Antigen Retrieval

One of the earliest methods of antigen retrieval was proteolytic digestion of tissue sections employed prior to the application of the primary antibodies. A number of proteolytic enzymes served this purpose, including trypsin, proteinase K, pronase, pepsin, ficin, DNase, and others. Not only are the enzymes different but there is also variation in concentration, duration, and temperature of digestion.

Furthermore, not all antigens benefit from proteolytic digestion, and some show deleterious effects with loss of staining. In addition, inappropriate protocols result in tissue breakdown and loss of morphology with high levels of background and falsepositive staining.

The introduction of heat-induced antigen retrieval signified a major milestone in immunohistology, greatly enhancing our ability to demonstrate antigens in FFPT with greater consistency.

The initial technique was achieved with MWs, which has remained the most convenient method for antigen retrieval, but a variety of other methods of generating heat have since been spawned including water baths, hot plates, wet autoclaves, pressure cookers, and vegetable steamers. Shi et al (1991) described MW heating of FFPT in the presence of heavy metal solutions, such as lead thiocyanate, up to temperatures of 100o C to “unmask” a wide variety of antigens for immunostaining. It was subsequently shown that MW-irradiation of deparaffinised-rehydrated sections in 10 mmol citrate buffer at pH 6.0 produced, with few exceptions, increased intensity and extent of immunostaining of a wide variety of tissue antigens. The use of citrate buffer eleminated the need to employ heavy metal solutions which, ehen heated, generate toxic fumes. Several commercial antigen retrieval reagents are available but they mostly do not produce any better results than that obtained with citrate buffer.

MWs are a form of non-ionizing radiation with a typically standard frequency of 2.45 GHz, a wavelength of 12.2 cm and photon energy of 10-5 electron volts. When dipolar molecules such as water or the polar side chains of proteins are exposed to the rapidly alternating electromagnetic fields, they oscillate through 180o at the rate of 2.45 billion cycles per second. The molecular movement or kinetics so induced results in the generation of instantaneous heat that is proportional to the energy flux and continues until radiation ceases.

It was only recently recognized that molecules other than water and the polar side chains of proteins may oscillate in the electromagnetic field generated by MWs. Molecules with an uneven distribution of electrical charge such as inorganic material and copper oxides can also be rotated.

All methods of heat generation listed above suffer from problems with accurate temperature and time control. These two variables have been shown to be critical to the process of heat-induced antigen retrieval. They are inversely related so that antigen retrieval at lower temperatures requires longer durations to achieve the same results as that obtained with higher temperatures. The time taken to attain the desired temperature from variable starting temperatures, time required to cool to room temperature, and actual temperature attained are variables that cannot be controlled with most methods of heating. Furthermore, there is the problem of unevenness of heating within microwave cavities, making the entire process impossible to standardize with resulting inconsistencies in methodology. Computerized control of time and temperature that is available with some commercial MW instruments takes the guesswork out of heat-induced antigen retrieval.

Accurate time and temperature control not only produces superior antigen retrieval across the spectrum of diagnostic antigens but accurate heating to 120oC or “superheating” has proven to produce notably better antigen staining.

Our understanding of the effects of formaldehyde on proteins dates back to work done in the 1940s (Fraenkel-Conrat et al, 1947; Fraenkel-Conrat and Olcott, 1948a, 1948b). A recent comprehensive review of the fixative action of formaldehyde and antigen masking is available. The amino acid side chain of proteins includes many groups that may react with aldehydes that contribute to the stabilization of proteins. However, despite the vast

literature on the subject of protein modification by formaldehyde, there is no clear consensus as to which are the predominant molecular species resulting from this method of fixation.

There is no doubt that some of the cross-linked adducts are very stable and remain irreversibly changed even after extensive washing, while others revert under varying conditions to free formaldehyde and the amino acid. Without a complete understanding of the actions of formaldehyde on proteins, it is not surprising that we do not fully understand the mechanisms of antigen retrieval.

Heat appears to be a common denominator in antigen retrieval produced by a variety of methods including MWs. Heat is hypothesized to cause protein denaturation based on the observation that some antigens or endogenous enzymatic activities may be lost after heat treatment and heat induces reversal of various chemical modifications of the protein structure that result from formalin fixation. Other actions that produce antigen retrieval include the loosening or breakage of the cross-linkages caused by formalin fixation, hydrolysis of schiff bases, and multiple pathways including extraction of diffusible blocking proteins, precipitation of proteins and dehydration of the tissue sections to allow better penetration of antibody and increased accesibility to epitopes, all or some of which may be achieved by other methods of retrieval including enzyme digestion and change in pH. MW energy may itself mobilize the last traces of paraffin that may not have been extractable by standard techniques, there by improving antibody penetration.

It was proposed that the calcium complex formation that occurs with formalin fixation may mask antigens and that the release of calcium from this cage-like complex may require a considerable amount of energy such as high temperature heating and calcium chelation by citrate. However, it has been argued that while this calcium effect may be acting with some antigens it may not be sufficient to explain the loss of immunoreactivity for many other antigens and is unlikely to represent the general mechanism of antigen retrieval.

The role of kinetics in antigen retrieval is also not known. While the focus has been on heat as the responsible factor in MW retrieval, the rapidly oscillating electromagnetic field of MWs may itself have an effect on chemical reactions and proteins. While heat or thermal energy will increase molecular kinetics and hasten chemical reactions, the rapid rotation of molecules directly induced by the MWs will give rise to greatly increased collision of molecules, which will in turn accelerate chemical reactions. The heat generated may represent only an epiphenomenon secondary only to the kinetics. One study that examined MW stimulation of CEA/anti-CEA reaction in an enzyme-linked immunosorbent assay system found that despite continuous cooling by ice MW stimulation increased reaction rates by a factor of 1000, allowing the investigators to conclude that such rate increases were far too large to be explained solely by the modest increase in temperature.

Another study went further to elucidate the existence of a “microwave effect” (Choi et al,1997) The authors showed that the rate of droplet temperature increase obtained in a thermal cycler was similar to that achieved by MW irradiation. However, the immunostaining obtained from a 3-minute incubation at 37oC in the thermal cycler followed by 2-minute incubation without heating was much weaker than that seen with MWs. Similarly it was demonstrated that 7-s MW irradiation followed by 5-min room temperature incubation for each step of the avidin-biotin peroxidase complex procedure produced good immunolabelling.

