOLOGY, FOUNDER, BREAST, GLIOBLASTOMA MULTIFORME | The authors declare the following competing interests. J.S.P.: equity and consulting from Reveal Genomics; royalties from patent from Veracyte. B.S.: participation in speaker’s Bureau for AstraZeneca. E.P.W.: honoraria and equity, board member for Oncoclinicas; consultant honoraria from Carrick Therapeutics, GSK, Jounce Therapeutics; Consultant/Honoraria Research to Institute from Genentech/Roche; honoraria from Genomic Health; scientific advisory board honoraria from Leap Therapeutics. S.E.-A.: grant from Novartis within the submitted work and from Roche/Genentech and Pfizer outside the submitted work. M.P.: invited speaker for AstraZeneca, Lilly, MSD, Novartis, Pfizer, Roche-Genentech; consultant for Camel-IDS/Precirix, Roche-Genentech; advisory board for Frame Therapeutics, Gilead, Immunomedics, Immutep, Menarini, NBE Therapeutics, Odonate, Roche-Genentech, SeaGen, Seattle Genetics; member of boards of directors, scientific board for Oncolytics; research grants to her Institution from AstraZeneca, Immunomedics, Lilly; funding to her Institution from Menarini, MSD, Novartis, Pfizer, Radius, Roche-Genentech, Servier, Synthon. S.DC.: fees for medical education from Novartis, Pierre-Fabre, and IQVIA; institutional grant IG 20774 of Fondazione Associazione Italiana Ricerca contro il Cancro (AIRC); “ad hoc” medical advisor for Medica Scientia Innovation Research (MEDSIR), Barcelona (Spain). W.F.S.: founder stock in Delphi Diagnostics and publicly traded stock in IONIS Pharmaceuticals and Eiger BioPharmaceuticals; consultant/advisor to Merck, AstraZeneca; co-inventor of pending patent “Targeted Measure of Transcriptional Activity Related to Hormone Receptors”, United States, Provisional Patent Application Serial No. 62/329,774; support for unrelated research from Pfizer; uncompensated scientific advisor to Delphi Diagnostics. I.E.K.: advisory board participation/consultant and received honoraria from Bristol Meyers Squibb, Daiichi/Sankyo, Macrogenics, Genentech/Roche, Seagen, AstraZeneca, Novartis, Merck; institutional research funding/grants (paid to Institution) from Genentech/Roche, Pfizer, Macrogenics. S.L.: research funding to her institution from Novartis, Bristol Meyers Squibb, Merck, Puma Biotechnology, Eli Lilly, Nektar Therapeutics, AstraZeneca, Roche-Genentech and Seattle Genetics; consultant (not compensated) to Seattle Genetics, Novartis, Bristol Meyers Squibb, Merck, AstraZeneca, Eli Lilly, Pfizer, Gilead Therapeutics and Roche-Genentech; consultant (paid to her institution) to Aduro Biotech, Novartis, GlaxoSmithKline, Roche-Genentech, AstraZeneca, Silverback Therapeutics, G1 Therapeutics, PUMA Biotechnologies, Pfizer, Gilead Therapeutics, Seattle Genetics, Daiichi Sankyo, Merck, Amunix, Tallac Therapeutics, Eli Lilly and Bristol Meyers Squibb. L.P.: consulting fees and honoraria from Seagen, Pfizer, AstraZeneca, Merck, Novartis, Bristol-Myers Squibb, Pfizer, Genentech, Eisai, Pieris, Immunomedics, Clovis, Syndax, H3Bio, Radius Health, Personalis, Daiichi, Natera and institutional research funding from Seagen, AstraZeneca, Merck, Pfizer and Bristol Myers Squibb. R.S.: non-financial support from Merck and Bristol Myers Squibb (BMS); research support from Merck, Puma Biotechnology and Roche; personal fees from Roche, BMS and Exact Sciences for advisory boards. C.M.P.: equity stock holder and consultant of BioClassifier LLC; listed as an inventor on patent applications for the Breast PAM50 Subtyping assay; equity stock holder and consultant of Reveal Genomics. L.A.C.: research funding to her Institution from Sindax, Novartis, NanoString Technologies, Seattle Genetics, Veracyte, AstraZeneca; Royalty-sharing agreement, investorship interest in licensed intellectual property to startup company, Falcon Therapeutics, that is designing neural stem cell–based therapy for glioblastoma multiforme (immediate family member); uncompensated relationship for Eisai, Sanofi, Lilly, SeaGen, Novartis (Institution), G1 Therapeutics (Institution), Genentech/Roche (Institution), GlaxoSmithKline (Institution), AstraZeneca (Institution), Daiichi Sanyo (Institution), Exact Sciences (Institution). C.S.: advisory board (receipt of honoraria or consultations fees) for Astellas, Cepheid, Vertex, Seattle genetics, Puma, Amgen, Exact Sciences; participation in company sponsored speaker’s bureau for Eisai, Prime Oncology, Teva, Foundation Medicine, Exact Sciences; other support (travel, accommodation expenses) from Roche, Genentech, Pfizer. The remaining authors declare no non-financial or financial competing interests. | PMC10624889 |
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References | PMC10624889 |
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Background | depressive disorder, acute suicidal ideation or behavior, MDD, depressive symptoms | REMISSION | Esketamine (ESK) nasal spray, taken with oral antidepressant therapy, is approved for the treatment of depressive symptoms in adults with major depressive disorder (MDD) with acute suicidal ideation or behavior. In pooled analyses of two pivotal phase 3 studies, ASPIRE I and II, remission rates were consistently higher among patients with MDD with active suicidality who were treated with ESK + standard of care (SOC) versus placebo (PBO) + SOC at all time points in the double-blind and most time points in the follow-up phases. The current analysis of the ASPIRE data sets assessed the effect of ESK + SOC versus PBO + SOC on additional remission-related endpoints: time to achieving remission and consistent remission, proportion of patients in remission and consistent remission, and days in remission. | PMC10416356 |
Methods | Post hoc analysis of pooled data from ASPIRE I and II ( | PMC10416356 |
