Aramini, Beatrice

Casali, Christian

Stefani, Alessandro

Bettelli, Stefania

Wagner, Susanne

Sangale, Zaina

Hughes, Elisha

Lanchbury, Jerry

Maiorana, Antonino

Morandi, Uliano

Casolari, Federico

Almae Matris Studiorum Campus

Slides lezione 11 dicembre 2017bis

Slides lezione 6 novembre 2017

Beatrice Aramini

Christian Casali

Alessandro Stefani

Stefania Bettelli

Susanne Wagner

Zaina Sangale

Elisha Hughes

Jerry Lanchbury

Antonino Maiorana

Uliano Morandi

Crossref

Journal of Thoracic Oncology

Prediction of distant recurrence-free survival in resectable lung adenocarcinoma

Elsevier - Publisher Connector 

February 2016 Abstracts S25Conclusions: Mexican NSCLC patients exhibit a speciﬁc
mutation proﬁle with alterations in several cancer-
related genes mainly in EGFR, TP53, GNAQ, HNF1A, VHL
and KRAS. The NGS technology showed greater sensi-
tivity than PCR to detect relevant mutations in NSCLC.
Several mutations found in high incidence in this study
could become relevant targets for novel targeted thera-
pies in NSCLC.
Detection of viral induced
double-stranded RNA intermediates
in archival parafﬁn blocksGalen Hostetter, Eric Collins, Bree Berghius,
Lisa Turner, Eric Hudson, Lorenzo Sempere,
Scott Jewell Van Andel Research Institute,
Grand Rapids, MI
Double strand RNA (dsRNA) species were previously
thought to be a ‘junk DNA’ equivalent are related to
endogenous retroviral elements (ERV) inserted into
the human genome. Genomic integration sites and
blocking of these processes have been well docu-
mented in HIV and Hepatitis C related diseases. Viral
integration into human genome has been shown in a
range of solid tumors, but mechanisms less under-
stood. The detection of dsRNA in the research setting
has been largely limited to cell line models and
controlled transfections. To better characterize func-
tion signiﬁcance of ERV and interactions at the cellular
level, we outline efforts to detect and quantify such
viral genomic elements with a focus on archival clin-
ical samples in the commonly stored parafﬁn block.
Tissue blocks issues with clinical and biochemical
documented viral infection and associated viral cyto-
pathic changes were selected from the Department of
Pathology and Biorepository and standard 4 micron
sections were prepared. Two (2) commercially avail-
able antibodies raised to dsRNA fragments (J2 and K1
antibodies) were directly compared by chromogenic
and immunoﬂuorescent methods. In addition, down-
stream biomarkers as identiﬁed by literature searches
include RIG-1 and IRF 7 as moderate probable success
and MDA-5 and STAT 1 as higher level success.
Correlative analysis of downstream pathway markers
with labeling results of dsRNA antibodies suffers from
lack of sensitive measures of dsRNA fragments as
opposed to the downstream cellular pathway markers.
This lack of concordance likely reﬂects the short
nature of dsRNAs in decade old parafﬁn tissue and/or
differences in abundance. Future work will focus on
developing more sensitive probes or IF probe signal
ampliﬁcation.Prediction of distant recurrence-free
survival in resectable lung
adenocarcinomaBeatrice Aramini,1 Christian Casali,1
Alessandro Stefani,1 Stefania Bettelli,1Susanne Wagner,2 Zaina Sangale,2 Elisha Hughes,2
Jerry Lanchbury,2 Antonino Maiorana,1
Uliano Morandi1 1University Hospital of Modena and
Reggio Emilia, Modena, Italy, 2Myriad Genetics, Inc., Salt
Lake City, UT
Background: Recurrence and lung cancer mortality in
resected, early stage lung cancer is likely due to the
presence of micro-metastatic disease not detected
during surgery or the pre-surgical assessment. The
likelihood of such latent disease increases with higher
stages and thus treatment with adjuvant therapy is
currently determined by pathological stage. However,
signiﬁcant recurrent disease and cancer-related
mortality even in stage I patients suggest that path-
ological stage alone does not adequately identify
resected patients that could beneﬁt from further
treatment. Tumor molecular features can improve
stratiﬁcation of patients for increased risk of distant
recurrence.
Methods: Formalin-ﬁxed surgical samples from 318
stage I and II lung adenocarcinoma patients, treated
with surgery alone, were examined for the expres-
sion of 31 proliferation genes (CCP score) by multi-
plex, quantitative RT-PCR. A prognostic score (PS)
was calculated from pathological stage and the CCP
score. The added prognostic value of the CCP score
for the prediction of ﬁve–year distant recurrence-free
survival and ﬁve-year cancer-speciﬁc survival was
tested in Cox proportional hazards regression models
with adjustment for clinical parameters. Estimates of
disease-free survival and cancer-speciﬁc survival
were calculated by the Kaplan-Meier method.
Results: Among 289 samples with successful expres-
sion analysis, 85 had developed a distant recurrence
at ﬁve years post-surgery. After adjustment for age,
gender, tumor size and pleural invasion, pathological
stage (HR 2.28, 95%CI 1.16-4.50 for IA vs IB,
p¼0.0015) and the CCP score (HR 1.62 per IQR, 95%
CI 1.15-2.29, p¼0.0055) were independent predictors
of distant recurrence and as well as for cancer-
speciﬁc survival [pathological stage (HR 1.72, 95%CI
0.93-3.17 for IA vs IB, p¼0.024), CCP score (HR 1.40
per IQR, 95%CI 1.03-1.90, p¼0.031)]. The prognostic
score was a better predictor of distant recurrence
than pathological stage alone (PS: HR 2.22 95%CI