The droplet temperature raised no more than 5oC following 7-s irradiation at 100% power in a 850-watt oven so that temperature was not a significant component of the accelerated reaction. Others have argued that there is no significant MW effect and the accelerated reactions are a function of heat. It has been concluded that MW irradiation did not produce cleavage or polymerisation of proteins and irradiation resulted an electrophoretic pattern that was similar to that obtained when lysozyme and hemoglobin was heated in formaldehyde to 60o C for 30 min. Interestingly, results to the contrary have been shown in a study of S-adenosylhomocysteine hydrolase and 5’-methylthioadenosine phosphorylase, two thermophilic and thermostable enzymes, where exposure to MWs caused a non-thermal, irreversible and time-dependent inactivation of both enzymes, In a model immunostaining system using short synthetic peptides to mimic the antibodybinding site of common diagnostic protein targets, Sompuran et al (2006), found that not all of the peptides studies exhibited the formalin-fixation and antigen retrieval phenomenon. One group of peptides was recognized by antibody even after prolonged exposure to formalin while another group exhibited the formalin-fixation and antigen-retrieval phenomenon only after another irrelevant protein was mixed with the peptide before fixation. Amino acid sequence analysis indicated that fixation and antigen retrieval were associated with a tyrosine in or near the antibody-binding site bound covalently to a nearby arginine implicating the Mannich reaction as an important factor in the process.

The Mannich reaction is a complicated, multistep interaction, which firstly involves a reaction between formaldehyde and an amine to produce an iminium ion. The iminium ion may then react with another carbonyl-containing molecule to form an intermediate product and for this to occur, the carbonyl-containing molecule must be in an enol configuration. In the final step of the reaction, the iminium ion and the enol react together to form a stable product. The findings of Sompuran et al (2004) concurred with those of Fraenkel-Conrat et al (1947, 1948) who had indicated that of all the protein cross-linking reactions that occur as a result of formalin fixation, the Mannich reaction is different, in that the cross-linkages can be hydrolysed with heat or alkaline treatment. Antibodies appear to recognize linear protein epitopes in FFPT and antigen retrieval may simply remove cross-linked proteins that are sterically interfering with antibody binding. The recent demonstration that antigen retrieval produces immunohistological staining results in FFPT that are comparable or better than that in acetone-fixed fresh frozen section and that heat-induced antigen retrieval enhances immunostaining in unfixed fresh frozen sections and dot-blot protein extracts is further support of the concept that intrinsic natural steric barriers exist and interfere with antibody binding. The demonstration that MWs can also be employed to enhance the demonstration of HER2/neu gene in chromogenic in-situ hybridization (CISH) is particularly interesting and it suggests that similar mechanisms may be operative in the ‘masking’ of DNA.

However, it would seem that these observations provide some insights into the action of antigen retrieval with some peptides but answers to the majority still remain unknown.

The demonstration that exposure to ultrasound can significantly increase antibody-antigen reaction in immunostaining lends further support to the relevance of molecular movement as an important factor in the acceleration of the chemical reaction as the amount of heat generated by this physical modality is negligible. A number of other hypothetical physical mechanisms may also play a role in the actions of MWs.

Although the proton energy generated in MW fields is too small to alter covalent bonding, they may readily affect the integrity of non-covalent secondary bonding, including hydrophobic interactions, hydrogen bonds and van der Waal’s interactions that make up the precise steric interactions at the cell membrane.

The combination of heat retrieval with enzymatic digestion has allowed enhanced demonstration and localization of a number of antigens including the immunoglobulins. Proteolytic digestion can be performed with a number of enzymes, and at varying concentrations and for varying durations. It can precede or follow heat induced antigen retrieval with different results. For optimal outcomes, it is necessary to explore all possible combinations and permutations of these variables with the realization that excesses can result in loss of antigen and cell morphology.

The chemical composition of the retrieval solution may affect the efficacy of the process and a wide variety of solutions have been advocated including citrate buffer, Tris buffer, glycine-hydrochloric acid, EDTA, urea, heavy metal solutions, and other proprietary reagents.

The molarity of the solution may also significantly influence immunostaining. The pH of the retrieval solution has been shown to be one of the most important factors in antigen retrieval. Three patterns of staining reflect the influence of pH.

Some antigens (CD20, AE1, EMA, NSE and PCNA) showed no variation at pH values ranging from 1.0 to 10.0, other antigens (MIB1, ER) displayed a dramatic decrease in staining intensity at middle pH values (pH 3.0-6.0) with strong staining above and below the range, and a third pattern was demonstrated by other antigens (CD43, HMB45) which were weakly stained at low pH (1.0-2.0) and displayed a sharp rise in intensity with increasing pH.

Use of MWs to accelerate antibody-antigen reactions in the staining of labile lymphocyte membrane antigens in cryostat sections and the exposure of cryostat sections briefly to MWs before the commencement of immunolabelling produced better quality cytomorphology and staining. A similar procedure has been adopted for freshly frozen brain sections with notable enhancement of immunostaining, without affecting the integrity of cytomorphology. MWs have been successfully used to accelerate immunolabelling in paraffin-embedded sections and the same technique has been applied for immunofluorescence labeling.

MWs have been applied between sequential rounds of a three-layer immunoenzyme staining (mouse Mab, goat anti-mouse IgG and mouse PAP or mouse APAAP) and color development technique for multiple antigen detection. The MWs denatured bound antibody molecules resulting in the blocking of cross reactivity between the sequential staining steps, allowing the use of primary and other antibodies raised in the same species.

Besides serving a role in antigen retrieval, MWs also inactivated peroxidase and alkaline phosphatase enzymes present in PAP and APAAP complexes, which would otherwise have led to inappropriate color development.

Source :

Biochemistry and Hystocytochemistry Research Developments : Editor by Stefan Fuchs and Max Auer.

Higher Vitamin D Levels Linked to Lower Diabetes Risk

(San Diego, California) — Higher levels of vitamin D in the blood appear to be associated with a reduced risk for incident diabetes among people at high risk for the disease, according to a new report.

Anastassios G. Pittas, MD, from the division of endocrinology, diabetes, and metabolism at the Tufts New England Medical Center in Boston, Massachusetts, and colleagues presented the findings here at the American Diabetes Association 71st Scientific Sessions.

According to Dr. Pittas, vitamin D might play a role in diabetes by improving insulin secretion and insulin sensitivity. "Most of the evidence focuses on a favorable effect in pancreatic beta cells," he told.

To determine the relation between vitamin D status and risk for incident diabetes, the researchers analyzed data from the Diabetes Prevention Program (DPP), a 3-group trial comparing intensive lifestyle modification or metformin with placebo for the prevention of diabetes in patients with prediabetes.

