scholarly journals Cranial irradiation mediated spine loss is sex-specific and complement receptor-3 dependent in male mice

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Joshua J. Hinkle ◽  
John A. Olschowka ◽  
Tanzy M. Love ◽  
Jacqueline P. Williams ◽  
M. Kerry O’Banion
Keyword(s):  
Quality Of Life ◽  
Dendritic Spine ◽  
Cranial Irradiation ◽  
Common Mechanism ◽  
Complement Receptor ◽  
Spine Density ◽  
Male Mice ◽  
Activation Markers ◽  
Complement Receptor 3

AbstractCranial irradiation is the main therapeutic treatment for primary and metastatic malignancies in the brain. However, cranial radiation therapy produces long-term impairment in memory, information processing, and attention that contribute to a decline in quality of life. The hippocampal neural network is fundamental for proper storage and retrieval of episodic and spatial memories, suggesting that hippocampal signaling dysfunction could be responsible for the progressive memory deficits observed following irradiation. Previous rodent studies demonstrated that irradiation induces significant loss in dendritic spine number, alters spine morphology, and is associated with behavioral task deficits. Additionally, the literature suggests a common mechanism in which synaptic elimination via microglial-mediated phagocytosis is complement dependent and associated with cognitive impairment in aging as well as disease. We demonstrate sexual dimorphisms in irradiation-mediated alterations of microglia activation markers and dendritic spine density. Further, we find that the significant dendritic spine loss observed in male mice following irradiation is microglia complement receptor 3 (CR3)-dependent. By identifying sex-dependent cellular and molecular factors underlying irradiation-mediated spine loss, therapies can be developed to counteract irradiation-induced cognitive decline and improve patient quality of life.

Pharmacologic manipulation of complement receptor 3 prevents dendritic spine loss and cognitive impairment after acute cranial radiation

2020 ◽  
Author(s):  
Joshua J. Hinkle ◽  
John A. Olschowka ◽  
Jacqueline P. Williams ◽  
M. Kerry O’Banion
Keyword(s):  
Quality Of Life ◽  
Cognitive Impairment ◽  
Cognitive Deficits ◽  
Dendritic Spine ◽  
Cranial Irradiation ◽  
Complement Receptor ◽  
Spine Density ◽  
Male Mice ◽  
Complement Receptor 3

AbstractCranial irradiation induces healthy tissue damage that can lead to neurocognitive complications and negatively impact patient quality of life. One type of damage associated with cognitive impairment is loss of neuronal spine density. Based on developmental and disease studies implicating microglia and complement in dendritic spine loss, we hypothesized that irradiation-mediated spine loss is microglial complement receptor 3 (CR3)-dependent, and associated with late-delayed cognitive deficits. Utilizing a model of cranial irradiation (acute, 10 Gy gamma) in C57BL/6 mice we found that male mice demonstrate irradiation-mediated spine loss and cognitive deficits whereas female mice and CR3 knockout mice do not. Moreover, pharmacological blockade of CR3 with leukadherin-1 (LA1) prevented these changes in irradiated male mice. Interestingly, CR3 KO mice showed reduced behavioral task performance suggesting that CR3 is important for normal learning and memory. Improving our understanding of irradiation-mediated mechanisms and sexual dimorphic responses is essential for the identification of novel therapeutics to reduce irradiation-induced cognitive decline and improve patient quality of life.

scholarly journals MANAGEMENT OF ENDOCRINE DISEASE: Neuroendocrine surveillance and management of neurosurgical patients

2017 ◽  
Vol 176 (5) ◽  
pp. R217-R233 ◽  
Author(s):  
Aoife Garrahy ◽  
Mark Sherlock ◽  
Christopher J Thompson
Keyword(s):  
Quality Of Life ◽  
Time Course ◽  
Dynamic Testing ◽  
Hormone Replacement ◽  
Survival Rates ◽  
Cranial Irradiation ◽  
Pituitary Dysfunction ◽  
Neurosurgical Patients ◽  
Life Threatening

