Archive for March, 2009

Neurological lectures… Treating migraine

March 22, 2009 at 9:30 am · Filed under Neurological section ·Tagged

The author: Professor Yasser Metwally

http://yassermetwally.com

INTRODUCTION

March 22, 2009 — In this edition of the publication “Neurological lectures” Professor Metwally discusses Treating migraine.

References

  1. Metwally, MYM: Textbook of neuroimaging, A CD-ROM publication, (Metwally, MYM editor) WEB-CD agency for electronic publication, version 10.1a January 2009 [Click to have a look at the home page]

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Preoperative Evaluation of Patients With Neurological Disease

March 20, 2009 at 7:47 am · Filed under Neurological section

The author: Professor Yasser Metwally

http://yassermetwally.com

INTRODUCTION

March 20, 2009 — A thorough evaluation of patients with neurological diseases undergoing surgery can reduce perioperative morbidity and mortality, especially stroke. Various neurological disorders and neurosurgical procedures may influence the nature and extent of preoperative evaluation, selection and conduct of anesthesia, and perioperative management and care. Although anesthesiologists primarily perform a preoperative evaluation of neurological patients, neurologists can contribute further valuable information about the neurological condition and perioperative management of various neurological diseases to obtain the best possible outcome. This post outlines the basic elements of preoperative evaluation and highlights specific considerations for neurological patients undergoing surgery.

Neurological patients tend to be older and sicker than their nonneurological counterparts. As the population ages, the number of elderly patients with comorbid neurological conditions undergoing various surgical procedures is expected to increase. A thorough preoperative evaluation is important, as it allows careful assessment of the patient’s overall health status, stratifying his or her perioperative risk, determining if further tests, consultations or treatments are needed to optimize the patient’s health before surgery, and planning the most appropriate management to ultimately reduce perioperative morbidity and mortality.[1]

Preoperative evaluation of patients with preexisting neurological conditions undergoing nonneurological surgery and patients undergoing neurosurgery involves a thorough clinical assessment and diagnostic workup to determine the cause and extent of the patient’s condition, and to ensure that the patient’s comorbid conditions are under appropriate medical therapy, especially prior to elective procedures. Neurological and neurosurgical patients represent a heterogeneous population. The preexisting neurological disease may impact preoperative management and preparation for the surgical procedure, the choice of anesthetic agents and techniques, and the perioperative care. Optimal perioperative care requires an understanding of the pathophysiology of each patient’s neurological condition. In this article, strategies for performing a complete preoperative evaluation in neurological and neurosurgical patients are discussed, and special considerations for perioperative management of specific neurological conditions to minimize morbidity and mortality are highlighted.

  • Basic Preoperative Evaluation

A complete history and physical and neurological examination are essential to identify patient-related characteristics and abnormalities that could influence the perioperative risk. A review of medical records and prior consultations is important because some neurological and neurosurgical patients may not be able to provide a complete history. Reviewing records of prior surgical procedures and anesthesia with particular attention to associated complications can help to predict future complications and to plan alternative surgical or anesthetic strategies to minimize the risk.

  • Medical Conditions

Several chronic conditions such as diabetes, hypertension, heart disease, arrhythmias, and epilepsy are commonly encountered in neurological and neurosurgical patients. Inquiring about existing and past medical conditions is important to identify patients at increased risk for perioperative complications. For example, patients with poorly controlled diabetes have an increased propensity toward infection and impaired wound healing.[2,3] Hypertension is an important cause of perioperative bleeding, and chronic hypertension may shift the cerebral blood flow autoregulation curve to the right, resulting in increased susceptibility to cerebral hypoperfusion after perioperative hypotensive events. These concerns necessitate adequate control of blood pressure and glucose throughout the perioperative period. Eliciting a history of cardiac disease is of critical importance. The use of epinephrine or ketamine during anesthesia should be avoided in patients with coronary artery disease because of their vasoconstrictive and cardiostimulatory effects.[4,5] In addition, the patient’s ability to increase cardiac output in response to fluid shifts during surgery is an important determinant of survival after major surgeries. A history of a bleeding disorder is important to detect and reverse prior to surgery. Similarly, severe hepatic disease can result in impaired coagulation and wound healing, and should prompt the physicians to avoid sedatives, antibiotics, and anesthetics that are metabolized in the liver. Patients with a history of stroke or transient ischemic attacks (TIA) undergoing cardiac surgery are at increased risk for perioperative stroke.[6] These patients should be thoroughly evaluated to determine the cause of stroke and to ensure that they are adequately treated to minimize the risk of stroke recurrence. Obtaining a dietary history and weight changes are important because malnutrition may lead to increased perioperative mortality.

  • Medications

Medications for chronic pain should be continued as normal in the perioperative period as this will help to achieve postoperative pain and blood pressure control. Similarly, most antihypertensive and antiarrhythmic agents should be continued without interruption throughout the perioperative period. A sudden cessation of antihypertensives, especially clonidine and guanfacine, should be avoided to minimize the danger of rebound hypertension. The exception is angiotensin-converting enzyme inhibitors and angiotensin receptor blockers, which should be stopped on the day of surgery because their use can be associated with refractory intraoperative hypotension.[7,8] Oral hypoglycemics should be held before surgery and substituted with sliding-scale insulin to improve perioperative glycemic control. For patients undergoing minor procedures, omitting oral hypoglycemic agent(s) on the morning of surgery and resuming it postoperatively may be acceptable.[9] The exception is metformin, which is associated with the development of lactic acidosis. It should be discontinued at least one day prior to surgery and restarted 2 to 3 days postoperatively after testing for renal function.[10]

A large number of neurological patients are on antithrombotic therapies for secondary stroke prevention or nonsteroidal antiinflammatory agents (NSAIDs) for pain. Some advocate that NSAIDs be discontinued 2 to 3 days preoperatively to minimize the risk of intraoperative bleeding. However, continuation of NSAIDs throughout most nonneurosurgical procedures is likely safe.[11] Oral anticoagulation with warfarin should be withheld 5 to 6 days before major invasive and neurosurgical procedures. The time off anticoagulation should be minimized in patients at high risk for thromboembolic complications, such as those with mechanical valves, atrial fibrillation, or history of systemic embolism including embolic stroke. Bridging therapy with heparin or heparinoids after discontinuation of warfarin and early reinitiation of postprocedure anticoagulation in these patients is advised as soon as the risk of bleeding from the surgical site is minimal. Heparin may be stopped a few hours preoperatively and restarted after surgery.[12] Continuation of warfarin during surgery is likely safe in cutaneous surgeries, dental extractions and other limited oral procedures, and diagnostic, but not invasive, endoscopy or colonoscopy.[11] Aspirin and clopidogrel are discussed in the section on cerebrovascular diseases.

Patients treated with steroids prior to surgery may require steroid supplementation during the perioperative period. Patients undergoing minor surgery should take 1.5 to 2 times their usual dose on the morning of surgery and the normal dosage the following day.[13] In case of a prolonged surgery, an additional dosage may be given perioperatively. Those undergoing major surgery should take 2 times their usual dosage preoperatively, receiving additional intravenous hydrocortisone during surgery and postoperatively, and resume the normal dosage within 48 to 72 hours.[13]

Several antiepileptic drugs can induce hepatic enzymes and alter the pharmacokinetics of anesthetic agents. Recommendations for the management of medications used to treat specific neurological disorders are summarized in Table 1 .

Table 1. Preoperative Management of Neurological and Psychiatric Medications

Neurological Medications

Antiparkinsonian Agents

Carbidopa/ levodopa

Continue until the morning of surgery and restart as soon as possible after surgery to avoid withdrawal syndrome

Selegiline

Stop 2 weeks prior to surgery when possible

Bromocriptine, amantadine, pergolide

Continue

Entacapone, tolcapone

Continue to avoid withdrawal syndrome; check liver enzymes before surgery

Antiepileptic Medications

Phenytoin, carbamazepine, valproic acid, clonazepam, phenobarbital, primidone, gabapentin, topiramate

Continue to avoid perioperative seizures

Antidepressants

Amitriptyline, nortriptyline, imipramine, desipramine

Continue but exercise caution with perioperative drug choices due to perioperative additive anticholinergic effects

MAO inhibitors Pargyline, phenelzine

Stop 14-21 days prior to surgery to avoid perioperative medication interactions; for emergency procedures, avoid sympathomimetics, anticholinergics, and meperidine

SSRIs:

Fluoxetine, sertraline, paroxetine, citalopram, fluvoxamine Venlafaxine, mirtazapine, nefazodone

Continue to avoid withdrawal syndrome

Venlafaxine, mirtazapine, nefazodone

No association with withdrawal syndrome known; no known interactions with anesthetic agents[14]

Antipsychotics, Mood Stabilizers, Anxiolytics

Phenothiazines

To avoid withdrawal dyskinesia or rebound agitation continue perioperatively if possible[15]

Butyrophenones

Lithium

Continue pre- and perioperatively; check serum levels prior to surgery;[10] obtain thyroid function tests if indicated; monitor serum sodium, avoid sodium wasting diuretics[12]

Benzodiazepines

Continue to avoid withdrawal seizures

MAO = monoamine oxidase; SSRIs = selective serotonin reuptake inhibitors.
Adapted from Mercado DL, Petty BG.[10]

  • Physical and Neurological Examinations

Assessing the cardiovascular system and airway is an integral part of any preoperative evaluation. Special attention should be paid to the cervical spine; an unstable cervical spine, limited neck movements, and cervical cord compression are not uncommon in neurological and neurosurgical patients, especially after traumatic injuries. These patients may require cervical immobilization or in-line traction during intubation or fiberoptic intubation. A complete neurological examination is required to assess the patient’s preoperative baseline neurological status. The severity of presenting neurological deficits in these patients could determine the degree of surgical urgency. Patients with a preoperative Glasgow Coma Scale score < 9 are more prone to develop hypoxia and hypercarbia, which may lead to elevated intracranial pressure.[16] These patients should be ventilated at the earliest opportunity and stabilized prior to surgery.[17]

  • Preoperative Investigations

Routine laboratory tests, including complete blood count, coagulation parameters, and serum chemistry profile, including electrolytes, serum glucose, and renal function tests should be obtained prior to surgery. Previously performed tests that show normal results can be used if there has been no intervening clinical event.[12] Ordering additional preoperative laboratory tests should be guided by medical history, physical examination, and type and nature of the planned procedure.[18] A pregnancy test should be obtained for women of childbearing potential. Urinalysis may be indicated in patients susceptible to urinary tract infections, such as those with multiple sclerosis or spinal injury, and in patients undergoing a urological procedure.

Assessments of nutritional and fluid and electrolyte status is an essential component of preoperative evaluation. Malnourished patients are at increased risk for surgical morbidity and mortality.[19] Assessing serum albumin level provides information about the patient’s nutritional condition. Electrolyte abnormalities, as a result of the cerebral salt wasting, inappropriate antidiuretic hormone secretion (SIADH), or central diabetes insipidus, should be closely monitored and corrected prior to surgery. Serum potassium and magnesium should be carefully monitored and corrected in patients taking diuretics because these abnormalities can predispose to perioperative arrhythmias. Similarly, it is important to monitor serum glucose during the perioperative period, especially in diabetics or patients taking steroids.

A preoperative electrocardiogram is required for patients with cardiovascular or respiratory diseases, male patients older than 40 to 45 years of age and women older than 50 years of age, and patients with multiple risk factors undergoing high-risk cardiovascular surgeries. Clinical characteristics that may necessitate a preoperative chest x-ray include smoking, recent upper respiratory infection, chronic obstructive pulmonary disease, and cardiac disease.[18] Further cardiac or pulmonary testing other than electrocardiogram or x-ray should be guided by the findings of the basic preoperative evaluation. For example, consider obtaining a transesophageal echocardiogram in patients with a history of stroke of undetermined etiology before cardiac surgery to evaluate for aortic sources of embolization. The finding of significant aortic atherosclerosis can lead to modification of the planned surgical technique to minimize the risk of recurrent stroke. Preoperative spirometry may be appropriate in patients with existing chronic pulmonary disease or asthma.[20] Furthermore, preexisting hypoalbuminemia is a powerful predictor of increased risk for postoperative pulmonary complications.[21] Pulmonary function tests should be assessed preoperatively in patients with a low serum albumin level.[20]

The type of planned surgery and the patient’s clinical situation should dictate preoperative neurological testing. A frequently encountered scenario is the preoperative assessment of patients with suspected carotid stenosis undergoing major surgery. The decision should be individualized on a patient-by-patient basis. Patients with a history of stroke or TIA should be screened with Doppler ultrasound, or magnetic resonance imaging (MRI) or computed tomography (CT) angiography, if previous evaluation has not been done or if the patient’s neurological status has worsened since the stroke.[22] In patients in whom an asymptomatic high-grade stenosis is detected before undergoing a major cardiovascular surgery, consider brain imaging with CT or MRI to exclude clinically silent ipsilateral territorial infarcts and intracranial MRA or CTA, or transcranial Doppler to determine the hemodynamic significance of the area of stenosis and the status of intracranial blood flow. Patients in whom carotid stenosis is judged to be symptomatic or hemodynamically significant may require preoperative carotid revascularization to minimize their perioperative stroke risk.

  • General Preoperative Measures

Any respiratory infection should be treated prior to surgery to minimize postoperative pulmonary complications. Premedication with H2-receptor blockers for patients at risk of aspiration due to gastroesophageal reflux disease, and ß-blockers in patients with cardiac disease is advised.[23-26] The use of long-acting sedatives should be avoided, whenever possible, to facilitate assessment of neurological status throughout the perioperative period. Neurological patients, particularly those with stroke, spinal injury, and brain tumors, are at increased risk for developing deep vein thrombosis (DVT)[27] due to prolonged immobility, leg weakness, and secondary hypercoagulability states.[28] It is important to start DVT prophylaxis preoperatively and continue until the patient is mobilized after the surgery. Perioperative use of subcutaneous or low-molecular weight heparin and/or intermittent pneumatic pressure is advised. Severely malnourished patients and patients without food intake for more than 3 days prior to surgery should receive preoperative nutritional supplementation.[19,29] It is important to correct dehydration preoperatively, especially in patients taking diuretics or edema-lowering agents such as mannitol or hypertonic saline, to maintain adequate cerebral perfusion during the perioperative period. An important, yet often understated, aspect of preoperative evaluation is to provide patients with information about their planned surgery, possible complications, and their individual risk factors for perioperative complications. This should include discussing strategies for risk reduction, such as the importance of blood pressure and glycemic control, and compliance with medications. Patients should be encouraged to stop smoking preoperatively. Smoking cessation is an important overall health intervention, and surgery could provide the impetus for the patient to quit. There is some evidence to suggest that smoking cessation before surgery may minimize perioperative pulmonary complications and improve wound healing.[30] Patients are likely to benefit from preoperative knowledge of their risk stratification and be more compliant with suggested preoperative instructions.

  • Preoperative Evaluation for Patients With Specific Neurological Disease

  • Neuromuscular Diseases (Muscular Dystrophies, Myotonias, Amyotrophic Lateral Sclerosis, Myasthenia Gravis)

Patients with muscular dystrophy, myotonia, or amyotrophic lateral sclerosis (ALS) undergoing surgery have an increased risk for respiratory and cardiac complications. The risk of life-threatening cardiac dysrhythmia and depression of cardiac contractility should be carefully considered, and cardiac function should be evaluated preoperatively by electrocardiography, echocardiography, and telemetry. Patients with an atrioventricular conduction delay should not receive halothane or other medications, such as atropine, that can further slow cardiac conduction. Preoperative pulmonary assessment should include spirometry with measurements of forced-vital capacity (FVC), maximal inspiratory and expiratory (MEP) pressures, and peak cough flow (PCF). For patients with FVC < 30%, preoperative use of noninvasive positive pressure ventilation should be considered. For patients with ineffective cough, defined as PCF < 270 L/min or MEP < 60 cm H2O, preoperative manual- and mechanically assisted cough should be considered. Patients with muscular dystrophy are more sensitive to the myocardial depressant effects of inhaled anesthetics, and are prone to cardiac arrest during induction of anesthesia that uses volatile anesthetics alone or in combination with succinylcholine.[31] Succinylcholine may also cause hyperkalemia that can cause lethal cardiac dysrhythmias and is linked to malignant hyperthermia in patients with neuromuscular disease. Inhalational anesthetic agents have also been implicated as a cause of acute rhabdomyolysis, resembling malignant hyperthermia, in these patients.[32] Sensitivity to nondepolarizing neuromuscular blocking agents is also enhanced, resulting in an increase in both peak effect and duration of action. Therefore, all malignant hyperthermia triggering agents and succinylcholine must be avoided.[33] A total intravenous anesthetic technique for induction and maintenance of general anesthesia, such as propofol and a short-acting opioid, are preferred.[33] Patients with ALS can also have autonomic dysfunction, increasing their risk for cardiovascular complications, and pharyngeal muscle dysfunction, which increases the risk for aspiration pneumonia.

Patients with myasthenia gravis are at significant risk for pulmonary complications. Risk factors that increase the likelihood of postoperative respiratory insufficiency are duration of the disease longer than 6 years, history of chronic respiratory disease, treatment doses of pyridostigmine > 750 mg/day, and preoperative vital capacity under 3 L.[34] Although preoperative drug treatment may reduce the need for postoperative mechanical ventilation,[35] anticholinesterase drugs should be stopped the day before surgery, if the clinical status of the patient allows it, or on the morning of surgery because they increase the effect of succinylcholine (which is inactivated by plasma cholinesterase) and inhibit the effect of nondepolarizing neuromuscular blocking agents. The need for anticholinesterase drugs is decreased in the first 48 postoperative hours. These drugs must be restarted carefully and titrated to avoid the risk of a cholinergic crisis.[35] Intravenous neostigmine can be used to avoid fluctuating blood levels of these drugs during the perioperative period. Patients with myasthenia are highly sensitive to nondepolarizing agents, needing only 20 to 50% of the drug compared with other patients.[35] Even small amounts of nondepolarizing agents can cause a significant respiratory muscle paralysis. Succinylcholine should also be avoided and carefully titrated short-acting nondepolarizing muscle relaxants, such as mivacurium or atracurium, should be considered for paralysis.[36] Agents affecting the neuromuscular junction, such as antiarrhythmics, calcium-channel blockers, and certain antibiotics, should be avoided.[35] Similarly, all the risk factors which predispose to neuromuscular functional impairment must be controlled; i.e., hypothermia, hypokalemia, and acidosis.

Patients with neuromuscular disorders have greater sensitivity to the respiratory depressant effects of opioids, barbiturates, and benzodiazepines. Such agents should be avoided or used with caution, particularly during the perioperative period. Preoperative cessation of smoking, chest physical therapy, use of bronchodilators, and treatment of respiratory infections are encouraged to minimize postoperative pulmonary complications. Postoperative deep breathing exercises or incentive spirometry are also recommended.[20]

  • Cerebrovascular Diseases: Stroke and TIA

Patients with a history of stroke or TIA are at increased risk for perioperative stroke after major cardiac and vascular surgical procedures.[6] In contrast, a previous stroke or TIA appears to be a minor clinical predictor for the risk of perioperative cardiac complications.[37] In most cases, patients with few risk factors for perioperative stroke undergoing low-risk noncardiac surgery do not need further testing. However, in patients with stroke history and planned cardiac procedure, including aortic manipulation, performing a transesophageal echocardiography to identify aortic atherosclerotic plaques should be considered. Perioperative strokes are predominantly embolic, and are related in large part to perioperative atrial fibrillation, especially after cardiac procedures.[38,39] Preoperative initiation of amiodarone or ß-blockers may decrease the incidence of postoperative atrial fibrillation and stroke.[40]

Antithrombotics are widely used for secondary stroke prevention. Abrupt discontinuation of antiplatelet agents before surgery may be associated with increased risk for stroke recurrence due to rebound hypercoagulability.[41] Aspirin should be stopped only 2 to 3 days before major neurosurgical procedures. Continuation of aspirin therapy is acceptable during regional spinal anesthesia, nerve blocks, dermatological cutaneous surgeries, dental procedures, ophthalmological procedures, peripheral vascular procedures, cardiac surgeries, and endoscopies.[11] Clopidogrel, on the other hand, appears unsafe and should be discontinued 5 to 7 days before surgical procedures.[42] There are no studies regarding the safety of dipyridamole, alone or in combination with aspirin, during surgery. It is therefore prudent to withhold it 5 to 7 days preoperatively. We recommend substituting clopidogrel and dipyridamole with aspirin in patients at high risk for stroke during the preoperative period. For many patients taking warfarin for stroke prevention, the risk of perioperative discontinuation of anticoagulation exceeds the risk of bleeding complications. Preoperative bridging therapy with heparin is advised and warfarin is discontinued. Heparin can be stopped hours prior to the procedure and warfarin restarted 24 hours after surgery.

