Carcinoid syndrome

Endocrinology, Metabolism and Nutrition

Clinicals - History

Fact Explanation
Flushing Carcinoid syndrome is the bio-chemical manifestation of a carcinoid tumor , which is a slow-growing tumor of neuro-endocrine origin . The bio-chemical substances secreted (mainly serotonin) by the tumor gives rise to clinical features of the carcinoid syndrome. Only 10% of patients get the carcinoid syndrome when the tumor has metastasized to lungs/liver, when these organs are no longer able to metabolize the substances secreted by the carcinoid tumor. Flushing is a vaso-active symptom caused by vaso dilation by these secretory substances . Flushing
Carcinoid syndrome is the bio-chemical manifestation of a carcinoid tumor , which is a slow-growing tumor of neuro-endocrine origin . The bio-chemical substances secreted (mainly serotonin) by the tumor gives rise to clinical features of the carcinoid syndrome. Only 10% of patients get the carcinoid syndrome when the tumor has metastasized to lungs/liver, when these organs are no longer able to metabolize the substances secreted by the carcinoid tumor. Flushing is a vaso-active symptom caused by vaso dilation by these secretory substances .
Diarrhea/ passage of loose stools Diarrhea is thought to be caused by the excitatory effect of serotonin on the smooth muscle causing increased gastro-intestinal motility . Diarrhea/ passage of loose stools
Diarrhea is thought to be caused by the excitatory effect of serotonin on the smooth muscle causing increased gastro-intestinal motility .
Symptoms of right heart failure (ankle & abdominal swelling/fatigue/ exertional dyspnea) Right heart failure is a consequence of right side valvular heart disease (pulmonary stenosis/ tricuspid insufficiency) caused by the prolonged exposure of the endocardium to serotonin. Hence this is a late effect of carcinoid syndrome. Serotonin causes endocardial fibrosis resulting in the valvular defects and ultimately right heart failure .
Note: left side valves are affected less as serotonin is metabolized by the lungs .
Symptoms of right heart failure (ankle & abdominal swelling/fatigue/ exertional dyspnea)
Right heart failure is a consequence of right side valvular heart disease (pulmonary stenosis/ tricuspid insufficiency) caused by the prolonged exposure of the endocardium to serotonin. Hence this is a late effect of carcinoid syndrome. Serotonin causes endocardial fibrosis resulting in the valvular defects and ultimately right heart failure .
Note: left side valves are affected less as serotonin is metabolized by the lungs .
New onset wheezing This is due to bronchospasm caused by serotonin & bradykinin secreted by the tumor .
Note: the above symptoms can be precipitated by exertion or by consuming food that are high in tyramine (blue cheese/chocolate) or ethanol (red wine) .
New onset wheezing
This is due to bronchospasm caused by serotonin & bradykinin secreted by the tumor .
Note: the above symptoms can be precipitated by exertion or by consuming food that are high in tyramine (blue cheese/chocolate) or ethanol (red wine) .
Family history of parathyroid/ pancreatic/ bronchial/ gastric/pituitary & adrenal tumors This should raise the suspicion of multiple endocrine neoplasia (MEN-1), which has a genetic susceptibility to carcinoid tumors . Most patients initially present with symptoms of hypercalcemia due to parathyroid disease .
Note: patients with MEN-1 present about 15 years earlier than the sporadic cases with carcinoid tumor .
Family history of parathyroid/ pancreatic/ bronchial/ gastric/pituitary & adrenal tumors
This should raise the suspicion of multiple endocrine neoplasia (MEN-1), which has a genetic susceptibility to carcinoid tumors . Most patients initially present with symptoms of hypercalcemia due to parathyroid disease .
Note: patients with MEN-1 present about 15 years earlier than the sporadic cases with carcinoid tumor .
Family history of hemangioblastomas of the central nervous system/pancreatic tumors/ retinal angiomas/ renal cell carcinomas & phechromocytomas This should raise the suspicion of Von Hippel Lindau’s disease (VHL) ), which has a genetic susceptibility to carcinoid tumors . Family history of hemangioblastomas of the central nervous system/pancreatic tumors/ retinal angiomas/ renal cell carcinomas & phechromocytomas
This should raise the suspicion of Von Hippel Lindau’s disease (VHL) ), which has a genetic susceptibility to carcinoid tumors .
Family history of parathyroid/medullary thyroid cancer/ phechromocytomas and skin lumps/ depigmented lesions These findings lead to the possibility of Neurofibromatosis type 1 (NF-1) which is associated with mid gut carcinoid tumors . As the carcinoid syndrome is highly associated with small bowel carcinoid tumors which are a derivative of the mid gut , asking about NF-1from the patient is very important in taking history. Family history of parathyroid/medullary thyroid cancer/ phechromocytomas and skin lumps/ depigmented lesions
These findings lead to the possibility of Neurofibromatosis type 1 (NF-1) which is associated with mid gut carcinoid tumors . As the carcinoid syndrome is highly associated with small bowel carcinoid tumors which are a derivative of the mid gut , asking about NF-1from the patient is very important in taking history.

