PMID- 25186104
OWN - NLM
STAT- MEDLINE
DCOM- 20150512
LR  - 20211203
IS  - 1349-3329 (Electronic)
IS  - 0040-8727 (Linking)
VI  - 234
IP  - 1
DP  - 2014 Sep
TI  - Immunohistochemical evidence for the association between attenuated mTOR 
      signaling and diffuse alveolar damage, a fatal lung complication.
PG  - 67-75
AB  - Targeted anticancer therapies have been developed to interfere with specific 
      target molecules including those of downstream pathways required for tumor growth 
      and progression. Mammalian target of rapamycin (mTOR) has been considered as one 
      of the target molecules of cancer growth, and its inhibitors have been reported 
      to exert an anticancer effect in various malignant tumors. The pulmonary disorder 
      is one of the major side effects of anticancer drugs including mTOR inhibitor 
      (mTORi), and the diagnosis of lung injury induced by medication is difficult 
      because of non-specific nature of the radiological findings. In this study, we 
      present the detailed autopsy findings of a patient who developed diffuse alveolar 
      damage (DAD) following mTORi treatment for metastatic renal cell carcinoma. We 
      also studied 19 cases of DAD derived from other diseases and 9 cases with 
      non-pathological lung. Of interest, pneumocytes of the patients with DAD, who 
      received other anticancer drugs or contacted bacteria, demonstrated significantly 
      lower mTOR activities than pneumocytes of those with non-pathological lung 
      tissue, as judged by the immunohistochemical analysis. In contrast, both 
      pneumocytes and T cells in DAD tissues of the patient treated with mTORi showed 
      higher mTOR activities than those of patients with DAD of other causes, 
      suggesting that the enhanced mTOR signaling may be involved in the development of 
      DAD after mTORi treatment. This unexpected finding needs to be confirmed in other 
      patients treated with mTORi. In conclusion, the attenuated mTOR signaling in 
      pneumocytes may contribute to the pathogenesis of DAD in patients without mTORi 
      treatment.
FAU - Saito, Ryoko
AU  - Saito R
AD  - Department of Pathology, Tohoku University School of Medicine.
FAU - Yanai, Mitsuru
AU  - Yanai M
FAU - Miki, Yasuhiro
AU  - Miki Y
FAU - Fukasawa, Yuichiro
AU  - Fukasawa Y
FAU - Tominaga, Junya
AU  - Tominaga J
FAU - Ebina, Masahito
AU  - Ebina M
FAU - Sasano, Hironobu
AU  - Sasano H
LA  - eng
PT  - Case Reports
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - Japan
TA  - Tohoku J Exp Med
JT  - The Tohoku journal of experimental medicine
JID - 0417355
RN  - 9HW64Q8G6G (Everolimus)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Alveolar Epithelial Cells/metabolism
MH  - Analysis of Variance
MH  - Autopsy
MH  - Carcinoma, Renal Cell/*drug therapy
MH  - Everolimus
MH  - Fatal Outcome
MH  - Humans
MH  - Immunohistochemistry
MH  - Lung Diseases/*chemically induced/pathology
MH  - Male
MH  - Middle Aged
MH  - Pulmonary Alveoli/*pathology
MH  - Signal Transduction/drug effects/*physiology
MH  - Sirolimus/adverse effects/*analogs & derivatives/therapeutic use
MH  - Statistics, Nonparametric
MH  - TOR Serine-Threonine Kinases/*antagonists & inhibitors/metabolism
EDAT- 2014/09/05 06:00
MHDA- 2015/05/13 06:00
CRDT- 2014/09/05 06:00
PHST- 2014/09/05 06:00 [entrez]
PHST- 2014/09/05 06:00 [pubmed]
PHST- 2015/05/13 06:00 [medline]
AID - DN/JST.JSTAGE/tjem/234.67 [pii]
AID - 10.1620/tjem.234.67 [doi]
PST - ppublish
SO  - Tohoku J Exp Med. 2014 Sep;234(1):67-75. doi: 10.1620/tjem.234.67.