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Results | MDD | REMISSION | The median times to remission and consistent remission of MDD were significantly shorter in ESK + SOC versus PBO + SOC (15 versus 23 [ | PMC10416356 |
Conclusion | MDD | REMISSION | Treatment with ESK + SOC versus PBO + SOC resulted in significantly shorter time to remission, greater proportion of patients in remission, and greater percent of days in remission using increasingly rigorous definitions of remission. These findings underscore the clinical benefits of ESK for adults with MDD with suicidality. | PMC10416356 |
Trial registration | ClinicalTrials.gov registry NCT03039192 (registered February 1, 2017) and NCT03097133 (registered March 31, 2017). | PMC10416356 |
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Supplementary Information | The online version contains supplementary material available at 10.1186/s12888-023-05017-y. | PMC10416356 |
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Keywords | PMC10416356 |
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Introduction | ideation, acute suicidal ideation or behavior, ®, psychiatric illness, depressive, psychiatric, depressive symptoms, MDD, Depression, ideation or behavior, disability | DISEASE, REMISSION | Depression is a devastating psychiatric illness that is a main cause of disability worldwide [The presence of active suicidal ideation with intent in patients with MDD constitutes a psychiatric emergency requiring urgent treatment of the underlying disease (ie, MDD). Current standard practice for these patients frequently includes hospitalization to ensure close monitoring along with treatment of symptoms of MDD with an antidepressant medication and development of a comprehensive crisis management plan before discharge from inpatient care [In 2020, the U.S. Food and Drug Administration approved SPRAVATO® (esketamine [ESK] nasal spray), taken with an oral antidepressant, for the treatment of depressive symptoms in adults with MDD with acute suicidal ideation or behavior [Among patients with MDD and suicidal ideation or behavior, the incidence of suicide attempts during a major depressive episode is 21-fold higher than during remission and the length of time spent in a major depressive episode is a risk factor for suicide attempts [ | PMC10416356 |
Aims of the study | suicidality | REMISSION | This post hoc analysis assessed the effect of ESK + SOC versus PBO + SOC on time to achieving remission and consistent remission (as assessed by the Montgomery-Åsberg Depression Rating Scale [MADRS] total score alone or combined with an assessment of suicidality by the Clinical Global Impression-Severity of Suicidality-revised version [CGI-SS-r] scale) as well as time spent in remission, using pooled data from two pivotal phase 3 trials, ASPIRE I and ASPIRE II. | PMC10416356 |
Methods | PMC10416356 |
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Patients | This post hoc analysis used data pooled from two identically designed, double-blind, randomized, placebo-controlled, multicenter, phase 3 studies: ASPIRE I (NCT03039192) and ASPIRE II (NCT03097133) [ | PMC10416356 |
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Study design | MDD, psychiatric, depressive disorder | ASPIRE I was conducted from June 2017 to December 2018 in the United States, Europe, Asia, and South Africa. ASPIRE II was conducted from June 2017 to April 2019 in North America, South America, and Europe. Both studies consisted of three phases: (1) a 24- to 48-h screening phase to assess patients’ eligibility for study enrollment, (2) a 4-week double-blind treatment phase (days 1–25), and (3) a 9-week post treatment follow-up phase (days 26–90). During the 4-week double-blind treatment phase, patients were randomly assigned (1:1) to receive either ESK 84 mg or PBO nasal spray twice weekly, in addition to comprehensive SOC treatment (initial psychiatric hospitalization for a recommended ≥ 5 days and newly initiated or optimized oral antidepressant(s), per clinical judgement and practice guidelines) (Fig. Study design of ASPIRE I and ASPIRE II. Two patients in each treatment group were excluded from these analyses because they did not receive a dose of intranasal study drug after randomization. Changes in MADRS total score and CGI-SS-r were assessed at 4 and 24 h post first dose, twice per week pre-dose during the double-blind phase, and at varied time intervals during the follow-up phase (days 28–39: twice weekly; days 46–53: weekly; days 67–90: biweekly). AD, antidepressant; ESK, esketamine; MDD, major depressive disorder; PBO, placebo; SOC, standard of care | PMC10416356 |
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Assessments | Depressive | Depressive symptoms were assessed by the MADRS total score (range: 0–60) [ | PMC10416356 |
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Time to remission and percent of days in remission | MDD | EVENT, REMISSION | Two definitions of remission were evaluated, remission and consistent remission, that were defined as a MADRS total score ≤ 12 at any given visit and for two consecutive visits, respectively. Time to remission was calculated as the time (in days) between the randomization date and the first time the patient achieved remission. Time to consistent remission was calculated as the time (in days) between the randomization date and the date of the first of two consecutive visits where remission was achieved. For each definition of remission of MDD, a single criterion (i.e., MADRS total score ≤ 12) and a combined endpoint (i.e., MADRS total score ≤ 12 and CGI-SS-r ≤ 1 [not suicidal/questionably suicidal]) were examined. For consistent remission, both criteria (i.e., MADRS total score ≤ 12 and CGI-SS-r ≤ 1) had to be met for two consecutive visits. Patients