How to End the Autism Epidemic
Breast cancer is the most common therapy-related solid SN after HL, largely due to the high dose of chest radiation used to treat HL SIR of subsequent breast cancer, 25— Homocysteine implicated in Schizophrenia In conclusion, the more we learn about what kicks off and accelerates brain aging, the clearer it becomes: Increasingly, the former seems to be the case, with Serotonin levels , do they need boosting with amino acids? When I first started, most of my time was spent with medical journals, but 15 years into my research, much of my time is spent with cookbooks. So how do they compare with anti-depressants?
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Should you be concerned? Many clinicians are concerned about potential harms related to radiation exposure associated with annual mammography in these young women. In this regard, it is important to consider that the estimated mean breast dose with contemporary standard two-view screening mammograms is about 3.
The benefits of detection of early breast cancer lesions in high-risk women must be balanced by the risk predisposed by a 0. To keep young women engaged in breast health surveillance, the COG Guideline recommends the following for females who received a radiation dose of 20 Gy or higher to the mantle, mediastinal, whole lung, and axillary fields:.
The risk of breast cancer in patients who received less than 20 Gy of radiation with potential impact to the breast is of a lower magnitude compared with those who received more than 20 Gy.
If a decision is made to screen, the recommendations for women exposed to more than 20 Gy are used. Cardiovascular disease, after recurrence of the original cancer and development of second primary cancers, has been reported to be the leading cause of premature mortality among long-term childhood cancer survivors. The specific late effects covered in this section include the following:.
The section will also briefly discuss the influence of related conditions such as hypertension, dyslipidemia, and diabetes in relation to these late effects, but not directly review in detail those conditions as a consequence of childhood cancer treatment.
A comprehensive review on long-term cardiovascular toxicity in childhood and young adult survivors of cancer, issued by the American Heart Association, has been published.
Overall, there has been a wealth of studies focused on the topic of cardiac events among childhood cancer survivors. In addition to many smaller studies not covered in detail here, the literature includes very large cohort studies that are either hospital based,[ 6 , 8 - 12 ] clinical trial based,[ 13 , 14 ] or population based,[ 2 , 4 ] many with up to several decades of follow-up.
However, even with decades of follow-up, the average age of these populations may still be relatively young young or middle adulthood. And while the risk of serious cardiovascular outcomes may be very high relative to the age-matched general population, the absolute risk often remains low, limiting the power of many studies. Among the very large studies featuring thousands of survivors, the main limitation has been inadequate ability to clinically ascertain late cardiovascular complications, with a greater reliance on either administrative records e.
While each study design has some inherent biases, the overall literature, based on a combination of self-reported outcomes, clinical ascertainment, and administrative data sources, is robust in concluding that certain cancer-related exposures predispose survivors toward a significantly greater risk of cardiovascular morbidity and mortality.
Although late effects research often lags behind changes in contemporary therapy, many therapies linked to cardiovascular late effects remain in common use today. Using data from four large, well-annotated childhood cancer survivor cohorts CCSS, National Wilms Tumor Study Group, the Netherlands, and SJCRH , a heart failure risk calculator based on readily available demographic and treatment characteristics has been created and validated, which may provide more individualized clinical heart failure risk estimation for 5-year survivors of childhood cancer who have recently completed therapy and up through age 40 years.
One limitation of this estimator is that because of the young age of participants at the time of baseline prediction 5-year survival , information on conventional cardiovascular conditions such as hypertension, dyslipidemia, or diabetes could not be incorporated. In another collaborative study, data from the CCSS, Netherlands, and SJCRH were used to develop risk-prediction models for ischemic heart disease and stroke among 5-year survivors of childhood cancer through 50 years.
Risk scores derived from a standard prediction model that included sex, chemotherapy exposure, and radiation therapy exposure identified statistically distinct low-risk, moderate-risk, and high-risk groups. Chemotherapy in particular, anthracyclines and anthraquinones along with radiation therapy both independently and in combination, increase the risk of cardiovascular disease in survivors of childhood cancer and are considered to be the most important risk factors contributing to premature cardiovascular disease in this population refer to Figure 3.