Preoperative assessment of stroke patients undergoing carotid revascularization should ensure that blood pressure is adequately controlled throughout the perioperative period, particularly in hypertensive patients, to minimize the risk for postoperative hyperperfusion syndrome.

  • Subarachnoid Hemorrhage

Cardiac ischemia resulting from increased sympathetic outflow, increased cardiac afterload, or impaired contractility is common after subarachnoid hemorrhage (SAH). Preoperative evaluation of these patients should include electrocardiography, echocardiography, and measurement of serum markers of myocardial damage. These patients are also more susceptible to develop electrolyte abnormalities, in particular hyponatremia secondary to cerebral salt wasting or SIADH, which could predispose them to seizures or cardiac arrhythmias. The patient’s cardiac function and electrolytes should be optimized before undergoing surgery. Inotropic agents, such as dopamine, may be required preoperatively in patients with reduced cardiac output because this could impair the ability to tolerate barbiturates administered during surgery due to their myocardial suppressant effects. Maintaining adequate hydration and euvolemia is important to minimize the risk of vasospasm during the perioperative period. In addition, the mean arterial blood pressure must be maintained within the autoregulatory range while avoiding high mean pressure to prevent rebleeding in patients with SAH due to ruptured aneurysm.

  • Multiple Sclerosis

Some reports indicate that anesthesia, especially regional anesthesia, may worsen multiple sclerosis.[43,44] Therefore, the patient should be advised preoperatively that surgery and anesthesia could produce a relapse despite careful perioperative management.[36] Bladder dysfunction is not uncommon in multiple sclerosis. Therefore, testing urinalysis for urinary infection should be performed prior to surgery. Intermittent catheterization or use of anticholinergic agents may be necessary,[28] requiring cautious use of other anticholinergics such as atropine. Patients treated with corticosteroids may need steroid supplementation during the perioperative period. For patients treated with baclofen in whom oral intake is interrupted perioperatively, a gradual change may be made to diazepam. Baclofen is not available for injection, and abrupt withdrawal may precipitate seizures or hallucinations.[28] Interferons and glatiramer acetate can be continued throughout the perioperative period.

  • Epilepsy

Perioperative seizures can lead to significant complications. The preoperative evaluation affords an opportunity to identify patients at high risk for seizure, such as patients with brain tumors, cerebrovascular disease, head injury, and metabolic disturbances,[45] and to prepare patients with known epilepsy for the surgery. It is important to ensure that the serum levels of antiepileptic drug(s) are therapeutic during the perioperative period. The prescribed medication should be continued until the morning of surgery and, if necessary, administered parenterally until oral intake can be resumed.[36] Furthermore, possible interactions between the anticonvulsant agent and the anesthetic drug have to be considered. For example, phenobarbital may accelerate and increase the magnitude of biotransformation of the anesthetic agent.[36] Conversely, the anesthetic agent may increase the likelihood of seizure activity. Anticonvulsant anesthetic drugs like barbiturates, benzodiazepines, propofol, halothane, or isoflurane should be considered.[35]

  • Parkinson Disease

The established medication regimen should be continued until the morning of surgery ( Table 1 ). Dependent on the length of the surgery, the short half-life of levodopa has to be considered. An interruption of more than 6 to 12 hours may result in severe muscle rigidity interfering with the ventilation management. This syndrome mimics neuroleptic malignant syndrome, including autonomic instability, fever, delirium, and muscle rigidity. Postoperatively, levodopa should be resumed via nasogastric feeding if the patient is not capable of swallowing. Alternatives routes include parenteral or topical administration or parenteral administration of dopamine agonists such as bromocriptine if gastric administration is not possible. Phenothiazines and butyrophenones should be avoided because of their antidopaminergic properties.[36] Excessive salivation, dysphagia, and esophageal dysfunction in patients with Parkinson disease may result in aspiration pneumonia. Parkinson disease is also associated with a reduction in respiratory reserve capacity, which increases the risk of postoperative atelectasis and pneumonia.[28,46] Preoperative pulmonary function testing and postoperative breathing exercises should be considered.

  • Alzheimer Disease (Dementia)

Currently used cholinesterase inhibitors may impair hepatic function requiring careful use of halogenated, volatile anesthetics. In patients treated with anticholinergic agents, measurement of liver enzyme levels should be considered. Glycopyrrolate should be used instead of atropine or scopolamine if anticholinergic drugs are necessary. Using anesthetic agents like propofol or sevoflurane may hasten postanesthetic recovery of mental status.[36]

  • Spinal Cord Injury

Preoperative assessment of patients with spinal injuries should attempt to detect and treat secondary complications, such as sympathetic dysfunction, spinal shock, impaired respiratory muscle strength, and bradycardia or hypotension. These patients may require fluid and vasopressors and ventilatory support preoperatively.

  • Conclusions

The preoperative time is critical for any neurological patient undergoing surgery. Neurological patients are at an increased risk for perioperative cardiac and pulmonary complications after surgery. The secondary complications of neurological diseases such as aspiration pneumonia, respiratory difficulties, electrolyte abnormalities, autonomic dysfunction, and muscle weakness can adversely influence postsurgical outcome. A thorough preoperative assessment considering the complex pathophysiology of each individual patient is essential to improve perioperative care and to optimize patient’s outcome.

References

  1. Roizen MF. Preoperative evaluation In: Miller RD, Eds.; Anesthesia. Vol. 1. Churchill. Livingstone New York, NY: 2000, p. 927-997

  2. Malone DL, Genuit T, Tracy JK. Surgical site infections: reanalysis of risk factors. J Surg Res 2002; 103(1): 89-95

  3. Patel KL. Impact of tight glucose control on postoperative infection rates and wound healing in cardiac surgery patients. J Wound Ostomy Continence Nurs 2008; 35(4): 397-404

  4. Cohn SL, Goldman L. Preoperative risk evaluation and perioperative management of patients with coronary artery disease. Med Clin North Am 2003; 87(1): 111-136

  5. Chiu JW, White PF. Nonopioid intravenous anesthesia In: Barash PG, Cullen BF, Stoelting RK, Eds.; Clinical Anesthesia. 4th ed. Lippincott Williams and Wilkins Philadelphia, PA: 2001, p. 327-343

  6. Landercasper J, Merz BJ, Cogbill TH. Perioperative stroke risk in 173 consecutive patients with a past history of stroke. Arch Surg 1990; 125: 986-989

  7. Colson P, Ryckwaert F, Coriat P. Renin angiotensin system antagonists and anesthesia. Anesth Analg 1999; 89(5): 1143-1155

  8. Bertrand M, Godet G, Meersschaert K. Should the angiotensin II antagonists be discontinued before surgery?. Anesth Analg 2001; 92(1): 26-30

  9. Tamai D, Awad AA, Chaudhry HJ. Optimizing the medical management of diabetic patients undergoing surgery. Conn Med 2006; 70(10): 621-630

  10. Mercado DL, Petty BG. Perioperative medication management. Med Clin North Am 2003; 87: 41-57

  11. Armstrong MJ, Schneck MJ, Biller J. Discontinuation of perioperative antiplatelet and anticoagulant therapy in stroke patients. Neurol Clin 2006; 24(4): 607-630

  12. Traber KB. Preoperative evaluation In: Longnecker DE, Murphy FL, Eds.; Introduction to Anesthesia. 9th ed. WB Saunders Co Philadelphia, PA: 1997, p. 11-19

  13. Brussel T, Chernow B. Perioperative management of endocrine problems: thyroid, adrenal cortex, pituitary. J Am Soc Anesthesiol 1990; 18: 33-48

  14. Sarko J. Antidepressants, old and new: a review of their adverse effects and toxicity in overdose. Emerg Med Clin North Am 2000; 18: 637-654

  15. Goldberg JF. New drugs in psychiatry. Emerg Med Clin North Am 2000; 18(2): 211-231

  16. Fleisher LA. Preoperative evaluation, In: Barash PG, Cullen BF, Stoelting RK, Eds.; Clinical Anesthesia. 4th ed. Lippincott Williams and Wilkins Philadelphia, PA: 2001, p. 473-489

  17. Bradley PG, Menon DK. Preoperative evaluation of neurosurgical patients. Anaesth Intensive Care Med 2004; 5(10): 336-339

  18. Practice Advisory for Preanesthesia Evaluation. A report by the American Society of Anesthesiologists Task Force on preanesthesia evaluation. Anesthesiology 2002; 96: 485-496

  19. Dempsey DT, Mullen JL, Buzby GP. The link between nutritional status and clinical outcome: can nutritional intervention modify it?. Am J Clin Nutr 1988; 47(S2): 352-356

  20. Qaseem A, Snow V, Fitterman N. Risk assessment for and strategies to reduce perioperative pulmonary complications for patients undergoing noncardiothoracic surgery: a guideline from the American College of Physicians. Ann Intern Med 2006; 144(8): 575-580

  21. Gibbs J, Cull W, Henderson W. Preoperative serum albumin level as a predictor of operative mortality and morbidity: results from the National VA Surgical Risk Study. Arch Surg 1999; 134(1): 36-42

  22. Brown RDJr , Evans BA, Wiebers DO. Transient ischemic attack and minor ischemic stroke: an algorithm for evaluation and treatment. Mayo Clinic Division of Cerebrovascular Diseases. Mayo Clin Proc 1994; 69(11): 1027-1039

  23. Joyce THIII . Prophylaxis for pulmonary acid aspiration. Am J Med 1987; 83(6A): 46-52

  24. Fleisher LA, Beckman JA, Brown KA. ACC/AHA 2007 Guidelines on Perioperative Cardiovascular Evaluation and Care for Noncardiac Surgery: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 2002 Guidelines on Perioperative Cardiovascular Evaluation for Noncardiac Surgery) developed in collaboration with the American Society of Echocardiography, American Society of Nuclear Cardiology, Heart Rhythm Society, Society of Cardiovascular Anesthesiologists, Society for Cardiovascular Angiography and Interventions, Society for Vascular Medicine and Biology, and Society for Vascular Surgery. J Am Coll Cardiol 2007; 50(17): e159-e241

  25. Poldermans D, Boersma E, Bax JJ. Bisoprolol reduces cardiac death and myocardial infarction in high-risk patients as long as 2 years after successful major vascular surgery. Eur Heart J 2001; 22(15): 1353-1358

  26. Mangano DT, Layug EL, Wallace A. Effect of atenolol on mortality and cardiovascular morbidity after noncardiac surgery. Multicenter Study of Perioperative Ischemia Research Group. N Engl J Med 1996; 335(23): 1713-1720

  27. Hamilton MG, Hull RD, Pineo GF. Venous thromboembolism in neurosurgery and neurology: a review. Neurosurgery 1994; 34: 280-296

  28. Lefevre F, Woolger JM. Surgery in the patient with neurologic disease. Med Clin North Am 2003; 87(1): 257-271

  29. Meguid MM, Campos AC, Hammond WG. Nutritional support in surgical practice: Part II. Am J Surg 1990; 159(4): 427-443

  30. Warner MA, Offord KP, Warner ME, Lennon RL, Conover MA, Jansson-Schumacher U. Role of preoperative cessation of smoking and other factors in postoperative pulmonary complications: a blinded prospective study of coronary artery bypass patients. Mayo Clin Proc 1989; 64(6): 609-616

  31. Larach MG, Rosenberg H, Gronert GA. Hyperkalemic cardiac arrest during anesthesia in infants and children with occult myopathies. Clin Pediatr (Phila) 1997; 36(1): 9-16

  32. Kunst G, Graf BM, Schreiner R. Differential effects of sevoflurane, isoflurane, and halothane on Ca2+ release from the sarcoplasmic reticulum of skeletal muscle. Anesthesiology 1999; 91(1): 179-186

  33. Birnkrant DJ, Panitch HB, Benditt JO. American College of Chest Physicians consensus statement on the respiratory and related management of patients with Duchenne muscular dystrophy undergoing anesthesia or sedation. Chest 2007; 132(6): 1977-1986

  34. Baraka A. Anesthesia and myasthenia gravis. Can J Anaesth 1992; 39: 476-486

  35. Seifert HS, Smith DS. Neuroanesthesia and neurologic disease In: Longnecker DE, Murphy FL, Eds.; Introduction to Anesthesia. 9th ed. WB Saunders Co Philadelphia, PA: 1997, p. 400-414

  36. Dierdorf SF. Anesthesia for patients with rare and coexisting disease In: Barash PG, Cullen BF, Stoelting RK, Eds.; Clinical Anesthesia. 4th ed. Philadelphia, PA: 2001, p. 491-520

  37. Turnbull JM, Buck C. The value of preoperative screening investigations in otherwise healthy individuals. Arch Intern Med 1987; 147(6): 1101-1105

  38. Limburg M, Wijdicks EF, Li H. Ischemic stroke after surgical procedures: clinical features, neuroimaging, and risk factors. Neurology 1998; 50(4): 895-901

  39. Restrepo L, Wityk RJ, Grega MA. Diffusion- and perfusion-weighted magnetic resonance imaging of the brain before and after coronary artery bypass grafting surgery. Stroke 2002; 33(12): 2909-2915

  40. Kluger J, White CM. Amiodarone prevents symptomatic atrial fibrillation and reduces the risk of cerebrovascular accidents and ventricular tachycardia after open heart surgery: results of the Atrial Fibrillation Suppression Trial (AFIST). Card Electrophysiol Rev 2003; 7(2): 165-167

  41. Sibon I, Orgogozo JM. Antiplatelet drug discontinuation is a risk factor for ischemic stroke. Neurology 2004; 62(7): 1187-1189

  42. Fox KA, Mehta SR, Peters R. Benefits and risks of the combination of clopidogrel and aspirin in patients undergoing surgical revascularization for non-ST-elevation acute coronary syndrome: the Clopidogrel in Unstable angina to prevent Recurrent ischemic Events (CURE) Trial. Circulation 2004; 110(10): 1202-1208, Epub 2004 Aug 16e

  43. Siemkowicz E. Multiple sclerosis and surgery. Anaesthesia 1976; 31(9): 1211-1216

  44. Kyttä J, Rosenberg PH. Anaesthesia for patients with multiple sclerosis. Ann Chir Gynaecol 1984; 73(5): 299-303

  45. Annegers JF. Epidemiology and genetics of epilepsy. Neurol Clin 1994; 12: 15-29

  46. Bogaard JM, Hovestadt A, Meerwaldt J. Maximal expiratory and inspiratory flow-volume curves in Parkinson’s disease. Am Rev Respir Dis 1989; 139(3): 610-614

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Treatment of Depression in Diabetes

March 18, 2009 at 4:24 pm · Filed under Psychiatric section

The author: Professor Yasser Metwally

http://yassermetwally.com

INTRODUCTION

March 18, 2009 — Purpose of Review: The combination of depression and diabetes is common and especially harmful because depression has a strong impact on psychosocial as well as medical outcomes in patients with diabetes. Consequently, treatment for depression in diabetes is also aimed at improvement in glycemic control and risk reduction for diabetes complications and mortality. This review provides an overview of all published, randomized controlled trials on the treatment of depression in patients with diabetes and summarizes current, ongoing research.

Recent Findings: The best results for medical and psychological outcomes were observed for psychological treatments; however, the generalizability of these results is restricted by methodological limitations. Most antidepressants were effective treatments for depression in diabetes but failed to show benefits regarding diabetes-related medical variables. Algorithm-based care, including psychological and psychopharmacological approaches, provides the best scientific evidence for successful depression treatment but not for glycemic control.

Summary: Depression can be treated with antidepressants, psychotherapy or a flexible combination of both with relatively good results that are comparable to those for patients who have depression but not diabetes. Up to now, no single treatment that consistently leads to better medical outcomes in patients with both depression and diabetes has been clearly identified.

Depression is a common and life-threatening comorbidity in diabetes and is associated with hyperglycemia, microvascular and macrovascular complications, and increased risk of death; yet, despite this substantial evidence base of adverse outcomes, depression remains underdiagnosed and undertreated in patients with diabetes. This review provides an overview of all published, randomized controlled trials (RCTs) on treatment of depression in patients with diabetes and summarizes ongoing research.

  • Depression and Diabetes: The Size of the Problem

According to a meta-analysis of controlled studies, 9% of patients with diabetes are affected by depressive disorders. When subclinical depression is included, the proportion of patients who have clinically relevant depressive symptoms increases to 26%. Diabetes doubles the odds of depression independent of the study design, source of patients, and method of assessing depression.[1] Recent data on type 2 diabetes demonstrate that the increased risk of elevated depressive symptoms applies only to individuals with treated – but not with untreated – type 2 diabetes.[2] These findings may reflect the psychological stress or burden associated with diabetes management and the greater number of diabetic complications and comorbidities in adults receiving diabetes treatment compared with those who are untreated. On the basis of estimates of the global prevalence of diabetes in the year 2000, approximately 43 million people with diabetes worldwide have symptoms of depression.[3] Recent results of the Sequenced Treatment Alternatives to Relieve Depression (STAR-D) study, the largest study of depression ever conducted in the United States, indicated an overrepresentation of men elderly people, and minority populations (blacks and Hispanics) in patients with major depression and diabetes.[4] The economic burden of diabetes alone is significant,[5] but when depression is present along with diabetes, there is an additional increase in health-service costs of 50-75%.[6]

The interaction between depression and diabetes has been studied extensively in cross-sectional and longitudinal studies in the last decade.[7,8,9] Most results demonstrated that depression is associated with nearly all important medical and psychosocial outcome parameters of diabetes. Results from a meta-analysis demonstrated that depression was associated with an increased risk for ’subsequent’ type 2 diabetes in adults by 37%.[10] In people diagnosed with type 1 or type 2 diabetes, depression increases the risk for persistent hyperglycemia,[11] microvascular and macrovascular complications, and mortality.[12,13,14] It is important to note that the associations with complications and mortality are present even when patients have mild depression. Elderly patients with type 2 diabetes seem to represent a high-risk group; this outcome was demonstrated, in a 7-year longitudinal study, by a five-fold increase in mortality without any substantial differences between mild and severe depression.[13]

Depression has a strong impact not only on medical outcomes in diabetes but also on psychological and social outcomes. Generic quality of life is considerably reduced with respect to psychological, physical and social functioning (e.g. the ability to work).[15] Diabetes-related burdens are perceived as more severe, and satisfaction with diabetes treatment is lower when a depressive comorbidity is present.[16] Furthermore, it was demonstrated that patients with depression and diabetes were physically less active, were more likely to smoke tobacco, had less healthy eating habits and adhered less to diabetes treatment.[17,18]

Unfortunately, depression in diabetes is considerably underdiagnosed and undertreated. As an example, results of a US study that included more than 9000 patients with diabetes revealed a recognition rate for major depression of 51%, whereas 43% of the patients received one or more antidepressant prescriptions and only 6.7% had received four or more psychotherapy sessions over a 12-month period.[19]

Considering the significant evidence base that depression has an adverse effect on both psychological well being and diabetes outcomes, treatment of depression in diabetes should be directed toward improving both psychological and medical outcomes. Improvement in depressive symptoms or remission is the major objective regarding the mental aspects. The physical treatment targets include an improvement in glycemic control and a reduction in risk for short-term and long-term complications and premature mortality.

  • Treatment of Depression in Diabetes: Current Knowledge and Future Directions

For an overview of current knowledge, a literature search for all published RCTs that evaluated treatment of depression in diabetes was conducted; the search yielded 11 RCTs ( Table 1 ).[20-22,23,24-28,29,30] The RCTs were grouped according to the interventions that were used: pharmacological, psychological or mixed (pharmacological and psychological).