were censored at the date of the last non-missing assessment if no event was identified over the entire study follow-up (days 1–90). Intermittent missingness was treated as a non-response. Monotone missingness was censored at the last non-missing assessment visit.Number of days in remission (based on MADRS total score ≤ 12) was calculated for the double-blind treatment and follow-up phases. Percent of days in remission was calculated as the number of days in remission divided by the number of days in the study. When calculating the number of days in remission, the last observation carried backward was used within the double-blind treatment and post treatment follow-up phases separately (i.e., the last observed remission or non-remission status was carried backward until the visit with a non-missing value), due to the intermittent assessments at scheduled visits per protocol. For monotone missingness, values were not included in the number of days in the study. | PMC10416356 |
Statistical analysis | MDD | REGRESSION, REMISSION | The analysis set included all randomized patients from ASPIRE I and ASPIRE II. The Kaplan–Meier product-limit method was used to estimate the median time (95% confidence interval [CI]) to remission of MDD from baseline. Univariate and multivariable Cox proportional hazards regression models were used to estimate hazard ratio (HR). The multivariable Cox hazards regression model included treatment and baseline score as covariates, and analysis center and SOC antidepressant treatment at baseline as stratification factors. For the number of days in remission, a Mann–Whitney U test was used to compare the median percent of days in remission between treatment arms. No adjustment for multiple comparisons was made. | PMC10416356 |
Time to consistent remission of major depressive disorder | MDD | REMISSION | Time to consistent remission of MDD (MADRS total score ≤ 12 for two consecutive visits) was significantly shorter in patients treated with ESK + SOC versus PBO + SOC: median time, 23 versus 50 days; adjusted HR (95% CI), 1.50 (1.12, 2.00); Kaplan–Meier curves of (Based on the single criterion of MADRS total score ≤ 12 for two consecutive visits, the cumulative probability of consistent remission was 54.2% in the ESK + SOC group versus 39.8% in the PBO + SOC group by day 25; and 75.0% in the ESK + SOC group versus 55.0% in the PBO + SOC group by day 90 ( | PMC10416356 |
Discussion | ideation, treatment-resistant depression, depressive, psychiatric, depressive symptoms, MDD, suicidality | REMISSION | In ASPIRE I and II, ESK demonstrated a rapid reduction of depressive symptoms in patients with MDD with active suicidal ideation and intent who were experiencing a psychiatric emergency [In practice, temporary hospitalization leaves patients with MDD and suicidality vulnerable in the near term while antidepressant treatment takes weeks to be effective [A large body of literature points to the importance of rapidly achieving remission in patients with MDD and suicidality [In addition to the humanistic benefits of achieving remission, there are economic benefits as well. In patients with treatment-resistant depression, healthcare resource utilization (HRU) is lower during remission than during a major depressive episode [A strength of our analysis is that multiple, increasingly stringent assessments of remission were used and that the results obtained were robust and consistent. The benefits of ESK + SOC over PBO + SOC were maintained during the follow-up phase, when ESK treatment had been discontinued.Limitations of this analysis include the post-hoc nature of the evaluation and the lack of adjustment for multiple comparisons. In addition, the suicidality endpoint (CGI-SS-r), while an important component of the remission assessment, did not show a statistically significant difference favoring ESK in the ASPIRE studies. Therefore, the results should be interpreted in line with the exploratory nature of the analysis. Finally, MADRS and CGI-SS-r assessments were performed intermittently, thus the remission analyses used values at each visit or two consecutive visits and days of remission in between two assessments were based on the calculation of last observation carried backward as described in the Methods. | PMC10416356 |
Conclusions | MDD, ideation or behavior, depressive symptoms | REMISSION | In summary, in this post hoc analysis of patients with MDD with suicidal ideation or behavior, treatment with ESK + SOC, compared to PBO + SOC, resulted in greater proportions of patients achieving remission and significantly shorter time to remission (using increasingly stringent definitions of remission incorporating depressive symptoms and severity of suicidality), as well as a significantly greater percent of time spent in remission. These findings highlight the clinical benefits of ESK treatment to address high unmet needs in adults with MDD with acute suicidality. | PMC10416356 |
Acknowledgements | Yutian Mu, of Evidera-PPD, provided support for the statistical analysis. Writing assistance was provided by Allison Marin, PhD, of System One. Additional editorial support was provided by Harry Ma, PhD, of Janssen Global Services, LLC. | PMC10416356 |
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Authors’ contributions | DJF and CMC contributed to the study concept and design. LS and SG performed the statistical analysis and prepared the figures. All authors contributed to the interpretation of results. DJF wrote the main manuscript text. All authors participated in the critical revision of the manuscript for important intellectual content and approved the final manuscript. | PMC10416356 |
