Background: Sarcopenia, as measured at the 3rd lumbar (L3) level, has been shown to prognosticate survival in cancer patients. However, many patients with early-stage non-small cell lung cancer (NSCLC) do not undergo abdominal imaging. We hypothesized that preoperative thoracic sarcopenia is associated with survival in patients undergoing lung resection for early-stage NSCLC.Methods: Patients who underwent anatomic resection for NSCLC between 2010-2019 were retrospectively identified. Exclusion criteria included induction therapy, less than 90 days of follow-up, and absence of computed tomography (CT) imaging. Cross sectional skeletal muscle area was calculated at the fifth thoracic vertebra (T5), twelfth thoracic vertebra (T12), and L3 level. Gender-specific lowest quartile values and previously defined values were used to define sarcopenia. Overall survival and disease-free survival were assessed using the Kaplan-Meier method.Results: Overall, 221 patients met inclusion criteria with a median body mass index (BMI) of 26.5 kg/m 2 [interquartile range (IQR), 23.3-29.9 kg/m 2 ], age of 69 years (IQR, 62.4-74.9 years), and follow-up of 46.9 months (IQR,. At the T5 level, sarcopenic males demonstrated worse overall survival [median 41.0 (IQR, 13.8-53.7) vs. 42.0 (IQR, 23.1-55.1) months, P=0.023] and disease-free survival [median 15.8 (IQR,) months, P=0.007] when compared to non-sarcopenic males.There was no difference in survival between sarcopenic and non-sarcopenic females when assessed at T5. Sarcopenia at T12 or L3 was associated with worse overall survival (P<0.05).Conclusions: Sarcopenia at T5 is associated with worse survival in males, but not females. When using upper thoracic vertebral levels to assess for sarcopenia, it is necessary to account for gender.
Background: The objective of this study was to evaluate disease stage-associated differences in receptor tyrosine kinase (RTK) signaling in A549 cells using pretreatment sera from cases of pathologically-confirmed lung adenocarcinoma or control cases derived from a lung cancer screening study. This was accomplished as a means to explore the hypothesis that circulating concentrations of decoy receptors and/or ligands, as well as disease-specific ligand degradation all regulate RTK signaling in vivo. Methods: Pretreatment peripheral blood were prepared from either from non-cancer control patients (n=30) or those with lung adenocarcinoma, consisting of stage I (T1-2N0M0, n=25); locoregionally progressed (T1-2N1-2M0, n=36) or disseminated, stage IV disease (n=43). All patients were enrolled with written informed consent to our IRB-approved, institutional biorepository. Confluent cultures of A549 cells were stimulated for 10 minutes with patient sera diluted 1:1 in RPMI-1640 followed by immediate whole cell lysate preparation. After protein determinations by BCA, 8.5 µg of each sample was interrogated using the Human RTK (phosphoprotein) kit from MilliporeSigma according to manufacturer’s instructions. After being normalized to the kit-supplied (stimulated) HeLa cell lysates, all resulting data were evaluated by one-way ANOVA (LSD and Tukey post-hoc) for categorical comparisons. Results: The most commonly observed differences in RTK signaling was noted upon comparing cohorts with locoregional (T1-2N1-2M0) progression and disseminated (stage IV) disease. Levels of in c-Met and insulin receptor (IR) signaling were higher in patients with stage IV disease relative to those with locoregional disease by 24% and 10%, respectively (both p<0.01); whereas induction of c-Kit, VEGFR3, and Tie-1 were reduced by 12.8%, 6.67%, and 17.3%, respectively (all p<0.05). Circulating levels of HGF were previously observed by our group to be 25% higher in stage IV patients relative to those with locoregional progression (p=0.005) - agreeing with our observation in direction of change, though not scale. This is in contrast to levels of VEGF-C and VEGF-D previously being observed elevated 51% and 452% (both p<0.001) in these same cohorts. Also of note was the 1.9 fold decrease in ability of sera from stage I patients to stimulate IGF-1R signaling relative to control patients (p=0.002). We have previously reported a 12% increase in IGF-1 levels between these groups (p=0.002), though we observed no changes in IGF binding proteins that could account for the observed differences in IGF-1R signaling. Conclusions: We observed an apparent discoupling of certain circulating ligands in patient sera to stimulate their respective RTKs in a disease stage-specific manner. We are currently evaluating levels of circulating ligands, potential disease stage-associated (partial) proteolytic degradation, and decoy receptors to help explain these observations. Citation Format: Gabriela C. Lobato, Jared D. Fialkoff, Imad Tarhoni, Nicholas Lund, Vineela Chukkapalli, Selina Sayidine, Cristina L. Fhied, Sanjib Basu, Wen-Rong Lie, Michael J. Liptay, Philip Bonomi, Jeffrey A. Borgia. Induction of receptor tyrosine kinase signaling by sera from patients with lung adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4665. doi:10.1158/1538-7445.AM2017-4665
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