Von Hippel-Lindau syndrome (VHL) is a familial neoplastic condition seen in approximately 1 in 36,000 live births. It is caused by germline mutations of the tumor suppressor gene VHL, located on the short arm of chromosome 3. While the majority of the affected individuals have a positive family history, up to 20% of cases arise from de novo mutations. VHL syndrome is characterized by the presence of benign and malignant tumors affecting the central nervous system, kidneys, adrenals, pancreas, and reproductive organs. Common manifestations include hemangioblastomas of the brain, spinal cord, and retina; pheochromocytoma and paraganglioma; renal cell carcinoma; pancreatic cysts and neuroendocrine tumors; and endolymphatic sac tumors. Diagnosis of VHL is prompted by clinical suspicion and confirmed by molecular testing. Management of VHL patients is complex and multidisciplinary. Routine genetic testing and surveillance using various diagnostic techniques are used to help monitor disease progression and implement treatment options.Common VHL-associated clinical manifestations include central nervous system hemangioblastoma (CHB), renal cell carcinoma or renal cyst (RCC), retinal angioma (RA), pancreatic tumor or cyst (PCT), pheochromocytoma and paragangliomas (PHEO), endolymphatic sac tumor, and epididymis or broad ligament cystadenoma.
Hemangioblastomas, which are formed by blood vessels, can develop in the brain and spinal cord and cause weakness, headaches and light sensitivity. hemangioblastoma is a benign, highly vascular tumor that can occur in the brain, spinal cord, and retina (the light-sensitive tissue that lines the back of the eye). This tumor accounts for about 2% of brain tumors. As it enlarges, it presses on the brain and can cause neurological symptoms, such as headaches, weakness, sensory loss, balance and coordination problems, and/or hydrocephalus (a buildup of spinal fluid in the brain). Most hemangioblastomas occur sporadically. However, some people develop hemangioblastomas as part of a genetic syndrome called von Hippel-Lindau syndrome. These people usually develop multiple tumors within the brain and spinal cord over their lifetime.
Hemangioblastomas account for approximately 2% of the intracranial neoplasms and 2–10% of the primary spinal cord neoplasms (2, 3). These highly vascularized tumors are most commonly located in the cerebellum (45%–50%), followed by the spinal cord (40–45%) and brain stem (5–10%) (4–6). CNS hemangioblastomas usually present with unpredictable growth . Although CNS hemangioblastomas do not invade or metastasize, they can cause symptoms by tumor-related bleeding or compression of the adjacent structure.
Neuroendocrine tumors (NETs) are highly vascularized, but the process of proliferation and maturation of vascular structures during tumor development and progression has remained unknown.
Exploring possible relationships between RNASET2 expression and a series of immunohistochemical markers related to hypoxic stress, apoptosis, proliferation and angiogenesis. Our results showed a significantly higher expression of RNASET2, HIF-1α,
The RNASET2 gene provides instructions for making a protein called ribonuclease T2 (RNAse T2), which is abundant in the brain. Ribonucleases help break down RNA, a chemical cousin of DNA. Studies suggest that ribonuclease T2 may also be involved in other functions within cells, such as controlling the development of blood vessels (angiogenesis) and helping to prevent the growth of cancerous tumors. These potential roles of the protein are not well understood.
showing higher proliferation and apoptotic rates, as well as a lower microvessel density (MVD) than the latter. Moreover, we were able to demonstrate in vitro an overexpression of RNASET2 in consequence of the activation of HIF-1α. In conclusion, we suggest that in poorly differentiated Lu-NENs, RNASET2 expression may be induced by HIF-1α, behaving as an alarmin-like molecule. In this aggressive group of cancers, which have highly deregulated proliferation pathways, RNASET2 fails to exert the growth-inhibiting effects described in other types of neoplasms. Its increased expression, however, may contribute to the typical phenotypic alterations seen in poorly differentiated Lu-NENs, such as the high apoptotic rate and the extensive necrosis, and may also enhance the low MVD observed in these neoplasms.
The VHL gene product, VHL protein (pVHL), inhibits the accumulation of hypoxia-inducible messenger RNA (mRNA), including vascular endothelial growth factor (VEGF), under normoxic conditions.The mutant pVHL is unable to regulate transcription of VEGF mRNA, resulting in neovascularization.The VHL gene product, VHL protein (pVHL), inhibits the accumulation of hypoxia-inducible messenger RNA (mRNA), including vascular endothelial growth factor (VEGF), under normoxic conditions. The mutant pVHL is unable to regulate transcription of VEGF mRNA, resulting in neovascularization.
It is also important to remember that the VHL gene is not located on the sex chromosomes. Therefore, mutations can be inherited from either the mother or the father's side of the family.
Brain metastases (BM) are rarely reported in patients with neuroendocrine carcinoma (NEC) of non-lung origin and neuroendocrine tumors (NET) of the gastroenteropancreatic (GEP) or bronchopulmonary system. However, symptomatic brain metastases are associated with dismal prognosis, so early detection and treatment could be advisable.
Besides common distant manifestations including lymph node ( 43% have lymph nodal metastases)
liver and bone metastases, brain metastases (BM) in NET are rare with an estimated incidence < 5% . Based on results, the incidence for brain metastases is 1–2%. However, the current data suggest a worse prognosis in patients with BM . Known factors influencing overall survival are primary tumour localization and TNM classification- A system to describe the amount and spread of cancer in a patient's body, using TNM ( Stage I means the cancer is small and only in one area. This is also called early-stage cancer. Stage II and III mean the cancer is larger and has grown into nearby tissues or lymph nodes. Stage IV means the cancer has spread to other parts of your body)
In general, for BM most data are available in bronchopulmonary NEN. Particularly, in large-cell NEC of the lung BM are frequently detected in up to 50% of cases Only small retrospectively collected case series or individual reports of BM in NET patients have been published. In this light, our data provide important clinico-pathological information of patients with BM.
