CRHR1 and CRHR2 pre-treatment gene expression may predict malignant melanoma patients neuropsychiatric responses to IL-2 therapy Open Access

Barbarita, Caitlin Noel (2010)

Permanent URL: https://etd.library.emory.edu/concern/etds/dn39x177r?locale=en
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Abstract

Abstract
CRHR1 and CRHR2 pre-treatment gene expression may predict malignant melanoma
patients' neuropsychiatric responses to IL-2 therapy
By Caitlin N. Barbarita

Although, Interleukin-2 (IL-2) immunotherapy has been shown to be successful in initiating tumor regression in up to 20% of malignant melanoma patients, it induces an array of toxicities that hinder effective treatment. Corticotropin Releasing Hormone receptors 1 and 2 (CRHR1 and CRHR2, respectively) expression on the pituitary are known to affect the HPA axis, the functioning of which is believed to be altered in these patients. The following study examines the relationship between CRHR1 and CRHR2 pre-treatment expression in patient blood samples and patients' neuropsychiatric responses to IL-2 therapy.

After providing informed consent, 20 patients with Stage IV melanoma eligible for IL-2 immunotherapy were recruited. Prior to, during, and after IL-2 administration we measured genetic expression of CRHR1 and CRHR2, plasma concentrations of ACTH and IL-6, neurobehavioral symptoms, and tolerance of IL-2 treatment. A neurobehavioral analysis was performed utilizing two symptom complexes, mood and neurovegetative. Non-parametric statistics were used to examine changes in biological and behavioral variables. Spearman's correlation and simple linear regression determined relationships between CRHR1 and CRHR2 gene expression, IL-2 dose tolerance, and neurobehavioral symptoms.

Linear regression models were statistically insignificant; however we did see a statistically significant positive partial correlation between IL-2 doses tolerated and CRHR1 gene expression within the model. This small study illustrates the need for further understanding of the mechanisms of symptom development and treatment response during IL-2 immunotherapy.

Table of Contents

Table of Contents

Introduction……………………………………………………………………………..............................1
IL-2 Immunotherapy………………………………………………………..…..................................1
IL-2 Immunotherapy and Pro-inflammatory Cytokines.….....................................3
HPA axis and IL-2 Immunotherapy……………………………………...................................4
CRH Receptors 1 & 2 and IL-2 Immunotherapy.………………...................................7
Symptom Complexes in Immunotherapy.…………………………...................................8
Predictions...………………………………………………………………………………..........................10
Methods....………………………..………………………………………………………............................11
Clinical Procedures.……………………………………………………………....................................11
Genetic Laboratory Methods………………………………………………….................................12
Biostatistical Methodology……..…………………………………………....................................14
Results……………………………………...……………………………………………...............................16
Study Patient Demographics.………………………………………………..................................16
Changes in Doses Tolerated…….…………………………………………...................................18
Symptom Complexes: Mood Symptoms…..………………………....................................19
Symptom Complexes: Neurovegetative Symptoms….………...................................22
CRH Receptor Expression…………………………………..………………....................................24
CRHR1 Pre-treatment Expression, Mood Symptoms, IL-2 Doses Tolerated.…..........25
CRHR2 Pre-treatment Expression, Neurovegetative Symptoms, IL-2 Doses
Tolerated
………………………………………………………………………….......................................28
ACTH, IL-6 and Gene expression……………………………………………….............................30
Discussion………………………………………………………………………………...............................31
References………………………………………………………………………………...............................41

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