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@ARTICLE{Spektor:286664,
      author       = {A.-M. Spektor and E. Gutjahr and M. Lang and F. M.
                      Glatting$^*$ and T. Hackert and T. Pausch and C. Tjaden and
                      M. Schreckenberger and U. Haberkorn$^*$ and M. Röhrich},
      title        = {{I}mmunohistochemical {FAP} {E}xpression {R}eflects
                      68{G}a-{FAPI} {PET} {I}maging {P}roperties of {L}ow- and
                      {H}igh-{G}rade {I}ntraductal {P}apillary {M}ucinous
                      {N}eoplasms and {P}ancreatic {D}uctal {A}denocarcinoma.},
      journal      = {Journal of nuclear medicine},
      volume       = {65},
      number       = {1},
      issn         = {0097-9058},
      address      = {New York, NY},
      publisher    = {Soc.},
      reportid     = {DKFZ-2024-00028},
      pages        = {52-58},
      year         = {2024},
      note         = {2024 Jan 2;65(1):52-58},
      abstract     = {Pancreatic intraductal papillary mucinous neoplasms (IPMNs)
                      are grossly visible (typically > 5 mm) intraductal
                      epithelial neoplasms of mucin-producing cells, arising in
                      the main pancreatic duct or its branches. According to the
                      current 2-tiered grading scheme, these lesions are
                      categorized as having either low-grade (LG) dysplasia, which
                      has a benign prognosis, or high-grade (HG) dysplasia, which
                      formally represents a carcinoma in situ and thus can
                      transform to pancreatic ductal adenocarcinoma (PDAC).
                      Because both entities require different treatments according
                      to their risk of becoming malignant, a precise
                      pretherapeutic diagnostic differentiation is inevitable for
                      adequate patient management. Recently, our group has
                      demonstrated that 68Ga-fibroblast activation protein (FAP)
                      inhibitor (FAPI) PET/CT shows great potential for the
                      differentiation of LG IPMNs, HG IPMNs, and PDAC according to
                      marked differences in signal intensity and tracer dynamics.
                      The purpose of this study was to biologically validate FAP
                      as a target for PET imaging by analyzing immunohistochemical
                      FAP expression in LG IPMNs, HG IPMNs, and PDAC and comparing
                      with SUV and time to peak (TTP) measured in our prior study.
                      Methods: To evaluate the correlation of the expression level
                      of FAP and α-smooth muscle actin (αSMA) in
                      neoplasm-associated stroma depending on the degree of
                      dysplasia in IPMNs, 98 patients with a diagnosis of LG IPMN,
                      HG IPMN, PDAC with associated HG IPMN, or PDAC who underwent
                      pancreatic surgery at the University Hospital Heidelberg
                      between 2017 and 2023 were identified using the database of
                      the Institute of Pathology, University Hospital Heidelberg.
                      In a reevaluation of hematoxylin- and eosin-stained tissue
                      sections of formalin-fixed and paraffin-embedded resection
                      material from the archive, which was originally generated
                      for histopathologic routine diagnostics, a regrading of
                      IPMNs was performed by a pathologist according to the
                      current 2-tiered grading scheme, consequently eliminating
                      the former diagnosis of 'IPMN with intermediate-grade
                      dysplasia.' For each case, semithin tissue sections of 3
                      paraffin blocks containing neoplasm were
                      immunohistologically stained with antibodies directed
                      against FAP and αSMA. In a masked approach, a
                      semiquantitative analysis of the immunohistochemically
                      stained slides was finally performed by a pathologist by
                      adapting the immunoreactive score (IRS) and human epidermal
                      growth factor receptor 2 (Her2)/neu score to determine the
                      intensity and percentage of FAP- and αSMA-positive cells.
                      Afterward, the IRS of 14 patients who underwent 68Ga-FAPI-74
                      PET/CT in our previous study was compared with their SUVmax,
                      SUVmean, and TTP for result validation. Results: From 98
                      patients, 294 specimens (3 replicates per patient) were
                      immunohistochemically stained for FAP and αSMA.
                      Twenty-three patients had LG IPMNs, 11 had HG IPMNs, 10 had
                      HG IPMNs plus PDAC, and 54 had PDAC. The tumor stroma was in
                      all cases variably positive for FAP. The staining intensity,
                      percentage of FAP-positive stroma, IRS, and Her2/neu score
                      increased with higher malignancy. αSMA expression could be
                      shown in normal pancreatic stroma as well as within peri-
                      and intraneoplastic desmoplastic reaction. No homogeneous
                      increase in intensity, percentage, IRS, and Her2/neu score
                      with higher malignancy was observed for αSMA. The
                      comparison of the mean IRS of FAP with the mean SUVmax,
                      SUVmean, and TTP of 68Ga-GAPI-74 PET/CT showed a matching
                      value increasing with higher malignancy in 68Ga-FAPI-74 PET
                      imaging and immunohistochemical FAP expression. Conclusion:
                      The immunohistochemical staining of IPMNs and PDAC validates
                      FAP as a biology-based stromal target for in vivo imaging.
                      Increasing expression of FAP in lesions with a higher degree
                      of malignancy matches the expectation of a stronger FAP
                      expression in PDAC and HG IPMNs than in LG IPMNs and
                      corroborates our previous findings of higher SUVs and a
                      longer TTP in PDAC and HG IPMNs than in LG IPMNs.},
      keywords     = {FAPI (Other) / IHC (Other) / IPMN (Other) / PDAC (Other) /
                      fibroblast activation protein (Other) / α-SMA (Other)},
      cin          = {E055 / E060},
      ddc          = {610},
      cid          = {I:(DE-He78)E055-20160331 / I:(DE-He78)E060-20160331},
      pnm          = {315 - Bildgebung und Radioonkologie (POF4-315)},
      pid          = {G:(DE-HGF)POF4-315},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:38167622},
      doi          = {10.2967/jnumed.123.266393},
      url          = {https://inrepo02.dkfz.de/record/286664},
}