Clinicals - Examination

Fact Explanation
Tachycardia & hypotension Caused by the various vaso-active substances secreted by the carcinoid tumor. Some of these substances include serotonin, bradykinin, prostaglandins & substance P . Tachycardia & hypotension
Caused by the various vaso-active substances secreted by the carcinoid tumor. Some of these substances include serotonin, bradykinin, prostaglandins & substance P .
Heart murmur Ejection click/ ejection systolic murmur at the right 2nd intercostal space of pulmonary stenosis or pansystolic murmur at the lower sternal edge of tricuspid insufficiency may be heard . Heart murmur
Ejection click/ ejection systolic murmur at the right 2nd intercostal space of pulmonary stenosis or pansystolic murmur at the lower sternal edge of tricuspid insufficiency may be heard .
Signs of right heart failure (bilateral ankle edema/ ascites/ tender hepatomegaly/ elevated jugular venous pulse) These can be found as a complication of pulmonary stenosis/ tricuspid insufficiency, at the late stages of carcinoid tumor as prolonged exposure to excessive serotonin is needed to cause endocardial fibrosis resulting in the valve defects . Signs of right heart failure (bilateral ankle edema/ ascites/ tender hepatomegaly/ elevated jugular venous pulse)
These can be found as a complication of pulmonary stenosis/ tricuspid insufficiency, at the late stages of carcinoid tumor as prolonged exposure to excessive serotonin is needed to cause endocardial fibrosis resulting in the valve defects .
Signs of bronchospasm in chest examination Signs similar to asthma may be seen due to bronchospasm induced by serotonin . the signs include hyper-resonance on percussion, rhochi & prolonged expiration with wheezing on auscultation. Signs of bronchospasm in chest examination
Signs similar to asthma may be seen due to bronchospasm induced by serotonin . the signs include hyper-resonance on percussion, rhochi & prolonged expiration with wheezing on auscultation.
Hepatosplenomegaly on abdominal examination This can be a finding in the presence of metastatic disease. Hepatosplenomegaly on abdominal examination
This can be a finding in the presence of metastatic disease.
Skin lumps (fibromas/lipomas/neurofibromas) and associated lesions Presence of fibromas & lipomas raise the suspicion of MEN-1 while neurofibromas associated with café-au-lait spots & axillary freckles suggest a diagnosis of NF-1, both of which are susceptible genetic conditions for carcinoid tumors . Skin lumps (fibromas/lipomas/neurofibromas) and associated lesions
Presence of fibromas & lipomas raise the suspicion of MEN-1 while neurofibromas associated with café-au-lait spots & axillary freckles suggest a diagnosis of NF-1, both of which are susceptible genetic conditions for carcinoid tumors .

