PMID- 30539796
OWN - NLM
STAT- MEDLINE
DCOM- 20191022
LR  - 20191022
IS  - 1532-8392 (Electronic)
IS  - 0046-8177 (Linking)
VI  - 82
DP  - 2018 Dec
TI  - Immune checkpoint blockade as a potential therapeutic strategy for 
      undifferentiated malignancies.
PG  - 39-45
LID - S0046-8177(18)30257-0 [pii]
LID - 10.1016/j.humpath.2018.06.034 [doi]
AB  - Undifferentiated malignancies (UMs) encompass a diverse set of aggressive tumors 
      that pose not only a diagnostic challenge but also a challenge for clinical 
      management. Most tumors in this category are currently treated empirically with 
      nonspecific chemotherapeutic agents that yield extremely poor clinical response. 
      Given that UMs are inherently genetically unstable neoplasms with the potential 
      for immune dysregulation and increased neoantigen production, they are likely to 
      be particularly amenable to immune checkpoint inhibitors, which target programmed 
      cell death protein 1 (PD-1) or its ligands, PD-L1 and PD-L2, to promote T-cell 
      antitumor activity. Aberrant expression of PD-L1 and, more recently, chromosomal 
      9p24.1/CD274(PD-L1)/PDCD1LG2(PD-L2) alterations can be used as biomarkers to 
      predict responsiveness to checkpoint inhibitors. Here we evaluated 93 cases 
      previously diagnosed as an "undifferentiated" malignancy and found that 56% 
      (52/93) of UMs moderately to strongly express PD-L1 by immunohistochemistry 
      (IHC). Concurrent CD274(PD-L1) and PDCD1LG2(PD-L2) fluorescence in situ 
      hybridization (FISH) was performed on 24 of these cases and demonstrates a 
      genetic gain at both loci in 62.5% of UMs. Genetic alterations at the 
      CD274(PD-L1) and PDCD1LG2(PD-L2) loci were found to be completely concordant by 
      FISH. Overall, we found that a significant proportion of UMs express PD-L1 and 
      provide molecular support for using checkpoint inhibitors as a treatment approach 
      for this class of tumors.
CI  - Copyright (c) 2018 Elsevier Inc. All rights reserved.
FAU - Devereaux, Kelly A
AU  - Devereaux KA
AD  - Department of Pathology, Stanford University School of Medicine, Stanford, CA 
      94305, USA.
FAU - Charu, Vivek
AU  - Charu V
AD  - Department of Pathology, Stanford University School of Medicine, Stanford, CA 
      94305, USA.
FAU - Zhao, Shuchun
AU  - Zhao S
AD  - Department of Pathology, Stanford University School of Medicine, Stanford, CA 
      94305, USA.
FAU - Charville, Gregory W
AU  - Charville GW
AD  - Department of Pathology, Stanford University School of Medicine, Stanford, CA 
      94305, USA.
FAU - Bangs, Charles D
AU  - Bangs CD
AD  - Department of Pathology, Stanford University School of Medicine, Stanford, CA 
      94305, USA.
FAU - van de Rijn, Matt
AU  - van de Rijn M
AD  - Department of Pathology, Stanford University School of Medicine, Stanford, CA 
      94305, USA.
FAU - Cherry, Athena M
AU  - Cherry AM
AD  - Department of Pathology, Stanford University School of Medicine, Stanford, CA 
      94305, USA.
FAU - Natkunam, Yasodha
AU  - Natkunam Y
AD  - Department of Pathology, Stanford University School of Medicine, Stanford, CA 
      94305, USA. Electronic address: yaso@stanford.edu.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20180707
PL  - United States
TA  - Hum Pathol
JT  - Human pathology
JID - 9421547
RN  - 0 (Antineoplastic Agents, Immunological)
RN  - 0 (B7-H1 Antigen)
RN  - 0 (Biomarkers, Tumor)
RN  - 0 (CD274 protein, human)
RN  - 0 (PDCD1LG2 protein, human)
RN  - 0 (Programmed Cell Death 1 Ligand 2 Protein)
SB  - IM
MH  - Adolescent
MH  - Adult
MH  - Aged
MH  - Aged, 80 and over
MH  - Antineoplastic Agents, Immunological/*therapeutic use
MH  - B7-H1 Antigen/antagonists & inhibitors/genetics/*immunology
MH  - Biomarkers, Tumor/antagonists & inhibitors/genetics/*immunology
MH  - *Cell Differentiation
MH  - Chromosomes, Human, Pair 9
MH  - Databases, Factual
MH  - Female
MH  - Humans
MH  - Immunohistochemistry
MH  - Immunotherapy/*methods
MH  - In Situ Hybridization, Fluorescence
MH  - Male
MH  - Middle Aged
MH  - Neoplasms/drug therapy/genetics/*immunology/pathology
MH  - Programmed Cell Death 1 Ligand 2 Protein/antagonists & 
      inhibitors/genetics/*immunology
MH  - Signal Transduction/drug effects
MH  - Young Adult
OTO - NOTNLM
OT  - 9p24.1 alterations
OT  - Checkpoint inhibitors
OT  - Immune checkpoint
OT  - PD-L1
OT  - Undifferentiated carcinoma
OT  - Undifferentiated malignancy
EDAT- 2018/12/13 06:00
MHDA- 2019/10/23 06:00
CRDT- 2018/12/13 06:00
PHST- 2018/04/12 00:00 [received]
PHST- 2018/06/19 00:00 [revised]
PHST- 2018/06/29 00:00 [accepted]
PHST- 2018/12/13 06:00 [entrez]
PHST- 2018/12/13 06:00 [pubmed]
PHST- 2019/10/23 06:00 [medline]
AID - S0046-8177(18)30257-0 [pii]
AID - 10.1016/j.humpath.2018.06.034 [doi]
PST - ppublish
SO  - Hum Pathol. 2018 Dec;82:39-45. doi: 10.1016/j.humpath.2018.06.034. Epub 2018 Jul 
      7.