Table 1. Overview of all Published Randomized Controlled Trials on Depression Treatment in Diabetes Literature (Click to download table in PDF format)

  • Pharmacological Treatment Trials for Depression in Diabetes

Up to now, four pharmacological trials for depression therapy in diabetes have been published. In the first RCT, nortriptyline was tested in comparison with placebo in patients with depression and poorly controlled diabetes. There was a significant improvement in the intervention group regarding depression, but deterioration in glycemic control was observed in the intervention group in subsequent analyses.[20]

The next trial evaluated the effectiveness of fluoxetine compared with placebo in patients with diabetes and depression. Again, there was a significant improvement in depression after 2 months of treatment in the intervention group. There was a trend toward better glycemic control for fluoxetine; however, this trend did not reach statistical significance, a result that may be due to insufficient statistical power.[21]

A more recent RCT that included patients with type 1 or type 2 diabetes evaluated the effect of sertraline on prevention of relapse of depression.[22] The first phase of the trial was a noncontrolled, open-label treatment with sertraline in which 43% of the patients achieved remission of depression. Those treatment responders were subsequently included in a RCT comparing sertraline with placebo for relapse prevention. Patients were followed for a maximum of 12 months or until depression recurred. Depression recurred in one-third of the patients, but there was a clear and significant advantage of sertraline over placebo (median time to recurrence was 57 days in the placebo group compared with 226 days in patients treated with sertraline). Regarding glycemic control, there was a significant improvement in the whole sample in the nonrandomized phase 1 of the study when every participant was treated with antidepressants. In the second phase, in which those who had responded to antidepressant treatment were randomized to long-term sertraline or placebo, there was no significant difference in the change in glycemic control in the two groups. The clearest result from the RCT part of the study was that sertraline is an effective agent for the prevention of relapse of depression in diabetes.

In the most recent pharmacological RCT, paroxetine was compared with placebo in elderly patients with minor depression.[23] The results yielded no statistically significant differences between the groups on the primary psychological and medical outcome variables. In conclusion, there is no evidence to support the use of paroxetine for older patients with minor depression and diabetes.

  • Psychological Treatment Trials for Depression in Diabetes

The only trial of cognitive behavioral therapy (CBT) included 52 patients with type 2 diabetes and major depression.[24] For 10 weeks, patients were randomized to diabetes education and CBT for depression or to diabetes education only. The follow-up included a 6-month interval during which 70% of the patients in the CBT group achieved remission compared with just 33% in the education-only group. Regarding medical outcomes, there was a clear advantage of CBT compared with the control group 6 months after treatment was delivered but not during the 10-week intervention phase; HbA1c deteriorated in the control group (+0.9%), whereas it improved in the CBT group (-0.7%). This result was statistically significant (P = 0.04) and relevant from a clinical point of view; moreover, it was the first time that a psychotherapeutic approach was demonstrated to be effective for the treatment of depression in diabetes. Considering the various limitations of this trial (small sample, monocentric trial with only one therapist, and no replication of the results), more data are needed to generalize these results.

The second RCT regarding psychological treatment was a trial to evaluate group counseling in China; 59 patients were randomized to group counseling (with a focus on social support) or treatment as usual for 3 months.[25] Significant improvements were reported in the group counseling condition for depression and glycemic control; however, the methodological limitations were comparable to those of the aforementioned trial.

The most recent trial was a pilot study to evaluate supportive psychotherapy in patients with diabetic foot syndrome who also had depressive symptoms.[26] Patients were randomized to either supportive psychotherapy or standard medical treatment for a period of 6 weeks on average. Results, which were reported for posttreatment evaluation but not for follow-up data, demonstrated a moderate improvement in depressive symptoms. Given the trial’s short duration, it is not surprising that no difference was observed for glycemic control or other medical outcome variables.

  • Mixed (Psychological and Medical) Treatments for Depression in Diabetes

The effectiveness of algorithm-based, flexible interventions using a combination of psychological and pharmacological treatments compared with standard care was evaluated in four RCTs. The psychological modules of these treatments included problem solving training[27,28] and counseling[29] or interpersonal therapy.[30] In addition, in all four trials, antidepressants were given according to the patients’ preferences or following a predefined treatment algorithm.

A significant improvement in depression was observed for the combination of antidepressant medication with problem solving training[27,28] or counseling[29] compared with standard care; however, regarding metabolic control, no significant differences between the intervention and control groups were observed.

In a recent algorithm-based care trial that included 123 patients with depression and self-reported diabetes (among 584 patients without diabetes), interpersonal therapy and citalopram (in combination or alone) were compared with care as usual.[30] The results of a secondary analysis demonstrated that this intervention led to a significant decrease in mortality after 5 years. But because depression was not assessed or specified, no conclusion can be drawn regarding depression treatment.

Finally, in 2008, a RCT was conducted in which patients with diabetes and depression were randomized to a so-called multifaceted psychiatric intervention or to usual care.[29] The intervention group was given the options of counseling, a case conference or referral to a psychiatrist. Antidepressant medication was an option in all treatment conditions. The results were significantly better for the intervention group regarding depression, but no positive effect on medical outcome was observed.

  • What is the Best Treatment for Depression in Diabetes?

Because the ideal treatment for depression in diabetes would demonstrate positive effects on medical and psychological outcomes at the same time, this criterion of a combined effect was applied to evaluate the studies described in the following sections.

  • Psychological Interventions

The best results were observed for counseling[25] and CBT;[24] however, because of the limitations of these studies, more data are needed before the results can be generalized.

  • Pharmacological Interventions

With the exception of minor depression in elderly patients,[23] various antidepressants seem to be effective for the treatment of depression in patients with diabetes;[20-22] however, regarding the medical outcome variables of diabetes, no benefit of pharmacological treatments has yet been demonstrated conclusively.

  • Mixed Interventions

Flexible algorithm-based care, including various psychological and psychopharmacological approaches, are the treatments that provide the best scientific evidence of the successful treatment of depression; moreover, there is some evidence that treatment of depression could reduce mortality.[30] But no positive effect on glycemic control could be observed in the mixed interventions. Because of the combination of interventions in these mixed RCTs, it was not possible to identify the effective components of treatment or evaluate claims of the superiority of one new treatment in comparison with another.

  • What do we Need to Know to Improve Treatment of Depression in Diabetes?

We do not know very much about the mechanisms of action for positive treatment effects; better knowledge could stimulate the development of new treatment options. We need to learn more about the usefulness of specific interventions. Regarding pharmacological treatments, the question remains as to whether better outcomes for medical variables would be possible through the use of other substances. With respect to mixed treatments, we do not know what the effective components are. We should try to adjust our treatments for different subgroups of patients. Finally, we have literally no data to answer the question of what are the best treatments among effective treatments; this is a question that can be clarified only in comparison trials.

  • What Will we Learn From Ongoing Research on Depression Treatment in Diabetes?

According to the metaRegister of Controlled Trials and other sources, we can expect results within the next 3 years from at least 12 RCTs that cover the topic of depression and diabetes ( Table 2 ).[31,32,33,34-39,40,41]

Table 2. Overview of Ongoing or Unpublished Randomized Controlled Trials on Depression Treatment in Diabetes (Click to download table in PDF format)

  • Pharmacological Trials

The effects of fish oil added to antidepressants in patients with depression and diabetes are currently being assessed. Sertraline will be compared with placebo for underserved Hispanics and African-Americans who have diabetes and major depression.

  • Psychological Treatments

Five RCTs focus predominantly on minor-to-moderate depression. We can expect new knowledge about psychoeducation, web-based CBT, diabetes-specific CBT, CBT that focuses on adherence to treatment, and diabetes-specific CBT that is directed toward elderly patients in particular.

  • Mixed Interventions

Two more algorithm-based treatment trials are ongoing or completed; first, combined treatment with computer-based CBT and escitalopram vs. computer-based CBT and placebo; and second, diabetes-specific CBT compared with sertraline in patients who have both poorly controlled diabetes and major depression.

Hence, we can look forward to a significant increase in knowledge about psychological treatments regarding different subgroups of patients and specific interventions. We anticipate data concerning the question of whether antidepressant medication is superior to CBT in diabetes and major depression. Finally, we can expect answers to the question of whether combinations of antidepressants with CBT are more effective than CBT alone.

  • Conclusion

Currently, we have good scientific evidence that well established treatments for depression are effective in treating depression in people with diabetes. But regarding the effectiveness of medical diabetes-related outcomes, the results are quite different. As of now, there has been no clear identification of any treatment for depression that exerts a superior beneficial effect on glycemic control This is an emerging field of research, and, in the next 3 years, at least 12 currently ongoing or unpublished RCTs will contribute to the evidence base for best practice and provide new information on that topic.

References

  1. Anderson RJ, Freedland KE, Clouse RE, Lustman PJ. The prevalence of comorbid depression in adults with diabetes: a meta-analysis. Diabetes Care 2001; 24:1069-1078.

  2. Golden SH, Lazo M, Carnethon M, et al. Examining a bidirectional association between depressive symptoms and diabetes. JAMA 2008; 299:2751-2759.

  3. Wild S, Roglic G, Green A, et al. Global prevalence of diabetes: estimates for the year 2000 and projections for 2030. Diabetes Care 2004; 27:1047-1053.

  4. Bryan CJ, Songer TJ, Brooks MM, et al. A comparison of baseline sociodemographic and clinical characteristics between major depressive disorder patients with and without diabetes: a STAR*D report. J Affect Disord 2008; 108:113-120.

  5. American Diabetes Association. Economic costs of diabetes in the U.S. in 2007. Diabetes Care 2008, 31:596-615. This study presents recent data on the economic burdens of diabetes in the United States.

  6. Simon GE, Katon WJ, Lin EH, et al. Diabetes complications and depression as predictors of health service costs. Gen Hosp Psychiatry 2005; 27:344-351.

  7. Fenton WS, Stover ES. Mood disorders: cardiovascular and diabetes comorbidity. Curr Opin Psychiatry 2006; 19:421-427.

  8. Lustman PJ, Penckofer SM, Clouse RE. Recent advances in understanding depression in adults with diabetes. Curr Diab Rep 2007; 7:114-122.

  9. Kruse J, Petrak F, Herpertz S, et al. Diabetes and depression: a life-endangering interaction. Z Psychosom Med Psychother 2006; 52:289-309.

  10. Knol M, Twisk J, Beekman A, et al. Depression as a risk factor for the onset of type 2 diabetes mellitus. A meta-analysis. Diabetologia 2006; 49:837-845.

  11. Lustman PJ, Anderson RJ, Freedland KE, et al. Depression and poor glycemic control: a meta-analytic review of the literature. Diabetes Care 2000; 23:934-942.

  12. Katon WJ, Rutter C, Simon G, et al. The association of comorbid depression with mortality in patients with type 2 diabetes. Diabetes Care 2005; 28:2668-2672.

  13. Black SA, Markides KS, Ray LA. Depression predicts increased incidence of adverse health outcomes in older Mexican Americans with type 2 diabetes. Diabetes Care 2003; 26:2822-2828.

  14. Ismail K, Winkley K, Stahl D, et al. A cohort study of people with diabetes and their first foot ulcer: the role of depression on mortality. Diabetes Care 2007; 30:1473-1479.

  15. .Moussavi S, Chatterji S, Verdes E, et al. Depression, chronic diseases, and decrements in health: results from the World Health Surveys. Lancet 2007; 370:851-858.

  16. .Hermanns N, Kulzer B, Krichbaum M, et al. How to screen for depression and emotional problems in patients with diabetes: comparison of screening characteristics of depression questionnaires, measurement of diabetes-specific emotional problems and standard clinical assessment. Diabetologia 2006; 49:469-477.

  17. Lin EHB, Katon W, Von Korff M, et al. Relationship of depression and diabetes self-care, medication adherence, and preventive care. Diabetes Care 2004; 27:2154-2160.

  18. Gonzalez J, Delahanty L, Safren S, et al. Differentiating symptoms of depression from diabetes-specific distress: relationships with self-care in type 2 diabetes. Diabetologia 2008; 51:1822-1825.

  19. .Katon W, Simon G, Russo J, et al. Quality of depression care in a population-based sample of patients with diabetes and major depression. Med Care 2004; 42:1222-1229.

  20. Lustman PJ, Griffith LS, Clouse RE, et al. Effects of nortriptyline on depression and glycemic control in diabetes: results of a double-blind, placebo-controlled trial. Psychosom Med 1997; 59:241-250.

  21. Lustman PJ, Freedland KE, Griffith LS, Clouse RE. Fluoxetine for depression in diabetes: a randomized double-blind placebo-controlled trial. Diabetes Care 2000; 23:618-623.

  22. Lustman PJ, Clouse RE, Nix BD, et al. Sertraline for prevention of depression recurrence in diabetes mellitus: a randomized, double-blind, placebo-controlled trial. Arch Gen Psychiatry 2006; 63:521-529.

  23. Paile-Hyvarinen M, Wahlbeck K, Eriksson J. Quality of life and metabolic status in mildly depressed patients with type 2 diabetes treated with paroxetine: a double-blind randomised placebo controlled 6-month trial. BMC Fam Pract 2007; 8:34.

  24. .Lustman PJ, Griffith LS, Freedland KE, et al. Cognitive behavior therapy for depression in type 2 diabetes mellitus. A randomized, controlled trial. Ann Intern Med 1998; 129:613-621.

  25. Huang X, Song L, Li T. The effect of social support on type II diabetes with depression. Chin J Clin Psychol 2001; 9:187-189.

  26. Simson U, Nawarotzky U, Friese G, et al. Psychotherapy intervention to reduce depressive symptoms in patients with diabetic foot syndrome. Diabet Med 2008; 25:206-212.

  27. Williams JW Jr, Katon W, Lin EHB, et al. The effectiveness of depression care management on diabetes-related outcomes in older patients. Ann Intern Med 2004; 140:1015-1024.

  28. Katon WJ, Von Korff M, Lin EHB, et al. The Pathways Study: a randomized trial of collaborative care in patients with diabetes and depression. Arch Gen Psychiatry 2004; 61:1042-1049.

  29. Stiefel F, Zdrojewski C, Bel Hadj F, et al. Effects of a multifaceted psychiatric intervention targeted for the complex medically ill: a randomized controlled trial. Psychother Psychosom 2008; 77:247-256.

  30. Bogner HR, Morales KH, Post EP, Bruce ML. Diabetes, depression, and death: a randomized controlled trial of a depression treatment program for older adults based in primary care (PROSPECT). Diabetes Care 2007; 30:3005-3010.

  31. .Lamers F, Jonkers CC, Bosma H, et al. Effectiveness and cost-effectiveness of a minimal psychological intervention to reduce nonsevere depression in chronically ill elderly patients: the design of a randomised controlled trial [ISRCTN92331982]. BMC Public Health 2006; 6:161.

  32. Pouwer F. Addition of eicosapentaenoic acid to maintenance antidepressant therapy in diabetes patients with major depressive disorder: a double-blind, placebo-controlled pilot study. http://www.controlled-trials.com/ISRCTN30877831 . 2008.

  33. van Bastelaar KM, Pouwer F, Cuijpers P, et al. Web-based cognitive behavioural therapy (W-CBT) for diabetes patients with co-morbid depression: design of a randomised controlled trial. BMC Psychiatry 2008; 8:9.

  34. .Davidson M. The effects of pharmacologic treatment of depression on glycated hemoglobin, lipids and quality of life in underserved Hispanics and African Americans with diabetes: a randomized, placebo controlled trial. http://clinicaltrials.gov/ct2/show/record/NCT00624013 . 2008.

  35. Safren S. Effectiveness of cognitive behavioral therapy in improving adherence and depressive symptoms in people with diabetes. http://clinicaltrials.gov/ct2/show/record/NCT00564070 . 2008.

  36. Petrak F. Cognitive behavioural therapy in elderly type 2 diabetes patients with minor depression (MIND-DIA-Study). Study design of a randomised controlled trial. In: 13th Psychosocial Aspect in Diabetes Study Group (PSAD) Spring Scientific Meeting; 11-12 April 2008; Cagliari, Italy; 2008.

  37. Musselman DL. Diabetes mechanisms: urban African Americans. http://clinicaltrials.gov/ct2/show/record/NCT00209170 . 2008.

  38. Petrak F. Cognitive behavioural therapy vs. sertraline in patients with depression and poorly controlled diabetes mellitus: a randomized controlled trial. Diabetes and Depression Study (DAD-Study). http://www.controlled-trials.com/ISRCTN89333241 . 2008.

  39. Ell KR. Effectiveness of collaborative depression care management in treating depressed low-income Hispanics with diabetes. http://clinicaltrials.gov/show/NCT00709150 . 2008.

  40. Horn EK, van Benthem TB, Hakkaart-van Roijen L, et al. Cost-effectiveness of collaborative care for chronically ill patients with comorbid depressive disorder in the general hospital setting, a randomised controlled trial. BMC Health Serv Res 2007; 7:28.

  41. Katon W. Nurse-led case management for diabetes and cardiovascular disease patients with depression. http://clinicaltrials.gov/ct2/show/record/NCT00468676 . 2008.

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Stem Cells and Neurologic Diseases: Hope or Hype?

March 18, 2009 at 8:30 am · Filed under Neurological section

The author: Professor Yasser Metwally

http://yassermetwally.com

INTRODUCTION

March 18, 2009 — Are stem cells the therapy of the future for virtually all neurologic diseases. The answer is no. Stem cells will likely be a powerful part of the therapeutic armamentarium of neurologists in years and decades to come. In some cases they will slow disease progression. In others, stem cells, combined with other therapies, may modestly increase function. And rarely, stem cells may markedly reduce disability or cure disease. Conversely, in some diseases stem cells are likely to never be effective, and the journey from animal model success to clinical therapy will be longer than many expect. This editorial will assess the likely future role of stem cells in combating neurologic diseases 5-10 years in the future. We will discuss the biological foundation and current applications of stem cells, focusing on two specific areas: endogenous neural stem cells and their capacity to repair injury, and myelinating precursors and their application to demyelinating disorders.

  • Promise of Stem Cells

The promise of stem cells is an appealing one that has captured the attention of the lay public. Everybody knows individuals who have suffered greatly owing to to injury or disease and it is powerful and emotionally appealing to think that their suffering and disability could be reduced or eliminated. It is a regular occurrence that some medical advance is discussed in the media. But it is rare that the advance promises to reduce suffering. Rather, most promise more effective treatments for diseases or better diagnoses. Since advocates of stem cells promise more, they have garnered public attention probably in excess of their scientific advances. Many feel that stem cells have the potential to treat, cure and restore function to patients suffering from almost any disease. And for some, the model of how stem cells will work is the ‘gas-station’ model: come in to the hospital or clinic, get your stem cells and go home with the disease ameliorated or eliminated.

The reality will be much more sobering on several fronts. Some diseases will be intractable to recovery or even slowing of disease by virtue of the mechanism or extent of neural injury. At their best, stem cell therapies will need to be combined with prolonged rehabilitation therapies to ‘retrain’ the nervous system, much as the prolonged rehabilitation after an organ or joint replacement. But even with those cautionary notes, there is the likelihood that we will be able to alter the course of devastating neurologic diseases using stem cells in the future, and we will begin to see this potential in human patients in the next 5-10 years.

  • Biological Underpinning of Stem Cells

Stem cells have the potential to differentiate into mature cell types by responding to developmental cues appropriate to that cell type. These developmental cues may be provided when culturing the stem cells or after transplantation, by the local microenvironment within the transplanted site.

Recent advances have suggested that stem cells can be specifically and efficiently directed toward distinct cell lineages in vitro. These cells can then be utilized in biological studies of those cell types in vitro. Alternatively, they can be directed toward a mature cell type prior to transplantation to enhance the efficiency of engraftment of that cell type in vivo. However, it is also clear that in order to take advantage of this capability, scientists must understand the developmental factors required for inducing a particular cell lineage and we understand very little of this biology at present.

  • Applications of Stem Cells in Neurological Diseases

There are several categories of uses for stem cells in the research and treatment of neurological diseases. First, stem cells can be utilized as a biological tool to understand disease. For example, the ability to isolate and propagate embryonic stem (ES) cell lines from a variety of genetically defined animal models of human disease and to efficiently direct ES cells toward particular neural lineages allows researchers to examine the abnormal cellular and molecular processes in these cells. The goal is to create a cell-culture model of human disease that could serve as a valuable tool in understanding disease and in screening potential therapies. Second, the potential of endogenous stem cells present in the mammalian nervous system can be harnessed and expanded to repair damaged tissue. It is increasingly clear that endogenous stem cells exist within multiple regions of the mammalian nervous system, that they have the potential to guide extensive neural repair and that they fail to repair the nervous system in most instances of neural injury. By gaining an understanding of the cues that guide endogenous stem cell function, researchers may be able to harness the ability of these cells to repair neural tissue. Finally, stem cells or committed progenitors derived from stem cells can be transplanted into the injured nervous system as a therapeutic strategy.