In almost all cases, the presence of BM was a characteristic of a systemic dissemination and disease progression. In the only two cases without any other distant metastases the primary was located in the lung. Interestingly, although the majority of patients included in databases suffer from gastroenteropancreatic NEN, patients with BM the lung was the most frequent primary tumour localization, which is in accordance with the other retrospective series . In comparison to recently published studies the mean age of our group was rather young (< 60 years) and consistent between NET and NEC . Whereas in the whole cohort both genders were similarly affected, female patients dominated the long-term survivors and metachronous ( two (or more) independent primary malignancies, when the second (or third, etc.) malignancy arose more than six months after the diagnosis of the first malignancy )BM group. The median latency time for BM was rather short in our series (5 months; range 0–144 months) and interestingly, no significant difference within the grading has been observed. Median times from initial diagnosis to BM detection of 18 and 12.8 months, respectively the latter, despite the inclusion of a significant proportion of large-cell and small-cell lung carcinomas. Thus, we believe, cerebral imaging has been used early in cohort to detect or rule out disease progression in comparison to other studies. However, no routine cerebral imaging was implemented in the metastatic assessment of patients. When evaluating risk factors for impaired prognosis, the differentiation based on the grading distributed the patients’ course significantly. Neoplasms presented similar latency times for BM, these results reflected the diverse tumour biology and progression.
Beyond tumour-related characteristics, the optimal treatment for BM in patients with neuroendocrine neoplasms needs to be clarified. For patients with small cell lung cancer and BM, stereotactic radiosurgery combined with WBRT has generally been recommended as first choice treatment.In other neuroendocrine neoplasms, no data on the dual therapy are available. The current guidelines of BM from solid tumours recommend cytotoxic chemotherapy for chemosensitive tumors in patients with asymptomatic or small BM . Since temozolomide is an active drug in proliferating neuroendocrine tumours and can penetrate the blood-brain barrier, it is a valuable option besides surgery and radiation.
Our study is limited in several ways. There are inherent limitations in retrospective analyses. The presented study group is inhomogeneous and includes many different primary tumour localizations. The primary tumour localization itself has prognostic effects and also influences metastasis. On the other hand, neuroendocrine neoplasms can occur ubiquitously and the more exact pathological classifications allow a better characterization of this entity only since a few years. In addition, the study cohort integrates 2 local databases, which does not allow statistical statements on incidence and prevalence of brain metastases. Despite the recording of brain metastases, the process of therapy decision can no longer be traced. This also includes the selection of the available therapy modalities. In addition, response and duration of the response of the brain metastases to specific therapies and their influence on survival cannot be evaluated retrospectively in a proper way.
Metastatic disease is a major prognostic factor in neuroendocrine neoplasms in addition to differentiation and proliferation rate . Besides common distant manifestations including lymph node, liver and bone metastases, brain metastases (BM) in NET are rare with an estimated incidence < 5%
Peripheral signals reach the brain via neuronal and humoral pathways. The neuronal connection from the gut to the brain through vagal afferents originating from pseudo-unipolar cell bodies located in the nodose ganglia is the most extensively investigated. The vagus nerve is composed of over 80% of afferent fibers which convey chemical and mechanosensory signals involved in the regulation of food intake and body weight. Peptide hormones predominantly produced in the gut interact with cognate G protein seven transmembrane domain receptors localized on nodose ganglia neurons. The expression of these receptors is modulated by feeding and fasting underlining the importance of vagal pathways in the control of energy homeostasis.
It establishes one of the connections between the brain and the gastrointestinal tract and sends information about the state of the inner organs to the brain via afferent fibers. In this review article, we discuss various functions of the vagus nerve which make it an attractive target in treating psychiatric and gastrointestinal disorders. There is preliminary evidence that vagus nerve stimulation is a promising add-on treatment for treatment-refractory depression, posttraumatic stress disorder, and inflammatory bowel disease. Treatments that target the vagus nerve increase the vagal tone and inhibit cytokine production.
There is preliminary evidence that vagus nerve stimulation is a promising add-on treatment for treatment-refractory depression, posttraumatic stress disorder, and inflammatory bowel disease. Treatments that target the vagus nerve increase the vagal tone and inhibit cytokine production. Both are important mechanism of resiliency. The stimulation of vagal afferent fibers in the gut influences monoaminergic brain systems in the brain stem that play crucial roles in major psychiatric conditions, such as mood and anxiety disorders. In line, there is preliminary evidence for gut bacteria to have beneficial effect on mood and anxiety, partly by affecting the activity of the vagus nerve. Since, the vagal tone is correlated with capacity to regulate stress responses and can be influenced by breathing, its increase through meditation and yoga likely contribute to resilience and the mitigation of mood and anxiety symptoms.
The vagus nerve carries an extensive range of signals from digestive system and organs to the brain and vice versa. It is the tenth cranial nerve, extending from its origin in the brainstem through the neck and the thorax down to the abdomen. Because of its long path through the human body, it has also been described as the “wanderer nerve”
The vagus nerve represents the main component of the parasympathetic nervous system, which oversees a vast array of crucial bodily functions, including control of mood, immune response, digestion, and heart rate. It establishes one of the connections between the brain and the gastrointestinal tract and sends information about the state of the inner organs to the brain via afferent fibers. In this review article, we discuss various functions of the vagus nerve which make it an attractive target in treating psychiatric and gastrointestinal disorders. There is preliminary evidence that vagus nerve stimulation is a promising add-on treatment for treatment-refractory depression, posttraumatic stress disorder, and inflammatory bowel disease. Treatments that target the vagus nerve increase the vagal tone and inhibit cytokine production. Both are important mechanism of resiliency. The stimulation of vagal afferent fibers in the gut influences monoaminergic brain systems in the brain stem that play crucial roles in major psychiatric conditions, such as mood and anxiety disorders. In line, there is preliminary evidence for gut bacteria to have beneficial effect on mood and anxiety, partly by affecting the activity of the vagus nerve. Since, the vagal tone is correlated with capacity to regulate stress responses and can be influenced by breathing, its increase through meditation and yoga likely contribute to resilience and the mitigation of mood and anxiety symptoms.