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Funding | The study was supported by funding from Janssen Research & Development, LLC. Employees of Janssen, as noted under Authors’ Contributions, were involved in the design, collection, and analysis of the data; interpretation of the results; preparation of the manuscript; and the decision to submit the manuscript for publication. The sponsor also provided funding for the development of the manuscript. | PMC10416356 |
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Availability of data and materials | Johnson & Johnson is | The data sharing policy of Janssen Pharmaceutical Companies of Johnson & Johnson is available at: NCT03039192: NCT03097133: | PMC10416356 |
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Declarations | PMC10416356 |
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Ethics approval and consent to participate | Over 60 Institutional Review Boards and Independent Ethics Committees approved the study protocol and amendments. The full list can be found in Additional File | PMC10416356 |
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Consent for publication | Not applicable. | PMC10416356 |
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Competing interests | Johnson & Johnson company stocks or stock | Dong-Jing Fu, Qiaoyi Zhang, Joana Anjo, Marguerite O’Hara, and Carla Canuso are employees of Janssen Research & Development, LLC and may hold Johnson & Johnson company stocks or stock options. Stephane Borentain, Abigail Nash, and Maju Mathews were employees of Janssen Research & Development, LLC at the time of study and manuscript preparation and may hold Johnson & Johnson company stocks or stock options; Abigail Nash is currently employed by Neurocrine Biosciences Inc.; Maju Mathews is currently employed by Perception Neuroscience. Ling Shi and Shien Guo are employees of Evidera-PPD and received research funding support from Janssen Research & Development, LLC. | PMC10416356 |
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References | PMC10416356 |
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Purpose | humour | The effect of humour on end-of-life patients could be beneficial and is worth investigating. However, data on humour interventions for patients in palliative care are scarce. This study evaluated the effects of a humour intervention in a palliative care setting. | PMC9925513 |
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Methods | humour | A two-step intervention was developed based on the humour habits programme by McGhee. Patients were assisted to remember funny episodes from their past and recognize humorous aspects of the present and encouraged to produce humour. The intervention and control group completed questionnaires on life satisfaction, cheerfulness, symptom burden, and perceived stress and if possible gave saliva samples to investigate oxytocin levels. The study was a randomized controlled monocentre study on patients treated in a palliative care ward. Participants had to be conscious and alert enough to complete data collection. Overall, 55 patients were included and randomized to the intervention or control group. | PMC9925513 |
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Results | bad mood | Parameters in the control group did not change significantly. In the intervention group, seriousness, bad mood, and stress were reduced. Cheerfulness increased significantly after the intervention. However, the methodologically complex intervention setting was too exhausting for the majority of patients. | PMC9925513 |
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Conclusion | Patients who were able to participate benefited from the effects of the intervention on multiple levels. For future research simple interventions, biomarkers for well-being and assessments by staff or proxies are needed to include patients with reduced cognitive and physical performance status at the end of their lives. | PMC9925513 |
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Trial registration | DRKS00028978 German Registry of Clinical Studies. | PMC9925513 |
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Supplementary Information | The online version contains supplementary material available at 10.1007/s00520-023-07606-9. | PMC9925513 |
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Keywords | Open Access funding enabled and organized by Projekt DEAL. | PMC9925513 |
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Background | Humour has been investigated in various contexts in the past, but a range of diverging definitions has been used in these studies. Ruch [Humour interventions in patients with palliative diagnosis have rarely been implemented or systematically evaluated. Recent systematic reviews have summarized the available evidence from Pinna et al. [ | PMC9925513 |
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Objectives | humour, bad mood | We hoped to improve the foundation of knowledge of suitable evaluation instruments for interventions in a palliative care setting. We investigated the effect of a humour intervention on life satisfaction, cheerfulness, seriousness, bad mood, symptom burden, level of stress, and oxytocin in saliva. We hypothesized that the intervention would reduce levels of stress and symptom burden and improve mood and cheerfulness in comparison to a control group without the intervention. | PMC9925513 |
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Methods | PMC9925513 |
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Sample/study design | pain | We implemented a parallel study design with two groups with equal randomization. A pilot test used a more elaborate study setting with extensive questionnaires and quantitative sensory pain threshold testing [ | PMC9925513 |