The mean follow-up of the 2039-person cohort was 3.2 years. Plasma vitamin D levels were measured at yearly intervals, and subjects were assessed for incident diabetes. For this analysis, only participants in the intensive lifestyle and placebo groups of the DPP were considered.

Participants with vitamin D levels in the highest tertile (median concentration, 30.1 ng/mL) had a hazard ratio of 0.74 (95% confidence interval [CI], 0.59 to 0.93) for developing diabetes, compared with those with vitamin D levels in the lowest tertile (median concentration, 12.8 ng/mL).

The findings also suggest a dose-dependent effect for vitamin D levels; the hazard ratio for incident diabetes was lowest (0.46; 95% CI, 0.23 to 0.90) in the people with the highest vitamin D levels (50 ng/mL or higher), compared with those with the lowest levels (below 12 ng/mL).

In a subgroup analysis by tertiles of vitamin D, the association was similar in the placebo group (0.72; 95% CI, 0.53 to 0.96) and the lifestyle group (0.80; 95% CI, 0.54 to 1.14).

According to Dr. Pittas, "this study offers several methodological advantages over previous studies." Vitamin D status was assessed multiple times during follow-up, not just once at baseline, which might not reflect long-term vitamin D status.

"Our study also includes a large clinically relevant population at high risk for diabetes, with a substantial proportion of nonwhite participants, which improves the external validity of the results," he said. However, he added, "this is an observational study and therefore confounding cannot be excluded. It would be premature to recommend vitamin D specifically for prevention of diabetes."

"This prospective study confirms that there is an association between levels of vitamin D and risk of diabetes, even when correcting for body weight, with no absolute threshold of serum 25-hydroxy vitamin D," said independent commentator Clifford Rosen, MD, from the Jackson Laboratory in Bar Harbor, Maine. Dr. Rosen is a vitamin D researcher and member of the Institute of Medicine Committee that reviewed the evidence on calcium and vitamin D.

"The implications of this study relate to the importance of performing a randomized placebo-controlled trial of vitamin D for the prevention of type 2 diabetes in those at high risk," he told Medscape Medical News. "In the interim, clinicians should at least focus on maintaining vitamin D levels in high-risk individuals at or around 20 ng/mL," he added.

Source :

American Diabetes Association (ADA) 71st Scientific Sessions: Abstract 0117-OR. Presented June 25, 2011.

2010 AHA Guidelines: The ABCs of CPR Rearranged to "CAB"

Chest compressions should be the first step in addressing cardiac arrest. Therefore, the American Heart Association (AHA) now recommends that the A-B-Cs (Airway-Breathing-Compressions) of cardiopulmonary resuscitation (CPR) be changed to C-A-B (Compressions-Airway-Breathing).

The changes were documented in the 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care, published in the November 2 supplemental issue of Circulation: Journal of the American Heart Association, and represent an update to previous guidelines issued in 2005.

"The 2010 AHA Guidelines for CPR and ECC [Emergency Cardiovascular Care] are based on the most current and comprehensive review of resuscitation literature ever published," note the authors in the executive summary. The new research includes information from "356 resuscitation experts from 29 countries who reviewed, analyzed, evaluated, debated, and discussed research and hypotheses through in-person meetings, teleconferences, and online sessions ('webinars') during the 36-month period before the 2010 Consensus Conference."

According to the AHA, chest compressions should be started immediately on anyone who is unresponsive and is not breathing normally. Oxygen will be present in the lungs and bloodstream within the first few minutes, so initiating chest compressions first will facilitate distribution of that oxygen into the brain and heart sooner. Previously, starting with "A" (airway) rather than "C" (compressions) caused significant delays of approximately 30 seconds.

"For more than 40 years, CPR training has emphasized the ABCs of CPR, which instructed people to open a victim's airway by tilting their head back, pinching the nose and breathing into the victim's mouth, and only then giving chest compressions," noted Michael R. Sayre, MD, coauthor and chairman of the AHA's Emergency Cardiovascular Care Committee, in an AHA written release. "This approach was causing significant delays in starting chest compressions, which are essential for keeping oxygen-rich blood circulating through the body," he added.

The new guidelines also recommend that during CPR, rescuers increase the speed of chest compressions to a rate of at least 100 times a minute. In addition, compressions should be made more deeply into the chest, to a depth of at least 2 inches in adults and children and 1.5 inches in infants.

Persons performing CPR should also avoid leaning on the chest so that it can return to its starting position, and compression should be continued as long as possible without the use of excessive ventilation.

9-1-1 centers are now directed to deliver instructions assertively so that chest compressions can be started when cardiac arrest is suspected.

The new guidelines also recommend more strongly that dispatchers instruct untrained lay rescuers to provide Hands-Only CPR (chest compression only) for adults who are unresponsive, with no breathing or no normal breathing.

Other Key Recommendations

Other key recommendations for healthcare professionals performing CPR include the following:

• Effective teamwork techniques should be learned and practiced regularly.
• Quantitative waveform capnography, used to measure carbon dioxide output, should be used to confirm intubation and monitor CPR quality.
• Therapeutic hypothermia should be part of an overall interdisciplinary system of care after resuscitation from cardiac arrest.
• Atropine is no longer recommended for routine use in managing and treating pulseless electrical activity or asystole.

Pediatric advanced life support guidelines emphasize organizing care around 2-minute periods of continuous CPR. The new guidelines also discuss resuscitation of infants and children with various congenital heart diseases and pulmonary hypertension.

Source :
- 4th EIDCP National Symposium
- Medscape news

Spinal Cord Compression: An Obstructive Oncologic Emergency

Spinal cord compression (SCC) occurs in 5% to 30% of the oncology population and affects patient function, comfort, and general quality of life. Patients with lung cancer, breast cancer, prostate cancer, cancer with an unknown primary site, or renal cancer are at high risk for the development of SCC by metastatic tumor. Spinal cord compression can also occur in sarcoma, myeloma, leukemia, thyroid cancer, lymphoma, melanoma, and gastrointestinal malignancies. Favorable response to treatment directly correlates with early recognition of the signs and symptoms of SCC. Treatment includes administration of corticosteroids, radiation therapy, surgery, and chemotherapy. Early symptoms (particularly pain), obtain a thorough history, perform a complete physical examination, and teach the patient and his or her family about signs and symptoms of SCC that need to be reported as soon as they occur.