Investigations - Diagnosis

Fact Explanation
Serum analysis Serum analysis of chromogranin A is the ideal test to confirm the disease as it is almost always elevated in neuro-endocrine tumors , hence has high specificity . False positives can be seen in multiple myeloma .
Plasma pancreatic polypeptide and human chorionic gonadotrophin alpha subunits are other serum markers . Measurement of insulin, gastrin,glucagons and other peptides can be carried out depending on the clinical features . ].
Serum analysis
Serum analysis of chromogranin A is the ideal test to confirm the disease as it is almost always elevated in neuro-endocrine tumors , hence has high specificity . False positives can be seen in multiple myeloma .
Plasma pancreatic polypeptide and human chorionic gonadotrophin alpha subunits are other serum markers . Measurement of insulin, gastrin,glucagons and other peptides can be carried out depending on the clinical features . ].
Urinanalysis Measuring urinary excretion of 5-hydroxyindoleacetic acid (5-HIAA) is recommended for patients presenting with vasoactive symptoms (flushing), which is a metabolite of serotonin .
Measuring 5-HIAA in a 24 hour urine sample is the most common test done to detect excessive serotonin secretion in the carcinoid syndrome . However, the patient should refrain from taking food & medication rich in serotonin prior to the test, to prevent from getting a false positive result.
Urinanalysis
Measuring urinary excretion of 5-hydroxyindoleacetic acid (5-HIAA) is recommended for patients presenting with vasoactive symptoms (flushing), which is a metabolite of serotonin .
Measuring 5-HIAA in a 24 hour urine sample is the most common test done to detect excessive serotonin secretion in the carcinoid syndrome . However, the patient should refrain from taking food & medication rich in serotonin prior to the test, to prevent from getting a false positive result.
Imaging Imaging modality depends on the suspected site of the carcinoid tumor .
Barium contrast studies: may detect mucosal thickening/ submucosal mass/luminal narrowing .
Computed tomography (CT): may detect mucosal thickening/ submucosal mass/luminal narrowing. Infiltrated carcinoids show a characteristic stellate pattern on CT . CT has higher sensitivity in detecting carcinoid tumors of the thymus and bronchus than other imaging modalities. CT may also be useful in detecting second primary malignancy, which is a significant feature of carcinoid syndrome. The common sites are the gastro-intestinal tract, genitor-urinary tract and the respiratory tract .
Note: CT is very important in diagnosing carcinoid syndrome as it shows liver mets that supports the diagnosis. CT also shows mesenteric extension .
Magnetic resonance imaging (MRI): imaging results of carcinoid tumor is similar to that of CT .
Endoscopic ultrasonography (EUS): important in assessing the regional spread of the tumor, as it gives an account of local tumor invasion and lymph node metastases. EUS is indicated in thymic, bronchopulmonary, gastroduodenal and pancreatic tumors .
Note: all those imaging modalities can detect liver mets of size more than 1 cm, hence very important in patients with carcinoid syndrome . USS & CT also helps in taking specimens for histopathological diagnosis .
Imaging
Imaging modality depends on the suspected site of the carcinoid tumor .
Barium contrast studies: may detect mucosal thickening/ submucosal mass/luminal narrowing .
Computed tomography (CT): may detect mucosal thickening/ submucosal mass/luminal narrowing. Infiltrated carcinoids show a characteristic stellate pattern on CT . CT has higher sensitivity in detecting carcinoid tumors of the thymus and bronchus than other imaging modalities. CT may also be useful in detecting second primary malignancy, which is a significant feature of carcinoid syndrome. The common sites are the gastro-intestinal tract, genitor-urinary tract and the respiratory tract .
Note: CT is very important in diagnosing carcinoid syndrome as it shows liver mets that supports the diagnosis. CT also shows mesenteric extension .
Magnetic resonance imaging (MRI): imaging results of carcinoid tumor is similar to that of CT .
Endoscopic ultrasonography (EUS): important in assessing the regional spread of the tumor, as it gives an account of local tumor invasion and lymph node metastases. EUS is indicated in thymic, bronchopulmonary, gastroduodenal and pancreatic tumors .
Note: all those imaging modalities can detect liver mets of size more than 1 cm, hence very important in patients with carcinoid syndrome . USS & CT also helps in taking specimens for histopathological diagnosis .
Nuclear medicine Iodine labeled meta-iodobenzylguanidine (MIBG) and positron emission tomography (PET) can be used to detect neuroendocrine tumors. Nuclear medicine
Iodine labeled meta-iodobenzylguanidine (MIBG) and positron emission tomography (PET) can be used to detect neuroendocrine tumors.
Somatostatin receptor scintigraphy Neuro-endocrine cells containing receptors for somatostatin and other peptides is the basis for this test . This is superior to CT & MIBG and has greater than 90% sensitivity to patients with symptoms of carcinoid syndrome .
Note: tumors lacking somatostatin receptors such as benign insulinomas can escape from this test .
Somatostatin receptor scintigraphy
Neuro-endocrine cells containing receptors for somatostatin and other peptides is the basis for this test . This is superior to CT & MIBG and has greater than 90% sensitivity to patients with symptoms of carcinoid syndrome .
Note: tumors lacking somatostatin receptors such as benign insulinomas can escape from this test .
Histopathological diagnosis Observation of the characteristic cells by histopathology confirms the diagnosis . Surgical / coarse biopsy needle specimens give detailed appearance of the cells by light/electron microscopy whereas fine needle aspiration cytology (FNAC) specimens are unable to do so. Immunohistochemical analyses (ICA) using chromogranin A and synaptophysin as markers give a more accurate histopathological diagnosis . Tyramide Signal amplification procedure augments the sensitivity of ICA and helps in the diagnosis of poorly differentiated neuro-endocrine tumors . Histopathological diagnosis
Observation of the characteristic cells by histopathology confirms the diagnosis . Surgical / coarse biopsy needle specimens give detailed appearance of the cells by light/electron microscopy whereas fine needle aspiration cytology (FNAC) specimens are unable to do so. Immunohistochemical analyses (ICA) using chromogranin A and synaptophysin as markers give a more accurate histopathological diagnosis . Tyramide Signal amplification procedure augments the sensitivity of ICA and helps in the diagnosis of poorly differentiated neuro-endocrine tumors .

