Hypothalamic pituitary dysfunction amongst nasopharyngeal cancer survivors

Incidence and prevalence of hypopituitarism are estimated to be 4.2 per 100,000 per year and 45.5 per 100,000, respectively. Although the clinical symptoms of this disorder are usually unspecific, it can cause life-threatening events and lead to increased mortality. Current research has refined the diagnosis of hypopituitarism. Identification of growth hormone and corticotropin deficiency generally requires a stimulation test, whereas other deficiencies can be detected by basal hormones in combination with clinical judgment. Newly developed formulations of replacement hormones are convenient and physiological. Work has shown that many patients with brain damage--such as traumatic brain injury or aneurysmal subarachnoid haemorrhage--are at high risk of (sometimes unrecognised) hypopituitarism. Thus, a much increased true prevalence of this disorder needs to be assumed. As a result, hypopituitarism is not a rare disease and should be recognised by the general practitioner.

Exposure of cells to a variety of stresses induces compensatory activations of multiple intracellular signaling pathways. These activations can play critical roles in controlling cell survival and repopulation effects in a stress-specific and cell type-dependent manner. Some stress-induced signaling pathways are those normally activated by mitogens such as the EGFR/RAS/PI3K-MAPK pathway. Other pathways activated by stresses such as ionizing radiation include those downstream of death receptors, including pro-caspases and the transcription factor NFKB. This review will attempt to describe some of the complex network of signals induced by ionizing radiation and other cellular stresses in animal cells, with particular attention to signaling by growth factor and death receptors. This includes radiation-induced signaling via the EGFR and IGFI-R to the PI3K, MAPK, JNK, and p38 pathways as well as FAS-R and TNF-R signaling to pro-caspases and NFKB. The roles of autocrine ligands in the responses of cells and bystander cells to radiation and cellular stresses will also be discussed. Based on the data currently available, it appears that radiation can simultaneously activate multiple signaling pathways in cells. Reactive oxygen and nitrogen species may play an important role in this process by inhibiting protein tyrosine phosphatase activity. The ability of radiation to activate signaling pathways may depend on the expression of growth factor receptors, autocrine factors, RAS mutation, and PTEN expression. In other words, just because pathway X is activated by radiation in one cell type does not mean that pathway X will be activated in a different cell type. Radiation-induced signaling through growth factor receptors such as the EGFR may provide radioprotective signals through multiple downstream pathways. In some cell types, enhanced basal signaling by proto-oncogenes such as RAS may provide a radioprotective signal. In many cell types, this may be through PI3K, in others potentially by NFKB or MAPK. Receptor signaling is often dependent on autocrine factors, and synthesis of autocrine factors will have an impact on the amount of radiation-induced pathway activity. For example, cells expressing TGFalpha and HB-EGF will generate protection primarily through EGFR. Heregulin and neuregulins will generate protective signals through ERBB4/ERBB3. The impact on radiation-induced signaling of other autocrine and paracrine ligands such as TGFbeta and interleukin 6 is likely to be as complicated as described above for the ERBB receptors. Copyright 2003 by Radiation Research Society

Survivors of childhood brain tumors (CBTs) are at high risk for a variety of late adverse effects. Most research on long-term effects of CBTs has been comprised of single-institution case series without comparison groups. Research on CBT late effects often is focused on neurologic and sensory outcomes, with less emphasis on other potential targets such as the endocrine and circulatory systems. The current study was conducted to contrast the incidence of endocrine and cardiovascular conditions among CBT survivors as a function of treatment and to determine the risk of occurrence of these conditions relative to a sibling comparison group. As part of the Childhood Cancer Survivor Study (CCSS), treatment data were collected from medical records and self-reported late effects were ascertained from a survey questionnaire of 1,607 CBT patients who survived their disease for 5 or more years. For comparison purposes, questionnaire data were also collected from 3418 randomly selected siblings of participants in CCSS. One or more endocrine conditions were reported by 43% of CBT survivors. Compared with siblings, CBT survivors had a significantly increased risk of late-onset (>/= 5 years postdiagnosis) hypothyroidism (relative risk [RR] = 14.3; 95% confidence interval [95% CI] 9.7-21.0), growth hormone deficiency (RR = 277.8; 95% CI 111.1-694.9), the need for medications to induce puberty (RR = 86.1; 95% CI 31.1-238.2), and osteoporosis (RR = 24.7; 95% CI 9.9-61.4). One or more cardiovascular conditions were reported by 18% of CBT survivors, with an elevated late-onset risk for stroke (RR = 42.8; 95% CI 16.7-109.8), blood clots (RR = 5.7; 95% CI 3.2-10.0), and angina-like symptoms (RR = 2.0; 95% CI 1.5-2.7). Very few late effects were evident among those treated with surgery only, but risks were consistently elevated for those treated with radiation and surgery, and higher still for those who also received adjuvant chemotherapy. Childhood brain tumor survivors are at a significantly increased risk for several adverse endocrine and cardiovascular late effects, particularly if they were treated with radiation and chemotherapy. Lifetime medical surveillance and follow-up for potential toxicities are necessary because treatment-related complications may occur many years after therapy. Copyright 2003 American Cancer Society.DOI 10.1002/cncr.11095