The bidirectional communication between the brain and the gastrointestinal tract, the so-called “brain–gut axis,” is based on a complex system, including the vagus nerve, but also sympathetic (e.g., via the prevertebral ganglia), endocrine, immune, and humoral links as well as the influence of gut microbiota in order to regulate gastrointestinal homeostasis and to connect emotional and cognitive areas of the brain with gut functions . The ENS produces more than 30 neurotransmitters and has more neurons than the spine. Hormones and peptides that the ENS releases into the blood circulation cross the blood–brain barrier (e.g., ghrelin) and can act synergistically with the vagus nerve, for example to regulate food intake and appetite (2). The brain–gut axis is becoming increasingly important as a therapeutic target for gastrointestinal and psychiatric disorders, such as inflammatory bowel disease (IBD) (3), depression (4), and posttraumatic stress disorder (PTSD) (5). The gut is an important control center of the immune system and the vagus nerve has immunomodulatory properties (6). As a result, this nerve plays important roles in the relationship between the gut, the brain, and inflammation. There are new treatment options for modulating the brain–gut axis, for example, vagus nerve stimulation (VNS) and meditation techniques. These treatments have been shown to be beneficial in mood and anxiety disorders , but also in other conditions associated with increased inflammation. In particular, gut-directed hypnotherapy was shown to be effective in both, irritable bowel syndrome and IBD . Finally, the vagus nerve also represents an important link between nutrition and psychiatric, neurological and inflammatory diseases.
Basic Anatomy of the Vagus Nerve
The vagus nerve carries an extensive range of signals from digestive system and organs to the brain and vice versa. It is the tenth cranial nerve, extending from its origin in the brainstem through the neck and the thorax down to the abdomen. Because of its long path through the human body, it has also been described as the “wanderer nerve” .
The vagus nerve exits from the medulla oblongata in the groove between the olive and the inferior cerebellar peduncle, leaving the skull through the middle compartment of the jugular foramen. In the neck, the vagus nerve provides required innervation to most of the muscles of the pharynx and larynx, which are responsible for swallowing and vocalization. In the thorax, it provides the main parasympathetic supply to the heart and stimulates a reduction in the heart rate. In the intestines, the vagus nerve regulates the contraction of smooth muscles and glandular secretion. Preganglionic neurons of vagal efferent fibres emerge from the dorsal motor nucleus of the vagus nerve located in the medulla, and innervate the muscular and mucosal layers of the gut both in the lamina propria and in the muscularis externa . The celiac branch supplies the intestine from proximal duodenum to the distal part of the descending colon . The abdominal vagal afferents, include mucosal mechanoreceptors, chemoreceptors, and tension receptors in the oesophagus, stomach, and proximal small intestine, and sensory endings in the liver and pancreas. The sensory afferent cell bodies are located in nodose ganglia and send information to the nucleus tractus solitarii (NTS) .. The NTS projects, the vagal sensory information to several regions of the CNS, such as the locus coeruleus (LC), the rostral ventrolateral medulla, the amygdala, and the thalamus .
The effect of VNS on depressive symptoms, in patients with treatment-resistant depression . The application of VNS over a period of 3 months resulted in a response rate of 37% and a remission rate of 17%. After 1 year of treatment, the response rate reached 53% and the remission rate reached 33%. A meta analysis that compared the application of VNS to the usual treatment in depressed patients showed a response rate of approximately 50% in the acute phase of the disease and a long-term remission rate of 20% after 2 years of treatment. Several other studies also demonstrated an increasing long-term benefit of VNS in recurrent treatment-resistant depression . Further, a 5-year prospective observational study which compared the effects of treatment as usual and VNS as adjunctive treatment with treatment as usual only in treatment-resistant depression, showed a better clinical outcome and a higher remission rate in the VNS group . This was even the case in patients with comorbid depression and anxiety who are frequent non-responders in trials on antidepressant drugs. It is important to note that all these studies were open-label and did not use a randomised, placebo-controlled study design.
It has been shown that self-generated positive emotions via loving-kindness meditation lead to an increase in positive emotions relative to the control group, an effect moderated by baseline vagal tone . In turn, increased positive emotions produced increases in vagal tone, which is probably mediated by increased perceptions of social connections. Individuals suffering from depression, anxiety, and chronic pain have benefited from regular mindfulness meditation training, demonstrating a remarkable improvement in symptom severity
Vagus nerve stimulation is an effective anticonvulsant device and has shown in observational studies antidepressant effects in chronic treatment-resistant depression. Because the vagus nerve sends information to brain regions is important in the stress response (LC, orbitofrontal cortex, insula, hippocampus, and amygdala), this pathway might be involved in perceiving or manifesting various somatic and cognitive symptoms that characterize stress-related disorders.
Psychotropic drugs, such as serotonin reuptake inhibitors, have effects on both the brain and the gastrointestinal tract and consequently should be understood as modulators of the brain–gut axis.
The interaction between the gut and the brain is based on a complex system that includes not only neural but also endocrine, immune, and humoral links.
The vagus nerve is an essential part of the brain–gut axis and plays an important role in the modulation of inflammation, the maintenance of intestinal homeostasis, and the regulation of food intake, satiety, and energy homeostasis. An interaction between nutrition and the vagus nerve is well known, and vagal tone can influence food intake and weight gain.