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Inclusion and exclusion criteria | LLD, multi-resistant infections | All participants were being treated in the palliative care ward of the University Hospital Bonn in Germany. Patients had to be conscious and alert and understand the German language well enough to complete the questionnaires. They had to provide informed consent to participate in the study.Patients were excluded if they were unconscious or severely fatigued. Potential test persons with multi-resistant infections could not provide saliva samples due to laboratory restrictions.All included patients were randomized to intervention or control group using a simple randomization list (using the random number generation function in Excel). The study was not blinded nor allocation concealed as the ethics committee had requested to include information on the specific burden related to participation in the study for each group. One of the authors (LLD), who is a researcher in the Department of Palliative Medicine, but not involved in clinical care, enrolled and assigned the patients to one of the groups. The power calculation resulted in overall 240 patients to achieve a medium effect of | PMC9925513 |
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Instruments | The set of questionnaires included the State-Trait-Cheerfulness-Inventory (STCI-T and -S) [Cheerfulness was measured using the STCI-T and -S [Symptom burden and well-being were assessed with the MIDOS [Life satisfaction was measured with the SWLS [The distress thermometer consists of a scale from 0 to 10 where participants can mark their level of stress in the current situation [Saliva samples were collected by a study nurse by having the patient chew on a cotton wool roll (Salivette® Sarstedt) for at least 60 s. Then the concentration of oxytocin in saliva [The researcher assisted the patients in completing the questionnaires. Depending on their performance level, she read the questions aloud or supervised independent completion. | PMC9925513 |
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Intervention | humour | RED NOSE, EVENTS | The “humorous visit” was offered to the patients of the intervention group. Two professional hospital clowns who were dressed in the bright style of Mr. Bean (as clown outfits and the red nose seemed unsuitable for the setting) visited the patients one or two times. The training was performed by Laura Fernandez. The primary goal was to find the connection between the clown characters “Robert “ and”Lilly”, their joy, their humour, their differences, and their abilities. This was followed by exercises to “be in the moment”, “to get in touch”, and to find a playful or calm way from there on. Improvisation was one tool for training and to establish a trustful understanding between the clown actors. As both clown actors play instruments, making music together became not only an important part for the interventions, but also a nice warm-up for the clown actors to re-focus on their goals every week before the intervention. The intervention was based on McGhee’s humour habits programme, which was adapted by Falkenberg et al. [Entering the patient’s room, the humour coaches explored the mood of the patient and tried to find an adequate vibe to communicate. They asked a couple of questions concerning the biography and important life events to find out the patient’s preferred humour style. They then tried to find humorous aspects of the current situation using equipment in the room or making up a funny song about something the patient had mentioned. If the patients were still at the palliative care ward in the following week, they prepared a second visit focusing on aspects that were dear to the patient. As planning into the future is limited for patients in palliative care, they sometimes acted out unfulfilled wishes (such as a concert with songs of a specific singer or a cruise) in a caring and humorous manner.The control group filled out the questionnaires twice and then provided saliva samples as well 1 day before the intervention group. | PMC9925513 |
Procedure | Data collection was performed according to the scheme displayed in Table Procedure of data collection intervention group | PMC9925513 |
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Analyses | We implemented SPSS statistics for quantitative and MAXQDA for qualitative analyses. For pre- and post-workshop comparisons, An inductive-deductive approach was used to analyse the qualitative data. The inductively defined codes were condensed with additional codes until saturation was reached. The details of these analyses will be reported elsewhere. | PMC9925513 |
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Results | PMC9925513 |
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Sample | RECRUITMENT | Overall 984 patients were scanned for eligibility from October 2017 to April 2019, and 140 patients were recruited for the study. However, only 55 patients completed the questionnaires and were included in the evaluation (27 were in the control group and 28 in the intervention group; see Fig. Flowchart patient recruitment | PMC9925513 |
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Missing values | Only five of the 28 patients who received a second intervention were able to fill out the complete questionnaires again before and after the intervention to make an evaluation of quantitative data possible. Oxytocin in saliva could only be derived from 9 patients of the intervention and 9 of the control group, and thus, oxytocin data were not included in the analysis. | PMC9925513 |
