Neoadjuvant ipilimumab and nivolumab in resectable cutaneous squamous cell carcinoma: a randomized phase 2 trial.
Breukers SE, Traets JJH, van Dijk SW, Ostos MM, Fraterman I, Crommelin RD, van der Hulst H, Qiao X, Boere T, van de Poll-Franse LV, Retèl V, van der Noort V, Vos JL, Toppenberg AGL, van der Heijden M, Missale F, Balm F, van den Brekel M, Dirven R, Karakullukcu MB, Karssemakers L, Klop WMC, Lohuis PJFM, Schreuder WH, Smeele LE, van der Velden LA, Plasmeijer E, Smit LA, de Boer JP, Navran A, Westerink B, de Koekkoek-Doll PK, Castelijns J, Wondergem M, Vogel WV, Kuijpers A, van Houdt WJ, Onderwater S, Maas-Bannink E, Cornelissen S, Broeks A, Tijink BM, Devriese LA, de Bree R, Blank CU, Schumacher TN, Thommen DS, Haanen JBAG, Zuur CL
- DOI
- 10.1038/s41591-025-03943-w
- Record issued
- 2026-08-15
- Engine
- 7.39.0
- Exported
- 2026-09-20
Prepared by Alpha1. This document is confidential: it is intended for the recipient it was shared with and must not be redistributed. The live record at alpha1science.com/verify/1e8badff-63e3-4306-afed-026aaddf76a6 is authoritative.
How this rating was calculated
- IntegrityIntegrity concern ×3−1.5★
- ClaimsEfficacy rests on an unvalidated surrogate endpoint−0.5★
- ClaimsTreatment effect not shown to be clinically meaningful−0.5★
- No reported statistical tests were found to recompute.
- 01Efficacy rests on an unvalidated surrogate endpoint
The primary endpoint is pathological response rate (MPR/PPR), a surrogate for clinical benefit. The paper does not provide evidence of target engagement at the tested dose (e.g., PK/PD) nor does it cite validated evidence linking pathological response to long-term clinical outcomes in CSCC. Although 2-year DSS is reported, the primary claim of efficacy rests on the surrogate.
“The primary objective was to determine the histopathological response rate to neoadjuvant NIVO and NIVO + IPI at the time of SOC surgery with or without adjuvant RT. Histopathological tumor response was defined as the proportion of viable tumor cells left in…”
- 02Treatment effect not shown to be clinically meaningful
The reported pathological response rates (55% and 80%) are presented without anchoring to a minimal clinically important difference or to the natural history of the disease. The clinical significance of these surrogate endpoints is not established, and the survival outcomes are based on short follow-up and small numbers.
“resulting in pathological response rates of 55% and 80%, respectively. MPR or PPR was accompanied by 2-year disease-specific survival (DSS) of 100%.”
- 03Other integrity concern
Trial NCT04620200 was first submitted to ClinicalTrials.gov on 2020-08-20, after the registered study start date of 2020-08-11. Retrospective registration means the protocol and outcomes were not on the public record before the study ran, which is what prospective registration exists to establish.
NCT04620200
reviewer’s wording
This Kaimen Rigor review uses Kaimen Rigor reviewers trained on a curated corpus of high-fidelity and retracted papers, with expert supervision and curation. It can still make mistakes; verify each finding against the source before relying on it.
The MATISSE trial is a well-reported phase 2 study with clear scientific premise, adequate study design, and comprehensive ethical and data-sharing documentation. Minor reporting gaps include lack of explicit reporting guideline adherence, some threshold p-values, and a retrospective registration concern.
Both reviewers classified the study as interventional and agreed on all dimension statuses; no divergence to resolve. The statistics verification component could not recompute any tests due to lack of reported test statistics with df or effect estimates with CIs; the mathematical plausibility check was not applicable.
Numerical inconsistencies
1 finding · worst lowValues that contradict each other or are impossible for the stated sample: recomputed p-values and test statistics, GRIM/GRIMMER checks on summary numbers, percentages against their own counts, totals against their parts, and estimates against their own confidence intervals.