Moreover, the vagus nerve plays an important role in the pathogenesis of psychiatric disorders, obesity as well as other stress-induced and inflammatory diseases.
Vagus nerve stimulation and several meditation techniques demonstrate that modulating the vagus nerve has a therapeutic effect, mainly due to its relaxing and anti-inflammatory properties.
Extinction paired with VNS is more rapid than extinction paired with sham stimulation. As it is currently approved by the Federal FDA for depression and seizure prevention, VNS is a readily available and promising adjunct to exposure therapy for the treatment of severe anxiety disorders.
Vagus nerve stimulation is an effective anticonvulsant device and has shown in observational studies antidepressant effects in chronic treatment-resistant depression. Because the vagus nerve sends information to brain regions is important in the stress response (LC, orbitofrontal cortex, insula, hippocampus, and amygdala), this pathway might be involved in perceiving or manifesting various somatic and cognitive symptoms that characterize stress-related disorders.
Psychotropic drugs, such as serotonin reuptake inhibitors, have effects on both the brain and the gastrointestinal tract and consequently should be understood as modulators of the brain–gut axis.
Research investigating the interaction between nutritive factors, somatic factors, such as heart rate, psychological and pharmacological treatments, and vagal activity has the potential to lead to integrative treatment options that incorporate VNS, nutritional approaches, drugs, and psychological interventions, such as mindfulness-based approaches, which can be tailored to the needs of the individual patient.
Patients with depression have elevated plasma and cerebrospinal fluid concentrations of proinflammatory cytokines. The benefit of VNS in depression might be due to the inhibitory action on the production of proinflammatory cytokines and marked peripheral increases in anti-inflammatory circulating cytokines. Further, improvement after VNS was associated with altered secretion of CRH, thus preventing the overdrive the HPA axis. Altered CRH production and secretion might result from a direct stimulatory effect, transmitted from the vagus nerve through the NTS to the paraventricular nucleus of the hypothalamus. Finally, VNS has been shown to inhibit peripheral blood production of TNF-α which is increased in clinical depression
Stress influences the expression or circulating levels of several gastrointestinal peptides involved in the regulation of metabolic status under conditions of hunger or satiety . The impact of these alterations on the stress response has subsequently been investigated. The present review will highlight the impact of stress on peptidergic gut-brain hormones primarily involved in the regulation of food intake along with the functional implications.
Nodose ganglia is the most extensively investigated. The vagus nerve is composed of over 80% of afferent fibres which convey chemical and mechanosensory signals involved in the regulation of food intake and body weight. Peptide hormones predominantly produced in the gut interact with cognate G protein seven transmembrane domain receptors localised on nodose ganglia neurons. The expression of these receptors is modulated by feeding and fasting underlining the importance of vagal pathways in the control of energy homeostasis.
Ghrelin is produced by the stomach. Among its numerous functions, ghrelin increases appetite and stimulates the release of growth hormone.Ghrelin is a hormone that is produced and released mainly by the stomach with small amounts also released by the small intestine, pancreas and brain.
Ghrelin has numerous functions. It is termed the ‘hunger hormone’ because it stimulates appetite, increases food intake and promotes fat storage. When administered to humans, ghrelin increases food intake by up to 30%; it circulates in the bloodstream and acts at the hypothalamus, an area of the brain crucial in the control of appetite. Ghrelin has also been shown to act on regions of the brain involved in reward processing such as the amygdala.
Ghrelin also stimulates the release of growth hormone from the pituitary gland, which, unlike ghrelin itself, breaks down fat tissue and causes the build-up of muscle.
Ghrelin also has protective effects on the cardiovascular system and plays a role in the control of insulin release.
Levels of ghrelin in the blood rise just before eating and when fasting, with the timing of these rises being affected by our normal meal routine. Hence, ghrelin is thought to play a role in mealtime ‘hunger pangs’ and the need to begin meals. Levels of ghrelin increase when fasting (in line with increased hunger) and are lower in individuals with a higher body weight compared with lean individuals, which suggests ghrelin could be involved in the long-term regulation of body weight.One would expect higher levels in people with obesity. However, ghrelin levels are usually lower in people with higher body weight compared with lean people, which suggests ghrelin is not a cause of obesity; although there is a suggestion that obese people are actually more sensitive to the hormone.
Nesfatin-1 is a peptide secreted by peripheral tissues, central and peripheral nervous system. It is involved in the regulation of energy homeostasis related with food regulation and water intake. Nesfatin-1 can pass through the blood-brain barrier in both directions. It suppresses feeding independently from the leptin pathway and increases insulin secretion from pancreatic beta islet cells. That is why nesfatin-1 has drawn attention as a new therapeutic agent, especially for the treatment of obesity and diabetes mellitus. Its effects on nutrition have been studied in more detail in literature.Eating reduces concentrations of ghrelin. Different nutrients slow down ghrelin release to varying degrees; carbohydrates and proteins restrict the production and release of ghrelin to a greater extent than fats.Somatostatin also restricts ghrelin release, as well as many other hormones released from the digestive tract.
On the other hand, its effects on other physiological parameters and mechanisms of action still need to be clarified.
Corticotropin-Releasing Hormone Receptor
(CRH) and its receptors play a leading role in the inhibition of the hypothalamic–pituitary–gonadal (HPG) axis during acute stress.
Corticotrophin-releasing hormone is the main element that drives the body's response to stress. It is also present in diseases that cause inflammation. Too much or too little corticotropin-releasing hormone can have a range of negative effects.
Corticotrophin-releasing hormone also acts on many other areas within the brain where it suppresses appetite, increases anxiety, and improves memory and selective attention. Together, these effects co-ordinate behaviour to develop and fine tune the body’s response to a stressful experience.