A, B Marginal Kaplan-Meier and C—E cause-specific competing risk cumulative incidence of cardiac events CEs in childhood cancer survivors stratified according to different treatment groups. Risk factors for anthracycline-related cardiomyopathy include the following: Among these factors, cumulative dose appears to be the most significant refer to Figure 4.
Risk of anthracycline-induced clinical heart failure A-CHF according to cumulative anthracycline dose. Kremer, Clinical heart failure in a cohort of children treated with anthracyclines: A long-term follow-up study, Pages , Copyright , with permission from Elsevier. It remains unclear how best to add together doses of different anthracycline agents. A variety of anthracycline equivalence formulas in relation to doxorubicin have been used; however, they are largely based on hematologic toxicity equivalence, and may not necessarily be the same for cardiac toxicity.
Other agents such as idarubicin, epirubicin, and mitoxantrone an anthraquinone were designed to reduce cardiac toxicity while maintaining similar antitumor effect, although data supporting this are primarily limited to adult cancer patients.
Cardioprotective strategies that have been explored include the following:. There are more data for dexrazoxane as a cardioprotectant, but again, mainly in adult cancer patients, for whom it is approved by the U. While anthracyclines directly damage cardiomyocytes, radiation therapy primarily affects the fine vasculature of affected organs. Late effects of radiation therapy to the heart specifically include the following:.
Similar to anthracyclines, manifestation of these late effects may take years, if not decades, to present. Finally, patients who were exposed to both radiation therapy affecting the cardiovascular system and cardiotoxic chemotherapy agents are at even greater risk of late cardiovascular outcomes.
Cerebrovascular disease after radiation therapy exposure is another potential late effect for survivors. As with cardiac outcomes, risk increases with cumulative dose received. Various cancer treatment exposures may also directly or indirectly influence the development of hypertension, diabetes mellitus, and dyslipidemia.
Childhood cancer survivors should be closely screened for the development of these cardiovascular conditions because they represent potentially modifiable targets for intervention. This includes being aware of related conditions such as obesity and various endocrinopathies e. Some, but not all, studies suggest that female sex may be associated with a greater risk of anthracycline-related cardiomyopathy. While much knowledge has been gained over the past 20 years in better understanding the long-term burden and risk factors for cardiovascular disease among childhood cancer survivors, many areas of inquiry remain, and include the following:.
Various national groups, including the National Institutes of Health—sponsored COG refer to Table 2 , have published recommendations regarding screening and surveillance for cardiovascular and other late effects among childhood cancer survivors.
At this point, there is no clear evidence at least through age 50 years or 30—40 years posttreatment that there is a plateau in risk that occurs after a certain time among survivors exposed to cancer treatments associated with cardiovascular late effects.
However, a growing amount of literature is beginning to establish the yield from these screening studies, which will help inform future guidelines. Given the growing evidence that conventional cardiovascular conditions such as hypertension, dyslipidemia, and diabetes substantially increase the risk of more serious cardiovascular disease among survivors, clinicians should carefully consider baseline and follow-up screening and treatment of these comorbid conditions that impact cardiovascular health refer to Table 2.
There is also emerging evidence that adoption of healthier lifestyle factors may decrease future cardiovascular morbidity in at-risk survivors. In addition to releasing a comprehensive, publicly available online set of guidelines , the COG has also put together a series of handouts on cardiovascular and related topics, including lifestyle choices written for a lay audience, available on the same website. Neurocognitive late effects are most commonly observed after treatment of malignancies that require central nervous system CNS —directed therapies.
While there is considerable evidence published about this outcome, its quality is often limited by small sample size, cohort selection and participation bias, cross-sectional versus longitudinal evaluations, and variable time of assessment from treatment exposures. CNS-directed therapies include the following:. Children with brain tumors or acute lymphoblastic leukemia ALL are most likely to be affected. Risk factors for the development of neurocognitive late effects include the following: It should be noted that the cognitive phenotypes observed in childhood survivors of ALL and CNS tumors may differ from traditional developmental disorders.