- Internal contradictions in the reported numbersAssessed
- lowinternal contradictionThe abstract states '9 of 20 (45%) patients who received NIVO and 10 of 20 (50%) patients who received NIVO + IPI reached a major pathological response (MPR)', but the results section says '9 of 20 (45%) patients receiving NIVO and 10 of 20 (50%) patients receiving NIVO + IPI reached an MPR'. This is consistent. However, the total number of patients randomized is 50 (26 NIVO, 24 NIVO+IPI), but only 40 underwent SOC and were analyzed for the primary endpoint. The 10 patients who declined surgery are not included in the primary analysis, which is appropriate but should be clearly stated.
“9 of 20 (45%) patients who received NIVO and 10 of 20 (50%) patients who received NIVO + IPI reached a major pathological response (MPR)”
AbstractFind in source
Overstated conclusions
3 findings · worst highConclusions that reach past what the paper's own results support — including a significance claim that no longer holds when the statistic is recomputed, and efficacy resting on an unvalidated surrogate endpoint.
- Efficacy rests on an unvalidated surrogate endpointAssessed
- Treatment effect not shown to be clinically meaningfulAssessed
- Conclusions only partially backed by the presented evidenceAssessed
8 major claims checked against the paper's own evidence: 2 only partially supported (evidence backs part of the claim; gaps or caveats remain); the rest adequately supported.
- partialReviewers 1, 2Early changes in FDG-PET TLG can safely select patients for response-guided treatment de-escalation.The biomarker shows high sensitivity/specificity, but the claim of 'safely select' is an inference from a small cohort and not a prospective validation.Evidence: Results report 94% sensitivity, 86% specificity for primary tumor TLG decrease.
“A decrease in the TLG 50% at the primary tumor identified a response with 94% sensitivity, 86% specificity and 92% accuracy”
ResultsFind in source - partialReviewer 2The combination of nivolumab and ipilimumab has potential benefit over anti-PD-1 monotherapy.The trial was not powered to compare arms, and the higher response rate in arm B is not statistically tested; the claim is based on other cancers.Evidence: Discussion states 'the combination of nivolumab and ipilimumab has shown potential benefit over anti-PD-1 monotherapy across other solid cancers' and the trial was noncomparative.
“the MATISSE trial was a noncomparative trial and not powered to compare NIVO to NIVO + IPI, although the combination of nivolumab and ipilimumab has shown potential benefit over anti-PD-1 monotherapy across other solid cancers”
DiscussionFind in source - supportedReviewer 1Neoadjuvant nivolumab with or without ipilimumab results in high pathological response rates in resectable CSCC.The pathological response rates of 55% and 80% are directly reported from the trial data.Evidence: Results section reports 9/20 MPR and 2/20 PPR for NIVO, and 10/20 MPR and 6/20 PPR for NIVO+IPI, giving total response rates of 55% and 80%.
“resulting in pathological response rates of 55% and 80%, respectively.”
AbstractFind in source - supportedReviewers 1, 2MPR or PPR is accompanied by 2-year DSS of 100%.The Kaplan-Meier estimates show 100% DSS for MPR and PPR groups, as stated.Evidence: Figure 1c shows DSS curves with 100% at 2 years for MPR and PPR groups.
“Having an MPR or PPR was accompanied by excellent 2-year DSS of 100%, irrespective of the treatment arm”
ResultsFind in source - supportedReviewer 1Ten patients who declined surgery achieved durable organ preservation with clinical complete remission on two ICB infusions alone.Nine of the ten patients achieved CCR, and the paper reports 100% DSS for this group.Evidence: Results section describes 9 patients with CCR and their outcomes.
“The other nine patients (five receiving NIVO and four NIVO + IPI) reached a clinical complete remission (CCR) in 2–10 months after the start of neoadjuvant ICB, without surgery, RT or additional cycles of IT.”