Transplanted cells may serve a therapeutic role in any of a number of ways (presented in order of increasing complexity): they may provide trophic support to host cells, slow a degenerative process, facilitate axonal growth or glial function, secrete neurotransmitters deficient in the host, deliver toxic substances to CNS tumors, differentiate into oligodendrocytes and myelinate host axons, or differentiate into neurons and either form neuronal bridges across disconnected populations or replace damaged neuronal circuits.

However, arguably, the application of stem cells to neurological diseases is much more complex than in other systems such as the endocrine or musculoskeletal systems. Several challenges unique to the nervous system are as follows:

The need to integrate into a sophisticated array of interconnected cells that extend over great distances;

The absence of developmental cues in adults that guided the establishment of neural networks during development, thus making regeneration more difficult;

The possibility in progressive or recurrent neurologic diseases that the transplanted cells may be attacked and injured.

  • Endogenous Neural Stem Cells in Health & Disease

Stem cells exist within the adult mammalian nervous system and these stem cells contribute to newly born, functioning neurons (termed neurogenesis) throughout the life of all mammals, including humans. Although neurogenesis only occurs in discretely defined regions of the brain under normal conditions, endogenous progenitor cells can be recruited to non-neurogenic areas following injury and may contribute to repair of the injured area. Endogenous stem cells also exist within the spinal cord, although these cells do not contribute to the generation of new neurons under normal conditions or following injury.

It is interesting to note, however, that spinal cord stem cells do produce neurons when transplanted into the hippocampus, a known neurogenic region. Therefore, these spinal cord stem cells have the potential to become neurons but are prevented from doing so by the host environment. It is becoming increasingly clear that failure of endogenous neurogenesis contributes to clinical disorders such as major depression and memory impairment. Several laboratories are developing strategies to enhance the efficiency of neurogenesis and, therefore, it may ultimately be possible to utilize endogenous stem cells to modulate a broad array of neurological diseases.

  • Stem Cells & Remyelination in the Future

To restore function in demyelinating diseases, such as multiple sclerosis and transverse myelitis, a stem cell must be guided from proliferating progenitor to mature, myelinating oligodendrocyte. Whether endogenous or transplanted, it has become apparent that a number of obstacles block the potential of stem cells to follow such a fate. While inflammation may provide an initial and welcome stimulus for oligodendrocyte progenitor cell (OPC) proliferation following a demyelinating insult, ultimately it appears to impede functional remyelination. In the inflamed CNS, OPCs may follow cues that induce differentiation of astrocytes rather than oligodendrocytes. Formation of an astroglial scar provides further hindrance to remyelination. Future strategies that aim to preserve axonal function through remyelination must address these inflammatory-imposed blocks.

In cases where the endogenous population of OPCs may be depleted, such as following multiple demyelinating events, transplantation of exogenous stem cells may be an attractive option. However, central questions such as when (in terms of cellular maturation) and where these cells should be transplanted remain incompletely addressed.

If a stem cell is transplanted too early in the differentiation process, it may fail to adopt a myelinating phenotype. Conversely, transplantation of a more committed cell may compromise migratory potential so that it fails to reach the target region of demyelination. Our ability to strike the correct balance and facilitate remyelination will be greatly aided by the ongoing studies examining OPC migratory and differention cues.

  • Political Realities in the USA

It is unclear how quickly we will see stem cells become a clinical reality for several reasons. In the USA, researchers can receive federal funding for adult stem cells and for study on a limited number of ES cell lines. Most researchers believe these ES cell lines (the federally approved ones) are biologically corrupt and dangerous to use, in part because of genomic instability. Any preclinical or clinical research on ‘nonapproved’ ES cell lines must be funded by philanthropy or private industry. Because of the complexity involved in translating stem cell biology into a therapeutic reality, the amount of money required is daunting.

Hundreds of millions of dollars are required to fund a large trial. The commercialization strategy for a company is complex and in many cases it is not clear that a profit can be made from stem cell therapy for any single neurologic indication. This is where the federal government should be advancing science and advancing the care of people with disabling neurologic diseases. We, as a society, should not be driven in our advance of science by whether a profit can be made. The NIH has long advanced science because it serves its mission, which is the following: science in pursuit of fundamental knowledge about the nature and behavior of living systems and the application of that knowledge to extend healthy life and reduce the burdens of illness and disability.

Currently, the NIH has abrogated that role because of federal restrictions imposed upon it. The impact of this failure will be felt for decades to come as stem cell progress is slowed, clinical trials do not get started and other countries with greater governmental support seize the lead in this scientific arena.

  • Conclusion

Several conclusions can be drawn about the current and future use of stem cells in the nervous system:

  • Stem cells exist in the adult mammalian nervous system and the potential to augment and harness their function exists if the embryological and developmental principles that guide their differentiation can be fully understood;

  • The application of developmental principles leading to differentiation of stem cells into specific mature cell types is a dramatic advance and will become the most significant contribution to the application of stem cells in neurological diseases. This allows researchers to recreate differentiation and to analyze countless numbers of highly selected, mature cells in culture. The application of modern biological techniques such as high-throughput screening, proteomics and pharmacogenomic strategies to precisely define abnormalities in development may result in the development of novel therapies;

  • Exogenous stem cell transplantation is not the potential cure-all for neurological disease that it has been reported to be. The physiological complexities of the mature nervous system will always preclude widespread replacement following injury or damage;

  • It is clearly not necessary to achieve widespread replacement of the nervous system in order to enact meaningful functional recovery. The nervous system is a very plastic system and the attainment of even rudimentary remyelination or the re-establishment of simple neural networks, for example, can lead to restoration of function. The re-establishment of even a fraction of the initial complexity of a region of the nervous system may allow for augmentation and maintenance of this functional recovery using other strategies, such as trophic factor delivery and rehabilitation;

  • The type of stem cells that will be most beneficial will depend upon the setting in which they are used and the desired goal. It is clear that bone-marrow-derived and mesenchymal stem cells may have therapeutic benefit in neurological diseases. They may support host cells and they may halt or slow a degenerative process. However, it is clear that they are less likely than embryonic stem cells and fetal neural stem cells (NSCs) to differentiate into mature neural cells (i.e., oligodendrocytes and neurons). Thus, if the particular application requires the generation of new neurons, ES cells and fetal NSCs are more likely to be the most optimal sources;

  • Both biological and political hurdles remain to be overcome before stem cells can provide a therapeutic strategy in neurological diseases. However, it is a virtual certainty that stem cells will be used in neurological diseases within the next 2-5 years. It is realistic to believe that stem cells will be used clinically, not as a cure-all but as part of a therapeutic armamentarium. Some patients may get better, but as with any therapy, some patients may get worse. The key, however, will be in applying the right cell type to the right disease and conveying the right amount of expectation to the patient. Only then will stem cells become clinically relevant tools for the neurologist in the future.

  • Future Perspective

The near future promises several small trials using stem cells. A Phase I trial using human fetal tissue has been conducted in the USA and was found to be safe in patients with chronic spinal cord injury. Additionally, there are several planned Phase I trials of cell-based interventions for neurologic conditions. Athersys Inc. (OH, USA) plans to carry out a clinical trial using the Multistem™ platform based on the multipotent adult progenitor cell technology in Hurler’s disease, a lethal pediatric syndrome caused by enzyme deficiency. BrainStorm Cell Therapeutics (Israel) plans to carry out a trial of bone marrow-derived cells in Parkinson’s disease. Geron (CA, USA) plans to carry out a clinical trial using human ES cells in patients with acute spinal cord injury.

Q Therapeutics, Inc. (UT, USA) plans a clinical trial with glial-restricted precursors in patients with the focal demyelinating disorder transverse myelitis, and Living Cell Technologies, Ltd (Australia, New Zealand, Italy and RI, USA) will study porcine choroid plexus brain cells encased in a biopolymer capsule to avoid rejection in patients with Huntington disease.

Where we go after that depends on many things. First and foremost, will these trials demonstrate hints of the effectiveness of stem cells in treating neurologic disease? No trials promise to definitively demonstrate that stem cells are effective, as they involve small numbers of patients and often have an open-label design, but rather hope to be ’suggestive’, therefore justifying larger, more complex clinical trials. Second, do these trials reveal any adverse outcomes, including patient injury or death? If such an outcome occurs, as it did in gene-therapy trials, the field of stem cell transplantation will be slowed with appropriate requirements for more preclinical studies. But if they do demonstrate the potential for benefit, it may be that large pharmaceutical companies and federal governments throughout the world extend this research forward.

The field is likely to proceed in stops and starts. There will be hints of an amazing future interspersed with confusing and potentially sobering results. Ultimately, most of us in neurology practice today will be seeing patients who have received stem cell therapies. It will be a therapy that isn’t experimental anymore. It will be part of the therapeutic armamentarium available to treat patients. And we will be able to offer patients hope for not only halting or slowing their disease, but for reducing or curing it.

SUMMARY

  1. Stem cells are defined as precursor cells that have the capacity to self-renew and to generate multiple mature cell types.

  2. Embryonic stem (ES) cells are derived from the inner cell mass of cultured embryos at the blastocyst stage. These cells are pluripotent, as defined by the ability to form many mature cell types in tissue culture or by the generation of chimeric mice on injection into recipient blastocysts

  3. Several sources of stem cells exist, including blastocysts frozen after in vitro fertilization clinics (from which ES cells are derived), fetal and adult tissues

  4. Endogenous stem cells exist within the adult nervous system of higher mammals, generate functional neurons throughout the life of all mammals and can be successfully isolated and expanded from specific regions of the brain and spinal cord

  5. The biological underpinning of the use of stem cells in neurodegenerative disorders is that stem cells have the potential to differentiate into mature cell types by responding to developmental cues appropriate to that cell type

  6. Researchers have recently begun to develop strategies to specifically direct the differentiation of stem cells toward particular mature cell lineages in vitro. This is a critical advance in stem cell biology since it allows researchers to generate a potentially inexhaustible supply of relatively pure, committed or fully-differentiated mature cell types. These cells can then be utilized in biological studies of diseases in vitro or can be transplanted to treat disease

  7. Clinical trials with stem cells will begin in the next few years, but the full potential of stem cells will take decades to realize.

References

  1. Metwally, MYM: Textbook of neuroimaging, A CD-ROM publication, (Metwally, MYM editor) WEB-CD agency for electronic publication, version 10.1a January 2009 [Click to have a look at the home page]

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Implications Of The Cancer Stem Cell Hypothesis For Neuro-oncology and Neurology

March 17, 2009 at 7:26 am · Filed under Neurological section

The author: Professor Yasser Metwally

http://yassermetwally.com

INTRODUCTION

March 17, 2009 — The cancer stem cell hypothesis posits that cancers contain a subset of neoplastic cells that propagate and maintain tumors through sustained self-renewal and potent tumorigenecity. Recent excitement has been generated by a number of reports that have demonstrated the existence of cancer stem cells in several types of brain tumors. Brain cancer stem cells – also known as tumor-initiating cells or tumor-propagating cells – share features with normal neural stem cells but do not necessarily originate from stem cells. Although most cancers only have a small fraction of cancer stem cells, these tumor cells have been demonstrated in laboratory studies to contribute to therapeutic resistance, formation of new blood vessels to supply the tumor and tumor spread. As malignant brain tumors rank among the deadliest of all neurologic diseases, the identification of new cellular targets may have profound implications in neuro-oncology. Novel drugs that target stem cell pathways active in brain tumors have been efficacious against cancer stem cells, suggesting that anticancer stem cell therapies may advance brain tumor therapy. The cancer stem cell hypothesis may have several implications for other neurologic diseases as caution must be exercised in activating stem cell maintenance pathways in cellular therapies for neurodegenerative diseases. The ability for a small fraction of cells to determine the overall course of a disease may also inform new paradigms of disease that may translate into improved patient outcomes.

The War on Cancer was declared by President Nixon in 1971. In the intervening decades, cancer treatment has improved such that the diagnosis of cancer is not a certain death sentence, but victory remains out of grasp. In particular, patients diagnosed with malignant brain cancers continue to suffer high morbidity and mortality.[1] Multiple scientific advances – radiotherapy modalities, gene therapy, the Human Genome Project and targeted molecular drugs – have been hailed as signs of a coming revolution in brain cancer care only to disappoint when the benefits of each have proven more modest. Now, excitement is building around the cancer stem cell field. Viewing cancer through the prism of the cancer stem cell hypothesis may fundamentally transform brain cancer biology and translate into improved diagnosis, prognosis and treatment of brain tumor patients, but the reality is likely complex and challenging. The brain cancer stem cell field is immature – we are only beginning to recognize the rules governing cancer stem cell biology – but common themes are emerging in studies of cancer stem cells derived from a diversity of tumor types, suggesting that core mechanisms may underlie tumor formation and maintenance. However, controversies surround cancer stem cells, with some researchers disputing the existence of cancer stem cells.[2] Cancer stem cell biology has recently been reviewed in several publications[1,3-6] so I will focus this review on the potential for, and challenges of, cancer stem cells.

  • A Common Cancer Stem Cell Terminology

The cancer stem cell field suffers from an identity crisis. The use of the term ’stem cell’ engenders confusion over the meaning of ‘cancer stem cell’. Frequently, the question is immediately posed if brain cancer stem cells are derived from normal neural stem cells; essentially, stem cells as the cell-of-origin in brain tumors. While it is possible (perhaps even likely) that stem cells may be transformed to initiate tumor formation,[7-10] studies using genetically engineered cancer models also support more differentiated progenitor cells as possible cells-of-origin in cancer.[11-14] As convergent evolutionary forces may drive phenotypic similarities in divergent species, so too might genetic and epigenetic processes promote a tumor-initiating phenotype. Rather, a cancer stem cell more definitively identifies a tumor cell population with special properties that resemble stem cells – self-renewal and differentiation abilities – and potent generation of complex tumors that phenocopy parental tumors. To capture the essence of these features, many groups have employed a series of names: cancer stem cells, tumor stem cells, tumor-initiating cells, stem cell-like cancer cells, tumor-propagating cells and so on. The lack of standardized terminology limits our ability to effectively communicate the precise meaning of these labels and inform literature searches. While imperfect, the term cancer stem cell appears to be the most common moniker, but it should be distinguished from the cell-of-origin.

  • Defining Brain Cancer Stem Cells

The use of established brain cancer cell lines has permitted great advances in brain tumor biology, but provides an artificially simplistic model of tumor biology. In reality, brain tumors consist of not only neoplastic cells but also supporting vasculature, inflammatory cells and recruited astrocytes. Essentially, solid tumors mimic aberrantly developed organs or tissues.[15] Tumor cell populations are commonly heterogeneous with hierarchies of cellular populations that display a range of differentiation phenotypes, including specific morphologies and lineage markers. The majority of cells in bulk tumors may be nontumorigenic cells derived from stem and progenitor cells. With clearly defined roles for normal stem cells in organ development and reaction to injury, it is of little surprise that cancers contain cells with stem cell phenotypes as cancers share features of normal developmental processes and wound responses. Therefore, advances in stem cell biology in development and injury response may provide insights into cancer stem cell biology.

Defining a cancer stem cell is far from trivial (Figure 1). The requirements for a cancer stem cell are currently functional: extensive self-renewal and tumor initiation.[16] Self-renewal can only be measured if we have a measure of ’self’. Furthermore, uncommon cancer stem cells must be isolated from a large mass of mixed tumor cell populations. Several reports delineating the derivation of brain tumor stem cells have identified stem cells based on the formation of neurospheres, a cell culture phenotype associated with neural stem cells,[17] as a relevant phenotype.[18-24] The significance of the neurosphere phenotype is supported by the success of tumor-derived neurospheres to give rise to multiple lineages (neural, astrocytic and oligodendroglial) and potent tumor formation in immunocompromised rodents with as few as 100 cells. However, concerns have been raised about the true reflection of ’stemness’ with the generation of neurospheres as cells may coalesce to form similar structures.[25] In addition, the culturing of tumor cells until the formation of neurospheres precludes the direct comparison of cancer stem cells with the non-stem cell populations. Therefore, novel approaches have been developed to prospectively enrich for cancer stem cells through the use of cell surface markers, permitting the segregation of populations enriched or depleted in cancer stem cells. The laboratories of John Dick and Michael Clarke laid the foundation for the cancer stem cell field by applying techniques developed in normal stem cell biology based on differentiation markers to derive tumor populations enriched for cancer stem cells in leukemias and solid tumors.[26-28] Essentially, viable cancer stem cells are selected through the presence of specific stem cell markers and the absence of lineage markers. Importantly, cancer stem cells do not phenocopy normal stem cells. Cancer stem cells may display aberrant differentiation marker signatures that are divergent from matched normal stem cells. There are also controversies as to which markers are truly definitive for isolation of brain cancer stem cells. The cell surface marker CD133 (prominin 1) is expressed by embryonic neural stem cells[17,29] and has been used to select for brain cancer stem cells,[18,19,30] but other reports suggest that cells without CD133 expression may generate brain tumors.[31-33] Another group has found that the IQGAP1 scaffold protein regulates neural stem cells and is a marker for amplifying cancer cells in glioblastomas.[34,35] The diversity of markers that may be used to define cancer stem cells may be due to patient-to-patient differences in cancer stem cells or a lack of absolute marker fingerprints. Discrepancy in cancer stem cell markers from tumors with similar histopathology may reflect alternative cells-of-origin or oncogenic processes. It is clear that the expression of a cancer stem cell marker is not sufficient to claim a cancer stem cell phenotype. However, several brain cancer types share cancer stem cell signatures, suggesting that we may be able to apply findings from one cancer type to others. The precise methodologies employed for marker selection (even for the same marker) and in functional assays may be dramatically different between laboratory groups, limiting the ability to generalize conclusions regarding the cell biology of the derived populations. Thus, every laboratory performing cancer stem cell studies must confirm critical cancer stem cell functional assays to permit comparisons across studies. The cancer stem cell field would greatly benefit from an agreed set of defining studies required for publication in the cancer stem cell literature.

Figure 1. Neural stem cells and brain tumor-initiating stem cells.(Click to enlarge figure)

Cancer Stem Cells in Tumor Biology: Hanahan and Weinberg proposed a restricted set of capabilities for cancer cells:[36]

  1. Self-sufficiency in growth signals

  2. Insensitivity to antigrowth signals

  3. Evasion of apoptosis

  4. Limitless replicative potential

  5. Sustained angiogenesis

  6. Tumor invasion and metastasis

Genomic instability may be considered instrinsic to tumor formation (they considered this an enabling characteristic). This collection of traits may be reinterpreted within the context of the cancer stem cell hypothesis. Not only may cancers originate from single cells, but also relatively small numbers of cells may maintain tumors. Thus, not every tumor cell may need to be able to proliferate indefinitely. The definition of a cancer stem cell requires sustained proliferative potential and self-renewal, suggesting that the Hanahan-Weinberg hypothesis may identify key traits intrinsic to the cancer stem cell population. In development, neural stem cells display aspects of these behaviors, albeit under control from the external environment. Furthermore, key signaling pathways that regulate neural stem cell fate and differentiation – Olig2, sonic hedgehog, Notch, BMI-1, bone morphogenic proteins (BMPs), maternal embryonic leucine zipper kinase and so on – may contribute to brain tumor malignancy through regulation of proliferation, apoptosis and angiogenesis of brain tumor stem cells.[10,14,37-44] These stem cell regulatory pathways may function through different molecular mechanisms to regulate neural stem cell maintenance or differentiation, but intervention in each pathway regulates brain tumor stem cells and tumor growth. However, a key unresolved point is the absolute restriction of tumor formation to the cancer stem cell compartment.[2]

  • Cancer Stem Cells in Therapeutic Resistance

Despite the development of molecularly targeted therapies, radiation and cytotoxic chemotherapies (particularly the oral methylator, temozolomide) remain the mainstay of brain cancer treatment.[45] While unusual cancers, such as testicular cancers, can be cured at advanced stage with conventional therapy, therapeutic resistance is common among most advanced cancers. Many mechanisms may contribute to the development of therapeutic resistance, including the stochastic selection of resistant genetic subclones, microenvironmental factors (hypoxia, acidosis etc.) and cell extrinsic factors. Several groups, including my own laboratory, have demonstrated that brain tumor stem cells or cells expressing stem cell markers from multiple cancer types exhibit resistance to conventional cancer therapies. We demonstrated that cancer stem cells derived from human glioblastoma surgical biopsy specimens and xenografts are resistant to the effects of ionizing radiation with proficient capacity to repair DNA-damage due to preferential activation of the DNA damage checkpoint response.[30] Additional studies from other groups investigating brain tumor stem cell models confirmed that cells expressing cancer stem cell markers are resistant to radiation and chemotherapy.[46-48] If recurrent brain tumors contain greater numbers of brain tumor stem cells that are also selected for greater resistance to therapy, the lethality of high-grade brain tumors might be better explained. However, these early studies raise as many questions as they answer. First, other proposed mechanisms of the treatment resistance may interact with brain tumor stem cells, for example, cancer stem cells may reside in vascular or hypoxic niches[49] or secrete proteins that may act both in autocrine and paracrine manners.[50] Second, the role of cancer stem cells in tumor resistance must be validated in human subjects. This is not trivial as groups of patients will need to be followed during treatment with sequential characterization of cancer stem cells. Finally, it is unclear if mechanisms of cancer stem cell therapeutic resistance are shared across cancer types. Cancer stem cells with nonstem cell origins may respond differently to therapy than those derived from stem cells. The recognition of common resistance mechanisms that may be targeted in cancer stem cells may have broad utility.