Corticotrophin-releasing hormone is also produced throughout pregnancy in increasing amounts by the foetus and the placenta, with the effects of increasing cortisol. Ultimately, it is the high levels of corticotrophin-releasing hormone that, along with other hormones, are thought to start labour.
Finally, in smaller quantities, corticotrophin-releasinhormone is also made by certain white blood cells, where it stimulates swelling or tenderness known as inflammation, particularly of the gut.
The urocortins (Ucns) belong to the corticotropin-releasing factor (CRF) family of peptides and have multiple effects within the central nervous and the cardiovascular systems. With growing evidence indicating significant cardioprotective properties and cardiovascular actions of these peptides, the question arises as to whether the plasma profiles of the Ucns are altered in pathologic settings. While reports have shown conflicting results and findings have not been corroborated in multiple independent cohorts, it seems likely that plasma Ucnconcentrations are elevated in multiple cardiovascular conditions. The degree of increase and accurate determination of circulating values of the Ucns requires further validation.
Cholecystokinin
It is produced in the lining of the duodenum and is also released by some neurons in the brain. It acts on two types of receptors found throughout the gut and central nervous system.
The most recognised functions of this hormone are in digestion and appetite. It improves digestion by slowing down the emptying of food from the stomach and stimulating the production of bile in the liver as well as its release from the gall bladder. Bile acts like a detergent making the fat droplets smaller so that enzymes can break it down more easily. Cholecystokinin also increases the release of fluid and enzymes from the pancreas to break down fats, proteins and carbohydrates.
Cholecystokinin seems to be involved with appetite by increasing the sensation of fullness in the short-term, that is, during a meal rather than between meals. It may do this by affecting appetite centres in the brain as well as delaying emptying of the stomach. However, more research is needed to confirm this finding.
There is also evidence to suggest that cholecystokinin may have a role in anxiety and panic disorders. This is an effect of cholecystokinin released in the brain, not an effect of secretion from other parts of the body.Fat and protein in the stomach cause the release of cholecystokinin. Increased blood levels of cholecystokinin can be found 15 minutes after a meal has begun and levels remain raised for three hours afterwards. The release of cholecystokinin is blocked by the hormone somatostatin and by bile acids in the small intestine.Weight loss drugs contain cholecystokinin.
cholecystokinin when people are fasting or just after they have eaten. There appears to be evidence of less than average cholecystokinin in very obese people, unlike the levels in obese and slim people. This low level of cholecystokinin may contribute to reduced feelings of fullness and difficulty in losing weight in very obese people. However, more research is needed to confirm this finding. Variations in the cholecystokinin gene itself have been associated with obesity, with an increased risk of 60% if people carry the slightly different form (variant) called cholecystokinin H3. How this happens is currently unclear.
Central and pituitary CRH receptor signaling in the regulation of HPG axis activity. This schematic diagram summarizes our results and represents a working hypothesis regarding the distinct role of CRH receptors, at the pituitary and brain levels, under basal (non-stressful) and stressful conditions. As depicted in the first panel (from left to right), under basal conditions (no stress) the HPG axis demonstrates functional activity, which ultimately leads to normal LH release by gonadotropes (LH cells) in the pituitary. However, under acute stress (such as restraint stress or LPS injection; second panel), the HPG axis is disrupted (at all levels), resulting in reduced LH release. Interestingly, upon acute stress and deletion of either central CRHR1 or CRHR2 (third panel), but keeping CRHR1 and CRHR2 receptors at the pituitary level, we showed that the stress-induced LH release was also reduced. This finding indicates that upon stress the suppression of the HPG axis is not merely mediated through central CRHRs, but that other factors seem to be recruited and be responsible for the suppression of LH release. The last panel shows that CRH signals differently in the pituitary than in the brain: specifically, the deletion of CRHR2 (but not CRHR1) in the pituitary prevents the suppression of LH release from the pituitary (in vitro: pituitary cell cultures after stimulation with CRH), whereas the application of CRH (in vivo: i.c.v. infusion into the lateral ventricle) in unstressed mice lacking the CRHR1 (but not CRHR2) centrally also prevents the suppression of LH release. Both CRHR1 and CRHR2 are depicted in the same neurons for illustrative purposes.
Food is the main stimulus of glucagon-like peptide 1 release, with increased hormone levels detectable after 10 – 15 minutes of starting to eat and remaining raised in the blood circulation for several hours after that. Apart from food, stimulation of nerve activity and other hormones can affect glucagon-like peptide release. The hormone somatostatin reduces the production of glucagon-like peptide 1. Glucagon-like peptide 1 is rapidly broken down by an enzyme called dipeptidyl peptidase-4.
What happens if I have too much glucagon-like peptide 1?
There are no known cases of too much glucagon-like peptide
Drugs have been developed to behave like glucagon-like peptide
In the blood circulation to improve the control of glucose levels in type-2 diabetes. These drugs are known as GLP-1 analogues. Levels of glucagon-like peptide 1 are also naturally increased after some types of weight-related surgery, which is thought to contribute to the observed weight loss and improvement of type-2 diabetes in patients who have had these types of surgery. Recently one of these GLP-1 analogues (Liraglutide) has been approved for the treatment of obesity in the UK and other countries. Research studies are investigating other GLP-1 analogues, and these may also be approved for the treatment of obesity in the future.
What happens if I have too little glucagon-like peptide 1?
It has been suggested that too little glucagon-like peptide 1 released after a meal may increase the likelihood of, or worsen, obesity. Since glucagon-like peptide 1 reduces appetite after a meal, if the body releases less of this hormone, individuals may eat more during a meal and are more likely to snack between meals.