ResultsFind in source - supportedReviewer 1The combination of nivolumab and ipilimumab is safe with low grade 3 toxicity.Grade 3 irAE rates of 12% (NIVO) and 8% (NIVO+IPI) are reported, with no grade 4-5.Evidence: Table 2 reports irAE rates.
the rate of grade 3 irAEs after NIVO + IPI (8%) did not exceed that of NIVO only (12%)
Resultsreviewer’s wording - supportedReviewer 2Neoadjuvant NIVO and NIVO+IPI result in high pathological response rates of 55% and 80%.The response rates are directly reported from the trial data.Evidence: Results section reports 9/20 (45%) MPR and 2/20 (10%) PPR for NIVO, and 10/20 (50%) MPR and 6/20 (30%) PPR for NIVO+IPI, giving 55% and 80%.
“9 of 20 (45%) patients who received NIVO and 10 of 20 (50%) patients who received NIVO + IPI reached a major pathological response (MPR) and 2 of 20 (10%) patients with NIVO and 6 of 20 (30%) with NIVO + IPI reached a partial pathological response (PPR), resulting in pathological response rates of 55% and 80%, respectively.”
AbstractFind in source - supportedReviewer 2Ten patients who declined surgery achieved durable organ preservation with 2-year DSS of 100%.The paper reports that nine of ten patients who declined surgery achieved CCR and all nine remained cancer-free with 100% DSS.Evidence: Results section reports 'All nine patients with CCR remained cancer free (median FU of 34 months). Having a CCR was accompanied by 100% DSS, RFS and OS at 24 months.'
All nine patients with CCR remained cancer free (median FU of 34 months). Having a CCR was accompanied by 100% DSS, RFS and OS at 24 months.
Resultsreviewer’s wording
Premise concern: surrogate not validated for clinical benefit; effect size not shown to be clinically meaningful.
- INADEQUATESurrogate endpointThe primary endpoint is pathological response rate (MPR/PPR), a surrogate for clinical benefit. The paper does not provide evidence of target engagement at the tested dose (e.g., PK/PD) nor does it cite validated evidence linking pathological response to long-term clinical outcomes in CSCC. Although 2-year DSS is reported, the primary claim of efficacy rests on the surrogate.
“The primary objective was to determine the histopathological response rate to neoadjuvant NIVO and NIVO + IPI at the time of SOC surgery with or without adjuvant RT. Histopathological tumor response was defined as the proportion of viable tumor cells left in the surgical resection specimen.”
- INADEQUATEEffect sizeThe reported pathological response rates (55% and 80%) are presented without anchoring to a minimal clinically important difference or to the natural history of the disease. The clinical significance of these surrogate endpoints is not established, and the survival outcomes are based on short follow-up and small numbers.
“resulting in pathological response rates of 55% and 80%, respectively. MPR or PPR was accompanied by 2-year disease-specific survival (DSS) of 100%.”
Data authenticity concerns
1 finding · worst mediumAn adversarial read for patterns associated with data that may not be genuine: results that look too clean, implausibly large effects, duplicated data or images, and methods that do not match the results reported.
- Other integrity concernAssessed
3 integrity concerns flagged (0 high).
- mediumotherTrial NCT04620200 was first submitted to ClinicalTrials.gov on 2020-08-20, after the registered study start date of 2020-08-11. Retrospective registration means the protocol and outcomes were not on the public record before the study ran, which is what prospective registration exists to establish.
NCT04620200
reviewer’s wording - lowotherThe paper reports a 2-year DSS of 100% for MPR and PPR groups, which is unusually high. While plausible in a small cohort, the lack of any events in these groups may be due to short follow-up or selection bias.
“Having an MPR or PPR was accompanied by excellent 2-year DSS of 100%, irrespective of the treatment arm”
ResultsFind in source
Reporting gaps
None foundRequired detail the manuscript never states — study design, biological variables, ethics approval and consent, key resources, statistical reporting, data and code availability, and overall transparency.
Checked — nothing surfaced.