In addition to the direct effects of neurotoxic therapies like cranial radiation, Childhood Cancer Survivor Study CCSS investigators observed that chronic health conditions resulting from non-neurotoxic treatment exposures e. Survival rates have increased over recent decades for children with brain tumors; however, long-term cognitive effects caused by illness and associated treatments are a well-established morbidity in this group of survivors.
In childhood and adolescent brain tumor survivors, risk factors for adverse neurocognitive effects include the following:. The negative impact of radiation treatment has been characterized by changes in IQ scores, which have been noted to drop about 2 to 5 years after diagnosis; the decline continues 5 to 10 years afterward, although less is known about potential stabilization or further decline of IQ scores several decades after diagnosis.
These changes in cognitive functioning may be partially explained by radiation-induced reduction of normal-appearing white matter volume or integrity of white matter pathways, as evaluated through magnetic resonance imaging MRI.
Data are emerging regarding cognitive outcomes after proton radiation to the CNS. Study results demonstrating lack of difference in slopes of IQ change among photon- and proton-treated patients [ 31 ] and significant declines in cognitive processing speed among patients treated with proton radiation [ 32 ] underscore the importance of longitudinal follow-up to determine whether proton radiation provides a clinically meaningful benefit in sparing cognitive function compared with photon radiation.
In addition, studies are beginning to examine cognitive outcomes in histologically distinct subtypes of brain tumors. For example, data from a sample of medulloblastoma patients demonstrated variation in cognitive outcomes by four distinct molecular subgroups and differences in patterns of change over time. Longitudinal cohort studies have provided insight into the trajectory and predictors of cognitive decline among survivors of CNS tumors. Evidence predictors of cognitive decline among survivors of CNS tumors:.
Modeled intelligence quotient IQ scores after conformal radiation therapy CRT by age for pediatric low-grade glioma. Age is measured in years, and time is measured in months after the start of CRT. Conklin, Shengjie Wu, Robert H. Although adverse neurocognitive outcomes observed 5 to 10 years after treatment are presumed to be pervasive, and potentially worsen over time, few empirical data are available regarding the neurocognitive functioning in very long-term survivors of CNS tumors.
The neurocognitive consequences of CNS disease and treatment may have a considerable impact on functional outcomes for brain tumor survivors. The increase in cure rates for children with ALL over the past decades has resulted in greater attention to the neurocognitive morbidity and quality of life of survivors. The goal of current ALL treatment is to minimize adverse late effects while maintaining high survival rates.
To minimize the risk of late sequelae, patients are stratified for treatment according to their risk of relapse. Although low-risk, standard-risk, and most high-risk patients are treated with chemotherapy-only protocols, early reports of neurocognitive late effects for ALL patients were based on heterogeneously treated groups of survivors who received combinations simultaneously or sequentially of intrathecal chemotherapy, radiation therapy, and high-dose chemotherapy, making it difficult to differentiate the impact of the individual treatment components.
However, outcome data are increasingly available regarding the risk of neurocognitive late effects in survivors of childhood ALL treated with chemotherapy only. In survivors of ALL, cranial radiation therapy may result in clinical and radiographic neurologic late sequelae, including the following:. Because of its penetrance into the CNS, systemic methotrexate has been used in a variety of low-dose and high-dose regimens for leukemia CNS prophylaxis.
Systemic methotrexate in high doses with or without radiation therapy can lead to an infrequent but well-described leukoencephalopathy, which has been linked to neurocognitive impairment.
Compared with cranial irradiation, chemotherapy-only CNS-directed treatment produces neurocognitive deficits involving processes of attention, speed of information processing, memory, verbal comprehension, visual-spatial skills, visual-motor functioning, and executive functioning; global intellectual function is typically preserved.