The full name for peptide YY is pancreatic peptide YY. It is a hormone that is secreted from endocrine cells called L-cells in the small intestine. There are two major forms of the peptide; one is 36 amino acids long (PYY1-36) and the other lacks the first two amino acids (PYY3-36). It is secreted alongside the hormone glucagon-like peptide 1. Peptide YY is released after eating, circulates in the blood and works by binding to receptors in the brain. Binding of peptide YY to brain receptors decreases appetite and makes people feel full after eating. Peptide YY also acts in the stomach and intestine to slow down the movement of food through the digestive tract.
How is peptide YY controlled?
Peptide YY secretion is mainly stimulated by the presence of food in the digestive tract, particularly fat and protein. The amount of peptide YY that is released into the blood depends on the amount of calories eaten, with higher calorie foods causing more peptide YY release than lower calorie foods. Peptide YY secretion can also be stimulated by digestive juices (such as bile) and another gastrointestinal hormone called cholecystokinin. The highest levels of peptide YY are found in the second hour after eating. Peptide YY levels then gradually decrease. Low levels of peptide YY are seen during long periods without eating, for example overnight.
What happens if I have too much peptide YY?
High peptide YY concentrations are unusual. They will cause a decrease in appetite and food intake. High peptide YY concentrations are associated with diseases where there is dramatic weight loss, such as anorexia nervosa, coeliac disease, inflammatory bowel disease (Crohn’s disease and ulcerative colitis) and some cancers.
What happens if I have too little peptide YY?
Low peptide YY concentrations are associated with an increase in appetite and food intake. Low peptide YY levels are seen in obesity and before the onset of type 2 diabetes and may contribute to weight gain in these conditions. However, low peptide YY concentrations are very unlikely to be the main cause of obesity as the levels decrease after weight gain has started. There has been some research into using peptide YY as a medication for obesity, aiming to decrease the appetite of people who are overweight. This research is still ongoing.
It is extremely rare to have a genetic (inherited) deficiency of peptide YY.
A 62-year-old man presented with a history of atypical meningioma (World Health Organization grade II) and recurrent as anaplastic meningioma (World Health Organization grade III). His previous treatments included multiple surgical resections, fractionated radiation therapy, stereotactic radiosurgery, everolimus/octreotide long-acting release, bevacizumab, and hydroxyurea. Magnetic resonance imaging revealed rapid volumetric progression over the prior 9 months, with a near tripling in size from 29.9 cm3 to 80.4 cm3. Indium In 111 octreotide scanning confirmed the presence of somatostatin receptors within the tumor. Lutetium Lu 177 dotatate was administered intravenously at a dose of 200 mCi per dose every 8 weeks for 4 cycles. Treatment was tolerated very well, with no notable adverse events. Tumour volume initially increased to 98.3 cm3 after cycle 1 of treatment and subsequently decreased to 91.2 cm3 after cycle 2. Eight months after treatment onset, the tumour volume remained stable (93.4 cm3).
Meningiomas represent one of the largestsubgroups of intracranial neoplasms, accounting for about 34% of all central nervous system tumours. They are usually benign,
slow-growing tumours. The WHO subclassifies meningioma as grade I, grade II (atypical), andgrade III (anaplastic/A term used to describe cancer cells that divide rapidly and have little or no resemblance to normal cells.), with progressively more aggressive behaviour and poorer prognosis.
Surgical procedures remain the standard initial treatment for most meningiomas.However, it is not unusual for WHO grade II and III meningiomas to recur, thus leading to
multiple surgical resections and repeated
radiation therapy.Treatment options for relapsing and
treatment-refractory anaplastic ( cancer cells that divide rapidly and have little or no resemblance to normal cells.) meningiomas are limited. Recent studies have found that
tumour growth in meningioma is related to hormonal factors.14 Meningiomas have been found to express estrogen and progesterone ( I have leptomeningeal hemangioblastoma and get menstruation often in a month to control my gynaecologist uses progesterone)
receptors, androgens, and nonsteroid hormones, including somatostatin. In vitro and in vivo studies have found that meningioma, regardless of histology and classification, may express SSTRs, and immunohistochemical
studies document the presence of 5 SSTR sub-
types (SSTR1 through SSTR5) in tumour tissue, with predominance of SSTR2 and SSTR5.
The presence of SSTRs within meningiomas can be noninvasively documented by octreotide single-photon emission computed tomography, which historically has been the standard imaging modality for this purpose.
More recently, gallium Ga 68-dotatatepositron emission tomography has becomethe test of choice because it offers higher resolution and shorter imaging time and should more closely approximate the distribution of
177Lu-dotatate therapy. The use of SSTR analogues for meningioma treatment is recognized in European studies, with reported long-term stable disease and long overall survival in rapidly progressive multiple recurrent
anaplastic meningiomas.
177Lu-dotatate is a radioconjugate consisting
of the tyrosine-containing SSTR analogue
Tyr3-octreotate (Peptide receptor radionuclide therapy utilizes somatostatin analogs conjugated to radioactive isotopes in order to deliver high doses of radiation directly to tumor cells, which express somatostatin receptors. Peptide receptor radionuclide therapy with [(177)Lu-DOTA(0),Tyr(3)]-octreotate (DOTATATE) has been reported and investigated for more than a decade, and the randomized controlled NETTER-1 study of this agent has recently been reported to show promising results.)(TATE) conjugated with the
bifunctional, macrocyclic chelating agent
177Lu-dotatate is a theranostic radioisotope for targeted radionuclide therapy of SSTR-positive gastroenteropancreatic neuroendocrine tumours
that may also be a reasonable consideration in
SSTR-expressing meningiomas. Treatment was well tolerated and demonstrated biological effect by temporarily halting growth in a previous rapidly growing WHO grade III meningioma refractory to numerous previous therapies.
Although benefit was transient in this patient, this
observation nonetheless builds confidence that 177Lu-dotatate may be a safe and effective strategy
for the treatment of SSTR-positive recurrent meningiomas. Until additional data are available from larger efficacy studies and cost-benefit analyses, this approach should be considered only as a salvage therapy option once other standard therapies have been exhausted.