The introduction cites prior studies on CSCC incidence, immunogenicity, and neoadjuvant anti-PD-1 therapy, and notes the lack of data on combined PD-1/CTLA-4 blockade in this setting. The rationale linking high TMB and immunogenicity to the study hypothesis is clear. Limitations of prior work (e.g., small numbers, different regimens) are acknowledged in the discussion.
“prior studies in locally advanced resectable CSCCs have shown that 6 or 12 weeks of neoadjuvant anti-PD-1 with cemiplimab before curative-intent surgery induced major pathological responses (MPRs) in the surgical resection specimen of 75% and 64%, respectively”
“The combination of PD-1 and CTLA-4 checkpoint inhibition has not been previously evaluated in the neoadjuvant setting for CSCC.”
“Albeit small patient numbers, these data suggest that increasing the neoadjuvant anti-PD-1 treatment regimen may not bring increased MPR rates in CSCC.”
“prior studies in locally advanced resectable CSCCs have shown that 6 or 12 weeks of neoadjuvant anti-PD-1 with cemiplimab before curative-intent surgery induced major pathological responses (MPRs) in the surgical resection specimen of 75% and 64%, respectively”
“The combination of PD-1 and CTLA-4 checkpoint inhibition has not been previously evaluated in the neoadjuvant setting for CSCC.”
Randomization method (1:1 via ALEA Clinical Services) and unit (patient) are reported. Sample size calculation is provided. Inclusion/exclusion criteria are detailed. Blinding is explicitly not performed, which is acceptable for an open-label trial. Outlier handling is addressed through pre-specified analysis populations and missing data notes. Controls are inherent in the two-arm design. Independent replication is not applicable for a single pivotal trial.
“Patients were randomized 1:1 into either arm A, receiving two courses of nivolumab 3 mg kg −1 (weeks 0 and 2) or arm B, receiving two courses of nivolumab 3 mg kg −1 (weeks 0 and 2) and one course of ipilimumab 1 mg kg −1 (week 0 only), before SOC surgery (week 4) with or without RT (Fig. ), coordinated by the independent NKI-AVL trial bureau through ALEA Clinical Services.”
“The sample size calculation of 20 patients in each arm was powered on a 94% probability in both arms that 8 or more of 20 included patients who achieved a PCR and on a 89% probability that 4 or more of 20 included patients who achieved an NPR based on data derived from ref.”
“No blinding for the treatment arm was performed.”
“Patients were randomized 1:1 into either arm A, receiving two courses of nivolumab 3 mg kg −1 (weeks 0 and 2) or arm B, receiving two courses of nivolumab 3 mg kg −1 (weeks 0 and 2) and one course of ipilimumab 1 mg kg −1 (week 0 only), before SOC surgery (week 4) with or without RT (Fig. ), coordinated by the independent NKI-AVL trial bureau through ALEA Clinical Services.”
“The sample size calculation of 20 patients in each arm was powered on a 94% probability in both arms that 8 or more of 20 included patients who achieved a PCR and on a 89% probability that 4 or more of 20 included patients who achieved an NPR based on data derived from ref.”
“No blinding for the treatment arm was performed.”
Sex is reported for all patients (41 male, 9 female). Age (median 76 years) and performance status (WHO 0-1) are reported. Demographics include tumor site and stage. Since both sexes are enrolled, sex_justified is not applicable. Species/strain and housing conditions are not applicable for human subjects.
“Median age, years (range) | 76 (32–92) | 77 (32–83) | 76 (67–92) | | Sex, n (%) | | Male | 41 (82) | 23 (85) | 18 (78) | | Female | 9 (18) | 4 (15) | 5 (22)”
“Patients aged ≥18 years, with a World Health Organization’s performance status scale WHO 0–1”
“Median age, years (range) | 76 (32–92) | 77 (32–83) | 76 (67–92) | | Sex, n (%) | | Male | 41 (82) | 23 (85) | 18 (78) | | Female | 9 (18) | 4 (15) | 5 (22)”
“Patients aged ≥18 years, with a World Health Organization’s performance status scale WHO 0–1”
The study was approved by the Medical Ethics Committee of the Netherlands Cancer Institute—Antoni van Leeuwenhoek Hospital (METC-AVL) under file no. NL72486 031 20. Written informed consent was obtained from all participants. Compliance with the Declaration of Helsinki is stated.