Reduced cognitive status has been observed in association with reduced integrity in neuroanatomical regions essential in memory formation e. However, the long-term impact of these prevalent neurocognitive and neuroimaging abnormalities on functional status in aging adults treated for childhood ALL, particularly those treated with contemporary approaches using chemotherapy alone, remains an active area of research.
Evidence neurocognitive functioning in large pediatric cancer survivor cohorts:. The type of steroid used for ALL systemic treatment may affect cognitive functioning. In a study that involved long-term neurocognitive testing mean follow-up, 9. Intrathecal hydrocortisone also increased risk of attention problems RR, 1.
Neurocognitive abnormalities have been reported in other groups of cancer survivors. Factors such as diagnosis before age 6 years, female sex, cranial radiation therapy, and hearing impediment were associated with impairment. Neurocognitive abnormalities have been reported for the following cancers:. Later studies have yielded mixed results. For example, serial assessment of cognitive and adaptive functioning in a group of survivors younger than 6 years revealed declines in developmental functioning over time.
The most pronounced declines were observed in patients with 13q deletion. Cognitive and academic consequences of stem cell transplantation in children have also been evaluated and include, but are not limited to, the following:. Most neurocognitive late effects after stem cell transplantation are thought to be related to white matter damage in the brain.
This was investigated in children with leukemia who were treated with HSCT. In a series of 36 patients, performance on neurocognitive measures typically associated with white matter was compared with performance on measures thought to correlate with gray matter function.
Composite white matter scores were significantly lower than composite gray matter scores, thereby supporting the belief that white matter damage contributes to neurocognitive late effects in this population. In children with CNS tumors, mass effect, tumor infiltration, and increased intracranial pressure may result in motor or sensory deficits, cerebellar dysfunction, and secondary effects such as seizures and cerebrovascular complications.
Numerous reports describe abnormalities of CNS integrity and function, but such studies are typically limited by small sample size, cohort selection and participation bias, cross-sectional ascertainment of outcomes, and variable time of assessment from treatment exposures. In contrast, relatively few studies comprehensively or systematically ascertain outcomes related to peripheral nervous system function. Neurologic complications that may occur in survivors of childhood cancer include the following:.
Among adult survivors of extracranial solid tumors of childhood median time from diagnosis, 25 years , standardized assessment of neuromuscular function disclosed motor impairment in association with vincristine exposure and sensory impairment in association with cisplatin exposure. These studies underscore the importance of assessment and referral to rehabilitative services to optimize functional outcomes among long-term survivors.
In a cross-sectional study that evaluated neurologic morbidity and quality of life in survivors of childhood ALL median age at evaluation, Female sex, ten doses or more of intrathecal chemotherapy, cranial irradiation, CNS leukemia at diagnosis, and history of ALL relapse were associated with neurologic morbidity.
Neuroimaging studies of irradiated and nonirradiated ALL survivors demonstrate a variety of CNS abnormalities, including leukoencephalopathy, cerebral lacunes, cerebral atrophy, and dystrophic calcifications mineralizing microangiopathy.
Among these, abnormalities of cerebral white matter integrity and volume have been correlated with neurocognitive outcomes. Cavernomas have also been observed in ALL survivors treated with cranial irradiation. They have been speculated to result from angiogenic processes as opposed to tumorigenesis.
Table 3 summarizes CNS late effects and the related health screenings. Many childhood cancer survivors report reduced quality of life or other adverse psychosocial outcomes.
Evidence for adverse psychosocial adjustment after childhood cancer has been derived from a number of sources, ranging from patient-reported or proxy-reported outcomes to data from population-based registries. The former may be limited by small sample size, cohort selection and participation bias, and variable methods and venues clinical vs. The latter is often not well correlated with clinical and treatment characteristics that permit the identification of survivors at high risk of psychosocial deficits.
Survivors with neurocognitive deficits are particularly vulnerable to adverse psychosocial outcomes that affect achievement of expected social outcomes during adulthood. Childhood cancer survivors are also at risk of developing symptoms of psychological distress.