Investigations - Management

Fact Explanation
Serum analysis of chromogranin A This is used to follow up the course of the disease as it is highly specific to carcinoid tumor and is almost always elevated in carcinoid tumors . Serum analysis of chromogranin A
This is used to follow up the course of the disease as it is highly specific to carcinoid tumor and is almost always elevated in carcinoid tumors .
Full blood count (FBC) Investigation to asses basic fitness are needed as patients with carcinoid syndrome may undergo surgery to remove the tumor . Hemoglobin level is the most important component in the FBC as correction of anemia is required before surgery to prevent effects of bleeding related complications. Full blood count (FBC)
Investigation to asses basic fitness are needed as patients with carcinoid syndrome may undergo surgery to remove the tumor . Hemoglobin level is the most important component in the FBC as correction of anemia is required before surgery to prevent effects of bleeding related complications.
Electrocardiogram (ECG) & echogram Important to asses fitness for surgery, as morbidity & mortality is high in patients with poor cardio-resoiratory reserve . ECG should be done in every patient to detect rhythm abnormalities that can be aggrevated during surgery, while echo can be reserved for patents with co-morbodities. Electrocardiogram (ECG) & echogram
Important to asses fitness for surgery, as morbidity & mortality is high in patients with poor cardio-resoiratory reserve . ECG should be done in every patient to detect rhythm abnormalities that can be aggrevated during surgery, while echo can be reserved for patents with co-morbodities.
Spirometry Used to asses the pulmonary function before surgery as abdominal surgery may cause basal atelectasis followed by chest infection (pneumonia). Although this is carried out as a routine test prior to abdominal surgery, the actual effect of it in the assesment of pulmonary function remains controversial . Spirometry
Used to asses the pulmonary function before surgery as abdominal surgery may cause basal atelectasis followed by chest infection (pneumonia). Although this is carried out as a routine test prior to abdominal surgery, the actual effect of it in the assesment of pulmonary function remains controversial .
Serum creatinine & blood urea These are used as a general guide to asses the renal functions prior to surgery, Serum creatinine & blood urea
These are used as a general guide to asses the renal functions prior to surgery,
Fasting blood sugar (FBS) & lipid profile Used to asses co-existing diabetes & dyslipidemia.
Note: control of blood glucose is very crucial in the post-operative period for good wound healing and prevention of infection .
Fasting blood sugar (FBS) & lipid profile
Used to asses co-existing diabetes & dyslipidemia.
Note: control of blood glucose is very crucial in the post-operative period for good wound healing and prevention of infection .
Liver profile This is important in the surgery of carcinoid tumor, specially if the surgery is carried out for hapatic matastases, to have a baseline value of liver function before surgery. Liver profile
This is important in the surgery of carcinoid tumor, specially if the surgery is carried out for hapatic matastases, to have a baseline value of liver function before surgery.
Fine needle aspiration cytology (FNAC) Can be used as a screening test of the tumor as it aids in detecting granulated neoplastic neuroendocrine cells . Fine needle aspiration cytology (FNAC)
Can be used as a screening test of the tumor as it aids in detecting granulated neoplastic neuroendocrine cells .
Somatostatin receptor scintigraphy Neuro-endocrine cells containing receptors for somatostatin and other peptides is the basis for this test. As this is a whole-body investigation it helps in staging of the disease .
Note: the above staging tests are for the carcinoid tumor, not the carcinoid syndrome which is only a cliical manifestation of the carcinoid tumor.
Somatostatin receptor scintigraphy
Neuro-endocrine cells containing receptors for somatostatin and other peptides is the basis for this test. As this is a whole-body investigation it helps in staging of the disease .
Note: the above staging tests are for the carcinoid tumor, not the carcinoid syndrome which is only a cliical manifestation of the carcinoid tumor.