Advances in the management of traumatic brain injury, subarachnoid haemorrhage and intracranial tumours have led to improved survival rates and an increased focus on quality of life of survivors. Endocrine sequelae of the acute brain insult and subsequent neurosurgery, peri-operative fluid administration and/or cranial irradiation are now well described. Unrecognised acute hypopituitarism, particularly ACTH/cortisol deficiency and diabetes insipidus, can be life threatening. Although hypopituitarism may be transient, up to 30% of survivors of TBI have chronic hypopituitarism, which can diminish quality of life and hamper rehabilitation. Patients who survive SAH may also develop hypopituitarism, though it is less common than after TBI. The growth hormone axis is most frequently affected. There is also accumulating evidence that survivors of intracranial malignancy, who have required cranial irradiation, may develop hypopituitarism. The time course of the development of hormone deficits is varied, and predictors of pituitary dysfunction are unreliable. Furthermore, diagnosis of GH and ACTH deficiency require dynamic testing that can be resource intensive. Thus the surveillance and management of neuroendocrine dysfunction in neurosurgical patients poses significant logistic challenges to endocrine services. However, diagnosis and management of pituitary dysfunction can be rewarding. Appropriate hormone replacement can improve quality of life, prevent complications such as muscle atrophy, infection and osteoporosis and improve engagement with physiotherapy and rehabilitation.

Prophylactic cranial irradiation (PCI) versus observation in radically treated stage III non-small cell lung cancer (NSCLC): A randomized phase III NVALT11 study.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 8502-8502 ◽  
Author(s):  
Harry J.M. Groen ◽  
Anne-Marie C. Dingemans ◽  
Jose Belderbos ◽  
Caroline Tissing-Tan ◽  
Gertruda Herder ◽  
...  
Keyword(s):  
Quality Of Life ◽  
Brain Metastases ◽  
Cranial Irradiation ◽  
Prophylactic Cranial Irradiation ◽  
Phase Iii ◽  
Stage Iii ◽  
Rank Test ◽  
Global Quality Of Life ◽  
Pressure Headache

8502 Background: Brain metastases are one of the major sites of tumor failure in patients (pts) with radically treated stage III NSCLC. The value of PCI in these pts remains unsettled. This study is designed to investigate whether PCI reduces the incidence of symptomatic brain metastases (sBM). Methods: Pts were randomized between observation and PCI after concurrent or sequential chemo-RT with or without surgery. PCI dose was left to the physician(36 Gy/18F, 30 Gy/12F, 30 Gy/10F). Pts were registered before randomization, those progressing after chemo-RT were not randomized. Pts were followed for sBM (defined as increased intracranial pressure, headache, nausea, vomiting, cognitive, affective disturbances, seizures, focal neurological symptoms andMRI/CT), side effects, survival, quality of life (QLQ-C30, EuroQol 5D). The primary endpoint is the proportion of patients developing sBM. Randomizing 300 pts the study has 90% (2-sided p = 0.05) power to detect 17% decrease in pts developing sBM at 24 months (mo). Results: Between 2009 and 2015, 195 pts were registered, 175 were randomized, 87 received PCI and 88 pts were in the observation arm. In 2013 due to slow accrual, it was decided to reduce the number of randomized pts to 175 pts. With 75 events a 2-sided log-rank test would have 80% power to detect HR 0.52 and alpha 0.05. One pt in PCI arm was withdrawn after randomization. Pts characteristics were male (n = 114, 66%); adeno/squa/other 72 (41%), 62 (36%), 40 (23%); PS 0/1/2 66 (38%), 99 (57%), 9 (5%); stage IIIA/B 93 (53%), 80 (46%), unknown 1 (1%). Median follow up was 48.5 mo (95% CI, 39 - 54). Proportion of pts with sBM was 4/86 (4.6%) in PCI and 25/88 (28.4 %) in observation (p < 0.00001). Seven (8.1%) pts in PCI and 26 (29.7%) pts in observation arm had BM on imaging (p < 0.001). Median time to sBM was not reached in either arm. Median OS was 24.2 mo in PCI and 21.9 mo in observation arm (p = 0.52). Global QoL at 3 mo was worse in PCI arm (p = 0.02) but not afterwards. Conclusions: PCI significantly decreases the proportion of patients developing both symptomatic BM without influencing overall survival. PCI decreases 3 months global quality of life measures but not beyond. Clinical trial information: NTR 1601.