In a longitudinal study of more than 4, survivors, subgroups of survivors were found to be at risk of developing persistent and increasing symptoms of anxiety and depression during a year period. Survivors who reported pain and worsening health status were at the greatest risk of developing symptoms of anxiety, depression, and somatization over time. Adult survivors of childhood cancer are also at risk of suicide ideation compared with siblings, with survivors of CNS tumors being most likely to report thoughts of suicide.
In a CCSS study that evaluated the prevalence of recurrent suicidal ideation among 9, adult long-term survivors of childhood cancer, survivors were more likely to report late suicidal ideation odds ratio [OR], 1. History of seizure was associated with a twofold increased likelihood of suicide ideation in survivors. The presence of chronic health conditions can also impact aspects of psychological health.
HSCT survivors with severe or life-threatening health conditions and active chronic GVHD had a twofold increased risk of somatic distress. Incorporation of psychological screening into clinical visits for childhood cancer survivors may be valuable; however, limiting such evaluations to those returning to long-term follow-up clinics may result in a biased subsample of survivors with more difficulties, and precise prevalence rates may be difficult to establish.
On the Symptom Checklist 90 Revised, 32 subjects had a positive screen indicating psychological distress , and 14 subjects reported at least one suicidal symptom. In this study, the instrument was shown to be feasible for use in the clinic visit setting because the psychological screening was completed in less than 30 minutes. Anxiety and Distress for more information about psychological distress and cancer patients. Despite the many stresses associated with the diagnosis of cancer and its treatment, studies have generally shown low levels of post-traumatic stress symptoms and post-traumatic stress disorder PTSD in children with cancer, typically no higher than those in healthy comparison children.
Because avoidance of places and persons associated with the cancer is part of PTSD, the syndrome may interfere with obtaining appropriate health care. Those with PTSD perceive greater current threats to their lives or the lives of their children. Other risk factors include poor family functioning, decreased social support, and noncancer stressors. Most research on late effects after cancer has focused on individuals with a cancer manifestation during childhood.
Little is known about the specific impact of a cancer diagnosis with an onset in adolescence or the impact of childhood cancer on adolescent and young adult AYA psychosocial outcomes.
Overall results support that behavioral, emotional, and social symptoms frequently co-occur in adolescent survivors and are associated with treatment exposures cranial radiation, corticosteroids, and methotrexate and late effects obesity, cancer-related pain, and sensory impairments. It should be noted that social withdrawal in adolescence has been associated with adult obesity and physical inactivity. Because of the challenges experienced by adolescents and young adults at cancer diagnosis and during long-term follow-up, this group may benefit from access to programs to address the unique psychosocial, educational, and vocational issues that impact their transition to survivorship.
Chemotherapy, radiation therapy, and local surgery can cause multiple cosmetic and functional abnormalities of the oral cavity and dentition. The quality of current evidence regarding this outcome is limited by retrospective data collection, small sample size, cohort selection and participation bias, and heterogeneity in treatment approach, time since treatment, and method of ascertainment.
Oral and dental complications reported in childhood cancer survivors include the following:. Abnormalities of dental development reported in childhood cancer survivors include the following: The prevalence of hypodontia has varied widely in series depending on age at diagnosis, treatment modality, and method of ascertainment.
Cancer treatments that have been associated with dental maldevelopment include the following: Key findings related to cancer treatment effect on tooth development include the following:. Developing teeth may be irradiated in the course of treating head and neck sarcomas, Hodgkin lymphoma, neuroblastoma, central nervous system leukemia, nasopharyngeal cancer, brain tumors, and as a component of total-body irradiation TBI.
Doses of 10 Gy to 40 Gy can cause root shortening or abnormal curvature, dwarfism, and hypocalcification. Xerostomia, the sensation of dry mouth, is a potential side effect after head and neck irradiation or HSCT that can severely impact quality of life.
Complications of reduced salivary secretion include the following: The prevalence of salivary gland dysfunction after cancer treatment varies based on measurement techniques patient report vs.