“Study protocol approval was granted by the Medical Ethics Committee of the Netherlands Cancer Institute—Antoni van Leeuwenhoek Hospital (METC-AVL) under file no. NL72486 031 20, dated 26 June 2020.”
“Written informed consent was obtained from all participants.”
“This study was performed in line with the principles’ approval of the Declaration of Helsinki.”
“Study protocol approval was granted by the Medical Ethics Committee of the Netherlands Cancer Institute—Antoni van Leeuwenhoek Hospital (METC-AVL) under file no. NL72486 031 20, dated 26 June 2020.”
“Written informed consent was obtained from all participants.”
“This study was performed in line with the principles’ approval of the Declaration of Helsinki.”
The drugs nivolumab and ipilimumab are named with doses and schedule. Software tools for analysis (R, RStudio, DESeq2, etc.) are identified with versions. Antibodies, cell lines, mycoplasma, and organisms are not applicable as this is a human drug trial without wet-lab assays.
“arm A, receiving two courses of nivolumab 3 mg kg −1 (weeks 0 and 2) or arm B, receiving two courses of nivolumab 3 mg kg −1 (weeks 0 and 2) and one course of ipilimumab 1 mg kg −1 (week 0 only)”
“performed in RStudio (R, v.4.3.2) and, for plotting the ‘ggplot2’ (v.3.4.2), the R package was used.”
“arm A, receiving two courses of nivolumab 3 mg kg −1 (weeks 0 and 2) or arm B, receiving two courses of nivolumab 3 mg kg −1 (weeks 0 and 2) and one course of ipilimumab 1 mg kg −1 (week 0 only)”
“Demultiplexing of the sequencing reads was performed with Illumina bcl2fastq (v.2.20). Adapters of the reads were trimmed with Skewer (v.0.2.2)”
Tests are named (Fisher's exact, Mann-Whitney U, Wilcoxon rank-sum, log-rank). Effect sizes with CIs are reported for HRQoL and cost-effectiveness. Software is identified. Exact p-values are reported in many places, but some comparisons use 'P = 0.3' (exact) and others use 'P ≤ 0.05' (threshold). Data presentation includes Kaplan-Meier curves and forest plots. Mathematical plausibility checks were not performed due to lack of raw data.
“Comparison between treatment responses was performed using two-sided Fisher’s exact test or a two-sided linear-to-linear test for categorical variables and a two-sided Mann–Whitney U -test was used for independent continuous variables.”
“Exact P values were calculated using a two-sided log(rank test).”
“P ≤ 0.05 was considered statistically significant.”
“Comparison between treatment responses was performed using two-sided Fisher’s exact test or a two-sided linear-to-linear test for categorical variables and a two-sided Mann–Whitney U -test was used for independent continuous variables.”
“Exact P values were calculated using a two-sided log(rank test).”
“The error bars indicate the 95% confidence intervals.”
The data availability statement provides EGA accessions for WES and RNA-seq data with a managed access procedure. Code is available on GitHub with a URL. Repository deposit and accession numbers are applicable for the sequencing data. For patient-level clinical data, managed access is appropriate.
“The raw and processed DNA and RNA-seq data for this project were access restricted and can be accessed at the European Genome–phenome Archive (EGA) under accession nos.: EGAD50000001469 (https://ega-archive.org/datasets/EGAD50000001469) (WES data) and EGAD50000001470 (https://ega-archive.org/datasets/EGAD50000001470) (RNA-seq data).”
“The code is available via GitHub at https://github.com/MATISSE (https://github.com/ZuurLab/MATISSE_ms_code_2025) .”
“The raw and processed DNA and RNA-seq data for this project were access restricted and can be accessed at the European Genome–phenome Archive (EGA) under accession nos.: EGAD50000001469 (https://ega-archive.org/datasets/EGAD50000001469) (WES data) and EGAD50000001470 (https://ega-archive.org/datasets/EGAD50000001470) (RNA-seq data).”