  • Cancer Stem Cells in Tumor Spread & Angiogenesis

Tumor invasion into normal brain tissue is a hallmark of the gliomas,[1] but the mechanisms underlying this behavior are very poorly understood. Cell culture techniques are very useful for the study of cellular proliferation and apoptosis but are of very limited value for measuring invasion. Although animal models may be more helpful than cell-culture systems for tumor dispersal studies, we remain largely ignorant of the relative contributions of cell autonomous versus niche characteristics (seed-and-soil theory) in tumor spread. Gliomas are commonly invasive into distant sites at diagnosis even in areas without radiographic abnormalities, and patients with some systemic cancers (e.g., breast cancer) have widespread micrometastases that are not clinically evident. Incorporating the concept of cancer stem cells as the initiator of tumor spread may inform the study of cancer invasion and metastasis. Quiescent cancer stem cells may be capable of surviving in distant locations for prolonged periods but may become activated in response to external signals. For example, numerous patients with systemic cancers suffer sudden growth of metastases after resection of primary tumors. This behavior has been linked to antiangiogenic effects of the primary tumor, but it is also possible that loss of signals from the primary tumor mass instruct remote cancer stem cells to repopulate the tumor mass. Recent studies have suggested that micrometastases of breast cancers display a stem/progenitor cell signature consistent with cancer stem cells,[51] and pancreatic stem cells may have a greater propensity to undergo metastasis in animal models.[52] Similar studies in brain tumors have not yet been published. Many more studies will be required before we can primarily attribute tumor spread to cancer stem cells, but the ability to identify the populations within cancer responsible for tumor spread would be a tremendous advance.

Tumor growth beyond 1 mm in size requires the formation of new blood vessels to supply the tumor, a process called neoangiogenesis.[53] The mechanisms of neoangiogenesis in tumor growth are complex, but one key mechanism is the elaboration of growth factors by tumor cells that support the proliferation and survival of the endothelial cells of the tumor vasculature. We recently demonstrated that brain tumor stem cells generate highly vascular tumors through the secretion of high levels of VEGF.[50] This finding is important since VEGF is a validated therapeutic target in glioma therapy.[54-56] The relationship with the tumor vasculature is bidirectional as the Gilbertson group has demonstrated that the vasculature also supports brain tumor stem cell maintenance.[57]

  • Cancer Stem Cells in Diagnosis

The greatest advances in modern oncology to decrease cancer mortality have involved cancer prevention and early detection and treatment, which unfortunately do not impact neuro-oncology as we are unable to modify risks for the over-whelming majority of these cancers. Even if the study of brain tumor stem cells elucidates the causes of tumor spread, high-grade brain tumors are likely to remain therapeutic challenges. If cancer stem cell techniques provide tools to detect systemic cancers at earlier stages, we may be able to modify the impact of these cancers on society. Brochoalveolar, gastric and colon carcinomas develop from dysplastic lesions that may be visualized and biopsied by endoscopy. No fully reliable method currently informs the management of patients with early lesions. The presence of cancer stem cells in dysplastic tissues may support aggressive early intervention. While this approach will not benefit brain tumor patients, detection of circulating cancer stem cells may provide a minimally invasive cancer diagnostic assay. Genetically engineered cancer models may prove ideal for the development of these techniques before translation into clinical trial.

  • Cancer Stem Cells in Prognosis

Immediately after patients receive a brain tumor diagnosis, they want to know how long they have to survive. Neuro-oncologists are often remarkably poor at predicting individual patient survival because apparently identical cancers can behave with strikingly different outcomes. Current prognosis (and thus clinical management) of brain tumor patients utilizes patient characteristics (age, performance status, etc.) and tumor characteristics (histology, grade, extent of resection and presence of metastasis in some tumor types). To date, molecular testing has only modestly contributed to patient management[1,58,59] as these markers are imperfect and require refinement as the status of the direct molecular target for any therapy does not solely determine the outcome of treatment. Numerous studies employ genomic signatures to predict patient prognosis and response to therapy. Generally, these studies have used whole tumor specimens as RNA sources. If brain tumor stem cells account for only a small fraction of the overall tumor (notably some investigators have found potential stem cells as the majority of medulloblastoma tumor cells), then the expression pattern from cancer stem cells may be lost in the larger signals from the non-stem cancer cells. However, a recent study found that a cancer stem cell gene-expression profile derived from breast cancers did predict patient survival,[60] perhaps indicating that stem cell prevalence can dictate both gene expression and tumor growth. While similar studies are not yet published in brain tumor patient populations, one study has found that the percentage of glioblastoma cells that express CD133, a potential glioma stem cell marker, correlates with patient survival and risk of tumor regrowth.[61] It remains possible that prognostic models may be strengthened if cancer stem cell populations are directly characterized. Cancer markers such as CA-125 have been developed to follow the course of patients in response to therapy and predict recurrence. Many of these markers are expressed by the more differentiated cancer cell compartments. Characterizing cancer stem cells at diagnosis and during treatment may yield novel cancer markers that more closely predict the clinical course of cancer patients.

  • Imaging of Cancer Stem Cells

Current imaging techniques utilized in brain tumor patient management frequently quantify tumor burden indirectly through edema, vascular integrity (i.e., contrast enhancement) or metabolic activity. Small numbers of brain tumor cells present formidable challenges to detect in live subjects. As brain tumor stem cells may occur at low density and exhibit an early propensity towards dissemination (a key behavior that underlies the need to identify these cells), imaging cancer stem cells is likely to present severe technical challenges. Potential methodologies under development for cancer stem cell identification are based on the expression of specific channels/pumps (e.g., the side population[62-65]), enzymatic activity (aldehyde dehydrogenase[66,67]) or marker expression. Since these aspects may be shared with normal stem cells, interpretation of cancer stem cell imaging modalities will face anatomic restrictions near high-density areas of normal stem cells. Cancer stem cell imaging may have implications in the evaluation of clinical outcome. The US FDA requires improved survival as the end point for approval of most cancer therapies. Surrogate end points, such as radiographic tumor response, are attractive for clinical trials, but tumor response (i.e., shrinkage of tumor) may not correlate with survival. Non-stem tumor cells account for the bulk of the tumor and may display preferential sensitivity to some cancer therapies, while cancer stem cells may represent restricted subsets of tumor populations but contribute to tumor progression and recurrence – and thus, tumor lethality. Based on this model, the majority of the tumor may respond to treatment but survival may be determined by the residual cancer stem cells. If correct, imaging of cancer stem cells becomes of even greater importance.

  • Anticancer Stem Cell Therapies

Cancer cures require control of 100% of tumor cells. Obviously, brain tumor stem cells must be addressed for therapeutic success, but cancer stem cells may present special challenges and opportunities. Pharmaceutical drug discovery platforms commonly employ cancer models, including established cancer cell lines that poorly replicate cancer stem cell phenotypes. Therefore, most high-throughput screening efforts may fail to identify brain tumor stem cell targets. A recent report suggests that these techniques may be extended to normal neural stem cells and brain cancer stem cells,[68] although in vivo validation of efficacy remains to be addressed. Furthermore, cancer stem cell maintenance mechanisms in culture may differ in vivo, adding to the complexity of screening for anticancer stem cell therapies. With the poor capacity of current preclinical cancer models to predict therapeutic efficacy in human subject clinical trials, it would be of profound significance if cancer stem cell models demonstrated improved outcome predictions.

The first generation of anticancer stem cell therapies has focused on signal transduction pathways that regulate cell differentiation: Notch, BMP, hedgehog and so on.[37-39,41] Growth-factor pathways may function in stem cell maintenance (e.g., EGF and bFGF[23]) and the relationship with the cancer stem cell niche may be targeted.[57,69] A cautionary note may be struck with potential toxicities to normal stem cells. The role of neural stem cells remains to be defined but neural stem cells are clearly important in the pediatric population. Hematopoietic stem cells facilitate recovery from chemotherapy-induced myelosuppression, but the essential role of normal stem cells in other organs in adults is less clear. Normal organ-specific stem cells may promote tissue responses to injury but may be otherwise quiescent or dispensable (e.g., in the breast or prostate). Therefore, anti-stem cell therapies may display significant therapeutic indices. Target identification studies may identify novel molecular cancer stem cell targets that are differentially expressed or regulated relative to normal stem cells. Additionally, other modalities are being adapted towards brain tumor stem cell ablation, particularly vaccine approaches[70] and viral therapy.[71] Cancer stem cell targeting may be used in isolation or, more likely, in combination with conventional therapies to improve patient outcomes.

  • Implications for Neurology

The importance of the cancer stem cell hypothesis may have broader implications for other neurologic diseases. Cellular therapies are in development for neurodegenerative diseases, but a recent study suggested that modified embryonic stem cells can generate undifferentiated mitotic neuroepithelial cells that could be potentially tumorigenic.[72] The presence of a critical tumor population that initiates tumors and contributes to tumor malignancy suggests that constitutive activation of stem cell pathways may lead to lethal side effects. The concept of cancer stem cells may also inform new paradigms in neurology as most disease states are considered as a condition affecting the full diseased tissue, but it is possible that restricted cellular compartments within diseased tissues may determine the course of the condition and the response to therapy.

  • Future Perspective

The complexity of cancer parallels that of evolution with our ability to recognize the end product without fully understanding the rules governing the underlying process. Cancer stem cells may be considered the correlate of evolutionary nodes from which the diversity of progeny may be derived. The cancer stem cell hypothesis dates back decades,[73] but has gained momentum in the last decade due to novel techniques that have enabled the characterization of the tumor cells. The cancer stem cell hypothesis remains controversial and the significance of cancer stem cells in clinical practice is poorly understood; however, the study of cancer stem cell biology has the potential to inform the field of tumor biology, but there may not be immediate translation into better oncologic care. The use of cancer stem cells could improve preclinical cancer models and therapeutic development but will require much greater understanding of normal stem cell biology. We may be entering a new phase in cancer research based on the cancer stem cell paradigm in which the ability of oncologists to provide improved prognosis and therapy may be at hand, but setbacks and false leads are almost certain to occur.

References

  1. Furnari FB, Fenton T, Bachoo RM et al.: Malignant astrocytic glioma: genetics, biology, and paths to treatment. Genes Dev. 21(21), 2683-2710 (2007).

  2. Kelly PN, Dakic A, Adams JM, Nutt SL, Strasser A: Tumor growth need not be driven by rare cancer stem cells. Science 317, 337 (2007).

  3. Vescovi AL, Galli R, Reynolds BA: Brain tumour stem cells. Nat. Rev. Cancer 6(6), 425-436 (2006).

  4. Ward RJ, Dirks PB: Cancer stem cells: at the headwaters of tumor development. Annu. Rev. Pathol. 2, 175-189 (2007).

  5. Rich JN: Cancer stem cells in radiation resistance. Cancer Res. 67(19), 8980-8984 (2007).

  6. Sanai N, Alvarez-Buylla A, Berger MS: Neural stem cells and the origin of gliomas. N. Engl. J. Med. 353(8), 811-822 (2005).

  7. Taylor MD, Poppleton H, Fuller C et al.: Radial glia cells are candidate stem cells of ependymoma. Cancer Cell 8(4), 323-335 (2005).

  8. Zhu Y, Guignard F, Zhao D et al.: Early inactivation of p53 tumor suppressor gene cooperating with NF1 loss induces malignant astrocytoma. Cancer Cell 8(2), 119-130 (2005).

  9. Holland EC, Celestino J, Dai C, Schaefer L, Sawaya RE, Fuller GN: Combined activation of Ras and Akt in neural progenitors induces glioblastoma formation in mice. Nat. Genet. 25(1), 55-57 (2000).

  10. Ligon KL, Huillard E, Mehta S et al.: Olig2-regulated lineage-restricted pathway controls replication competence in neural stem cells and malignant glioma. Neuron 53(4), 503-517 (2007).

  11. Bachoo RM, Maher EA, Ligon KL et al.: Epidermal growth factor receptor and Ink4a/Arf: convergent mechanisms governing terminal differentiation and transformation along the neural stem cell to astrocyte axis. Cancer Cell 1, 269-277 (2002).

  12. Uhrbom L, Dai C, Celestino JC, Rosenblum MK, Fuller GN, Holland EC: Ink4a-Arf loss cooperates with KRas activation in astrocytes and neural progenitors to generate glioblastomas of various morphologies depending on activated Akt. Cancer Res. 62(19), 5551-5558 (2002).

  13. Uhrbom L, Kastemar M, Johansson FK, Westermark B, Holland EC: Cell type-specific tumor suppression by Ink4a and Arf in Kras-induced mouse gliomagenesis. Cancer Res. 65(6), 2065-2069 (2005).

  14. Bruggeman SW, Hulsman D, Tanger E et al.: BMI1 controls tumor development in an Ink4a/Arf-independent manner in a mouse model for glioma. Cancer Cell 12(4), 328-341 (2007).

  15. Reya T, Morrison SJ, Clarke MF, Weissman IL: Stem cells, cancer, and cancer stem cells. Nature 414, 105-111 (2001).

  16. Dalerba P, Cho RW, Clarke MF: Cancer stem cells: models and concepts. Annu. Rev. Med. 58, 267-284. (2007).

  17. Uchida N, Buck DW, He D et al.: Direct isolation of human central nervous system stem cells. Proc. Natl Acad. Sci. USA 97(26), 14720-14725 (2000).

  18. Singh SK, Hawkins C, Clarke ID et al.: Identification of human brain tumour initiating cells. Nature 432, 396-401 (2004).

  19. Singh SK, Clarke ID, Terasaki M et al.: Identification of a cancer stem cell in human brain tumors. Cancer Res. 63(18), 5821-5828 (2003).

  20. Galli R, Binda E, Orfanelli U et al.: Isolation and characterization of tumorigenic, stem-like neural precursors from human glioblastoma. Cancer Res. 64(19), 7011-7021 (2004).

  21. Ignatova TN, Kukekov VG, Laywell ED, Suslov ON, Vrionis FD, Steindler DA: Human cortical glial tumors contain neural stem-like cells expressing astroglial and neuronal markers in vitro. Glia 39(3), 193-206 (2002).

  22. Hemmati HD, Nakano I, Lazareff JA et al.: Cancerous stem cells can arise from pediatric brain tumors. Proc. Natl Acad. Sci. USA 100(25), 15178-15183 (2003).

  23. Lee J, Kotliarova S, Kotliarov Y et al.: Tumor stem cells derived from glioblastomas cultured in bFGF and EGF more closely mirror the phenotype and genotype of primary tumors than do serum-cultured cell lines. Cancer Cell 9(5), 391-403 (2006).

  24. Yuan X, Curtin J, Xiong Y et al.: Isolation of cancer stem cells from adult glioblastoma multiforme. Oncogene 23(58), 9392-9400 (2004).

  25. Singec I, Knoth R, Meyer RP et al.: Defining the actual sensitivity and specificity of the neurosphere assay in stem cell biology. Nat. Methods 3(10), 801-806 (2006).

  26. Lapidot T, Sirard C, Vormoor J et al.: A cell initiating human acute myeloid leukaemia after transplantation into SCID mice. Nature 367, 645-648 (1994).

  27. Bonnet D, Dick JE: Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat. Med. 3, 730-737 (1997).

  28. Al-Hajj M, Wicha MS, Benito-Hernandez A, Morrison SJ, Clarke MF: Prospective identification of tumorigenic breast cancer cells. Proc. Natl Acad. Sci. USA 100, 3983-3988. (2003).

  29. Pfenninger CV, Roschupkina T, Hertwig F et al.: CD133 is not present on neurogenic astrocytes in the adult subventricular zone, but on embryonic neural stem cells, ependymal cells, and glioblastoma cells. Cancer Res. 67(12), 5727-5736 (2007).

  30. Bao S, Wu Q, McLendon RE et al.: Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature 444, 756-760 (2006).

  31. Beier D, Hau P, Proescholdt M et al.: CD133+ and CD133- glioblastoma-derived cancer stem cells show differential growth characteristics and molecular profiles. Cancer Res. 67, 4010-4015 (2007).

  32. Zheng X, Shen G, Yang X, Liu W: Most C6 cells are cancer stem cells: evidence from clonal and population analyses. Cancer Res. 67(8), 3691-3697 (2007).

  33. Wang J, Sakariassen Pø, Tsinkalovsky O et al.: CD133 negative glioma cells form tumors in nude rats and give rise to CD133 positive cells. Int. J. Cancer 122(4), 761-768 (2008).

  34. Balenci L, Saoudi Y, Grunwald D et al.: IQGAP1 regulates adult neural progenitors in vivo and vascular endothelial growth factor-triggered neural progenitor migration in vitro. J. Neurosci. 27(17), 4716-4724 (2007).

  35. Balenci L, Clarke ID, Dirks PB et al.: IQGAP1 protein specifies amplifying cancer cells in glioblastoma multiforme. Cancer Res. 66(18), 9074-90782 (2006).

  36. Hanahan D, Weinberg RA: The hallmarks of cancer. Cell 100, 57-70 (2000).

  37. Clement V, Sanchez P, de Tribolet N, Radovanovic I, Ruiz i Altaba A: HEDGEHOG-GLI1 signaling regulates human glioma growth, cancer stem cell self-renewal, and tumorigenicity. Curr. Biol. 17(2), 165-172 (2007).

  38. Bar EE, Chaudhry A, Lin A et al.: Cyclopamine-mediated hedgehog pathway inhibition depletes stem-like cancer cells in glioblastoma. Stem Cells 25(10), 2524-2533 (2007).

  39. Fan X, Matsui W, Khaki L et al.: Notch pathway inhibition depletes stem-like cells and blocks engraftment in embryonal brain tumors. Cancer Res. 66, 7445-7452 (2006).

  40. Molofsky AV, Pardal R, Iwashita T et al.: Bmi-1 dependence distinguishes neural stem cell self-renewal from progenitor proliferation. Nature 425, 962-967 (2003).

  41. Piccirillo SG, Reynolds BA, Zanetti N et al.: Bone morphogenetic proteins inhibit the tumorigenic potential of human brain tumour-initiating cells. Nature 444(7120), 761-765 (2006).

  42. Ehtesham M, Sarangi A, Valadez JG et al.: Ligand-dependent activation of the hedgehog pathway in glioma progenitor cells. Oncogene 26(39), 5752-5761 (2007).

  43. Lee J, Son MJ, Woolard K et al.: Epigenetic-mediated dysfunction of the bone morphogenetic protein pathway inhibits differentiation of glioblastoma-initiating cells. Cancer Cell 13(1), 69-80 (2008).

  44. Nakano I, Masterman-Smith M, Saigusa K et al.: Maternal embryonic leucine zipper kinase is a key regulator of the proliferation of malignant brain tumors, including brain tumor stem cells. J. Neurosci. Res. 86(1), 48-60 (2007).

  45. Stupp R, Mason WP, van den Bent MJ et al.: Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N. Engl. J. Med. 352(10), 987-996 (2005).

  46. Blazek ER, Foutch JL, Maki G: Daoy medulloblastoma cells that express CD133 are radioresistant relative to CD133- cells, and the CD133+ sector is enlarged by hypoxia. Int. J. Radiat. Oncol. Biol. Phys. 67(1), 1-5 (2007).

  47. Liu G, Yuan X, Zeng Z et al.: Analysis of gene expression and chemoresistance of CD133+ cancer stem cells in glioblastoma. Mol. Cancer 5, 67 (2006).