In the CCSS, the prevalence of self-reported xerostomia in survivors was 2. Key findings related to cancer treatment effect on salivary gland function include the following:. The impact of infectious complications and alterations in the microflora during and after therapy is not known. Craniofacial maldevelopment is a common adverse outcome among children treated with high-dose radiation therapy to the head and neck that frequently occurs in association with other oral cavity sequelae such as dental anomalies, xerostomia, and trismus.
Remediation of cosmetic and functional abnormalities often requires multiple surgical interventions. Some studies suggest that fluoride products or chlorhexidine rinses may be beneficial in patients who have undergone radiation therapy. The use of topical fluoride can dramatically reduce the frequency of caries, and saliva substitutes and sialagogues can ameliorate sequelae such as xerostomia. It has been reported that the incidence of dental visits for childhood cancer survivors falls below the American Dental Association's recommendation that all adults visit the dentist annually.
These findings give health care providers further impetus to encourage routine dental care and dental hygiene evaluations for survivors of childhood treatment. Table 4 summarizes oral and dental late effects and the related health screenings. The gastrointestinal GI tract is sensitive to the acute toxicities of chemotherapy, radiation therapy, and surgery.
However, these important treatment modalities can also result in some long-term issues in a treatment- and dose-dependent manner. Reports published about long-term GI tract outcomes are limited by retrospective data collection, small sample size, cohort selection and participation bias, heterogeneity in treatment approach, time since treatment, and method of ascertainment.
Factors predicting higher risk of specific GI complications include the following:. In general, fractionated radiation doses of 20 Gy to 30 Gy can be delivered to the small bowel without significant long-term morbidity.
Doses greater than 40 Gy are associated with a higher risk of bowel obstruction or chronic enterocolitis. Intra-abdominal tumors represent a relatively common location for several pediatric malignancies, including rhabdomyosarcoma, Wilms tumor, lymphoma, germ cell tumors, and neuroblastoma.
Thus, these tumors would be expected to be particularly prone to long-term digestive tract issues. A limited number of reports describe GI complications in pediatric patients with genitourinary solid tumors treated with radiation therapy: Table 5 summarizes digestive tract late effects and the related health screenings.
Hepatic complications resulting from childhood cancer therapy are observed primarily as acute treatment toxicities. Severe acute hepatic complications rarely occur. Survivors of childhood cancer can occasionally exhibit long-standing hepatic injury. Some general concepts regarding hepatotoxicity related to childhood cancer include the following:.
Asymptomatic elevation of liver enzymes is the most common hepatobiliary complication. Dutch investigators observed hepatobiliary dysfunction in 8. Cases with a history of viral hepatitis and a history of veno-occlusive disease were excluded. Less commonly reported hepatobiliary complications include the following:. These lesions are thought to be iatrogenic benign manifestations of vascular damage and have been associated with veno-occlusive disease, high-dose alkylating agents e.
The lesions can mimic metastatic or subsequent tumors, but MRI imaging has a characteristic pattern and is generally diagnostic. Biopsy or resection is usually unnecessary unless the lesions grow or patients have worrisome symptoms. Biopsy may be necessary to distinguish nodular regenerative hyperplasia from a subsequent malignancy.
MRI has emerged as an accurate, noninvasive means for measuring iron in multiple organ systems. In a multivariable analysis, cumulative packed red blood cell volume and older age at diagnosis predicted elevated liver iron concentration.
The type and intensity of previous therapy influences risk for late-occurring hepatobiliary effects. In addition to the risk of treatment-related toxicity, recipients of HSCT frequently experience chronic liver dysfunction related to microvascular, immunologic, infectious, metabolic, and other toxic etiologies. Key findings related to cancer treatment effect on hepatobiliary complications include the following:. Radiation hepatopathy after contemporary treatment appears to be uncommon in long-term survivors without predisposing conditions such as viral hepatitis or iron overload.
The risk of injury in children increases with radiation dose, hepatic volume, younger age at treatment, previous partial hepatectomy, and concomitant use of radiomimetic chemotherapy such as dactinomycin and doxorubicin. Viral hepatitis B and C may complicate the treatment course of childhood cancer and result in chronic hepatic dysfunction. Hepatitis B tends to have a more aggressive acute clinical course and a lower rate of chronic infection.