Compression of the spinal cord and nerve roots is the second most frequent neurologic complication of cancer (brain metastases are the most frequent neurologic complication). Each year in the United States, approximately 20,000 persons with cancer develop SCC; this group represents 5% to 10% of the general cancer population. Because of improved treatments and prolonged survival in various cancers, the incidence of SCC may be increasing.

Cancers most likely to spread to the spine are lung, breast, and prostate cancer; kidney cancer and lymphoma tend to spread to the spinal cord as well. Patients with melanoma, renal cell carcinoma, multiple myeloma, or certain sarcomas are also at risk for SCC. Sarcomas and neuroblastoma cause more than 80% of cases of metastatic SCC in children.

Malignant SCC is defined as compressive indentation, displacement, or encasement of the spinal cord's thecal sac by metastatic or locally advanced cancer. Spinal cord compression produces edema, inflammation, and mechanical compression, which causes direct neural injury to the cord, as well as vascular damage and impairment of oxygenation.

Malignancies of the breast, prostate, lung, and kidney have a propensity to metastasize to bony structures, but any invasive cancer capable of hematogenous spread can produce SCC. Cancers that spread to the spine move to the bone marrow of the vertebral column by way of blood vessels. Spinal cord compression can also occur through direct tumor extension, which is frequently seen in non-Hodgkin's lymphoma. In such cases, there is direct extension of a paraspinal mass through the epidural foramen, and this extension produces the compression. Finally, metastasis results when tumor cells in the cerebrospinal fluid deposit tumor cells in the epidural space.This scenario most often occurs in leukemia.

Spinal cord compression results when a metastatic tumor grows into the epidural space and impinges on the dura (the tough membrane that covers the spinal cord), thereby producing pressure on neurologic tissue. As the mass grows, it destroys the bony structure of the vertebrae and weakens them to the point of collapse. The spinal column may then become weak and destabilized.

(Enlarge Image)

Figure 1. Spinal cord compression.

Spinal cord compression constitutes a true emergency because the initial injury to the spinal cord will lead to permanent loss of neurologic function if the pressure of the tumor on the cord is not relieved quickly. Prognosis depends greatly on the length of time of the cord impingement, the location of the mass in the spinal column, and the tissue type of the mass.

Prognosis of SCC also depends on the functional status and length of survival after treatment. Spinal cord compression is fatal only if it occurs in the cervical region of the spinal cord (C4 and above) and if it results in respiratory paralysis that is uncompensated by mechanical ventilation. Tumor tissue type must be considered when the treatment plan is being determined. Some tumors, such as Hodgkin's lymphoma and small cell lung cancer, are very sensitive to chemotherapeutic agents, whereas lymphoma and myeloma are more radiosensitive, and breast and prostate cancers may respond to hormonal agents.

Clinical Presentation

The presenting signs and symptoms depend on the location and level of the metastatic tumor. The thoracic spine is the site most often involved (70% of cases), followed by the lumbosacral spine (20%) and the cervical spine (10%). Other variables include the degree of cord impingement and the duration of tumor involvement. The cardinal initial symptom of SCC is back pain, reported by 90% to 95% of patients. The pain can be localized, radicular, or both and usually precedes other symptoms by 2-4 months.

Local pain occurs over the area of the tumor and is caused by vertebral destruction or stretching of the bone by an enlarging tumor mass. Radicular pain is caused by compression of nerve roots and is found in the dermatomes affected by the nerve roots. Radicular pain may travel down the extremity associated with the area of compression and may be aggravated by the Valsalva maneuver. Often the pain is described as a soreness or vague discomfort, which progresses to more severe symptoms such as weakness in one or both limbs, loss of sensation, and then autonomic dysfunction and paralysis. This pain often begins as a nonspecific soreness, which could be attributed to any number of other conditions, such as arthritis, muscle strain, or old injury to the vertebrae.

Physical Examination

Physical examination findings correspond to the location of the tumor, degree of cord impingement, and duration of involvement. Tenderness is an early sign of SCC and thus may indicate beginning neurologic injury, the prompt treatment of which will result in complete recovery of function. Often the patient will complain of soreness or tenderness over the vertebral body with tumor involvement.

Having the patient walk heel to toe will establish whether there are any gait problems. Checking the patient's ability to move specific muscles in response to resistance by the examiner can rule out muscle weakness and paresis. Pain that progresses down the patient's asymptomatic (or less symptomatic) leg when the leg is raised straight may suggest SCC.

If cord compression is left untreated, weakness often develops, preceded or accompanied by sensory loss. In a patient with a history of cancer, bilateral leg weakness that is noticeable with stair climbing, paresthesias in the legs, and bowel or bladder dysfunction are all red flags for SCC. Sensory function -- specifically, the ability to distinguish temperatures and feel vibration -- is evaluated using hot and cold tuning forks.Pain recognition is assessed using dull and sharp tools.

A rectal examination should be performed to assess sphincter tone. Weak rectal sphincter tone is a late sign of SCC, signaling worsening injury to the nerve roots affected by the increasing compression of the spinal cord. If the patient has urinary complaints, the bladder is catheterized for postvoiding residual urine. Urinary volumes > 200 mL may suggest a neurogenic bladder. Once such autonomic symptoms appear, SCC usually progresses rapidly, and it may result in irreversible paralysis in hours to days if untreated.

Diagnostic Tests

Laboratory tests include a complete blood cell count with differential, an erythrocyte sedimentation rate determination, urinalysis, and a chemistry profile including calcium and liver function studies. The complete blood cell count and erythrocyte sedimentation rate may be useful in differentiating SCC from infection, whereas the chemistry profile may indicate the primary cancer or the patient's general condition.

Imaging studies include plain radiography and magnetic resonance imaging (MRI) with contrast of the spine. Plain films of the spine frequently demonstrate associated vertebral blastic or lytic lesions. However, gadolinium-enhanced MRI provides the best definition of spinal lesions. Magnetic resonance imaging not only shows cord compression caused by extra dural masses but also shows paravertebral masses, intramedullary disease, and bone metastasis. Magnetic resonance imaging of the entire spine should be ordered, because approximately 10% to 30% of patients with clinical symptoms of SCC have multiple lesions. Lumbar puncture is contraindicated because removal of cerebrospinal fluid may worsen the SCC.

Treatment

Corticosteroid Therapy

Treatment is palliative in most cases, but goals are relief of pain and maintenance or restoration of neurologic function. Other goals include spinal column stabilization and local tumor control. Choice of therapy depends on the tumor type and location, the speed of onset, and the degree of function before onset of symptoms.