  48. Folkins C, Man S, Xu P, Shaked Y, Hicklin DJ, Kerbel RS: Anticancer therapies combining antiangiogenic and tumor cell cytotoxic effects reduce the tumor stem-like cell fraction in glioma xenograft tumors. Cancer Res. 67(8), 3560-3564 (2007).

  49. Gilbertson RJ, Rich JN: Making a tumour’s bed: glioblastoma stem cells and the vascular niche. Nat. Rev. Cancer 7(10), 733-736 (2007).

  50. Bao S, Wu Q, Sathornsumetee S et al.: Stem cell-like glioma cells promote tumor angiogenesis through vascular endothelial growth factor. Cancer Res. 66, 7843-7848 (2006).

  51. Balic M, Lin H, Young L et al.: Most early disseminated cancer cells detected in bone marrow of breast cancer patients have a putative breast cancer stem cell phenotype. Clin. Cancer Res. 12(19), 5615-56121 (2006).

  52. Hermann PC, Huber SL, Herrler T et al.: Distinct populations of cancer stem cells determine tumor growth and metastatic activity in human pancreatic cancer. Cell Stem Cell 1, 313-323 (2007).

  53. Jain RK, di Tomaso E, Duda DG, Loeffler JS, Sorensen AG, Batchelor TT: Angiogenesis in brain tumours. Nat. Rev. Neurosci. 8(8), 610-622 (2007).

  54. Vredenburgh JJ, Desjardins A, Herndon JE 2nd et al.: Bevacizumab plus irinotecan in recurrent glioblastoma multiforme. J. Clin. Oncol. 25(30), 4722-4729 (2007).

  55. Vredenburgh JJ, Desjardins A, Herndon JE 2nd et al.: Phase II trial of bevacizumab and irinotecan in recurrent malignant glioma. Clin. Cancer Res. 13(4), 1253-1259 (2007).

  56. Batchelor TT, Sorensen AG, di Tomaso E et al.: AZD2171, a pan-VEGF receptor tyrosine kinase inhibitor, normalizes tumor vasculature and alleviates edema in glioblastoma patients. Cancer Cell 11(1), 83-95 (2007).

  57. Calabrese C, Poppleton H, Kocak M et al.: A perivascular niche for brain tumor stem cells. Cancer Cell 11, 69-82 (2007).

  58. Mischel PS, Cloughesy T: Using molecular information to guide brain tumor therapy. Nat. Clin. Pract. Neurol. 2(5), 232-233 (2006).

  59. Louis DN: Molecular pathology of malignant gliomas. Annu. Rev. Pathol. 1, 97-117 (2006).

  60. Liu R, Wang X, Chen GY et al.: The prognostic role of a gene signature from tumorigenic breast-cancer cells. N. Engl. J. Med. 356, 217-226 (2007).

  61. Zeppernick F, Ahmadi R, Campos B et al.: Stem cell marker CD133 affects clinical outcome in glioma patients. Clin. Cancer Res. 14(1), 123-129 (2008).

  62. Ho MM, Ng AV, Lam S, Hung JY: Side population in human lung cancer cell lines and tumors is enriched with stem-like cancer cells. Cancer Res. 67, 4827-4833 (2007).

  63. Hirschmann-Jax C, Foster AE, Wulf GG et al.: A distinct ’side population’ of cells with high drug efflux capacity in human tumor cells. Proc. Natl Acad. Sci. USA 101, 14228-14233 (2004).

  64. Zhou S, Schuetz JD, Bunting KD et al.: The ABC transporter Bcrp1/ABCG2 is expressed in a wide variety of stem cells and is a molecular determinant of the side-population phenotype. Nat. Med. 7, 1028-1034 (2001).

  65. Chaudhary PM, Roninson IB: Expression and activity of P-glycoprotein, a multidrug efflux pump, in human hematopoietic stem cells. Cell 66, 85-94 (1991).

  66. Ginestier C, Hur MH, Charafe-Jauffret E et al.: ALDH1 is a marker of normal and malignant human mammary stem cells and a predictor of poor clinical outcome. Cell Stem Cell 1, 555-567 (2007).

  67. Pearce DJ, Taussig D, Simpson C et al.: Characterization of cells with a high aldehyde dehydrogenase activity from cord blood and acute myeloid leukemia samples. Stem Cells 23, 752-760 (2005).

  68. Diamandis P, Wildenhain J, Clarke ID et al.: Chemical genetics reveals a complex functional ground state of neural stem cells. Nat. Chem. Biol. 3(5), 268-273 (2007).

  69. Jin L, Hope KJ, Zhai Q, Smadja-Joffe F, Dick JE: Targeting of CD44 eradicates human acute myeloid leukemic stem cells. Nat. Med. 12, 1167-1174 (2006).

  70. Pellegatta S, Poliani PL, Corno D et al.: Neurospheres enriched in cancer stem-like cells are highly effective in eliciting a dendritic cell-mediated immune response against malignant gliomas. Cancer Res. 66, 10247-10252 (2006).

  71. Jiang H, Gomez-Manzano C, Aoki H et al.: Examination of the therapeutic potential of Delta-24-RGD in brain tumor stem cells: role of autophagic cell death. J. Natl Cancer Inst. 99(18), 1410-1414 (2007).

  72. Roy NS, Cleren C, Singh SK, Yang L, Beal MF, Goldman SA: Functional engraftment of human ES cell-derived dopaminergic neurons enriched by coculture with telomerase-immortalized midbrain astrocytes. Nat. Med. 12(11), 1259-1268 (2006).

  73. Wicha MS, Liu S, Dontu G: Cancer stem cells: an old idea – a paradigm shift. Cancer Res. 66, 1883-1890 (2006).

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Topic of the month…. Hereditary subcortical vascular dementia (CADASIL)

March 16, 2009 at 9:03 am · Filed under Neurological section ·Tagged

The author: Professor Yasser Metwally

http://yassermetwally.com

INTRODUCTION

March 16, 2008 — In this edition of the monthly publication “Topic of the month” Professor Metwally discusses “Hereditary subcortical vascular dementia (CADASIL)”. This topic is presented in downloadable PDF format.

Click here to download this monthly topic ( Hereditary subcortical vascular dementia (CADASIL)) in PDF format (734 KB)

Cerebral autosomal dominant arteriopathy with subcortical infarct and leukoencephalopathy (CADASIL) is the most common hereditary subcortical vascular dementia. It is caused by the defective NOTCH3 gene, which encodes a transmembrane receptor; over 170 different mutations are known. The main clinical features are migraine with aura (often atypical or isolated), strokes, cognitive decline/dementia and psychiatric symptoms. Executive and organizing cognitive functions are impaired first, memory is affected late. Typical MRI findings are T2 weighted hyperintensities in temporopolar white matter and the capsula externa. Smooth muscle cells in small arteries throughout the body degenerate and vessel walls become fibrotic. In the brain, this results in circulatory disturbances and lacunar infarcts, mainly in cerebral white matter and deep gray matter. The exact pathogenesis is still open: a dominant-negative toxic effect is suggested, possibly related to Notch3 misfolding. Diagnosis is reached either by identifying a pathogenic NOTCH3 mutation or by electron microscopic demonstration of granular osmiophilic material in a (skin) biopsy. Only symptomatic treatment is available at present.

Cerebral autosomal dominant arteriopathy with subcortical infarct and leukoencephalopathy (CADASIL) is the most common hereditary vascular dementia. The disease is caused by more than 170 different stereotypic mutations in the NOTCH3 gene encoding a 280 kDa transmembrane receptor [1, Suppl. table in 2]. The mutations lead to progressive vascular smooth muscle cell (VSMC) degeneration, thickening and fibrosis of the vessel walls and accumulation of the Notch3 extracellular domain (N3ECD) on the VSMCs. The four most common characteristic clinical symptoms of CADASIL are migraine with aura, recurrent ischemic attacks, cognitive decline and psychiatric symptoms. Only symptomatic therapy is available and thus, as a progressive disease, CADASIL leads to severe dementia and finally to death, commonly within 20-25 years after symptoms have occurred.

Click here to download this monthly topic ( Hereditary subcortical vascular dementia (CADASIL)) in PDF format (734 KB)

References

  1. Joutel A, Corpechot C, Ducros A et al. : Notch3 mutations in CADASIL, a hereditary late-onset condition causing stroke and dementia. Nature 383, 707-710 (1996).

  2. Tikka S, Mykkänen K, Ruchoux M-M et al. : Congruence between NOTCH3 mutations and GOM in 131 CADASIL patients. (2008) (In Press).

  3. van Bogaert L: Encephalopathie sous-corticale progressive (Binswanger) a evolution rapide chez deuz soeurs. Med. Hellen 24, 961-972 (1955).

  4. Sourander P, Wålinder J: Hereditary multi-infarct dementia. Morphological and clinical studies of a new disease. Acta Neuropathol. 39, 247-254 (1977).

  5. Low WC, Junna M, Börjesson-Hanson A et al. : Hereditary multi-infarct dementia of the Swedish type is a novel disorder different from NOTCH 3 causing CADASIL. Brain 130, 357-367 (2007).

  6. Tournier-Lasserve E, Joutel A, Melki J et al. : Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy maps to chromosome 19q12. Nat. Genet. 3, 256-259 (1993).

  7. Joutel A, Vahedi K, Corpechot C et al. : Strong clustering and stereotyped nature of Notch3 mutations in CADASIL patients. Lancet 350, 1511-1515 (1997).

  8. Markus HS, Martin RJ, Simpson MA et al. : Diagnostic strategies in CADASIL. Neurology 59, 1134-1138 (2002).

  9. Razvi SS, Davidson R, Bone I, Muir KW: The prevalence of cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL) in the west of Scotland. J. Neurol. Neurosurg. Psychiatry 76, 739-741 (2005).

  10. Dong Y, Hassan A, Zhang Z, Huber D, Dalageorgou C, Markus HS: Yield of screening for CADASIL mutations in lacunar stroke and leukoaraiosis. Stroke 34, 203-205 (2003).

  11. Metwally, MYM: Textbook of neuroimaging, A CD-ROM publication, (Metwally, MYM editor) WEB-CD agency for electronic publication, version 10.1a January 2009 [Click to have a look at the home page]

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Vascular Risk-Factor Burden Predicts Memory Performance

March 16, 2009 at 8:32 am · Filed under Neurological section

The author: Professor Yasser Metwally

http://yassermetwally.com

INTRODUCTION

March 16, 2009 — Vascular risk-factor burden is associated with a substantially increased risk for poor memory performance in individuals with coronary artery disease (CAD).

New research presented here at the American Association of Geriatric Psychiatry 2009 Annual Meeting showed that individuals with 5 vascular risk factors had almost a 7-fold increased risk of having borderline or impaired verbal memory measured by the California Verbal Learning Test, 2nd ed (CVLT–II).

“There was a very strong relationship between the number of cardiovascular risk factors in these individuals and their degree of cognitive impairment,” said lead investigator Krista Lanctôt, PhD, from Sunnybrook Health Sciences Centre, in Toronto, Ontario.

  • Marker of Hippocampal Volume

According to Dr. Lanctôt, a high proportion of CAD patients experience cognitive impairment, including verbal learning deficits. In addition, observational studies have shown a link between cognitive impairment and cardiovascular risk factors including hypertension, diabetes, and dyslipidemia.

However, while CAD may increase the risk of developing mild cognitive impairment (MCI) or Alzheimer’s disease (AD), the nature of this link is unclear, said Dr. Lanctôt.

To determine whether the cumulative burden of vascular risk factors is predictive of verbal memory deficits, researchers conducted a cross-sectional study of 100 patients with a diagnosis of CAD who were undergoing cardiac rehabilitation at a single center.

The average age of the study cohort was 64 years, and 78% of participants were men. Subjects had a 50% or greater blockage of at least 1 coronary artery or a history of prior myocardial infarction or revascularization.

Participants underwent an evaluation of vascular risk factors, including hypertension, dyslipidemia, diabetes, and obesity, as well as exercise stress testing and verbal memory assessment.

The researchers chose to measure verbal memory because it is widely considered to be a marker of hippocampal volume. Dr. Lanctôt pointed out that a recent study in a cohort of individuals with dementia with Braak stage 4 scores (a measure of pathological burden of plaques and tangles) showed that the main difference between subjects with and without cognitive impairment was hippocampal volume.

  • Intervention Opportunity?

The results of the current study revealed that each vascular risk factor was roughly equivalent to remembering 1 word fewer and that at a level of 5 vascular risk factors individuals had a much greater risk of having a borderline or impaired CVLT-II score compared with their counterparts with 2 or fewer vascular risk factors.

“We were surprised at how tight the correlation was between the number of risk factors and the risk of memory impairment. The good news is that many of these factors are modifiable, and this may offer us an opportunity to intervene at an earlier stage with a view to reducing the risk of MCI and possibly Alzheimer’s disease,” said Dr. Lanctôt.

Based on these findings, she added, the team is planning a large, multicenter interventional study of about 400 patients that will examine the impact of reducing vascular risk factors on subsequent memory loss.

References

  1. American Association for Geriatric Psychiatry 2009 Annual Meeting: Abstract NR 32. Presented March 6, 2009.

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Antiplatelet Drugs and Hemorrhagic Infarcts

March 15, 2009 at 3:31 pm · Filed under Neurological section

The author: Professor Yasser Metwally

http://yassermetwally.com

INTRODUCTION

March 15, 2009 — How soon can you start anticoagulation in an embolic stroke from a large left ventricular (LV) apical thrombus in the setting of severe LV dysfunction? Will you start on heparin and warfarin immediately, no heparin initially, or wait a few days before starting anticoagulation? The stroke in question is not dense and has shown no bleeding on initial computed tomography scan.

  • Answer

Cardioembolic stroke accounts for approximately 15% of all strokes and is thought to be one of the more preventable types. The prevalence of left ventricular thrombi, and probably also emboli, following an acute anterior myocardial infarction has been reduced by heparin, but the value of subsequent oral anticoagulation for persistent left ventricular thrombi has been disputed.[1] Management of patients with stroke from a cardiac source involves 2 steps: Treat the acute phase of stroke and provide prophylaxis for recurrent thromboembolism. Anticoagulant therapy has generally been found to be the most effective means of preventing cardiogenic brain embolism, but the intensity of anticoagulation needs to be optimized to reflect the risk-to-benefit ratio for the particular patient. Some authors suggest that the available evidence does not support routine immediate anticoagulation of acute cardioembolic stroke. Others suggest that acute anticoagulation (within 96-hours of the event, international normalized ration 2 to 3) can be used safely in most patients with cardioembolic stroke but that such treatment does not clearly benefit this population as a whole.[2] Warfarin seems superior to aspirin in preventing recurrent cardioembolic stroke although anticoagulation in patients with large infarctions (as detailed on computed tomography scan) may significantly increase the risk for hemorrhage.

References

  1. Prieto A, Eisenberg J, Thakur RK. Nonarrhythmic complications of acute myocardial infarction. Emerg Med Clin North Am. 2001;19:397-415. Abstract

  2. Kelley RE, Minagar A. Cardioembolic stroke: an update. South Med J. 2003;96:343-349. Abstract

  3. Metwally, MYM: Textbook of neuroimaging, A CD-ROM publication, (Metwally, MYM editor) WEB-CD agency for electronic publication, version 10.1a January 2009 [Click to have a look at the home page]

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Current Management of High-grade Astrocytic Neoplasms: Small but Tangible Progress

March 15, 2009 at 12:06 pm · Filed under Neurological section

The author: Professor Yasser Metwally

http://yassermetwally.com

INTRODUCTION

March15, 2009 — The last five years have seen an evolution in the management of highgrade astrocytic tumors comparable in scope yet greater in magnitude to that of the prior 40 years. This is thanks to the convergence of three factors: the introduction of an oral agent with antitumor activity beyond the blood–brain barrier and modest systemic toxicity (temozolomide); the demonstration through a well-conducted randomized trial of the superiority of multimodality therapy; and the fact that we now stand on the threshold of additional progress through key advances in translational biology, which, in many cancers, is providing new targets for therapeutic intervention.

Astrocytic tumors have long been the bane of neurosurgeons, radiation therapists, and neuro-oncologists. Although they account for only 2.3% of all cancer-related deaths in the US,1 little if any substantial progress in brain imaging and treatment had been made until the first years of this millennium. Characteristics of high-grade glial tumors compared with other cancers are its unique location, robust invasive and angiogenic capabilities without a significant propensity to metastasize outside of the central nervous system (CNS), and the profound histological and molecular heterogeneity within tumor specimens.

  • Advances in the Management of Glioblastomas— Multimodality Strategies

In 2003, a phase III study in 240 newly diagnosed patients with surgically resectable malignant gliomas—including 207 with glioblastoma multiforme (GBM)—compared surgery plus radiotherapy and placebo wafers with surgery plus radiotherapy and the addition of 3.8% bischloroethyl nitrosourea (BCNU, carmustine) wafers (Gliadel wafers) into the tumor bed. The study demonstrated a modest, albeit significant, prolongation of survival in the latter group (13.9 versus 11.6 months).2 Long-term follow-up of this study showed that the survival advantage with BCNU wafers was maintained at one, two, and three years, and was statistically significant (p=0.01) at three years compared with placebo, although the absolute number of patients evaluated at this latter timepoint was quite small.3

Perhaps the most significant advance in the management of glioblastomas emanates from the work of Stupp et al.4 who, in a safety and efficacy study, randomized 573 patients with newly diagnosed glioblastoma from 85 centers, primarily in Europe, to radiotherapy alone or to radiotherapy plus concomitant temozolomide followed by monthly temozolomide for six cycles. At a median follow-up of 28 months the median survival in the radiotherapy group alone was 12.1 months compared with 14.6 months in the group receiving both treatment modalities (p<0.001). The two-year survival rate was 10.4% with radiotherapy alone versus 26.5% with radiotherapy and temozolomide. The results of this study produced level 1A evidence for the benefit of this combined modality treatment in initially diagnosed patients, and was incorporated into the new National Comprehensive Cancer Network (NCCN) guidelines for CNS tumors in 2005.

Thus, as a next logical step, a fusion of these two prior studies was evaluated in a phase II setting in patients with newly diagnosed, highgrade GBM undergoing resection with BCNU wafer insertion followed by the combination of radiotherapy plus temozolomide. Early interim data have been presented in abstract form.5 The study end-points include survival and progression-free survival (PFS). Of 35 patients enrolled so far, 34 were diagnosed with GBM. At median follow-up of 10.4 months, 25 patients had documented recurrence and 19 patients had died. Six patients remain on active treatment. The one-year survival rate is 64%, and median survival is 18.6 months. These early data suggest that combination therapy with BCNU wafers followed by therapy plus temozolomide may be an effective regimen in patients with initial highgrade resectable malignant gliomas, although randomized trials will ultimately be needed to assess the efficacy of this treatment modality. Other treatment modalities that have been investigated for the treatment of high-grade astrocytic tumors—especially in terms of targeting disease localized to the surgical bed or the surrounding area—have included stereotactic radiosurgery and brachytherapy. A randomized trial conducted by the Radiation Therapy Oncology Group (RTOG) compared post-operative conventional radiotherapy plus systemic BCNU alone or preceded by stereotactic radiosurgery—including both linear accelerator or gamma-knife—in patients with GBM (>4cm tumor size). The results of the trial were disappointing with no improvement in local control or survival with stereotactic radiosurgery.6

The US Food and Drug Administration (FDA) has recently approved GliaSite, a novel brachytherapy device, to provide local post-operative irradiation to high- grade gliomas. However, to date, no efficacy trials have been conducted with the system. In a retrospective, multiinstitutional analysis, median survival— measured from the date of GliaSite placement—was 35.9 weeks for patients with an initial diagnosis of GBM. The patient population consisted of patients with recurrent high-grade gliomas who had previously undergone resection and had received external beam radiotherapy as part of their initial treatment. Following surgical debulking of the recurrent lesion, an expandable balloon catheter (GliaSite) was placed in the tumor cavity. Although reirradiation of malignant gliomas with the GliaSite system appeared to provide a modest survival benefit, it is difficult to assess the value of any survival without the benefit of a control group.7

Convection-enhanced delivery (CED) of toxins to the tumor site is a new treatment modality under investigation for malignant gliomas. It was developed as a method to treat brain tumors by circumventing the normal limitations imposed by the blood–brain barrier. CED involves the stereotactically guided implantation of delivery catheters directly into the residual tumor or around the resection cavity to facilitate the local delivery by high-flow micro-infusion of the targeted toxin to tumor cells. A combined summary of three phase I clinical trials investigating the use of cintredekin besudotox—a recombinant protein consisting of interleukin-13 (IL-13) and a truncated form of Pseudomonas exotoxin— delivered via CED in the treatment of recurrent malignant glioma following tumor resection, demonstrated an overall median survival after treatment of 45.9 weeks.8 The Phase III Randomized Evaluation of Convection Enhanced Delivery of IL13-Pe38qqr with Survival Endpoint (PRECISE) Trial was designed to compare CED of cintredekin besudotox to treatment with the BCNU wafers in 294 patients with first recurrence or progression of GBM. Unfortunately, the study was stopped in December 2006 after the efficacy end-point of a statistically significant difference in overall survival was not met. Indeed, the median survival in the CED arm was 36.4 weeks, while that of the BCNU wafer arm was 35.3 weeks. An NCI-sponsored phase I trial is currently evaluating CED of 131I-chTNT-1/B, a chimeric tumor necrosis therapy antibody attached to the radioisotope iodine 131 in malignant glioma. Although CED is a promising alternative for targeted delivery, it remains a complex, interdisciplinary technique that needs further investigation to optimize catheter positioning and drug distribution.