"Multiple calcified nodular lesions are seen in both lung fields, relatively larger and more in number in the upper lobes,
Fibrotic bands are also noted in both lungs. Air trapping is noted in both lung
fields. Few small thin walled cysts are also noted in both lungs.
Few small calcified mediastinal lymph nodes are also noted.
Multiple ill-defined calcified & non-calcified nodules are seen scattered in both lungs, predominantly in upper lobes, largest measuring 2x1.3 cm in right upper lobe.
A thin walled cyst in the left upper lobe.
Few calcified subcm mediastinal lymph-nodes. No enlarged mediastinal lymph-nodes.
No pleural/pericardial effusion is seen. Bone window shows no significant abnormality.
Note is made of few subcm calcified foci in bilateral breasts."- a combination of reports from my old Mahajan Imaging Rajiv Gandhi Hospital
Symptoms of a lung NET
There are 2 ways in which a lung NET can cause symptoms. A tumor itself can block the airway, causing a cough or shortness of breath. Or, hormones released by the tumor can cause carcinoid syndrome (see below). A lung NET is much less likely to cause carcinoid syndrome than a GI tract NET.
People with a lung NET may experience the following symptoms or signs:
Cough, with or without bloody sputum or phlegm(with bloody mucus from my right nose) blood from my right nose??
Wheezing
Post-obstructive pneumonia, which is when a tumor blocking a large air passage causes an infection( ? For me) Never had one. Only had terrifying breathing problem in the Delhi airport wishing I could gulp in air.
Chest pain
Carcinoid syndrome
Spleen is normal in size. Multiple small calcific nodular foci are noted in spleen.Spleenomegaly with feel fluid was noted in my Liver Transplant discharge certificate.
Spleen is normal in size. Multiple small calcific nodular foci are noted in spleen.Spleenomegaly with feel fluid was noted in my Liver Transplant discharge certificate.
Right kidney is normal in position and size. Few small subcentimeter sized cysts are noted in right kidney, the largest in its
upper pole measuring 0.9 x 0.8cm. The largest cyst in upper pole of right kidney shows relatively higher attenuation in non
contrast sections, suggestive of a complex cyst (Bosniak type 2). There is no hydronephrosis or ureteric dilatation.
Cysts are fluid filled structures that range from being "simple cysts" which are benign to more complex cysts which could be cancerous. Cysts are graded on a scale from 1 to 4 (Bosniak Classification)
Bosniak 1 and 2 lesions are likely to be benign whereas Bosniak 3 and 4 lesions are more likely to be cancerous.
Left kidney is normal in position and size. Areas of cortical scarring are noted in left kidney, more prominent in the upper
polar region. A simple cyst is seen in its mid polar region in peripelvic location, measuring 2.7cm in diameter. Another small subcentimeter sized simple cyst is also noted peripherally in its mid polar region. There is no hydronephrosis or ureteric dilatation.
Left Kidney had RCC and a simple cyst -In contrast, a complex kidney cyst might have thicker walls and an irregular shape. It might also contain solid material.
Urinary bladder is normal. Uterus measures 5x4x10 cm (APXTRXCC). A well-defined avidly enhancing
subserosal lesion measuring 3x2.6 cm is seen at the uterine fundus.
Enhancement that is more pronounced at the periphery of a mass. It can have varying appearances, ranging from a thin pattern to one that is thicker. This internal enhancement characteristic is an established characteristic of malignant lesions
Subserosal fibroids: These are the most common fibroids. They can push outside of the uterus into the pelvis. Subserosal fibroids can grow large at times and sometimes have a stalk that attaches to the uterus (pedunculated fibroid).
Intramural fibroids: These fibroids develop in the muscular wall of the uterus.
Submucosal fibroids: These fibroids are uncommon. They can grow into the open space inside the uterus and may also include a stalk.
An extra-axial nodular lesion, showing homogeneous contrast enhancement is seen along the lateral cerebral convexity in
right frontal region, measuring 2.0 x 0.9cm in size. There is overlying hyperostosis of skull vault at this level. A small
subcentimeter sized extra-axial nodular lesion with homogenous contrast enhancement is also seen along the lateral
cerebral convexity in left frontal region at the same level, measuring 0.6 x 0.3cm in size. No edema is seen in the cerebral
parenchyma adjacent to these nodular lesions.
Another small extra-axial nodular lesion with homogenous contrast enhancement, showing peripheral calcification, is seen in
right medial temporal region, abutting the tentorium, measuring 0.9 x 0.7cm in size. A tiny such nodule is also noted laterally
in right anterior temporal region. No edema is seen in the adjacent cerebral parenchyma.
Small subcentimeter sized homogenously enhancing nodular lesions are also noted in bilateral parasellar regions, the
larger on right side measuring 0.8 x 0.7cm.
A small densely calcified nodule is noted in right basifrontal region, based on the perpendicular plate of sphenoid,
measuring 0.5cm in diameter.
Post operative appearance of skull vault is noted on right side (parietal craniotomy). An underlying focal hypodense area,
with no contrast enhancement, is noted in right parietal lobe at this level, suggestive of focal gliosis.
Suggesting that the differentiation between calcification and brain stones might be based on size. These pathologies typically manifest as seizures and are occasionally identified during routine brain tomography. Meningiomas constitute an important portion of extra-axial calcifications, whereas tumorous and vascular causes are more prevalent among intra-axial calcifications.
Mostly my altered emotions or change the way things look, smell, feel, taste or sound, but I never lose consciousness. Feeling angry, joyful or sad is so often I have developed abibliophobia, asymphonyphobia… a word coined to describe my love of Mozart, Vivaldi, Beethoven, I listen to classical music .