The patient is admitted to the hospital, usually by the medical oncologist, who has typically consulted with the radiation oncologist and the neurosurgeon. A course of treatment with the corticosteroid dexamethasone is started to reduce the edema and cord compression caused by the tumor mass and to thereby relieve the pain. Dexamethasone has lympholytic activity against lymphomas involving the epidural space. Some controversy exists regarding the optimal dose of dexamethasone; adult doses ordered range from 4 to 100 mg, given every 6 hours. However, many physicians administer a 4- to 100-mg intravenous (IV) bolus followed by 16-96 mg/d in divided doses over several days. The dose of dexamethasone, like any corticosteroid, must be tapered gradually. A common schedule for tapering calls for decreasing the dose by one third every 3-4 days. If tapering is not tolerated and neurologic deterioration occurs, a trial of an escalated dose may be attempted, followed by tapering.

Patients who take dexamethasone must be monitored carefully for side effects of corticosteroids, such as immunosuppression, gastrointestinal irritation, fluid retention, euphoria, depression, and hyperglycemia. Blood glucose levels are a particular concern in diabetic patients and must be monitored closely. The diabetic patient's diet and insulin dose may need to be changed. If the patient has been treated with an oral hypoglycemic drug, insulin may need to be temporarily substituted to manage the higher glucose levels. Bolus injections of dexamethasone must be given slowly to avoid rectal or vaginal burning.

Radiation Therapy

Radiation therapy is the standard of care for SCC caused by tumor involvement. Radiation therapy resolves pain by reducing the tumor mass and relieving the SCC. There are different regimens of radiation therapy for SCC. The commonly prescribed regimen is 2-3 Gy per fraction to a total dose not exceeding 30-40 Gy, directed to the spinal cord over 2-4 weeks.

Indicators of a response to radiation therapy include pain relief and a return to baseline function or improved function. Patients may experience some relief of symptoms within a few days after starting radiation therapy, and pain sometimes is relieved within hours. However, return to baseline function after radiation therapy can be delayed for months.

Surgery

In a small number of patients, particularly those with spinal instability or a rapidly progressing loss of neurologic function, surgery may be indicated. Often these oncology patients are severely compromised by their underlying cancer and numerous treatment regimens. Wound healing and recovery from surgery can be difficult in this population, so patients must be selected carefully for any surgical procedure. They may have failed to respond to radiation therapy, the site of the primary tumor may be unknown, they may have local tumor that recurs at a previously irradiated site, or they may have pathologic fracture with spinal instability or compression of the cord by bone.

Chemotherapy

Chemotherapy is indicated in adults with chemosensitive tumors such as lymphoma or Hodgkin's disease. Chemotherapy can also be used as an adjuvant therapy with irradiation or surgery in patients with breast cancer, prostate cancer, or multiple myeloma. The choice of chemotherapeutic agents depends on the primary tumor type and the chemotherapy history of the patient. Hormone therapy is another option for patients with prostate or breast cancer.

Palliative Care

Patients who have failed to respond to chemotherapy and conventional radiation therapy (external beam radiotherapy) and are not candidates for standard surgical procedures (laminectomy) have few options. Palliative care consisting of analgesic administration, nerve blocks, corticosteroid therapy, and side effect management, best performed by hospice care workers, is indicated in these patients. Optimal nursing management after treatment for SCC is paramount for success.

Palliative care goals include prevention of further injury, good pain control, restoration and maintenance of bowel and bladder function, and provision of emotional support for both the patient and caregivers. The response to treatment depends in general on the level of function at the time of diagnosis. If a patient presents with bladder and bowel symptoms and paresthesias, it is less likely that he or she will recover bladder and bowel function or the ability to walk.

So, Hospice referral is appropriate for the patient with SCC whose cancer has progressed to end-stage disease. The members of the hospice team are experts in pain control and provision of emotional support to the patient and his or her family in the face of a steady progression of losses, ultimately leading to death.

Source :
Maryjo Osowski, RN, MSN, AOCN

Medscape Medical Students News

Cell Phones Possibly Carcinogenic, WHO Says

The World Health Organization (WHO) announced today that radiation from cell phones can possibly cause cancer. According to the WHO's International Agency for Research on Cancer (IARC), radiofrequency electromagnetic fields have been classified as possibly carcinogenic to humans (group 2B) on the basis of an increased risk for glioma that some studies have associated with the use of wireless phones.

This announcement was based on an extensive review of studies on cell phone safety by a working group of 31 scientists from 14 countries, who have been meeting regularly to evaluate the potential carcinogenic hazards from exposure to radiofrequency electromagnetic fields. They reviewed exposure data, studies of cancer in humans and experimental animal models, and other relevant data.

More specifically, the IARC Monograph Working Group discussed and evaluated literature that included several exposure categories involving radiofrequency electromagnetic fields:

• Occupational exposures to radar and to microwaves;
• Environmental exposures associated with transmission of signals for radio, television, and wireless telecommunication; and
• Personal exposures associated with the use of wireless telephones.

"Given the potential consequences for public health of this classification and findings," said IARC Director Christopher Wild, PhD, in a news release, "it is important that additional research be conducted into the long-term, heavy use of mobile phones. Pending the availability of such information, it is important to take pragmatic measures to reduce exposure such as hands-free devices or texting."

Inconsistent Data and Opinions

Cellular telephones have become an integral part of everyday life, and the number of users is estimated at 5 billion globally. However, as previously reported by Medscape Medical News, there has been growing concern over possible health risks associated with the use of cell phones. In particular, some data have suggested that their use, especially over the long term, represent a "significant" risk for brain tumors.

But study results have been inconsistent, although some European countries have taken precautionary measures aimed specifically at children.

Some of the strongest evidence supporting a link between brain tumors and cell phone use comes from a series of Swedish studies, led by Lennart Hardell, MD, PhD, from the Department of Oncology, Orebro Medical Center. These studies showed that risk increased with the number of cumulative hours of use, higher radiated power, and length of cell phone use. They also reported that younger users had a higher risk. (Int J Oncol. 2006;28:509-518;Int Arch Occup Environ Health. 2006;79:630-639; Arch Environ Health. 2004;59:132-137; Pathophysiology.2009;16:113-122).

The issue of cell phone safety was to have been settled once and for all by the huge 13-nation industry-funded Interphone study. But to date, the industry-funded Interphone studies found no increased risk for brain tumors from cell phone use, with only 4 exceptions. The findings contradicted the Swedish studies, which were independent of industry funding.