  • Molecular Targets and Prognostic Factors

Turning to recent advances in the genomic analysis of glioblastoma, four molecular markers are currently being explored. First is the identification of loss of the chromosome 1p/19q in anaplastic oligodendroglioma as a predictor of response to chemotherapy—particularly PCV (procarbazine, CCNU [chloroethylnitrosourea, lomustine], and vincristine). The initial results, published by Cairncross et al. in 1998,9 led to two randomized clinical trials. The first—European Organization for Research and Treatment of Cancer (EORTC) 26951—evaluated radiotherapy versus radiotherapy followed by PCV in patients with newly diagnosed anaplastic oligodendroglioma or anaplastic oligo-astrocytomas.10 The second (RTOG 94-02) evaluated PCV given prior to radiotherapy.11 Both studies demonstrated that the addition of PCV improved PFS without impacting on overall survival (OS). Although chromosome-1p/19q loss does predict chemosensitivity, it did not identify patients who have a better outcome after adjuvant chemotherapy. Moreover, it became apparent that patients with the combined chromosomal 1p/19q loss have a better outcome after radiotherapy compared with patients whose tumor does not contain this chromosomal aberration. At a molecular level, up to 50% of glioblastoma specimens express dysregulated epidermal growth factor receptor (HER1/EGFR).12 This observation has spurred interest in the use of the small molecule HER1/EGFR-targeted therapy agents such as erlotinib and gefitinib. Initial phase II studies evaluating gefitinib failed to demonstrate significant objective tumor regressions, with a six-month PFS of only 13% in 53 patients with recurrent glioblastoma.13

In contrast, the data relating to erlotinib initially appeared somewhat more promising in one study of 31 patients with recurrent glioblastomas, in which six patients achieved a partial response and the six-month PFS was 26%.14,15 Of note is that these authors could not determine any correlation between response and EGFR expression or amplification within the tumor specimens. Also, a second phase II study of 30 patients treated with erlotinib failed to result in any objective responses or six-month PFS.16 Unfortunately, a recent EORTC trial comparing erlotinib with either temozolomide or BCNU in 110 patients with recurrent glioblastoma failed to demonstrate a benefit of the oral targeted therapy with respect to sixmonth PFS or 12-month survival.17 Optimal dosing of these oral agents, especially while patients are taking enzyme-inducing anti-epileptics or drugs with similar pharmacological effects, may be a significant confounding variable in determining their true clinical efficacy.18

Another molecular target of some promise in the management of patients with GBM is transforming growth factor beta (TGF-B). Not only does it stimulate cell migration, invasion, and angiogenesis, but it also appears to play an important role in the disruption of afferent and efferent immune responses.19 Several in vitro systems, as well as rodent glioma models, delineate the potential therapeutic impact of TGF-B antagonism, employing not only antisense strategies, but also specific TGF-B receptor kinase antagonists. In particular, the use of such agents in conjunction with vaccines, or perhaps novel approaches of cellular immunotherapy, bears further study. Another molecular marker of interest is the O6-methylguanine-DNA methyltransferase (MGMT) promoter gene, also known as O6-alkylguanine-DNA alkyltransferase or AGT. The gene itself expresses alkyltransferase, which plays a role in resistance to alkylating and methylating agents. Methylation of this gene disrupts the expression of alkyltransferase and thus renders the cell more susceptible to alkylating and methylating chemotherapy agents such as temozolomide. Hegi et al. analyzed tissue from newly diagnosed patients with glioblastoma enrolled into the EORTC 26981 trial, and documented a significant correlation between MGMT methylation and outcome from treatment.20 Methylation of the MGMT promoter was demonstrated in 45% of 206 tumors analyzed, and this was associated with a 46% survival rate at two years compared with only 13.8% in those patients with non-methylated promoter status.20 Although the preliminary conclusion from this translational study is that MGMT promoter methylation may be predictive of outcome to multimodality treatment in glioblastoma, validation from additional prospective studies is required.

A novel oral protein kinase C inhibitor that initially appeared to have activity in recurrent glioblastoma was enzastaurin. This agent, an oral inhibitor of PKCß and PI3K/AKT pathways, is well tolerated, possesses antiangiogenic properties in pre-clinical models, and induces tumor cell apoptosis.21 Enzastaurin is currently being evaluated in phase II trials for the treatment of patients with recurrent high-grade gliomas. Initial results in 87 evaluable patients with recurrent high-grade gliomas showed that enzastaurin treatment was well tolerated and objective radiographic responses were seen in 22% of patients with GBM. The exposure to enzastaurin was significantly lower in patients treated with enzyme-inducing antiepileptic drugs (EIADs).22 Enzastaurin also appears to be safe in conjunction with radiation therapy and temozolomide in patients with newly diagnosed GBM.23 GBM is highly angiogenic, and vascular endothelial growth factor (VEGF) is amplified in most GBM tumors.24 Over the last three years, there has also been an evolution in the understanding of the ‘brain tumor stem cell.’ If the concept of a brain tumor stem cell proves to be a real entity, identifiable perhaps by CD-133 expression, and correlated with a significant angiogenic effect associated with VEGF expression and production, this could confirm an important role for antiangiogenic therapy in this cancer.25 This prompted the evaluation of the recombinant humanized anti-VEGF monoclonal antibody bevacizumab in patients with malignant gliomas. A recent phase II trial studied the effect of bevacizumab in combination with the cytotoxic agent irinotecan in patients with recurrent high-grade astrocytic neoplasms.26 The investigators demonstrated a radiographic response rate of 63% with the combination therapy and six-month overall survival was estimated at 72%. A randomized phase II study in patients with recurrent glioblastomas evaluating bevacizumab alone versus bevacizumab with irinotecan was recently completed and the results are anxiously awaited . Additional agents with antiangiogenic properties such as the multitargeted agents sorafenib and sunitinib are also being investigated in malignant gliomas.27,28

  • Conclusion

Significant advances are being made in the understanding of the biology of high-grade gliomas, which are contributing to the development of promising targeted therapies and treatment modalities. Over the last couple of years, there has been an evolution in the understanding of the ‘brain tumor stem cell.’ If the concept of a brain tumor stem cell proves to be a real entity identifiable by CD-133 expression, and if this correlates with a significant angiogenic effect associated with VEGF expression and production, it opens new possibilities for targeted therapy.27 Multitargeted therapy is a necessity to manage high-grade brain tumors optimally. The potential of quadruple multimodality therapy for the management of brain tumors, which includes surgery, radiotherapy, systemic therapy, and localized chemotherapy, needs to be further investigated. Furthermore, with the promising results seen with bevacizumab, there is the possibility of a fifth modality—an antiangiogenesis inhibitor.

References

  1. American Cancer Society, Cancer Facts and Figures 2006, Atlanta, American Cancer Society, 2006. Available at: http://www.cancer.org/downloads/STT/CAFF2006PWSecured.pdf

  2. Westphal M, Ram Z, Riddle V, et al., on behalf of the Executive Committee of the Gliadel Study Group, Gliadel wafer in initial surgery for malignant glioma: long-term follow-up of a multicenter controlled trial, Acta Neurochir (Wien), 2006;148:269–75.

  3. Stupp R, Mason WP, van den Bent MJ, et al., Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma, N Engl J Med, 2005;352:987–96.

  4. Westphal M, Hilt DC, Bortey E, et al., A phase III trial of local chemotherapy with biodegradable carmustine (BCNU) wafers (Gliadel wafers) in patients with primary malignant glioma, Neuro-oncol, 2003;5:79–88.

  5. LaRocca RV, Hodes J, Villaneuva WG, et al., A phase II study of radiation with concomitant and then sequential temozolomide (TMZ) in patients (pts) with newly diagnosed supratentorial high grade malignant glioma (MG) who have undergone surgery with carmustine (BCNU) wafer insertion, Annual Meeting of the Society of Neuro-Oncology, Neuro-Oncol, 2006;8:445, Abstract TA-28.

  6. Souhami L, Seiferheld W, Brachman D, et al., Randomized comparison of stereotactic radiosurgery followed by conventional radiotherapy with carmustine to conventional radiotherapy with carmustine for patients with glioblastoma multiforme: report of Radiation Therapy Oncology Group 93-05 protocol, Int J Radiat Oncol Biol Phys, 2004;60:853–60.

  7. Gabayan AJ, Green SB, Sanan A, et al., GliaSite brachytherapy for treatment of recurrent malignant gliomas: a retrospective multiinstitutional analysis, Neurosurgery, 2006;58(4):701–9.

  8. Kunwar S, Prados MD, Chang SM, et al., Direct intracerebral delivery of cintredekin besudotox (IL13-PE38QQR) in recurrent malignant glioma: a report by the Cintredekin Besudotox Intraparenchymal Study Group, J Clin Oncol, 2007;25(7):837–44.

  9. Cairncross JG, Ueki K, Zlatescu MC, et al., Specific genetic predictors of chemotherapeutic response and survival in patients with anaplastic oligodendrogliomas, J Natl Cancer Inst, 1998;90:1473–9.

  10. van den Bent MJ, Carpentier AF, Brandes AA, et al., Adjuvant procarbazine, lomustine, and vincristine improves progressionfree survival but not overall survival in newly diagnosed anaplastic oligodendrogliomas and oligoastrocytomas: a randomized European Organisation for Research and Treatment of Cancer phase III trial, J Clin Oncol, 2006;24:2715–22.

  11. Intergroup Radiation Therapy Oncology Group Trial 9402, Cairncross G, Berkey B, Shaw E, et al., Phase III trial of chemotherapy plus radiotherapy compared with radiotherapy alone for pure and mixed anaplastic oligodendroglioma: Intergroup Radiation Therapy Oncology Group Trial 9402, J Clin Oncol, 2006;24:2707–14.

  12. Halatsch ME, Schmidt U, Behnke-Mursch J, et al., Epidermal growth factor receptor inhibition for the treatment of glioblastoma multiforme and other malignant brain tumors, Cancer Treat Rev, 2006;32:72–89.

  13. Rich JN, Reardon DA, Peery T, et al., Phase II trial of gefitinib in recureent glioblastoma, J Clin Oncol, 2004;22:133–42.

  14. Vogelbaum MA, Peereboom D, Stevens G, et al., Response rate to single agent therapy with the EGFR tyrosine kinase inhibitor erlotinib in recurrent glioblastoma multiforme: results of a phase II trial, Neuro-Oncol, 2004;6(4):384, Abstract TA-59.

  15. Vogelbaum MA, Peereboom D, Stevens G, et al., Phase II trial of the EGFR tyrosine kinase inhibitor erlotinib for single agent therapy of recurrent Glioblastoma Multiforme: Interim results, J Clin Oncol, 2004 ASCO Annual Meeting Proceedings, 2004;22(14S):Abstract 1558.

  16. Raizer JJ, Abrey LE,Wen P, et al., A phase II trial of erlotinib (OSI- 774) in patients (pts) with recurrent malignant gliomas (MG), not on EIAEDS, J Clin Oncol, 2004 ASCO Annual Meeting Proceedings, 2004;22(14S):Abstract 1502.

  17. Van Den Bent MJ, Brandes A, Rampling R, et al., Randomized phase II trial of erlotinib versus temozolomide or BCNU in recurrent glioblastoma multiforme (GBM): EORTC 26034, J Clin Oncol, 2007 ASCO Annual Meeting Proceedings Part I, 2007;25:Abstract 2005.

  18. Mellinghoff IK,Wang MY, Vivanco I, et al., Molecular determinants of the response of glioblastomas to EGFR kinaase inhibitors, N Engl J Med, 2005;353:2012–24.

  19. Wick W, Naumann U and Weller M, Transforming growth factorbeta: a molecular target for the future therapy of glioblastoma, Curr Pharm Des, 2006;12:341–9.

  20. Hegi ME, Diserens AC, Gorlia T, et al., MGMT gene silencing and benefit from temozolomide in glioblastoma, N Engl J Med, 2005;352:997–1003.

  21. Graff JR, McNulty AM, Hanna KR, et al., The protein kinase Cbeta-selective inhibitor, Enzastaurin (LY317615.HCl), suppresses signaling through the AKT pathway, induces apoptosis, and suppresses growth of human colon cancer and glioblastoma xenografts, Cancer Res, 2005;65:7462–9.

  22. Fine HA, Kim L, Royce C, et al., Results from phase II trial of enzastaurin (LY317615) in patients with recurrent high grade gliomas, J Clin Oncol, 2005 ASCO Annual Meeting Proceedings, 2005;23(16S Pt I of II):Abstract 1504.

  23. Butowski NA, Lamborn K, Chang S, et al., Study of enzastaurin plus temozolomide during and following radiation therapy in patients with newly diagnosed glioblastoma multiforme (GBM) or gliosarcoma, J Clin Oncology, 2007 ASCO Annual Meeting Proceedings, 2007;25(18S):Abstract 12511.

  24. Kaur B, Tan C, Brat DJ, et al., Genetic and hypoxic regulation of angiogenesis in gliomas, J Neurooncol, 2004;70:229–43.

  25. Bao S,Wu Q, Sathornsumetee S, et al., Stem cell-like glioma cells promote tumor angiogenesis through vascular endothelial growth factor, Cancer Res, 2006;66:7843–8.

  26. Vredenburgh JJ, Desjardins A, Herndon JE 2nd, et al., Phase II trial of bevacizumab and irinotecan in recurrent malignant glioma, Clin Cancer Res, 2007;13(4):1253–9.

  27. Farhadi MR, Capelle HH, Erber R, et al., Combined inhibition of vascular endothelial growth factor and platelet-derived growth factor signaling: effects on the angiogenesis, microcirculation, and growth of orthotopic malignant gliomas, J Neurosurg, 2005;102:363–70.

  28. Kesari S, Ramakrishna N, Sauvageot C, et al., Targeted molecular therapy of malignant gliomas, Curr Neurol Neurosci Rep, 2005;5:186–97.

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Glioblastoma Multiforme: Past, Present, and Future

March 15, 2009 at 9:05 am · Filed under Neurological section

The author: Professor Yasser Metwally

http://yassermetwally.com

INTRODUCTION

March 15, 2009 — Bailey and Cushing observed that gliomas become more aggressive with time, writing – all of these lesions, so far as our records permit us to judge, show an increasing degree of malignancy, the recurrent tumors giving evidence of more active cell division than the original lesion. 2 It is now understood that the accumulation of molecular abnormalities1 underlies the increasingly aggressive clinical behavior of an individual patient s glioma over time. Moreover, while GBMs may be histologically identical, they are molecularly distinct,51 and each tumor may require individually tailored treatment with the combination of agents predicted to impact multiple molecular abnormalities. Successful therapy of a molecularly complex disease such as GBM may also require simultaneous administration of multiple agents, including both traditional chemotherapies and several pathway inhibitors.

  • Past

The most common cancer arising from the brain is the glioblastoma multiforme (GBM). It is also the most deadly,1 representing the most aggressive subtype among the gliomas, a collection of tumors including astrocytomas and oligodendrogliomas (see Table 1). In 1926, Bailey and Cushing, in describing spongioblastoma multiforme , the label then used for GBM, noted that:

- It is from this group doubtless that the generally unfavorable impression regarding gliomas as a whole has been gained. It is not only the largest single group in the series& but at the same time is one of the most malignant& In the five unoperated cases, the average duration of life from the onset of symptoms was only three months, which speaks well on the whole for the average survival period of twelve months for those surgically treated. 2

Since their seminal work, the median survival of 12 months has not changed markedly. Both data from the 1960s3 and current data4 confirm that the extent of surgical resection is an important prognostic factor. However, as Bailey and Cushing observed, GBMs have – infiltrating propensities, and& when enucleation is attempted, the growth is found at the depth to spread into and merge with the normal cerebral tissue without recognizable demarcation. 2 In prior eras, radical surgical excisions, including removal of the entire cerebral hemisphere containing the tumor,5 were occasionally attempted, yet patients who survived the hemispherectomy died of recurrent tumor,6 clinically proving the importance of the histologic observation that tumor cells invade throughout the brain. In the modern age, brain imaging may disclose macroscopic tumor in the opposite hemisphere (see Figure 1) or even gliomatosis cerebri literally a brain full of tumor. In the years leading to up to World War II, the German pathologist Scherer, whose scientific discoveries were tainted by his Nazi activities,7 described secondary structures 8,9 that further characterized invasive tumor cells. These structures are secondary because they are dependent for their formation on underlying normal brain structures, as opposed to primary structures of the tumor such as pseudopalisading necrosis and microvascular proliferation. Examples include perineuronal and perivascular satellitosis (accumulation of tumor cells around neurons and blood vessels), subpial spread, and intrafascicular tracking such as infiltration along corpus callosum and other white matter tracks (see Figure 2).

Advances in surgical technique, imaging, and targeting of radiotherapy (RT) are important contributions to local control. However, changing GBM from a disease that kills quickly to one that can be managed as a chronic illness, such as hypertension or diabetes mellitus, will require systemic therapies targeting tumor cells infiltrating throughout the brain, such as chemotherapy, immunotherapy, and small molecule pathway inhibitors.

  • Present

Currently, treatment for GBM involves both local and systemic therapy. Surgery and partial brain RT are the standard locally directed therapies. Some physicians also advise intra-operative placement of chemotherapy containing polymers (i.e. Gliadel wafers ) directly into the surgical bed in an attempt to prolong local control.10 While there is a modest survival benefit, the use of these polymers remains controversial because of the potential for toxicity. Other treatment modalities that target disease localized to the surgical bed or the surrounding area have included brachytherapy and stereotactic radiosurgery (with either a linear accelerator or gammaknife), neither of which are commonly advised. Convection-based chemotherapies delivered by catheter infusion, such as local delivery of pseudomonas exotoxin linked to either interleukin 13 (IL-13) or transforming growth factor-a (TGFa),11 are available in clinical trials for some patients. These trials take advantage of differences in the expression of proteins (such as growth factor receptors) on the surface of residual tumor cells in the periphery of the operative bed to deliver the toxin to tumor cells, but spare normal brain.

By contrast, systemic chemotherapy targets tumor cells beyond the reach of local therapies. The most commonly prescribed systemic chemotherapy for GBM is temozolomide (Temodar®), an alkylator that became available during the last decade. The effectiveness of temozolomide in the management of GBM at diagnosis was recently demonstrated by a large multinational study.4 A modest survival benefit of 2.5 months for concurrent temozolomide with RT (14.6 months median survival) was observed relative to RT alone (12.1 months median survival).4 In addition, while the survival benefit was still present two years after diagnosis, only 10.7% of patients were progression-free and only 26.5% of patients were alive at that point.4 While systemic chemotherapy improves the outcome for some patients, long-term disease control therefore remains elusive.