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Group comparisons | There were no significant differences in the pre-test scores for life satisfaction (Pre-test group differencesUnivariate analysis for variances between intervention and controlIn the control group, none of the investigated parameters changed significantly between pre- and post-measurement (see Table Mean values pre- and post-measures in the control groupAs expected, the Mean values pre- and post-measures in the intervention group** | PMC9925513 |
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Qualitative data | fatigue | Field notes were documented for all patients in the intervention group by the researcher. The field notes were coded and afterwards categorized into condition, contact, situation and life, expression of emotion, positive aspects, and symptoms. In the category condition, the code “deep breath” was coded most frequently. Frequent topics for contact were “participation”, “reception”, and “thank you/expression of gratitude”. “Reported memories” were predominant in situation and life. Expressions of emotion were very versatile, but signs of emotion were frequently coded. The category positive aspects included the highest number of codes including “smile”, “laugh”, “I like/that was great”, “joke”, and “applause”. Symptom codes were related to fatigue and exhaustion. During the coding of the data, new codes were added during the first half of the protocols, after which saturation occurred and the existing codes were sufficient for the analysis of the protocols. Exemplary quotes can be accessed in a table in the | PMC9925513 |
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Discussions and conclusions | PMC9925513 |
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Limitations | humour, depression, fatigue, ill | There was major attrition in this study, leading to many incomplete datasets and only very few patients that were treated according to protocol, even though we had shortened and simplified assessment instruments and intervention following a pilot testing. Most randomized patients did not consent to participate in the study due to feeling fatigued or being sedated, and most of those who participated were not available for a second humour intervention as they had been discharged or transferred to another place of care. Therefore an intention-to-treat analysis was not feasible. With almost zero questionnaire data available from these patients, imputation was not possible, and an elevation of The control group did not receive an alternative intervention, due to feasibility reasons. This inactive control group setting creates the risk of performance bias. Lack of an active control also prevented adequate blinding and allocation concealment. These limitations may limit the transferability of the results. However, inclusion rates did not differ significantly between the intervention and control group, indicating a low risk of allocation bias. Methodologically, it would have been useful to set a cut-off value for cheerfulness to rule out bias by higher levels of cheerfulness in the persons who agreed to participate in the study. However, since levels of state cheerfulness did not show significant differences between intervention and control group, it can at least be assured that there was no bias due to allocation. The effect of cheerfulness on the willingness to participate might not be specific to humour interventions though, as a higher level of depression has been shown to limit the willingness to participate in any kind of study [The comparison of control and intervention group at the start of data collection showed that there was no significant difference between groups. Even though allocation was not concealed, these data seem to ensure comparability of both groups.Ethical aspects of collecting complex data with severely ill patients at the end of their lives need to be discussed [In the original study plan, we had included a semi-structured interview for day 5 of the data collection. This was only possible in very few cases due to patient discharge, fatigue, and exhaustion of patients after the data collection and interventions. | PMC9925513 |
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Discussion | humour, dry mouth, far-advanced disease, bad mood | DRY MOUTH | Although we had already simplified the intervention after the pilot test and reduced the number of intervention appointments, still only a very small proportion of palliative care patients were eligible, and even fewer were able to provide sufficient data from the first intervention. This phenomenon of high attrition rates has been reported in palliative care previously [Even though the analysis of variance did not show a significant effect of the intervention in the pre- and post-comparison, the comparison of pre- and post-data between the intervention and control group presented some promising results despite the small sample size. Whereas there were no significant changes in the control group, the perceived level of stress, seriousness, and bad mood were reduced in the intervention group, and cheerfulness increased. The positive effects of the humour intervention were supported in the qualitative analysis of the field notes. However, Bland and Altman [In the intervention group, life satisfaction was slightly lower after the intervention, in contrast to the positive findings for level of stress, seriousness, bad mood, and cheerfulness. A possible explanation could be that completing the questionnaires might have had a negative effect on patients’ life satisfaction. This effect has been reported in literature in the past [Our study confirmed that short and simple assessment instruments are a mandatory precondition for palliative care research. However, evaluation of the effectiveness of humour interventions in patients with far-advanced disease might require proxy-reported instead of patient-reported outcome measures and observational assessment instruments as well as suitable biomarkers. Again, problems with sampling have to be considered, such as the high frequency of dry mouth or swallowing problems which can interfere with saliva sampling. | PMC9925513 |