Consistent with the literature, there is no consensus among physicians and scientists about the severity of risk, or if one even exists. One issue in attempting to evaluate the potential connection between brain tumors and cell phone use is the relatively short period of time that these devices have been heavily used in a large population and the long latency period for many tumors.

The National Cancer Institute, for example, has stated that although a consistent link has not been established between cell phone use and cancer, "scientists feel that additional research is needed before firm conclusions can be drawn." In a similar fashion, the American Cancer Society points out that even though the weight of the evidence has shown no association between cell phone use and brain cancer, information on the potential health effects of very long-term use, or use in children, is simply not available.

Evidence Strong Enough

The WHO established the International Electromagnetic Fields (EMF) Project in 1996, in response to public and governmental concern, with the goal of evaluating the possibility of adverse health effects from electromagnetic fields. In a press release issued last year, the WHO stated that it would conduct a formal health risk assessment of radiofrequency fields exposure by 2012, but in the interim, the IARC would review the carcinogenic potential of mobile phones this year.

Jonathan Samet, MD, chairman of the working group, notes that "the evidence, while still accumulating, is strong enough to support a conclusion and the 2B classification.

"The conclusion means that there could be some risk, and therefore we need to keep a close watch for a link between cell phones and cancer risk," he said in a news release.

Source :

Medscape Medical News 2011

Aplikasi Terapeutik Sel Stem Embrionik pada Berbagai Penyakit Degeneratif

Sel stem embrionik mempunyai kemampuan untuk berproliferasi secara terus menerus dalam kultur optimal dan dalam keadaan tertentu mampu berdiferensiasi menjadi berbagai tipe sel jaringan, seperti otot polos, kardiomiosit, neuron, sel beta pankreas, khondrosit, dsb. Karena sifat ini maka sel stem embrionik ini dapat dipakai untuk mengobati berbagai penyakit degeneratif yang sekarang termasuk dalam bidang kedokteran regeneratif.
Penggunaan sel stem embrionik masih dibayangi oleh berbagai masalah etik dan masih dilarang di beberapa negara seperti di AS, Jerman, Perancis dsb. sehingga menghambat kemajuan penelitian.
Tetapi di berbagai negara lain seperti, UK, Singapura, Korea, India, China dsb. penggunaan sel stem embrionik manusia untuk kedokteran regeneratif diperbolehkan, sehingga penelitian di negara-negara tersebut telah mengalami banyak kemajuan. Untuk mencegah kontroversi ini, maka alternatif lain adalah menggunakan human Umbilical Cord Blood (hUBC) yang mengandung banyak adult stem cells dan mempunyai kemampuan proliferasi lebih baik daripada sel stem sumsum tulang (hBM=human Bone Marrow).

1. Sumber Sel Stem

Sel stem embrionik adalah sel yang diambil dari inner cell mass - suatu kumpulan sel yang terletak di satu sisi blastocyst yang berumur 5 hari dan terdiri dari 100 sel. Sel stem ini mempunyai sifat dapat berkembang biak secara terus menerus dalam media kultur optimal dan pada keadaan tertentu dapat diarahkan untuk berdiferensiasi menjadi berbagai sel yang terdiferensiasi seperti sel jantung, sel kulit, neuron, hepatosit dan sebagainya.
Sel stem dewasa (Adult stem cells) adalah sel stem yang terdapat di semua organ tubuh, terutama di dalam sumsum tulang dan berfungsi melakukan regenerasi untuk mengatasi berbagai kerusakan yang selalu terjadi dalam kehidupan. Tubuh kita mengalami pengrusakan oleh berbagai faktor dan semua kerusakan yang mengakibatkan nekrosis (kematian jaringan dan sel) akan dibersihkan oleh sel makrofag yang beredar dalam darah. Sel stem dewasa sebaliknya berfungsi untuk memperbaiki jaringan yang mengalami kerusakan. Sel stem dewasa dapat diambil dari fetus (fetal stem cells), sumsum tulang (bone marrow stem cells), darah perifer atau tali pusat (umbilical cord blood stem cells, UCB).
Sel stem embrionik maupun sel stem dewasa sangat besar potensinya untuk mengobati berbagai penyakit degeneratif, seperti infark jantung, stroke, penyakit Parkinson, diabetes, berbagai macam kanker terutama kanker darah, osteoarthritis dan sebagainya.

Sel stem embrionik sangat plastis dan mudah dikembang-kan menjadi berbagai macam jaringan sel, seperti neuron, kardiomiosit, osteoblast, fibroblast dan sebagainya., sehingga dapat dipakai untuk trans-plantasi jaringan yang rusak. Lagipula immunogenicity nya rendah, selama belum meng-alami diferensiasi.
Sel stem dewasa juga bisa dipakai untuk mengobati berbagai penyakit degeneratif, tetapi plastisitasnya sudah berkurang. Mengingat masalah etik, maka banyak negara lebih mengutamakan penelitian pemanfaatan sel stem dewasa pada berbagai penyakit degeneratif, sehingga tidak dihadapkan pada masalah dan kontroversi etika.
Karena sel stem tali pusat (Umbilical cord blood= UCB) mudah didapat dan ternyata banyak mengandung sel stem, maka sekarang banyak diteliti mengenai manfaatnya untuk mengatasi berbagai penyakit degeneratif. Sel stem UCB mudah diperbanyak, immunogenicitynya rendah dan plastisitasnya cukup baik.

SCNT, atau somatic cell nuclear transfer merupakan teknik untuk menghasilkan klon sel stem embrionik yang seratus persen sama seperti donor nukleusnya. Bilamana oosit manusia dikeluarkan nukleusnya (enukleasi) kemudian pada oosit tersebut dimasukkan nukleus somatik dari seorang donor dan kemudian pada oosit tersebut diberi aliran listrik, maka oosit mengalami “reprogramming” DNA, sehingga berkembang biak menjadi embrio. Keberhasilan SCNT masih sangat rendah dan embrio yang dihasilkan banyak mengalami kelainan kongenital. Tetapi bilamana berhasil maka embrio ini akan merupakan klon dari donor nukleus, sehingga DNA donor nukleus dan embrio seratus persen sama, sehingga jika dilakukan transplantasi tidak akan terjadi penolakan terhadap transplan Teknik SCNT teoretis dapat dipergunakan untuk transplantasi berbagai organ dan jaringan tubuh manusia.