Table 1. Common Gliomas. The gliomas are assigned a grade by the World Health Organization (WHO) depending on histologic features that predict behavior.This classification scheme is derived from the clinicopathologic studies of Bailey and Cushing.2 Grade I tumors, such as juvenile pilocytic astrocytomas, are generally focal rather than diffuse and are potentially curable by surgical excision.WHO grade II–IV tumors are diffusely infiltrative.WHO grade III–IV tumors are termed ‘high grade’ or malignant. GBMs, or grade IV astrocytomas, are the most aggressive subtype. (Click to enlarge table)

Discoveries during the last several years have improved the understanding of glioma and general cancer biology markedly. Generally, a cancer comprises cells that either divide or survive when they should instead undergo either cell cycle arrest or die. These abnormalities are also not mutually exclusive, and most cancers, including GBMs, are driven by several molecular abnormalities. The signal to divide is typically provided by a growth factor (ligand). Examples include TGF?, epidermal growth factor (EGF), platelet-derived growth factor (PDGF), and vascular endothelial growth factor (VEGF). Such ligands interact with cells through receptors including EGF receptors (EGFRs), PDGF receptors (PDGFRs), and VEGF receptors (VEGFRs). Receptor activity is linked with cellular processes such as mitosis or invasion by signal transduction cascades. Examples of signal transduction cascades important in human GBMs include those activated by the oncogenes Ras, Akt, and Src.12 In cancer cells, these pathways are disrupted through several mechanisms. For example, EGFR is overexpressed in up to 92% of astrocytomas,13 and up to 62% of GBMs express EGFRvIII,14 a mutant receptor that is active independently of ligand. Co-expression of EGF and EGFR15,16 in GBMs leads to a potential autocrine loop.An analogous loop is created by PDGF and PDGFR co-expression in up to 94% of high-grade oligodendrogliomas.17–19 Regardless of ligand or receptor status, close to 100% of GBMs exhibit activation of Ras,20,21 and approximately 70% exhibit activated Akt,21,22 the latter typically through loss of the tumor suppressor gene phosphatase tensin homolog on chromosome ten (PTEN),23–25 which normally represses Akt activation. Src is detected in 67% of GBMs.26 Finally, control over cell division is normally maintained by tumor suppressors, such as an inhibitor of CDK4A (INK4A) and its alternative reading frame (ARF), as well as p53, which also contributes to DNA repair and apoptosis, and other enzymes. Disruptions of normal cell cycle control of one form or another have been observed in almost all GBMs.12,27

Figure 1. Magnetic Resonance Imaging Findings in Glioblastoma Multiforme. Contrast enhanced magnetic resonance image (MRI) of the brain demonstrating a large GBM with a smaller site in the contralateral hemisphere. This infiltrative nature of GBMs, essentially effecting the entire brain, underscores the failure of even radical surgery, such as hemispherectomy, to effect cure. (Click to enlarge figure)

Moreover, the modeling of gliomas in mice has demonstrated that abnormalities of ligands, receptors, signal transducers, and proliferation cause gliomas. For example, combined activation of Ras with Akt in glial progenitors is sufficient to induce GBMs in mice,22 and transgenic expression of activated forms of Ras28 or Src29 in glia leads to GBMs following spontaneous development of cooperative oncogenic abnormalities. Modeling has also demonstrated that PTEN loss is functionally equivalent to Akt activation,30 when combined with activated Ras. PDGF overexpression in glia causes high-grade oligodendrogliomas31,32 that also exhibit pathologic features of GBMs, including pseudopalisading necrosis and microvascular proliferation. The threshold to tumor formation is lowered by disruption of Ink4a-Arf or p53 expression.31,33,34

While more is learned about glioma biology, small molecule inhibitors are being developed that target the causal pathways.35 For example, several inhibitors of EGFRs are under investigation in clinical trials. These include the EGFR inhibitors erlotinib (OSI- 774/Tarceva), gefitinib (ZD-1839/Iressa), and lapatinib (GW572016). The PDGFR inhibitors imatinib (STI- 571/Gleevec) and PTK787, both of which have other targets, are also in use. Signal transduction cascade blockers are also being studied. One example is R11577, which targets the enzyme that activates Ras. Rapamycin (sirolimus), CCI-779 (temsirolimus), and Rad-001 (everolimus) target mTOR, one of the key enzymes activated by Akt.

Figure 2. Histology of Gliomas. (A) Pseudopalisading (arrow) necrosis (arrow head) and (B) microvascular proliferation (arrow) are the classic histologic findings in glioblastoma multiforme (GBM). Secondary Scherer structures (C) involve tumor cells (arrow heads) accumulating around blood vessels (BV, long arrow), and neurons (N, long arrow) in a low grade (WHO grade II) oligodendroglioma. Such perivascular and perineuronal satellitosis, along with intrafascicular growth and subpial accumulation (not shown), contribute to the diffusely infiltrative nature of gliomas throughout normal brain structures.. (Click to enlarge figure)

Unfortunately, despite initial enthusiasm, treatment of GBMs as well as systemic malignancies with these small molecule inhibitors as single agents has generally been disappointing. For example, published interim and final reports of trials involving gefitinib,36,37 erlotinib,38–40 imatinib,41,42 PTK787,43,44 and CCI-77945 monotherapy for recurrent high-grade gliomas have not shown response or survival rates that are markedly superior to those observed with traditional chemotherapies, such as temozolomide4,46–48 or carmustine (BCNU).49 However, there are individual patients treated with these agents who experience durable objective responses or sustained stable disease.Therefore, these agents are likely to have a role in GBM management.

Figure 3. Pathways Important in GBM Biology. An extracellular ligand such as EGF,TGFa, or PDGF induces dimerization of receptors such as EGFR or PDGFR. Receptor stimulation activates intrinsic tyrosine kinase (TK) activity and EGFR and PDGFR are therefore called receptor tyrosine kinases (RTKs). RTKs then activate the Akt, Src, and Ras signal transduction cascades.Tumor cell growth is driven by ligand or receptor overexpression, constitutively activating receptor mutations (e.g. EGFRvIII), or signal transduction activity. Pointed (green) and block (red) arrows indicate pathway activation and inhibition, respectively.The inhibitors shown and others are under investigation in the treatment of GBMs.(Click to enlarge figure)

  • Future

In addition to surgical resection and RT, the future of GBM therapy is likely to involve both additional measures to improve local control (such as convection or catheter delivery of antitumor agents into the operative cavity) and systemic treatment to address infiltrative disease distant from the main tumor bed. However, a major thrust of research will be tissue analyses looking for molecular features that predict sensitivity of GBMs to either traditional chemotherapies or small molecule inhibitors. Tailoring therapy with specific drugs to those patients is most likely to improve response rates and spare patients who are unlikely to benefit the expense and potential toxicity of these agents. Determination of a molecularly effective dose (MED) (inhibits a pathway), may also be more useful than the traditionally used maximally tolerated dose (MTD).

An example of a molecular prognostic factor is loss of heterozygosity for chromosomes 1p and 19q in anaplastic oligodendrogliomas, which predicts both sensitivity to chemotherapy and radiation, as well as longer overall survival.50 Consequently, some neurooncologists are currently using results of 1p/19q analysis to guide therapy,51 although this remains an area of controversy. Other genomic alterations are also predictive—PTEN loss is associated with poor survival for patients with anaplastic oligodendrogliomas52 and is likely to predict poor outcome from GBM.23,53,54 More recently it was reported that GBMs, in which O6-methylguanine- DNA methyltransferase (MGMT) expression was silenced by gene methylation, were more sensitive to temozolomide than tumors with unmethylated MGMT. The likely explanation is that MGMT may counteract temozolomide activity by removing alkyl groups on DNA.55 It is unclear whether MGMT methylation impacts sensitivity of other glioma subtypes to temozolomide, yet MGMT methylation status may be used in the near future to guide therapy.

Individualized medicine determined by molecular rather than simply histologic phenotype may also guide therapy with small molecule inhibitors. Somatic mutations in exons 18 21 of EGFR are associated with sensitivity of lung cancer to gefitinib56 58 or erlotinib.58 However, the authors and others have not found these mutations in gliomas.34,57,59,60 Efforts are under way to identify the molecular features that predict sensitivity of GBMs to EGFR and other receptor tyrosine kinase (RTK) inhibitors.

Response and survival rates may also be improved through combination therapy. For example, preliminary data suggest that concurrent therapy with imatinib (PDGFR/VEGFR inhibitor) and hydroxyurea (a more traditional chemotherapy) is more effective than imatinib monotherapy. A small series with 14 evaluable patients with recurrent GBMs demonstrated a disease control rate (complete response or partial response or stable disease) of 64% for patients treated with this combination.61 By contrast, imatinib monotherapy led to a disease control rate of 29%.42 Larger trials of this and other combinations, such as temozolomide with PTK787, are under way.

References

  1. Kleihues P, Cavanee W K, Pathology and Genetics of Tumours of the Nervous System, International Agency for Research on Cancer (IARC) Press, Lyon:WHO/IARC (2000).

  2. Bailey P, Cushing H, A classification of the tumors of the glioma group on a histo-genetic basis with a correlated study of prognosis, Philadelphia: J B Lippincott Co. (1926).

  3. Jelsma R K, Bucy P C, “The treatment of glioblastoma multiforme”, Trans.Am. Neurol. Assoc. (1967);92: pp. 90-93.

  4. Stupp R et al., “Radiotherapy plus Concomitant and Adjuvant Temozolomide for Glioblastoma”, N. Engl. J. Med. (2005);352(10): pp. 987-996.

  5. Dandy W E,”Removal of right cerebral hemisphere for certain tumors with hemiplegia”, JAMA (1928);90: pp. 823-825.

  6. Gardner W J et al., “Residual functioning following hemispherectomy for tumouir and for infantile hemiplegia”, Brain (1955);78(4): pp. 487-502.

  7. Peiffer J, Kleihues P,”Hans-Joachim Scherer (1906-1945), Pioneer in Glioma Research, Brain Pathol. (1999);9(2): pp. 241-245.

  8. Scherer H J, “Structural development in gliomas”, Am. J. Cancer (1938);34(3): pp. 333-351.

  9. Scherer H J, “The forms of growth in gliomas and their practical significance”, Brain (1940);63(part 1): pp. 1-35.

  10. Kleinberg L R et al., “Clinical course and pathologic findings after Gliadel and radiotherapy for newly diagnosed malignant gliama: implications for patient management”, Cancer Invest. (2004);22(1): pp. 1-9.

  11. Sampson J H et al.,”Sustained radiographic and clinical response in patient with bifrontal recurrent glioblastoma multiforme with intracerebral infusion of the recombinant targeted toxin TP-38: case study”, Neuro-oncol. (2005);7(1): pp. 90-96.

  12. Lassman A B, Holland E C, “Molecular Biology and Genetic Models of Gliomas and Medulloblastomas”, in Russell and Rubinstein s Pathology of Tumors of the Nervous System 7th Edition, McLendon et al. (eds) (2005), Arnold Health Sciences: London (in press).

  13. Schlegel J et al.,”Amplification and differential expression of members of the erbB-gene family in human glioblastoma”, J. Neurooncol. (1994);22(3): pp. 201-207.

  14. Wikstrand C J et al., “Monoclonal antibodies against EGFRvIII are tumor specific and react with breast and lung carcinomas and malignant gliomas”, Cancer Res. (1995);55(14): pp. 3,140-3,148.

  15. Mishima K et al., “Heparin-binding epidermal growth factor-like growth factor stimulates mitogenic signaling and is highly expressed in human malignant gliomas”, Acta. Neuropathol. (Berl) (1998);96: pp. 322-328.

  16. Ekstrand A J et al.,”Genes for epidermal growth factor receptor, transforming growth factor and their expression in human gliomas in vivo”, Cancer Res. (1991);51(8): pp. 2,164-2,172.

  17. Di Rocco F et al., “Platelet-derived growth factor and its receptor expression in human oligodendrogliomas”, Neurosurgery (1998);42(2): pp. 341-346.

  18. Robinson S et al., “Constitutive Expression of Growth-related Oncogene and Its Receptor in Oligodendrogliomas”, Neurosurgery (2001);48(4): pp. 864-873; discussion pp. 873-874.

  19. Shoshan Y et al., “Expression of oligodendrocyte progenitor cell antigens by gliomas: implications for the histogenesis of brain tumors”, Proc. Natl. Acad. Sci. USA (1999);96(18): pp. 10,361-10,366.

  20. Guha et al., “Proliferation of human malignant astrocytomas is dependent on Ras activation”, Oncogene (1997);15(23): pp. 2,755-2,765.

  21. Rajasekhar V K et al., “Oncogenic Ras and Akt signaling contribute to glioblastoma formation by differential recruitment of existing mRNAs to polysomes”, Mol. Cell. (2003);12(4): pp. 889-901.

  22. 22. Holland E C et al., Combined activation of Ras and Akt in neural progenitors induces glioblastoma formation in mice”, Nat. Genet. (2000);25(1): pp. 55-57.

  23. Sano T et al., “Differential Expression of MMAC/PTEN in Glioblastoma Multiforme: relationship to localization and prognosis”, Cancer Res. (1999);59(8): pp. 1,820-1,824.

  24. Choe G et al.,”Analysis of the phosphatidylinositol 3 -kinase signaling pathway in glioblastoma patients in vivo”, Cancer Res. (2003);63(11): pp. 2,742-2,746.

  25. Ermoian R P et al., “Dysregulation of PTEN and protein kinase B is associated with glioma histology and patient survival”, Clin. Cancer Res. (2002);8(5): pp. 1,100-1,106.

  26. Takenaka N et al.,”Immunohistochemical detection of the gene product of Rous sarcoma virus in human brain tumors”, Brain Res. (1985);337(2): pp. 201-207.

  27. Fulci G et al.,”p53 gene mutation and ink4a-p14 deletion appear to be two mutually exclusive events in human glioblastoma”, Oncogene (2000);19(33): pp. 3,816-3,822.

  28. Ding H et al.,”Astrocyte-specific expression of activated p21-ras results in malignant astrocytoma formation in a transgenic mouse model of human gliomas”, Cancer Res. (2001);61(9): pp. 3,826-3,836.

  29. Weissenberger J et al., “Development and malignant progression of astrocytomas in GFAF-v-src transgenic mice”, Oncogene (1997);14(17): pp. 2,005-2,013.

  30. Hu X et al.,”PTEN loss is equivalent to Akt and cooperates with Ras in the formation of GBMs”, Neoplasia (2005); in press.

  31. Dai C et al., “PDGF autocrine stimulation dedifferentiates cultured astrocytes and induces oligodendrogliomas and oligoastrocytomas from neural progenitors and astrocytes in vivo”, Genes Dev. (2001);15(15): pp. 1,913-1,925.

  32. Shih A H et al., “Dose-dependent effects of platelet-derived growth factor-B on glial tumorigenesis”, Cancer Res. (2004);64(14): pp. 4,783-4,789.

  33. Uhrbom L et al., “Ink4a-Arf loss cooperates with KRas activation in astrocytes and neural progenitors to generate glioblastomas of various morphologies depending on activated Akt”, Cancer Res. (2002);62(19): pp. 5,551-5,558.

  34. Holland laboratory, unpublished results.

  35. Mischel P S, Cloughesy T F,”Targeted molecular therapy of GBM”, Brain Pathol. (2003);13(1): pp. 52-61.

  36. Lieberman F S et al.,”Phase I-II study of ZD-1839 for recurrent malignant gliomas and meningiomas progressing after radiation therapy”, J. Clin. Oncol. (2003);22: p. 105 (abstract 421).

  37. Rich J N et al., “Phase II Trial of Gefitinib in Recurrent Glioblastoma”, J. Clin. Oncol. (2004);22(1): pp. 133-142.

  38. Vogelbaum M A et al., “Phase II trial of the EGFR tyrosine kinase inhibitor erlotinib for single agent therapy of recurrent Glioblastoma Multiforme: Interim results”, J. Clin. Oncol. (2004);22(14S): p. 1,558 (abstract).

  39. Raizer J J et al., “A phase II trial of erlotinib (OSI-774) in patients (pts) with recurrent malignant gliomas (MG) not on EIAEDs.”, J. Clin. Oncol. (2004);22(14S): p. 1,502 (abstract).

  40. Yung A et al., “Erlotinib HCL for glioblastoma multiforme in first relapse, a phase II trial”, J. Clin. Oncol. (2004);22(14S): p. 1,555 (abstract).

  41. van den Bent M et al., “Multicentre phase II study of imatinib mesylkate (Gleevec) in patients with recurrent glioblastoma”, Neuro-oncol. (2004);6(4): p. 383 (abstract).

  42. Wen P Y et al., “Phase I/II study of imatinib mesylate (STI571) for patients with recurrent malignant gliomas (NABTC 99- 08)”, Neuro-oncol. (2004);6(4): p. 385 (abstract).

  43. Yung W K A et al., “A phase I trial of PTK787/ZK 222584 (PTK/ZK), a novel oral VEGFR TK inhibitor in recurrent glioblastoma”, Proc.Am. Soc. Clin. Oncol. (2004), abstract no. 315.

  44. Conrad C et al.,”A phase I/II trial of single-agent PTK 787/ZK222584 (PTK/ZK), a novel, oral angiogenesis inhibitor, in patients with recurrent glioblastoma multiforme (GBM)”, J. Clin. Oncol. (2004);22(14S): p. 1,512 (abstract).

  45. Chang S et al.,”Phase II/pharmacokinetic study of CCI-779 in recurrent GBM”, Neuro-oncol. (2003);5(4): p. 349 (abstract).

  46. Yung W K et al., “A phase II study of temozolomide vs. procarbazine in patients with glioblastoma multiforme at first relapse”, Br. J. Cancer (2000);83(5): p. 588-593.

  47. Brada M, Hoang-Xuan K, Rampling R, “Multicenter phase II trial of temozolomide in patients with GBM at first relapse”, Ann. Oncol. (2001);12(2): pp. 259-266.

  48. Chang S M,Theodosopoulos P, Lamborn K, Malec M, Rabbitt J, Page M et al., “Temozolomide in the treatment of recurrent malignant glioma”, Cancer (2004);100(3): p. 605-611.

  49. Brandes A A,Tosoni A, Amista P, Nicolardi L et al., “How effective is BCNU in recurrent glioblastoma in the modern era? A phase II trial”, Neurology (2004);63(7): pp. 1,281-1,284.

  50. Cairncross J G, Ueki K, Zlatescu M C et al., “Specific genetic predictors of chemotherapeutic response and survival in patients with anaplastic oligodendrogliomas”, J. Natl. Cancer Inst. (1998);90(19): p. 1,473-1,479.

  51. Louis D N, Holland E C, Cairncross J G et al.,”Glioma classification: a molecular reappraisal”, Am. J. Pathol. (2001);159(3): pp. 779-786.

  52. Sasaki H et al.,”PTEN is a target of chromosome 10q loss in anaplastic oligodendrogliomas and PTEN alterations are associated with poor prognosis”, Am. J. Pathol. (2001);159(1): p. 359-367.

  53. Zhou Y H et al., “The expression of PAX6, PTEN, vascular endothelial growth factor, and epidermal growth factor receptor in gliomas: relationship to tumor grade and survival”, Clin. Cancer Res. (2003);9(9): pp. 3,369-3,375.

  54. Hill C, Hunter S B, Brat D J,”Genetic markers in glioblastoma: prognostic significance and future therapeutic implications”, Adv. Anat. Pathol. (2003);10(4): pp. 212-217.

  55. Hegi M E, Diserens A C, Gorlia T et al.,”MGMT gene silencing and benefit from temozolomide in glioblastoma”, N. Engl. J. Med. (2005);352(10): p. 997-1,003.

  56. Paez J G et al., “EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy”, Science (2004);304(5676): pp. 1,497-1,500.

  57. Lynch T J, Bell D W, Sordella R et al.,”Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib”, N. Engl. J. Med. (2004);350(21): p. 2,129-2,139.

  58. Pao W, Miller V, Zakowski M et al., “EGF receptor gene mutations are common in lung cancers from never smokers and are associated with sensitivity of tumors to gefitinib and erlotinib”, Proc. Natl.Acad. Sci.USA (2004);101(36): p. 13,306-13,311.

  59. Barber T D et al.,”Somatic mutations of EGFR in colorectal cancers and glioblastomas”,N.Engl. J.Med. (2004);351(27): p. 2,883.

  60. Rich J N, Rasheed B K,Yan H et al., “EGFR mutations and sensitivity to gefitinib”, N. Engl. J. Med. (16 September 2004);351(12): p. 1,260.

  61. Dresemann G, “Imatinib (STI571) plus hydroxyurea: Safety and efficacy in pre-treated, progressive glioblastoma multiforme (GBM) patients (pts)”, J. Clin. Oncol. (2004);22(14S): p. 1,550 (abstract).

  62. Metwally, MYM: Textbook of neuroimaging, A CD-ROM publication, (Metwally, MYM editor) WEB-CD agency for electronic publication, version 10.1a January 2009 [Click to have a look at the home page]

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