“The code is available via GitHub at https://github.com/MATISSE (https://github.com/ZuurLab/MATISSE_ms_code_2025) .”
Methods are comprehensive. Trial registration number is provided (NCT04620200). Limitations are discussed (noncomparative, small sample, not powered). Conclusions are appropriately cautious. Funding and competing interests are disclosed. Reporting guideline (CONSORT) is not explicitly mentioned, but the paper follows standard reporting.
“The ClinicalTrials.gov identifier is: NCT04620200 (https://clinicaltrials.gov/study/NCT04620200) .”
“the MATISSE trial was a noncomparative trial and not powered to compare NIVO to NIVO + IPI”
“This research was funded by a grant (no. CA209-7W9 received by C.L.Z.) from Bristol-Myers Squibb International Immune Oncology Network and the Riki Foundation.”
“The ClinicalTrials.gov identifier is: NCT04620200 (https://clinicaltrials.gov/study/NCT04620200) .”
“the MATISSE trial was a noncomparative trial and not powered to compare NIVO to NIVO + IPI”
“This research was funded by a grant (no. CA209-7W9 received by C.L.Z.) from Bristol-Myers Squibb International Immune Oncology Network and the Riki Foundation.”
Registered (3 IDs: ClinicalTrials.gov). No reporting guideline cited.
Broken references and links
None foundReferences checked against Crossref, OpenAlex and Retraction Watch for retractions and resolvability, plus declared data and code links probed for whether they resolve to content matching the paper.
Checked — nothing surfaced.
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- NO DOIPathological assessment of resection specimens after neoadjuvant therapy for metastatic melanomaNo DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
- NO DOINew response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1)No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
- NO DOIEvidence-based guidelines for determination of sample size and interpretation of the European Organisation for the Research and Treatment of Cancer Quality of Life Questionnaire Core 30No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
- NO DOIUpdate of the Dutch Manual for Costing in Economic EvaluationsNo DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
- NO DOIAssessing the value of cemiplimab for adults with advanced cutaneous squamous cell carcinoma: a cost-effectiveness analysisNo DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
- NO DOISkewer: a fast and accurate adapter trimmer for next-generation sequencing paired-end readsNo DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
- NO DOIFast and accurate short read alignment with Burrows–Wheeler transformNo DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
- NO DOIGenomics in the CloudNo DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
- NO DOIMultiQC: summarize analysis results for multiple tools and samples in a single reportNo DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
- NO DOIMosdepth: quick coverage calculation for genomes and exomesNo DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
- NO DOINGSCheckMate: software for validating sample identity in next-generation sequencing studies within and across data typesNo DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
- NO DOISTAR: ultrafast universal RNA-seq alignerNo DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
- NO DOIHTSeq—a Python framework to work with high-throughput sequencing dataNo DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
- NO DOIFACETS: allele-specific copy number and clonal heterogeneity analysis tool for high-throughput DNA sequencingNo DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
- NO DOIIdentification of the optimal combination dosing schedule of neoadjuvant ipilimumab plus nivolumab in macroscopic stage III melanoma (OpACIN-neo): a multicentre, phase 2, randomised, controlled trialNo DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
- NO DOIMaftools: efficient and comprehensive analysis of somatic variants in cancerNo DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
- NO DOIModerated estimation of fold change and dispersion for RNA-seq data with DESeq2No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
- NO DOIGene expression markers of tumor infiltrating leukocytesNo DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
- NO DOIGSVA: gene set variation analysis for microarray and RNA-seq dataNo DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
5 data/code links checked; 5 live.
- dataEGALIVEHTTP 200https://ega-archive.org/datasets/EGAD50000001469Resolves to EGA (data repository).
- dataEGALIVEHTTP 200https://ega-archive.org/datasets/EGAD50000001470Resolves to EGA (data repository).
- datahttps://ega.nki.nlLIVEHTTP 200Resolved page looks like data.