scholarly journals The long-term burden of war injuries in LMICs: Case of the Lebanese War of 2006

2020 ◽  
Vol 30 (Supplement_5) ◽  
Author(s):  
E Kobeissi ◽  
M Menassa ◽  
G Honein-AbouHaidar ◽  
R Abdul Khalek ◽  
B Chaya ◽  
...  
Keyword(s):  
Quality Of Life ◽  
Common Mechanism ◽  
Mixed Method Research ◽  
War Injuries ◽  
Preliminary Results ◽  
August 15Th ◽  
Long Term Impact ◽  
Study Participants

Abstract Background Armed conflict is a major cause of disability and mortality, particularly in LMICs. July 12, 2006 marks the start of a 33-day war in Lebanon which resulted in at least 1191 deaths and 4409 injured, the vast majority of whom were civilians. Little is known about the consequences of war-injuries inflicted on civilians. The AUB arm of the NIHR PrOTeCT Group aims to identify 1) war-injury characteristics associated with high burden of care 2) the long-term socioeconomic burden and 3) the quality of life of the injured civilians and their access to healthcare and medicine under conditions of war. Methods This study employs a mixed-method research design by reviewing medical records of patients admitted to hospitals in Lebanon between July 12th and August 15th, 2006, conducting interviews with patients, and administering the EQ5D5L questionnaire to understand the burden of injuries and the quality of life of patients 13 years after injury. Qualitative and quantitative data analysis methods will be used. Preliminary Results 25 interviews have been conducted so far. Injured civilians were mostly males, average age 27. The most common mechanism of injury was blast injury. Most patients underwent multiple surgeries as well as revision surgeries. The emerging themes include description of the 1-scene and type of injury; 2-referral process from the injury site to the hospital; 3-the types of services received; and 4-the financial and non-financial long-term impact. They described the long-term burden including chronic pain, poor mobility, anxiety or depression, and limited activities of daily living. Conclusions These preliminary results show that civilians injured during the July 2006 war are experiencing physical and psychological sequelae; thus, more services need to be offered to civilians injured during war. Key messages Physical impairments related to war injuries influenced the quality of life of study participants. Affordable or free rehabilitation services need to be offered to civilians injured during war.

scholarly journals The impact of cancer therapy on the endocrine system in survivors of childhood brain tumours

2004 ◽  
Vol 11 (4) ◽  
pp. 589-602 ◽  
Author(s):  
H K Gleeson ◽  
S M Shalet
Keyword(s):  
Quality Of Life ◽  
Cancer Therapy ◽  
Brain Tumours ◽  
Final Height ◽  
Cranial Irradiation ◽  
Early Puberty ◽  
Gh Therapy ◽  
Childhood Brain Tumours ◽  
The Impact

Survival rates are improving following cancer therapy for childhood brain tumours. There is therefore a growing cohort of survivors at risk of late effects of cancer therapy. Endocrine problems are very common in these patients. The recognition and prompt management of these are essential to prevent further morbidity and impairment of quality of life. Cranial radiation can damage hypothalamic–pituitary function, most frequently affecting GH status; however, higher radiation doses may cause more widespread hypothalamic–pituitary damage. Early puberty secondary to cranial irradiation is now being managed with gonadotrophin-releasing hormone analogues to improve final height. Prompt diagnosis and management of GH deficiency may improve final height outcome; continued GH therapy beyond final height aids the achievement of adult body composition (lean body mass and bone mass) and GH therapy in adulthood improves quality of life. Both cranial irradiation alone and with spinal irradiation can result in radiation damage to the thyroid resulting in hypothyroidism and thyroid nodules, a high proportion of which are malignant. Gonadal damage secondary to spinal irradiation and adjuvant chemotherapy may have long-term consequences including infertility.

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