23 research outputs found
The relationship between the insulin-like growth factor-1 axis, weight loss, an inflammation-based score and survival in patients with inoperable non-small cell lung cancer
<b>Background & aims:</b>
The involvement of a systemic inflammatory response, as evidenced by the Glasgow Prognostic Score (GPS), is associated with weight loss and poor outcome in patients with non-small cell lung cancer. There is good evidence that nutritional and functional decline in patients with advanced malignant disease is associated with catabolic changes in metabolism. However, defects in anabolism may also contribute towards nutritional decline in patients with cancer. The aim of the present study was to examine the relationship between IGF-1 and IGFBP-3, performance status, mGPS and survival in patients with inoperable NSCLC.
<b>Methods:</b>
56 patients with inoperable NSCLC were studied. The plasma concentrations of IGF-1, IGFBP-3 and leptin were measured using ELISA and RIA.
<b>Results:</b>
The patients were predominantly male (61%), over 60 years old (80%), with advanced (stage III or IV) disease (98%), with a BMI≥20 (84%), an ECOG-ps of 0 or 1 (79%), a haemoglobin (59%) and white cell count (79%) in the reference range. On follow-up 43 patients died of their cancer. On univariate analysis, BMI (p<0.05), Stage (p<0.05), ECOG-ps (p<0.05), haemoglobin (p<0.05), white cell count (p<0.05) and mGPS (p<0.05) were associated with cancer specific survival. There was no association between age, sex, treatment, IGF-1, IGFBP-3, IGF-1:IGFBP-3 ratio, or leptin and cancer specific survival. With an increasing mGPS concentrations of haemoglobin (p<0.005) and IGFBP-3 (p<0.05) decreased. mGPS was not associated with either IGF-1(p>0.20), or leptin (p>0.20).
<b>Conclusions:</b>
In summary, the results of this study suggest that anabolism (IGF-1 axis) does not play a significant role in the relationship between nutritional and functional decline, systemic inflammation and poor survival in patients with inoperable NSCLC
Adipose tissue pathways involved in weight loss of cancer cachexia
White adipose tissue (WAT) constitutes our most expandable tissue and largest
endocrine organ secreting hundreds of polypeptides collectively termed adipokines.
Changes in WAT mass induce alterations in adipocyte secretion and function, which
are linked to disturbed whole-body metabolism. Although the mechanisms controlling
this are not clear they are dependent on changes in gene expression, a complex process
which is regulated at several levels. Results in recent years have highlighted the role of
small non-coding RNA molecules termed microRNAs (miRNAs), which regulate gene
expression via post-transcriptional mechanisms. The aim of this thesis was to
characterize global gene expression levels and describe novel miRNAs and adipokines
controlling the function of human WAT in conditions with pathological increases or
decreases in WAT mass. Obesity and cancer cachexia were selected as two models
since they are both clinically relevant and characterized by involuntary changes in
WAT mass.
In Study I, expressional analyses were performed in subcutaneous WAT from cancer
patients with or without cachexia and obese versus non-obese subjects. In total, 425
transcripts were found to be regulated in cancer cachexia. Pathway analyses based on
this set of genes revealed that processes involving extracellular matrix, actin
cytoskeleton and focal adhesion were significantly downregulated, whereas fatty acid
metabolism was upregulated comparing cachectic with weight-stable cancer subjects.
Furthermore, by overlapping these results with microarray data from an obesity study,
many transcripts were found to be reciprocally regulated comparing the two conditions.
This suggests that WAT gene expression in cancer cachexia and obesity are regulated
by similar, albeit opposing, mechanisms.
In Study II, the focus was on the family of
fibroblast growth factors (FGFs), members of which have recently been implicated in
the development of obesity and insulin resistance. A retrospective analysis of global
gene expression data identified several FGFs (FGF1/2/7/9/13/18) to be expressed in
WAT. However, only one, FGF1, was actively secreted from WAT and predominantly
so from the adipocyte fraction. Moreover, FGF1 release was increased in obese
compared to non-obese subjects, but was not normalized by weight loss. Although the
clinical significance of these findings is not yet clear, it can be hypothesized that FGF1
may play a role in WAT growth, possibly by promoting fat cell proliferation and/or
differentiation.
In Study III, we identified adipose miRNAs regulated in obesity. Out
of eleven miRNAs regulated by changes in body fat mass, ten controlled the production
of the pro-inflammatory chemoattractant chemokine (C-C motif) ligand 2 (CCL2)
when overexpressed in fat cells and for two, miR-126 and -193b, signaling circuits
were defined.
In Study IV, a novel adipokine, semaphorin 3C (SEMA3C), was
identified by combining transcriptome and secretome data. Detailed studies focusing on
SEMA3C revealed that this factor was secreted from adipocytes and induced the
expression of extracellular matrix and matricellular genes in preadipocytes.
Furthermore, SEMA3C mRNA levels correlated with interstitial fibrosis and insulin
resistance in WAT derived from subjects with a wide range in BMI.
In summary, the results presented in this thesis have delineated transcriptional
alterations in WAT in two clinically relevant conditions, obesity and cancer cachexia.
This has allowed the identification of novel adipokines and microRNAs with potential
pathophysiological importance. These findings form the basis for further studies aiming
at understanding the central role of WAT in disorders associated with metabolic
complications
Body Composition, Symptoms, and Survival in Advanced Cancer Patients Referred to a Phase I Service
Background: Body weight and body composition are relevant to the outcomes of cancer and antineoplastic therapy. However, their role in Phase I clinical trial patients is unknown. Methods: We reviewed symptom burden, body composition, and survival in 104 patients with advanced cancer referred to a Phase I oncology service. Symptom burden was analyzed using the MD Anderson Symptom Assessment Inventory(MDASI); body composition was evaluated utilizing computerized tomography(CT) images. A body mass index (BMI)25 kg/m 2. Sarcopenic patients were older and less frequently African-American. Symptom burden did not differ among patients classified according to BMI and presence of sarcopenia. Median (95% confidence interval) survival (days) varied according to body composition: 215 (71–358) (BMI,25 kg/m 2; sarcopenic), 271 (99–443) (BMI,25 kg/m 2; non-sarcopenic), 484 (286–681) (BMI25 kg/m 2; non-sarcopenic). Higher muscle index and gastrointestinal cancer diagnosis predicted longer survival in multivariate analysis after controlling for age, gender, performance status, and fat index. Conclusions: Patients referred to a Phase I clinic had a high frequency of sarcopenia and a BMI$25 kg/m 2, independent o