- codeGitHubLIVEHTTP 200https://github.com/MATISSEResolves to GitHub (code repository).
- codeGitHubLIVEHTTP 200https://github.com/ZuurLab/MATISSE_ms_code_2025Resolves to GitHub (code repository).
Copyediting
7 minorWording, consistency and formatting errors that need correcting before submission.
No major wording or formatting errors. 7 minor suggestions below.
7 copyedit issues flagged: mostly consistency, clarity, typo.
- MINORtypoAbstract“The ClinicalTrials.gov identifier is: NCT04620200 (https://clinicaltrials.gov/study/NCT04620200) .”→ Remove extra space before period.Minor formatting.
- MINORconsistencyResults, Pathological response and survival“9 of 20 (45%) patients receiving NIVO and 10 of 20 (50%) patients receiving NIVO + IPI reached an MPR”→ Ensure consistent use of 'NIVO' vs 'NIVO + IPI' throughout.Consistency check.
- MINORclarityMethods, Statistical analyses“The sample size calculation of 20 patients in each arm was powered on a 94% probability in both arms that 8 or more of 20 included patients who achieved a PCR and on a 89% probability that 4 or more of 20 included patients who achieved an NPR based on data derived from ref.”→ Rephrase for clarity: 'The sample size calculation assumed a 94% probability of observing ≥8 PCRs and an 89% probability of observing ≥4 NPRs in each arm of 20 patients, based on data from ref.'Awkward phrasing.
- MINORgrammarMethods, Inclusion and ethics“This study was performed in line with the principles’ approval of the Declaration of Helsinki.”→ Change to 'This study was performed in accordance with the principles of the Declaration of Helsinki.'Grammatical error.
- MINORconsistencyTable 2“Colitis | 5 (10) | 1 (4) | 4 (17) |”→ Check that the percentage for NIVO+IPI is correct; 4/24 = 16.7%, which rounds to 17%, but the column header says n=24, so 4/24=16.7% is correct.Potential rounding inconsistency.
- MINORconsistencyMethods, Trial design“Ten patients opted to forgo surgery and were not evaluable for the primary trial endpoint. They were not excluded from the trial, received neoadjuvant ICB, trial interventions (tumor samples and HRQoL questionnaires) and equal FU when compared to patients receiving neoadjuvant ICB and SOC Ten additional patients were included to meet the primary trial endpoint.”→ Add a period after 'SOC' and start a new sentence.Missing punctuation.
- MINORclarityMethods, Statistical analyses“The sample size calculation of 20 patients in each arm was powered on a 94% probability in both arms that 8 or more of 20 included patients who achieved a PCR and on a 89% probability that 4 or more of 20 included patients who achieved an NPR based on data derived from ref.”→ Rephrase for clarity: 'The sample size calculation of 20 patients per arm was based on a 94% probability of observing 8 or more PCRs and an 89% probability of observing 4 or more NPRs, derived from ref.'Awkward phrasing.
The published paper is methodologically robust and transparent. An informed reader should note the retrospective registration (submitted after study start) and the small, noncomparative design as limitations. No erratum or correction is warranted based on this audit, but the authors could strengthen future reports by adhering to CONSORT and reporting exact p-values throughout.
- 1.HIGHreportingAdd an explicit statement of adherence to CONSORT reporting guidelines in the Methods section, and include a completed CONSORT checklist as supplementary material.Reporting guideline adherence is expected for clinical trials and its absence is a common reviewer request.
- 2.HIGHstatisticsReplace all threshold p-values (e.g., 'P ≤ 0.05') in figures and tables with exact p-values, or provide exact values in supplementary material.Exact p-values allow readers to assess evidence strength; threshold reporting is imprecise and discouraged by journals.
- 3.HIGHreportingIn the Methods (Trial design), add a brief rationale for the open-label design (e.g., feasibility, ethical considerations).Providing a rationale for lack of blinding improves transparency and addresses a reviewer concern.
- 4.HIGHreportingIn the Methods (Statistical analyses), describe how outliers were handled or state that no outliers were excluded.Explicit outlier handling is a standard reporting expectation for clinical trials.