Hepatitis C is characterized by a mild acute infection and a high rate of chronic infection. Chronic hepatitis predisposes the childhood cancer survivor to cirrhosis, end-stage liver disease, and hepatocellular carcinoma. Concurrent infection with hepatitis B and C in combination or in co-occurrence with other hepatotrophic viruses accelerates the progression of liver disease. Survivors with liver dysfunction should be counseled regarding risk-reduction methods to prevent hepatic injury.
Standard recommendations include maintenance of a healthy body weight, abstinence from alcohol use, and immunization against hepatitis A and B viruses. In patients with chronic hepatitis, precautions to reduce viral transmission to household and sexual contacts should also be reviewed. Table 6 summarizes hepatobiliary late effects and the related health screenings.
The pancreas has been thought to be relatively radioresistant because of a paucity of information about late pancreatic-related effects. However, children and young adults treated with TBI or abdominal irradiation are known to have an increased risk of insulin resistance and diabetes mellitus. Endocrine dysfunction is very common among childhood cancer survivors, especially those treated with surgery or radiation therapy that involves hormone-producing organs and those receiving alkylating agent chemotherapy.
Prevalence of endocrine disorders at the last follow-up visit, by sex. The prevalence of specific endocrine disorders is affected by the following: The following sections summarize research that characterizes the clinical features of survivors at risk of endocrine dysfunction that impacts pituitary, thyroid, adrenal, and gonadal function. Thyroid dysfunction is a common delayed effect of radiation therapy fields that include the thyroid gland incidental to treating Hodgkin lymphoma HL , brain tumors, head and neck sarcomas, and acute lymphoblastic leukemia ALL.
There is considerable evidence linking radiation exposure to thyroid abnormalities, but the prevalence of specific conditions varies widely because studies are limited by cohort selection and participation bias, heterogeneity in radiation treatment approach, time since radiation exposure, and method of ascertainment e.
Thyroid abnormalities observed in excess in childhood cancer survivors include the following:. Of children treated with radiation therapy, most develop hypothyroidism within the first 2 to 5 years posttreatment, but new cases can occur later.
Reports of thyroid dysfunction differ depending on the dose of radiation, the length of follow-up, and the biochemical criteria utilized to make the diagnosis. Compensated hypothyroidism includes an elevated TSH with a normal T 4 and is asymptomatic.
The natural history is unclear, but most endocrinologists support treatment. Uncompensated hypothyroidism includes both an elevated TSH and a depressed T 4. Thyroid hormone replacement is beneficial for correction of the metabolic abnormality, and has clinical benefits for cardiovascular, gastrointestinal, and neurocognitive function.
An increased risk of hypothyroidism has been reported among childhood cancer survivors treated with head and neck radiation exposing the thyroid gland, especially among survivors of HL.
Any radiation field that includes the thyroid is associated with an excess risk of thyroid neoplasms, which may be benign usually adenomas or malignant most often differentiated papillary carcinoma.
CCSS investigators performed a nested case-control study to evaluate the magnitude of risk for thyroid cancer over the therapeutic radiation dose range of pediatric cancers.
The risk of thyroid cancer increased with radiation doses up to 20 Gy to 29 Gy odds ratio [OR], 9. The following factors are linked to an increased risk of thyroid nodule development:. In a pooled study of two cohorts of 16, survivors that included patients with secondary thyroid cancer, treatments with alkylating agents, anthracyclines, or bleomycin were associated with a significantly increased risk of thyroid cancer in individuals not exposed to radiation therapy.
Several investigations have demonstrated the superiority of ultrasound to clinical exam for detecting thyroid nodules and thyroid cancers and characterized ultrasonographic features of nodules that are more likely to be malignant. In fact, because these lesions tend to be indolent, are rarely life-threatening, and may clinically manifest many years after exposure to radiation, there are significant concerns regarding the costs and harms of overscreening.
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