Conclusion | humour, cognitive impairment | DISEASE | Major problems with attrition led to a smaller as planned sample size in our intervention study. However, we found some promising results for a positive effect of the humour interventions for patients in palliative care. Further research could be planned for the outpatient and home care setting, recruiting patients less advanced in the disease trajectory and thus with less physical or cognitive impairment compared to those on a palliative care unit. However, standardized training of clowns for this kind of humour intervention would be a necessary prerequisite for such a roll-out. | PMC9925513 |
Acknowledgements | The study has been registered at the German Registry of Clinical Studies under the number DRKS00028978. We thank Martin Mücke and Sarit Quirin for proofreading the manuscript and giving valuable advice, as well as the medical staff of the palliative care unit of the University Hospital Bonn for cooperating and supporting our study at all times. Most importantly we thank the patients who agreed to take part in this study. | PMC9925513 |
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Author contribution | humour | The article was drafted and written by Lisa Linge-Dahl. All other authors contributed to previous versions and approved the final manuscript. Lisa Linge-Dahl, Sonja Heintz, Willibald Ruch, Eckart von Hirschhausen, and Lukas Radbruch constructed the conceptualisation of the data collection. Mieke Stoffelen and Rainer Kreuz performed the humour interventions and gave feedback to the manuscript. Lukas Radbruch and Lisa Linge-Dahl performed the data analysis. | PMC9925513 |
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Funding | humour, Humor | Open Access funding enabled and organized by Projekt DEAL. The non-profit organization Humour Helps to Cure (Humor Hilft Heilen) provided partial financial support. The salary for the humour coaches who conducted the humour interventions. Their feedback was focused on the description of the intervention in this manuscript. The data collection, analysis, and interpretation were performed by the first author. The 6th author is funding member of Humour Helps to Cure. He gave feedback to the manuscript from a professional point of view. | PMC9925513 |
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Data availability | Due to privacy regulations considering data from patients being treated in a German university hospital, we cannot provide the data to others. The ethics committee also demanded a paragraph stating that the data will only be used by us in pseudonymized form for the publication of the results of our study. | PMC9925513 |
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Declarations | PMC9925513 |
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Ethics approval and consent to participate | The Ethics Committee of the University Hospital Bonn examined and approved the questionnaires and methodology of the study under the number 003/16 on the10th of February 2016. It works in accordance with the 1964 Helsinki Declarations. All participants had to provide informed written consent to be able to participate in the study. | PMC9925513 |
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Consent for publication | All participants also agreed to the publication of data in anonymized form. | PMC9925513 |
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Competing interests | The authors declare no competing interests. | PMC9925513 |
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References
| PMC9925513 |
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Key Points | PMC10733798 |
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Question | dementia | Do 2 predominant modes of home-delivered meals (daily-delivered meals and mailed, or drop-shipped, frozen meals) differentially delay nursing home placement for homebound older adults with self-reported dementia? | PMC10733798 |
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Findings | dementia | This pilot pragmatic clinical trial included 243 homebound older adults with self- or proxy-reported dementia found a lower although nonsignificant likelihood of nursing home placement among those receiving daily-delivered meals compared with those receiving drop-shipped frozen meals. However, the feasibility of conducting a clinical trial with Meals on Wheels programs was shown. | PMC10733798 |
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Meaning | These results suggest that further exploration in an adequately powered clinical trial is possible and warranted. | PMC10733798 |
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Importance | dementia | Home-delivered meals promote food security and independence among homebound older adults. However, it is unclear which of the 2 predominant modes of meal delivery, daily-delivered vs mailed (or drop-shipped) frozen meals, promotes community living for homebound older adults with dementia. | PMC10733798 |
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Objective | To assess the risk of nursing home admission within 6 months between homebound individuals receiving daily-delivered vs drop-shipped frozen meals. | PMC10733798 |
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Design, Setting, and Participants | dementia | This pilot, multisite, 2-arm, pragmatic clinical trial included older adults with self-reported dementia on waiting lists for meals at 3 Meals on Wheels (MOW) programs in Texas and Florida between April 7 and October 8, 2021, to assess time to nursing home placement. | PMC10733798 |