Management - Supportive

Fact Explanation
Patient education Explaining the patient about the disease condition & related counselling is of utmost importance as carcinoid syndrome occur in the later stage of carcinoid tumor with the matastatic disease , and mostly symptomatic treatment is carried out. Patient education
Explaining the patient about the disease condition & related counselling is of utmost importance as carcinoid syndrome occur in the later stage of carcinoid tumor with the matastatic disease , and mostly symptomatic treatment is carried out.
Treatment of heart failure: Diuretics are used and occasionally valvular replacement is carried out . Treatment of heart failure:
Diuretics are used and occasionally valvular replacement is carried out .
Flushing: Advice to avoid precipitating food & alcohol. Use of serotonin antagonists and somatostatin analogues, interferon can be beneficial. Hepatic artery embolization also may be effective . Flushing:
Advice to avoid precipitating food & alcohol. Use of serotonin antagonists and somatostatin analogues, interferon can be beneficial. Hepatic artery embolization also may be effective .
Diarrhea: Anti-diarrheal agents, serotonin antagonists and somatostatin analogues, interferon and hepatic artery embolization can be effective . Diarrhea:
Anti-diarrheal agents, serotonin antagonists and somatostatin analogues, interferon and hepatic artery embolization can be effective .
Wheezing: Bronchodilators, serotonin antagonists and somatostatin analogues, interferon and hepatic artery embolization can be effective . Wheezing:
Bronchodilators, serotonin antagonists and somatostatin analogues, interferon and hepatic artery embolization can be effective .