2. Sel stem pada berbagai penyakit degenerasi SSP

Stroke iskemik pada tikus maupun domba dapat disembuhkan dengan pemberian hUCB. Percobaan pada binatang dengan memberikan CD34+ hUCB dapat menimbulkan perbaikan fungsional dengan terbentuknya angiogenesis dan neurogenesis. Berdasarkan hasil percobaan binatang yang sangat prospektif maka beberapa pusat penelitian sedang merencanakan untuk melakukan uji klinis pada manusia.

Penyakit Parkinson yang banyak menghinggapi orang tua juga mempunyai prospek baik untuk dapat disembuhkan oleh sel stem. Patogenesis penyakit Parkinson adalah karena degenerasi sel neuron dopaminergik di substansia nigra. Berbagai percobaan telah berhasil untuk mengubah sel stem menjadi neuron dopaminergik dan jika sel ini disuntikkan ke otak dapat menimbulkan perbaikan. Tetapi sayang sampai sekarang belum ada laporan percobaan klinik yang baik sehingga masih belum dapat diambil kesimpulan yang objektif.

Spinal cord injury, disertai demielinasi menyebabkan hilangnya fungsi neuron. Remielinasi dengan sel stem dapat mengembalikan fungsi yang hilang. Percobaan pendahuluan dengan ES tikus dapat menghasilkan oligodendrosit yang kemudian dapat menyebabkan remielinisasi akson yang rusak.

Sel stem dan diabetes tipe I
Pada diabetes tipe I sel pankreas beta yang mensekresi insulin mengalami kerusakan oleh faktor genetik, lingkungan dan imunologik. Akibatnya terjadi defisiensi insulin dan menyebabkan hiperglikemi. Transplantasi seluruh organ pankreas kadaver dapat menyembuhkan penderita. Tetapi jumlah kadaver sangat sedikit dan obat imunosupresi yang dibutuhkan untuk mencegah reaksi imunologik menimbulkan banyak efek samping. Transplantasi sel stem merupakan alternatif baik dan telah menunjukkan hasil positif pada mencit. Tetapi masih banyak kendala yang harus diatasi supaya penggunaan sel stem untuk menyembuhkan pasien diabetes tipe I dapat terlaksana.

Sel stem pada infark jantung
Pada infark miokard akut, sel stem sumsum tulang (bone marrow) yang beredar dalam darah perifer dan sel stem yang sudah berada di jantung akan menuju ke daerah infark, tetapi jumlahnya tidak cukup untuk dapat mengatasi dan menyembuhkan daerah infark tersebut. Sel stem akan membentuk sel kardiomiosit dan juga mengadakan neovaskularisasi. Karena jumlah sel stem endogen kurang banyak maka logis untuk mecarikan bantuan sel stem dari luar yang bisa berasal dari sumsum tulang atau sumber lain seperti UCB. Hal ini telah dilakukan dengan hasil yang cukup menggembirakan. Bartinek juga telah melakukan intracoronary infusion BM stem cell otolog pada 22 pasien dengan AMI dan melaporkan hasil yang sangat baik. Sekarang dalam literatur sudah banyak dilaporkan hasil positif pemberian sel stem BM intrakoroner pada AMI.

Sel stem pada osteoarthritis
Osteoarthritis merupakan penyakit degeneratif yang banyak sekali menghinggapi orang tua maupun para atlet. Lutut, bahu, dan berbagai sendi mengalami degenerasi tulang rawan dan menyebabkan rasa nyeri pada pergerakan.
Sel stem dapat membentuk khondroblast dan osteoblast dan melalui tissue engineering sel stem dapat diarahkan sedemikian rupa sehingga dapat membentuk jaringan tulang rawan, yang dapat dimasukkan ke dalam sendi sehingga dapat berfungsi sebagai pengganti tulang rawan yang rusak. Jika kerusakan tulang rawan masih ringan maka sel stem dapat langsung dimasukkan ke dalam sendi; sel stem akan berubah menjadi chondroblast dan membentuk lapisan tulang rawan baru. Berbagai percobaan sudah membuktikan manfaat yang sangat besar sel stem untuk osteoarthritis.

Sel stem hematopoetik pada kanker
Salah satu sebab mengapa sel stem hematopoetik (sel stem sumsum tulang) dapat dipakai untuk pengobatan kanker adalah karena dalam keadaaan tertentu harus diberi kemoterapi atau radiasi dosis tinggi sehingga membunuh semua sel yang berkembang biak cepat (termasuk sel kanker, tetapi juga sel stem sumsum tulang, endotel usus dan sel rambut, sehingga pada radiasi atau kemoterapi dosis tinggi selain membunuh sel kanker, pasien akan menderita diare dan rambutnya rontok). Karena sel stem hematopoetik di dalam sumsum tulang yang membentuk leukosit untuk memerangi infeksi, eritrosit untuk membawa oksigen dan trombosit untuk pembekuan darah, bilamana diradiasi atau diberi obat kemoterapi akan mati semua, maka seseorang sebelum diradiasi/diberi obat kemoterapi dosis tinggi, sumsum tulangnya dipanen dulu. Setelah radiasi, dimasukkan lagi dalam darah dan sel stem hematopoetik akan kembali masuk sumsum tulang dan akan berkembang biak lagi. Penggunaan sel stem hematopoetik untuk kanker sudah dipakai sejak beberapa puluh tahun lamanya.
Selain sel stem sumsum tulang, juga dapat dipakai sel stem UCB dan darah perifer yang juga mengandung sel stem. Jika diambil dari darah perifer maka pasien diberi CGSF (Colony Growth Stimulating Factor) yang akan merangsang sumsum tulang untuk memproduksi dan melepaskan banyak sel stem ke sirkulasi dan kemudian dengan alat apheresis, sel stem dipisah dan darah dikembalikan ke dalam sirkulasi.
Jika sel stem diambil dari pasien yang sama maka disebut transplantasi otolog. Jika sel stem diambil dari saudara kembar maka disebut transplantasi syngeneik, sedangkan kalau sel stem diambil dari saudara maka disebut transplantasi alogeneik.