- 5.HIGHreportingIn the Methods (Statistical analyses), add a statement on verification of statistical assumptions (e.g., normality tests) for continuous outcomes.Assumption verification supports the validity of the chosen statistical tests.
- 6.MEDIUMreportingIn the Introduction, explicitly discuss limitations of prior research to strengthen the scientific premise.Acknowledging limitations of prior work contextualizes the study's contribution.
- 7.MEDIUMreportingIn the Methods (Statistical analyses), clarify how missing data were handled in the HRQoL analyses (e.g., mixed models handle missingness, but state assumptions).Missing data handling is critical for the validity of patient-reported outcome analyses.
- 8.MEDIUMreportingIn the Methods, clarify the definition of 'clinical complete response' as used for patients who declined surgery.Clear endpoint definitions are essential for reproducibility.
- 9.MEDIUMreportingIn the Discussion, avoid overgeneralizing the organ preservation results given the small number of patients (n=9) and the non-randomized nature of that subgroup.Overinterpretation of subgroup analyses can mislead readers.
- 10.MEDIUMreportingProvide a CONSORT flow diagram showing patient disposition from screening to analysis, including the 10 patients who declined surgery.A flow diagram improves transparency of patient flow and is a CONSORT requirement.
- 11.MEDIUMreportingFor the cost-effectiveness analysis, provide more detail on the model parameters and sensitivity analyses.Detailed reporting of health economic models is necessary for credibility and reproducibility.
- 12.LOWcopyeditIn the Abstract, remove the extra space before the period after the ClinicalTrials.gov URL.Minor formatting issue.
- 13.LOWcopyeditIn the Methods (Inclusion and ethics), rephrase 'in line with the principles’ approval of the Declaration of Helsinki' to 'in accordance with the principles of the Declaration of Helsinki'.Corrects a grammatical error.
- 14.LOWcopyeditIn the Methods (Trial design), add a period after 'SOC' and start a new sentence: '...and equal FU when compared to patients receiving neoadjuvant ICB and SOC. Ten additional patients...'Missing punctuation affects readability.
- 15.LOWcopyeditIn the Methods (Statistical analyses), rephrase the sample size calculation for clarity: 'The sample size calculation of 20 patients per arm was based on a 94% probability of observing 8 or more PCRs and an 89% probability of observing 4 or more NPRs, derived from ref.'Improves clarity of an awkwardly phrased sentence.
The star rating is the report’s one-glance summary. Every paper starts at 5★ and loses stars for the concrete problems the review finds — so a rating is never a vague average, it’s a running total you can read line by line under “How this rating was calculated.”
- Reporting — 8 dimensionseach dimension that fully fails−½★
- each dimension partially met−¼★
- Statistics · Integrity · Claimseach serious problem−1★
- each medium problem−½★
- Citationseach retracted or unverifiable reference−¼★
- Copyeditonly when the manuscript needs a full edit−½★
The rating never drops below 1★, and a demonstrable critical failure (an impossible statistic, a proven ethics violation) caps it at 1★ on its own — so the stars can never look healthy when the verdict is CRITICAL.
The rating draws on a panel of agents. Three independent Kaimen Rigor reviewers grade the eight dimensions below across several independent passes (the shown verdict is their majority vote — steadier than any single run), isolate the paper’s major claims and check its own evidence backs them, and flag integrity concerns. Alongside them, a citation agent resolves every reference against Crossref, OpenAlex, and Retraction Watch; a statistics agent recomputes reported tests; and rule-based checks verify that declared data/code links actually resolve. Full text is required — an abstract-only submission is not analyzed.
Graded against NIH, MDAR, ARRIVE 2.0, CONSORT, EQUATOR, and RRID guidelines. A dimension that doesn’t apply to the study type is skipped, never penalized.
This Kaimen Rigor review is model-assisted and is not a substitute for formal expert review. It complements human evaluation by surfacing potential methodological concerns — verify each finding against the source.