1.11-4.44, p¼0.023, stage: HR 1.70 95%CI 0.86-3.35
S26 Journal of Thoracic Oncology Vol. 11 No. 2Sfor IA vs IB, p¼0.29). Patients with a high-risk PS
(>27) had a three-fold increased risk of distant
recurrence compared to patients with a low-risk PS
score. In stage I patients, the estimated risk of distant
recurrence for tumors with high-risk prognostic
scores was signiﬁcantly higher (36%, 95%CI 28%-
46%) than in low-risk PS tumors (15%, 95%CI 8%-
29%, p¼0.0005).
Conclusions: The prediction of risk of distant recur-
rence in resected lung adenocarcinoma patients can be
improved over that obtained by the current standard of
pathological stage by incorporating tumor expression of
proliferation markers (CCP score). Improved risk strati-
ﬁcation can help identify patients in need of additional
treatment and prioritize patients for trials of emerging
new therapies.Strong pharmacological activity of
locally administered next-generation
antisense oligonucleotides (ASOs) in
orthotopic lung cancer mouse modelsMinji Jo, Joanna Schmidt, Tianyuan Zhou,
Xuefeng Wu, Jeffrey R. Crosby, Emily Brand,
Youngsoo Kim, A. Robert MacLeod ISIS
Pharmaceuticals, Inc., Carlsbad, CA
Lung cancer is the second most common cancer type
and the leading cause of cancer-related death in both
men and women in the United States. Although recent
advances in genomic expression proﬁling of lung
cancer has provided more individualized treatment
based on target speciﬁc genetic alteration(s) in pa-
tients, there is a still high unmet medical need as
many important driver mutations remain undruggable
by conventional therapeutic approaches. Antisense
oligonucleotide (ASO) technology offers a novel ther-
apeutic modality to selectively target currently
undruggable pathways. We have recently demon-
strated that systemic delivery of unformulated next
generation (Gen 2.5) ASO targeting human STAT3
mRNA (STAT3-Rx/AZD9150) leads to robust phar-
macological activity in various preclinical animal
models of lung cancer. Importantly, STAT3-Rx/
AZD9150 displayed strong anti-tumor activity in pa-
tients with advanced treatment-refractory lymphoma
as well as non-small cell lung cancer (NSCLC) in
clinical trials*.
Although local delivery of ASOs has been proposed as
a means to treat various pulmonary diseases, ASO
pharmacology in lung tumors has not been previously
evaluated. In this study, we evaluated the activity of anantisense inhibitor (targeting MALAT1 gene) given by
different administration routes {by either a local (intra-
tracheally¼IT) or a systemic (subcutaneously¼SC) de-
livery} in orthotopic lung cancer xenograft models. For
this, human NSCLC A549 or H460 cells were injected to
nude mice via tail vein and 2 weeks later, the tumor-
bearing animals were treated with Gen 2.5 MALAT1 ASO
either IT (at 10 to 20 mg/kg, 3 times per week) or SC (at
25 to 50 mg/kg, 5 times per week) for 3 weeks. Re-
ductions in MALAT1 RNA levels in human tumor cells
and mouse lung were greater with local delivery at lower
doses compared to systemic delivery as assessed by
qRT-PCR or in-situ hybridization using species-speciﬁc
primers/probes (73% reduction at 20 mg/kg by IT
dosing vs 50.5% reduction at 50 mg/kg by SC dosing in
tumors; 72.5% vs 70% reduction in mouse lung at the
same dosing regimen). Moreover, local administration of
ASOs led to no notable increase in liver transaminase
levels compared to systemic administration. Pharmaco-
kinetic property-wise, the local administration showed
greater and more even accumulation of drug in both
tumor and lung tissues compared to the systemic route.
Taken together, these ﬁndings suggest that local
administration of Gen2.5 ASOs to lung malignancies
may be a promising alternative approach to systemic
delivery with greater potency and improved safety pro-
ﬁle, especially in inhibiting lung cancer targets which
cannot be tolerated when depleted systemically.
*Hong D et al. AZD9150, a Next-Generation Antisense Oligo-
nucleotide Inhibitor of STAT3 with Early Evidence of Clinical
Activity in Lymphoma and Lung Cancer. Sci. Transl. Med. 2015
(in press).
Impact of interleukin-22 on K-ras
mutant lung cancer promotion and
stemness propertiesNasim Khosravi, Amber M. Cumpian,
Soudabeh Daliri, Mauricio S. Caetano,
Seyed Javad Moghaddam The University of Texas MD
Anderson Cancer Center, Houston, TX
Activating mutations of K-ras, which are found in
approximately 30% of non-small cell lung cancer
(NSCLC), are the most common genetic alterations
associated with tobacco exposure in lung cancer.
Unfortunately, pharmacologic attempts directly tar-
geting K-ras have thus far failed; clearly stating
the need for new strategies to bring clinical beneﬁts
to patients displaying such a molecular proﬁle.
Tumor-promoting inﬂammation is a cancer hallmark,
and it is now apparent that the cytokines and
growth factors released during inﬂammation inﬂuence


Prediction of distant recurrence-free survival in resectable lung adenocarcinoma 

Slides lezione 11 dicembre 2017

file:///data/remote/core/dit/data/elsevier/pdf/491/aHR0cDovL2FwaS5lbHNldmllci5jb20vY29udGVudC9hcnRpY2xlL3BpaS9zMTU1NjA4NjQxNTAwMTUyNQ==.pdf

Prediction of distant recurrence-free survival in resectable lung adenocarcinoma

Abstract

Similar works

Full text

Available Versions

Almae Matris Studiorum Campus

Almae Matris Studiorum Campus

Crossref

Almae Matris Studiorum Campus

Elsevier - Publisher Connector

Almae Matris Studiorum Campus