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Interventions | Participants were randomized to receive either meals delivered by an MOW driver or frozen meals that were mailed to participants’ homes every 2 weeks. Participants received their assigned intervention for up to 6 months. | PMC10733798 |
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Main Outcomes and Measures | The primary study outcome was days from randomization to a Minimum Data Set nursing home admission assessment within 6 months. Feasibility of conducting this type of study was examined by tracking enrollment, examining baseline characteristics, monitoring participants’ intervention fidelity, measuring the proportion of participants linked with Centers for Medicare & Medicaid Services (CMS) data, and analyzing the primary study outcome. | PMC10733798 |
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Results | death | EVENT | Among 325 eligible participants who were randomized, 243 enrolled in the study (mean [SD] age, 81 [8.0] years; 152 (62.6%) were female): 128 to the daily-delivered meals group and 115 to the drop-shipped frozen meals group; 119 participants (49.0%) lived alone. Among the total participants enrolled, 227 (93.4%) were linked deterministically to their CMS data; probabilistic methods were used to link the remaining 16 participants (6.6%). At 6 months from randomization, 160 participants (65.8%) were still receiving meals, and 25 (10.1%; 95% CI, 6.3%-14.0%) were admitted to a nursing home. After adjusting for sex, race and ethnicity, age, program, and living arrangement and the use of death as a censoring event, the adjusted log hazard ratio of nursing home placement between daily-delivered and drop-shipped frozen meals was −0.67 (95% CI, −1.52 to 0.19). | PMC10733798 |
Conclusions and Relevance | dementia | This pilot randomized clinical trial demonstrated the feasibility of enrolling participants with self-reported dementia on waiting lists at MOW programs, linking their data, and evaluating outcomes. While this pilot study was not powered to detect meaningful, statistically significant differences in nursing home placement, its feasibility and initial results warrant exploration in a follow-on, adequately powered trial. | PMC10733798 |
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Trial Registration | ClinicalTrials.gov Identifier: | PMC10733798 |
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Introduction | dementia | An overwhelming majority (81%) of the 5.3 million older adults with dementia live in the community, and an estimated 25% to 30% live alone.Home-delivered meals, by organizations such as Meals on Wheels (MOW), promote food security, socialization, and independence among older adults who are homebound. Partially funded by Title III of the Older Americans Act, about 5000 programs served more than 880 000 older adults in 2019, over half of whom lived alone, were older than 75 years, and indicated that the meals provided more than half of their total food for the day.Historically, home-delivered meals have been provided to clients in their homes 5 to 7 days each week (referred to as daily-delivered meals). Meals typically come ready to eat and are delivered by a volunteer or paid driver who may informally socialize with the client and report any concerns about their well-being to the meal program staff. In recent years, the model of mailing 1 to 2 weeks’ worth of frozen meals (referred to as drop-shipped meals) has emerged as a lower-cost alternative. While both models provide the same nutritional benefit, older adults receiving drop-shipped frozen meals do not experience the socialization, assistance, and identification of service needs, which are believed to drive many of the positive outcomes associated with receiving home-delivered meals. In addition, frozen meals require reheating; therefore, older adults receiving frozen meals may not have the convenience of ready-to-eat meals. The additional benefits afforded by the daily-delivered model are likely to be especially important for older adults who are homebound with dementia—a population who experiences social isolation,Therefore, the primary objective of this pilot, pragmatic randomized clinical trial was to assess the association between daily-delivered vs drop-shipped frozen meals and nursing home admission among homebound adults with dementia and to test the feasibility of tracking enrollment, examining baseline characteristics, monitoring participants’ intervention fidelity, measuring the proportion of participants linked with Centers for Medicare & Medicaid Services (CMS) data, and analyzing the primary study outcome. | PMC10733798 |
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Methods | PMC10733798 |
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Trial Design and Oversight | dementia | BROWN | The trial protocol was approved by the Brown University institutional review board and was overseen by a National Institute on Aging–appointed safety officer. The full trial protocol (The pilot study was designed as a multisite, pragmatic, randomized clinical trial to test the feasibility of enrolling people with dementia, randomizing them to 1 of 2 home-delivered meal interventions, monitoring their fidelity to the intervention, linking them to data from the CMS, and analyzing their outcomes. Enrollment began April 7 and ended October 8, 2021. Final, 6-month follow-up observations concluded April 8, 2022. The pilot study included a qualitative substudy in which a subset of participants and a subset of caregivers participated in in-depth telephone interviews. (The approach and results of the substudy are published elsewhere. | PMC10733798 |
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