Some people have nausea or unusual feelings that are difficult to describe. These seizures may also result in difficulty speaking, involuntary jerking of a body part, such as an arm or a leg, and spontaneous sensory symptoms such as tingling, dizziness and seeing flashing lights. Life I often do. Increased after losing balance I hit my head to the bookshelf and fell to the floor cracking back of the skull. Bleeding stopped soon due to high platelets
Symptoms
Without any reason for my choking and hoarse voice.
I can't stand fall
I vomit suddenly
I have neck pain and headaches
Swallowing problem.
I got choked on solid food and coughed my lungs out.
I bit my tongue while eating or speaking and the dentist said to use anaesthetic mouth wash
My gait and I bumped into stuff and hit my skull. Last hit was my loving bookshelf and got a bump.
My right legs have been hurt so many times and if you touch I fall
Dizziness
Blurry vision.
Stinging of the calf muscles and toes, recently fingers as well.
I am confused because of symptoms of the diarrhea and brain. I am going to the toilet after every meal.
One red eye in the right side, right cheeks rosy, lips bent twitching.
difficulty speaking or loss of voice
a voice that is hoarse or wheezy
trouble drinking liquids keep coughing
pain in the ear, liquid coming out and getting deaf with every passing day.
Unusual jaw pain
unusual pain in the middle of the chest
decreased/increases appetite
Fear of food that again I would run to the loo
nausea or vomiting
abdominal bloating /pain
Also I get diarrhea.
cough
tiredness
headache especially I started falling on my Birthday last December
aches and pains
a rash on skin,
red or irritated eyes are very common for me
difficulty breathing or shortness of breath
loss of speech or mobility, or confusion
During my craniotomy my parents noticed loss of consciousness and jerking of the left leg.
I’ve even heard one patient story where it was claimed a doctor called a metastatic NET case benign! Any standard cancer nomenclature definition of ‘benign’ from any respectable cancer site will include the statement that they do not spread to other parts of the body.
I’m sure there are scenarios in all cancers where tumours can be benign and will never harm the person but if a doctor says you have a Neuroendocrine Tumour and not to worry because it’s benign, ask questions. Start with “how do you know it will never turn malignant” and “what will be done going forward to check”. This is particularly important in cases a young girl was shooed away and she asked isn't there any treatment? The crying girl was disheartened because she was told she's destined to die. We all are but no human can say " she had so many repercussion that she'd die in her 40s was told about me several times.Vellore, Chennai disappointed during craniotomy but Dr Soin was firm and confident. A human passing out of medical school can't determine my fate.
I also acknowledge that many slow-growing localised NETs have much less prevalence for spread, i.e. Appendiceal NET, Rectal NET, and to a certain extent atypical Lung NET. Epidemiological data confirm these have less risk of spreading and there are curative scenarios in completing removing the localised primary with the right margins.
PRRT is a molecular targeted therapy used to treat neuroendocrine tumors (NET). Molecular targeted therapies use drugs or other substances to identify and attack cancer cells while reducing harm to healthy tissue. PRRT delivers high doses of radiation to tumors in the body to destroy or slow their growth and reduce disease side effects.
How does it work?
Patients who qualify for PRRT receive a dose of amino acid solution through an IV to protect the kidneys from radiation by reducing how much radiation they absorb. Then, octreotide, a synthetic cell-targeting protein, or peptide, is combined with a small amount of radioactive material, or radionuclide, to create a radiopeptide. When the radiopeptide is injected into a patient’s bloodstream, it binds to protein receptors called somatostatin receptors, located on NET cells, and delivers high doses of radiation to the tumor. Because it’s a systemic treatment, PRRT targets NETs with somatostatin receptors anywhere in the body.
The amino acid solution is also delivered to PRRT patients after they receive the radiopeptide injection. Because small amounts of radiation may remain in the body, patients are generally advised to take certain precautions after treatment, especially for the first one to two days.
Who may benefit from PRRT?
PRRT is recommended for patients who have somatostatin receptor-positive gastroenteropancreatic NETs, common neuroendocrine tumors that develop in the stomach, rectum, pancreas, and small and large intestine. Typically, NETs aren’t diagnosed until they’ve advanced, which means surgery may not be recommended because it may not remove all the patient’s tumors. Gastroenteropancreatic NETs that cannot be removed with surgery are typically treated with hormone therapy to control symptoms and tumor growth. But in cases when tumors continue to grow despite treatment, the PRRT drug 177-Lu-Dotatate, which combines the manufactured form of somatostatin with radioactive material, may be offered as a second-line treatment. In clinical trials, patients with tumors that were progressing despite first-line treatments and were given 177-Lu-Dotatate lived substantially longer, by almost three years, without cancer progression than patients who were treated with hormone therapy.
Not all gastroenteropancreatic NETs have somatostatin receptors, so PRRT is not an option for all NET patients. Imaging scans, such as Detectnet™ and NETSPOT, are used to determine whether the appropriate receptors are present.
What are the potential side effects?
The infusion of amino acids in PRRT helps decrease the amount of radiation the kidneys receive, but it may cause nausea and vomiting, which is typically managed with anti-nausea medication. In rare cases, patients may experience radiation toxicity to the liver and blood system, so patients who have already received heavy treatment to the liver may not be candidates for PRRT because of the toxicity risk. Regulating the dose of radiation may help.
What are the potential benefits to patients?
PRRT is generally delivered over the course of four four-hour infusions. The treatment is designed to slow the progression of disease in NET patients and to reduce the severity of disease side effects, such as diarrhoea.
As a targeted therapy, PRRT offers patients more personalised, precise treatment, with medications tailored to the unique characteristics of each patient’s biology and the molecular properties of the tumour, while limiting radiation exposure to healthy tissue.
