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@ARTICLE{Gambichler:302018,
      author       = {T. Gambichler and S. S. Weyer-Fahlbusch and J. Overbeck and
                      N. Abu Rached and J. Becker$^*$ and L. Susok},
      title        = {{I}mpaired {O}verall {S}urvival of {M}elanoma {P}atients
                      {D}ue to {A}ntibiotic {U}se {P}rior to {I}mmune {C}heckpoint
                      {I}nhibitor {T}herapy: {S}ystematic {R}eview and
                      {M}eta-{A}nalysis.},
      journal      = {Cancers},
      volume       = {17},
      number       = {11},
      issn         = {2072-6694},
      address      = {Basel},
      publisher    = {MDPI},
      reportid     = {DKFZ-2025-01216},
      pages        = {1872},
      year         = {2025},
      abstract     = {Background: The gut microbiome plays a pivotal role in
                      shaping systemic immunity and modulating anti-tumor
                      responses. Preclinical and clinical studies have shown that
                      higher gut microbial diversity and the presence of specific
                      commensal taxa correlate with improved responses to immune
                      checkpoint inhibitors (ICI) in melanoma. Conversely,
                      broad-spectrum antibiotics can induce dysbiosis, reducing T
                      cell activation and cytokine production, and have been
                      linked to diminished ICI efficacy in several cancer types.
                      Methods: We conducted a systematic review and meta-analysis
                      of seven retrospective cohorts (total n = 5213) comparing
                      overall survival in cutaneous melanoma (CM) patients who did
                      or did not receive systemic antibiotics within six weeks
                      before ICI initiation. From each study, we extracted hazard
                      ratios (HRs) for death, antibiotic-to-ICI interval, ICI
                      regimen (PD-1 monotherapy vs. PD-1 + CTLA-4 combination),
                      cohort size, and country. Pooled log-HRs were estimated
                      under fixed-effect and random-effects (REML) models.
                      Statistical heterogeneity was quantified by Cochran's Q and
                      I2 statistics, and τ2. We performed leave-one-out
                      sensitivity analyses, generated a Baujat plot to identify
                      influential studies, applied trim-and-fill to assess
                      publication bias, and ran meta-regressions for regimen,
                      antibiotic timing, sample size, and geography. Results:
                      Under the fixed-effect model, antibiotic exposure
                      corresponded to a pooled HR of 1.26 $(95\%$ CI 1.13-1.41; p
                      < 0.001). The random-effects model yielded a pooled HR of
                      1.55 $(95\%$ CI 1.21-1.98; p = 0.0005) with substantial
                      heterogeneity (Q = 25.1; I2 = $76\%).$ Prediction intervals
                      (0.78-3.06) underscored between-study variability.
                      Leave-one-out analyses produced HRs from 1.50 to 1.75,
                      confirming robustness, and the Baujat plot highlighted two
                      cohorts as primary heterogeneity drivers. Trim-and-fill
                      adjusted the HR to 1.46 $(95\%$ CI 1.08-1.97). In subgroup
                      analyses, combination therapy studies (k = 4) showed a
                      pooled HR of ~1.9 (I2 = $58\%)$ versus ~1.3 (I2 = $79\%)$
                      for monotherapy. Meta-regression attributed the largest
                      variance to the regimen (R2 = $32\%;$ β(monotherapy) =
                      -0.35; p = 0.13). Conclusions: Pre-ICI antibiotic use in CM
                      is consistently associated with a $26-55\%$ increase in
                      mortality risk, particularly with PD-1 + CTLA-4
                      combinations, reinforcing the mechanistic link between
                      microbiome integrity and ICI success. Looking ahead,
                      integrating prospective microbiome profiling into clinical
                      trials will be critical to personalize ICI therapy, clarify
                      causality, and identify microbial biomarkers for optimal
                      treatment selection. Prospective, microbiome-integrated
                      trials promise to refine melanoma immunotherapy by tailoring
                      antibiotic stewardship and microbial interventions to
                      enhance patient outcomes.},
      subtyp        = {Review Article},
      keywords     = {antibiosis (Other) / immunotherapy (Other) / infection
                      (Other) / ipilimumab (Other) / mortality (Other) / nivolumab
                      (Other) / pembrolizumab (Other)},
      cin          = {ED01},
      ddc          = {610},
      cid          = {I:(DE-He78)ED01-20160331},
      pnm          = {899 - ohne Topic (POF4-899)},
      pid          = {G:(DE-HGF)POF4-899},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:40507352},
      doi          = {10.3390/cancers17111872},
      url          = {https://inrepo02.dkfz.de/record/302018},
}