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EML4-ALK Fusion Gene and Therapy with ALK-Targeted Agents in Non-Small Cell Lung Cancer
Published in Sherry X. Yang, Janet E. Dancey, Handbook of Therapeutic Biomarkers in Cancer, 2021
Francisco E. Vera-Badillo, Janet E. Dancey
Several mechanisms of resistance to crizotinib have been described, with the most common being the development of a secondary mutations within the ALK tyrosine kinase domain. The most common resistance mutation is the gatekeeper L1196M mutation, followed by the G1269A mutation. The G1202R mutation is very important, as it confers high-level resistance to crizotinib and other next-generation EML4-ALK inhibitors. Amplification of the EML4-ALK fusion gene may cause resistance to ALK-TKIs and this event may arise de novo or emerge after initiation of crizotinib therapy. Lastly, but not less important, is the activation of alternative or bypass signaling pathways. These include abnormalities in EGFR, KIT, and insulin-like growth factor 1 receptor (IGFR1R) pathways [51, 52].
Late Effects of Treatment for Childhood Brain and Spinal Tumors
Published in David A. Walker, Giorgio Perilongo, Roger E. Taylor, Ian F. Pollack, Brain and Spinal Tumors of Childhood, 2020
Ralph Salloum, Katherine Baum, Melissa Gerstle, Helen Spoudeas, Susan R. Rose
Sara’s medulloblastoma was diagnosed when she was 4 years old. She underwent surgery, craniospinal irradiation, and chemotherapy. During the next 2 years, magnetic resonance imaging (MRI) scans showed no tumor and she seemed to grow well along the 25th percentile, although her stamina remained low. She required naps and laxatives and cried easily. On physical examination at age 6 years, her pulse was 65 beats/min, temperature 35°C, lung and heart examination normal, abdomen firm (with stool), breast development consistent with Tanner stage 3, and pubic hair stage consistent with Tanner 1. She was found to have precocious puberty, along with central hypothyroidism, ACTHD, and GHD. (Of note, her growth rate was normal probably because the precocious puberty sped up her growth, compensating for slowed growth from hypothyroidism and GHD (Figure 21.4).) She was started on hydrocortisone therapy, then after 2 days, on thyroid hormone therapy. Gonadotropin-releasing hormone (GnRH) analog therapy was initiated. Her growth rate slowed over the next 6 months. The use of GH therapy was reviewed with her oncologist and was approved in view of her continued stable MRI. She started GH replacement with improved growth rate. GH dose was adjusted to keep serum insulin-like growth factor-1 (IGF-1) concentration near the mean for age.
Personalized Nutrition in Children with Crohn Disease
Published in Nilanjana Maulik, Personalized Nutrition as Medical Therapy for High-Risk Diseases, 2020
Diagnostic baseline nutritional testing to screen for micronutrient deficiency should include iron studies and ferritin, vitamin D, vitamin B12 and folate. Assessment of zinc, vitamins A, vitamin E, vitamin C, selenium and magnesium also may be indicated. Micronutrient deficiencies should be corrected with follow-up measurement to confirm response. Measurement of insulin-like growth factor 1 (IGF-1) may be helpful if there is significant linear growth impairment at diagnosis.
Teprotumumab and hearing loss: hear the warnings
Published in Orbit, 2021
Alexander Chern, David A. Gudis, Lora R. Dagi Glass
This unexpected side effect profile may have its underpinnings in a more basic understanding of insulin-like growth factor-1 (IGF-1). IGF-1 has been implicated in inner ear development, as well as in the maintenance and protection of hearing function.3 Genetic IGF-1 deficiency has been associated with devastating hearing loss in a human and in mouse studies.4 Animal models of sound trauma have shown that IGF-1 application to the round window appears to confer significant protective effects.5,6 Moreover, IGF-1 is on the therapeutic horizon as a biological therapy for sensorineural hearing loss. It has been used as a salvage therapy via direct placement on the round window in a Phase 1 study of patients with sudden hearing loss refractory to standard corticosteroid treatment; at 24 weeks post-treatment, 56% of the 24 treated patients demonstrated hearing improvement.7 Decreased IGF-1 in aging mice has also been associated with presbycusis.8
Plasma insulin-like growth factor binding protein 1 in pulmonary arterial hypertension
Published in Scandinavian Cardiovascular Journal, 2021
Habib Bouzina, Roger Hesselstrand, Göran Rådegran
Insulin-like growth factor 1 (IGF-1) is a hormone with similar structure as insulin, which serves as an anabolic hormone in adults. When binding to the receptor tyrosine kinase IGF-1 receptor, IGF-1 initiates molecular cascades that play a pivotal role in cellular proliferation and survival [13]. An altered IGF-1 and IGF-1 receptor system is indeed associated with several malignancies [13]. IGF-1 and IGF-1 receptor signalling has also been implied to influence pulmonary hypertension (PH) [14–16]. In neonatal hypoxic PH models, IGF-1 depletion may reduce right ventricular (RV) hypertrophy and vascular remodelling in small pulmonary arteries [15]. IGF binding protein (IGFBP)-1, which acts as a carrier protein that binds to and modulates IGF-1 [13], has additionally been shown to predict survival in PAH patients [17].
Drug treatment strategies for secondary diabetes in patients with acromegaly
Published in Expert Opinion on Pharmacotherapy, 2020
Sylvère Störmann, Jochen Schopohl
Besides its direct effects on target tissues, GH also exerts numerous effects mediated by insulin-like growth factor 1 (IGF-I) that is mostly synthesized in hepatocytes upon growth hormone receptor binding [43]. Opposed to the diabetic effect of GH, IGF-I increases insulin sensitivity and glucose uptake [40]. IGF-I was considered for therapeutic use in type 2 diabetes mellitus in several studies [53–55]. While study designs differed slightly (dosage, length of administration) the findings were unanimous and showed improvements in insulin sensitivity by ameliorating hepatic and muscle insulin resistance. To achieve relevant effects the IGF-I levels had to be increased to such an extent that adverse events such as edema, headaches, and arthralgias occurred in an important number of patients. In an attempt to minimize side effects while retaining the beneficial effects of recombinant human IGF-I administration in these patients a study was carried out adding IGFBP-3 to the treatment [56]. Insulin usage could effectively be reduced while improving tolerability. However, despite the theoretical advantage of IGF-I in type 2 diabetes mellitus it had to be concluded that the window between therapeutic utility and toxicity is small [57]. As could be shown, IGF-I correlated more closely with glucose intolerance than random GH after adjusting for age, sex, weight, and acromegaly duration [29]. Given the above-mentioned positive effects of IGF-I, this might seem counter-intuitive at first sight, but IGF-I is an integrated measure of GH excess which primarily determines the abnormal glucose homeostasis [42].