Management - Specific

Fact Explanation
Surgery Treatment options vary on the tumor site and the presence of metastasis .
Surgical resection is the only curative method of neuro-endocrine tumors. Debulking and bypassing procedures for metastatic disease facilitates medical treatment .
Radiofrequency ablation is a more aggressive type of surgery to remove the tumor. Metastases are treated with laser treatment .
Surgery
Treatment options vary on the tumor site and the presence of metastasis .
Surgical resection is the only curative method of neuro-endocrine tumors. Debulking and bypassing procedures for metastatic disease facilitates medical treatment .
Radiofrequency ablation is a more aggressive type of surgery to remove the tumor. Metastases are treated with laser treatment .
Management of hepatic metastases Carcinoid syndrome is an indication for surgery of liver mets which can be performed either with curative or palliative intent. The types of resection include enucleation, segmental resection, hemi-hepatectomy and extended hemi-hepatectomy, depending on the site combined with radio-frequency ablation. Liver transplantation has been performed in young patients with no extrahepatic tumor tissue, but recurrence is reported almost always post surgery. Embolizationcan combined with cytotoxic therapy can also be carried out,which is a commonly used technique to treat clinical symptoms and hepatic mets. 5-fluorouracil, doxorubicin & mitomycin C are used for chemoemboliization and the symptomatic response takes about 15-30 months. Common side effects are post-embolization syndrome with nausea, right upper quadrant pain while major effects are gall bladder necrosis, pancreatitis, hepato-renal syndrome & liver absecess with a mortality rate of 7% .
Debulking surgery, radiofrequency ablation, cryoablation, laser therapy, chemoembolization & medical therapy are used to treat multiple liver mets .
Note: intra-operative USS should always be performed during surgery to detect all the mets and observe the relation to hepatic vessels & bile ducts .
Management of hepatic metastases
Carcinoid syndrome is an indication for surgery of liver mets which can be performed either with curative or palliative intent. The types of resection include enucleation, segmental resection, hemi-hepatectomy and extended hemi-hepatectomy, depending on the site combined with radio-frequency ablation. Liver transplantation has been performed in young patients with no extrahepatic tumor tissue, but recurrence is reported almost always post surgery. Embolizationcan combined with cytotoxic therapy can also be carried out,which is a commonly used technique to treat clinical symptoms and hepatic mets. 5-fluorouracil, doxorubicin & mitomycin C are used for chemoemboliization and the symptomatic response takes about 15-30 months. Common side effects are post-embolization syndrome with nausea, right upper quadrant pain while major effects are gall bladder necrosis, pancreatitis, hepato-renal syndrome & liver absecess with a mortality rate of 7% .
Debulking surgery, radiofrequency ablation, cryoablation, laser therapy, chemoembolization & medical therapy are used to treat multiple liver mets .
Note: intra-operative USS should always be performed during surgery to detect all the mets and observe the relation to hepatic vessels & bile ducts .
Somatostatin analogues These are used to reduce the hormonal effect, hence the clinical features. They exert both cytotoxic & cytostatic actions and mediate cell cycle arrest and thereby prevent release of the peptides from neuro-endocrine cells. Octerotide & lanreotide are used and this is the primary mode of treatment for peptide-related symptoms. These are used to facilitate surgery as they reduce the risk of carcinoid crises.
Possible side-effects are nausea, flatulence, diarrhea, steatorrhea and gall stones and substitution of pancreatic enzymes can reduce these symptoms .
Somatostatin analogues
These are used to reduce the hormonal effect, hence the clinical features. They exert both cytotoxic & cytostatic actions and mediate cell cycle arrest and thereby prevent release of the peptides from neuro-endocrine cells. Octerotide & lanreotide are used and this is the primary mode of treatment for peptide-related symptoms. These are used to facilitate surgery as they reduce the risk of carcinoid crises.
Possible side-effects are nausea, flatulence, diarrhea, steatorrhea and gall stones and substitution of pancreatic enzymes can reduce these symptoms .
Alpha-interferon Used to treat midgut carcinoids. It blocks the cell cycle and inhibit angiogenesis and has an indirect effect on the immune system as well. Combination with somatostatin analogues has a synergistic & additive effect by up regulating the somatostatin receptors. Side-effects include flu-like symptoms, chronic fatigue, depression, myositis & SLE syndrome . Alpha-interferon
Used to treat midgut carcinoids. It blocks the cell cycle and inhibit angiogenesis and has an indirect effect on the immune system as well. Combination with somatostatin analogues has a synergistic & additive effect by up regulating the somatostatin receptors. Side-effects include flu-like symptoms, chronic fatigue, depression, myositis & SLE syndrome .
Cytotoxic therapy The treatment of choice for highly proliferating neuro-endocrine tumors. Streptozotocin, 5-fluorouracil, cisplatinum and paraplatinum are some agents used. Common side-effects are nausea, vomiting and renal toxicity .
Important: combination therapy with somatostatin analogues is recommended for clinical syndromes associated with hormone overproduction, thus carcinoid syndrome can have a beneficial effect from this therapy .
Cytotoxic therapy
The treatment of choice for highly proliferating neuro-endocrine tumors. Streptozotocin, 5-fluorouracil, cisplatinum and paraplatinum are some agents used. Common side-effects are nausea, vomiting and renal toxicity .
Important: combination therapy with somatostatin analogues is recommended for clinical syndromes associated with hormone overproduction, thus carcinoid syndrome can have a beneficial effect from this therapy .
Anti-angiogenic therapy This is a new option used based on the high vascularity of carcinoid tumors. Endostatin and angostatin are used to inhibit angiogenesis and thereby suppress tumor growth . Anti-angiogenic therapy
This is a new option used based on the high vascularity of carcinoid tumors. Endostatin and angostatin are used to inhibit angiogenesis and thereby suppress tumor growth .
Tyrosine kinase inhibitors Imitanib and other inhibitors may be effective as some carcinoid tumors express tyrosine kinase receptors . Tyrosine kinase inhibitors
Imitanib and other inhibitors may be effective as some carcinoid tumors express tyrosine kinase receptors .
Radiotherapy As carcinoid tumors are radio-resistant, external beam therapy is used only for brain & bone metastases . Radiotherapy
As carcinoid tumors are radio-resistant, external beam therapy is used only for brain & bone metastases .

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