PMID- 24419422
OWN - NLM
STAT- MEDLINE
DCOM- 20140916
LR  - 20221207
IS  - 1556-1380 (Electronic)
IS  - 1556-0864 (Linking)
VI  - 9
IP  - 2
DP  - 2014 Feb
TI  - PI3K/mTOR signaling in mesothelioma patients treated with induction chemotherapy 
      followed by extrapleural pneumonectomy.
PG  - 239-47
LID - 10.1097/JTO.0000000000000055 [doi]
AB  - INTRODUCTION: The prognostic significance of activity biomarkers within the 
      phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) 
      signaling pathway was assessed in two independent cohorts of malignant pleural 
      mesothelioma (MPM) patients uniformly treated with a multimodal approach. We 
      specifically assessed expression signatures in a unique set of pre- and 
      postchemotherapy tumor samples. METHODS: Biomarker expression was assessed in 
      samples of two independent cohorts of 107 (cohort 1) and 46 (cohort 2) MPM cases 
      uniformly treated with platinum-based induction chemotherapy followed by 
      extrapleural pneumonectomy from two different institutions, assembled on tissue 
      microarrays. Expression levels of phosphatase and tensin homologue (PTEN), 
      phospho-mTOR, and p-S6 in addition to marker of proliferation (Ki-67) and 
      apoptosis (cleaved caspase-3) were evaluated by immunohistochemistry and 
      correlated with overall survival (OAS) and progression-free survival (PFS). To 
      assess PTEN genomic status, fluorescence in situ hybridization was performed. 
      RESULTS: Survival analysis showed that high p-S6 and Ki-67 expression in samples 
      of treatment naive patients of cohort 1 was associated with shorter PFS (p = 0.02 
      and p = 0.04, respectively). High Ki-67 expression after chemotherapy remained 
      associated with shorter PFS (p = 0.03) and OAS (p = 0.02). Paired comparison of 
      marker expression in samples before and after induction chemotherapy of cohort 1 
      revealed that decreased cytoplasmic PTEN and increased phospho-mTOR expression 
      was associated with a worse OAS (p = 0.04 and p = 0.03, respectively). 
      CONCLUSIONS: These novel data reveal a prognostic significance of expression 
      changes of PI3K/mTOR pathway components during induction chemotherapy if 
      confirmed in other patient cohorts and support the growing evidence to target the 
      PI3K/mTOR pathway in the treatment of MPM.
FAU - Bitanihirwe, Byron K Y
AU  - Bitanihirwe BK
AD  - *Division of Thoracic Surgery, University Hospital of Zurich, Zurich, 
      Switzerland; daggerInstitute of Surgical Pathology, University Hospital Zurich, 
      Zurich, Switzerland; double daggerLaboratory of Molecular Oncology, University of Zurich, 
      Zurich, Switzerland;  section signDepartment of Laboratory Medicine and Pathobiology, 
      University of Toronto, Toronto, Canada;  ||Division of Thoracic Surgery, Toronto 
      General Hospital, Toronto, Canada; and  paragraph signDivision of Biostatistics, Institute for 
      Social and Preventative Medicine, University of Zurich, Zurich, Switzerland.
FAU - Meerang, Mayura
AU  - Meerang M
FAU - Friess, Martina
AU  - Friess M
FAU - Soltermann, Alex
AU  - Soltermann A
FAU - Frischknecht, Lukas
AU  - Frischknecht L
FAU - Thies, Svenja
AU  - Thies S
FAU - Felley-Bosco, Emanuela
AU  - Felley-Bosco E
FAU - Tsao, Ming-Sound
AU  - Tsao MS
FAU - Allo, Ghassan
AU  - Allo G
FAU - de Perrot, Marc
AU  - de Perrot M
FAU - Seifert, Burkhardt
AU  - Seifert B
FAU - Moch, Holger
AU  - Moch H
FAU - Stahel, Rolf
AU  - Stahel R
FAU - Weder, Walter
AU  - Weder W
FAU - Opitz, Isabelle
AU  - Opitz I
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - J Thorac Oncol
JT  - Journal of thoracic oncology : official publication of the International 
      Association for the Study of Lung Cancer
JID - 101274235
RN  - 0 (Biomarkers, Tumor)
RN  - 0 (Glutamates)
RN  - 04Q9AIZ7NO (Pemetrexed)
RN  - 0W860991D6 (Deoxycytidine)
RN  - 5Z93L87A1R (Guanine)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.1.137 (Phosphatidylinositol 3-Kinase)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 3.1.3.67 (PTEN Phosphohydrolase)
RN  - EC 3.1.3.67 (PTEN protein, human)
RN  - Q20Q21Q62J (Cisplatin)
RN  - 0 (Gemcitabine)
SB  - IM
MH  - Adult
MH  - Aged
MH  - Antineoplastic Combined Chemotherapy Protocols/*therapeutic use
MH  - Biomarkers, Tumor/metabolism
MH  - Cisplatin/administration & dosage
MH  - Cohort Studies
MH  - Combined Modality Therapy
MH  - Deoxycytidine/administration & dosage/analogs & derivatives
MH  - Female
MH  - Follow-Up Studies
MH  - Glutamates/administration & dosage
MH  - Guanine/administration & dosage/analogs & derivatives
MH  - Humans
MH  - Immunoenzyme Techniques
MH  - In Situ Hybridization, Fluorescence
MH  - Induction Chemotherapy
MH  - Male
MH  - Mesothelioma/*metabolism/pathology/therapy
MH  - Middle Aged
MH  - Neoplasm Staging
MH  - PTEN Phosphohydrolase/genetics/metabolism
MH  - Pemetrexed
MH  - Phosphatidylinositol 3-Kinase/*metabolism
MH  - Pleural Neoplasms/*metabolism/pathology/therapy
MH  - *Pneumonectomy
MH  - Prognosis
MH  - Remission Induction
MH  - Signal Transduction
MH  - Survival Rate
MH  - TOR Serine-Threonine Kinases/*metabolism
MH  - Tissue Array Analysis
MH  - Gemcitabine
EDAT- 2014/01/15 06:00
MHDA- 2014/09/17 06:00
CRDT- 2014/01/15 06:00
PHST- 2014/01/15 06:00 [entrez]
PHST- 2014/01/15 06:00 [pubmed]
PHST- 2014/09/17 06:00 [medline]
AID - S1556-0864(15)30195-7 [pii]
AID - 10.1097/JTO.0000000000000055 [doi]
PST - ppublish
SO  - J Thorac Oncol. 2014 Feb;9(2):239-47. doi: 10.1097/JTO.0000000000000055.