Sel stem untuk Rejuvenasi
Belakangan diketahui bahwa kerusakan jaringan tubuh akan diperbaiki oleh sel stem yang mengalir di darah perifer dan berasal dari sumsum tulang beserta sel stem yang memang selalu berada di setiap organ. Cara kerja sel stem mungkin melalui 3 mekanisme : menciptakan lingkungan mikro yang kondusif untuk regenerasi sel endogen jaringan, transdiferensiasi (sel stem dewasa akan berubah menjadi sel jaringan pengganti yang rusak) dan mungkin melalui fusi sel.
Memang sampai sekarang pertanyaan yang timbul adalah bagaimana tubuh kita dapat memperbaiki jaringan yang rusak? Pada tanaman dan organisme sederhana seperti hydra, planaria, atau salamander dan newt, jika cabang pohon dipotong atau kaki salamander dipotong maka secara otomatis akan tumbuh kembali. Telah terbukti pada organisme sederhana ini sel stem sangat besar peranannya.
Dengan penemuan bahwa sel stem embrionik dan dewasa dapat berkembang biak secara tidak terbatas dan dapat mengalami transdiferensiasi, maka sekarang sudah jelas bahwa perbaikan kerusakan jaringan tubuh dapat diperbaiki oleh sel stem dewasa yang beredar dalam darah dan sel stem yang terdapat dalam setiap organ.
Dengan penemuan ini maka teoretis setiap kerusakan dapat diperbaiki dengan melakukan infus sel stem eksogen karena sel stem endogen tidak cukup banyak untuk dapat melakukan regenerasi. Sumber sel stem endogen yang paling mudah didapatkan adalah sel stem sumsum tulang dan sel stem UCB, jika kita menghendaki sel stem otolog. Karena itu pengambilan dan penyimpanan sel stem UCB akan sangat bermanfaat, tidak hanya untuk pengobatan kanker pasca radiasi atau pemberian kemoterapi dosis tinggi, tetapi juga untuk memperbaiki kerusakan jaringan dan organ tubuh. Sel stem ini dapat dipergunakan untuk melakukan rejuvenasi dan regenerasi jaringan dan organ tubuh yang rusak.

Sel stem juga dapat dimanfaatkan untuk transplantasi kulit, mengobati penyakit oto-imun, terapi gen, skrining obat dan mempelajari perkembangan embrio (developmental biology) dan masih banyak sekali potensi lain yang belum dapat dibayangkan dewasa ini.

KESIMPULAN
Manfaat sel stem untuk pengobatan regeneratif sangat besar dan potensinya masih belum digali secara optimal. Tetapi, masih banyak negara, misalnya yang dipelopori oleh AS yang menghambat penelitian mengenai sel stem ini. Dan beberapa negara Eropa dan negara Asia seperti Swedia, Finlandia, Rusia, Belgia, Korea, China, India, Singapura dan Malaysia sangat mendukung penelitian sel stem.
Pemerintah, dunia akademis dan industri sebaiknya membangun kerjasama yang erat untuk memanfaatkan kesempatan penelitian sel stem ini untuk kemudian dapat diaplikasikan untuk pengobatan regeneratif, rejuvenasi orang tua, skrining obat baru dan membantu terapi gen.
Banyak hal yang masih bisa dilakukan untuk meneliti sel stem ini dan semoga bisa membawa manfaat tak terhingga untuk mengurangi penderitaan orang sakit dan meningkatkan kesejahteraan manusia.

KEPUSTAKAAN
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Hypertensive Retinopathy

Hypertensive Retinopathy

Signs and Symptoms

The patient with hypertensive retinopathy, as expected, suffers from hypertension. However, the hypertension may be unknown to the patient and the eye exam may yield the first clue to this relative asymptomatic systemic disease. Most commonly, the patient is middle age or older. In addition, hypertension is more common in African-Americans than Caucasians. Patients with only hypertensive retinopathy are nearly always visually asymptomatic.

Findings in hypertensive retinopathy include cotton wool spots and flame shaped hemorrhages. Only rarely will there be retinal or macular edema. In advanced cases, there will be a macular star (ring of exudates from the disc to the macula) and disc edema. Arteriolosclerosis (arteriolar narrowing, arterio-venous crossing changes with venous constriction and banking, arteriolar color changes, vessel sclerosis) is often found concurrently.

Pathophysiology

The findings in hypertensive retinopathy all stem from hypertension-induced changes to the retinal microvasculature. Hypertension leads to a laying down of cholesterol into the tunica intima of medium and large arteries. This leads to an overall reduction in the lumen size of these vessels. In arteriolosclerosis, hypertension leads to focal closure of the retinal microvasculature. This gives rise to microinfarcts (cotton wool spots) and superficial hemorrhages. In extreme cases, disc edema develops. The mechanism behind this phenomenon is poorly understood, but it may be related to a hypertension-related increase in intracranial pressure, and hence is considered true papilledema.

Arteriolosclerotic changes in the retinal microvasculature persist even with the reduction of systemic blood pressure. However, hypertensive retinopathy changes resolve over time with the reduction of systemic blood pressure (BP). Cotton wool spots develop in 24 to 48 hours with the elevation of BP, and resolve in two to 10 weeks with the lowering of BP. A macular star develops within several weeks of the development of elevated BP and resolves within months to years after the BP is reduced. Papilledema develops within days to weeks of increased BP and resolves within weeks to months following BP lowering.

Management

Management of hypertensive retinopathy involves appropriate treatment of the underlying hypertension. Medical co-management with the primary physician is of paramount importance. However, if a patient presents with papilledema from hypertension, then the patient has malignant hypertension and should be considered to be in medical crisis. This patient needs immediate consult with a primary care physician and, most likely, immediate transport to a hospital emergency room.

It must be reiterated, however, that there are many causes of papilledema. Other causes of papilledema, such as an intracranial mass lesion, must also be considered in the patient with hypertension. However, in a case where blood pressure is extremely elevated (e.g. 250/150mmHg) and there is disc edema with a macular star, malignant hypertension is the likely cause.

Clinical Pearls

• In order for cotton wool spots to develop from hypertension, autoregulatory mechanisms must first be overcome. For this to happen, the patient must have at least 110mmHg diastolic readings.

• Patients who develop papilledema from hypertension have malignant hypertension and typically have BP in the range of 250/150mmHg

• Fluorescein angiography is not indicated in cases of hypertensive retinopathy as it yields no diagnostic information.

• Hypertensive retinopathy presents with a ‘dry’ retina (few hemorrhages, rare edema, rare exudate, and multiple cotton wool spots) whereas diabetic retinopathy, in comparison, presents with a ‘wet’ retina (multiple hemorrhage, multiple exudate, extensive edema, and few cotton wool spots).

CHOROIDAL MELANOMA

Malignant Choroidal Melanoma

SIGNS AND SYMPTOMS

The benign choroidal melanoma, referred to clinically as a choroidal nevus, appears as a flat or slightly elevated slate gray lesion of the posterior fundus. The margins are typically indistinct, and often there are overlying areas of drusen noted within the nevus. In most instances, choroidal nevi remain under two disc diameters (DD) in size, although they may attain sizes of up to 5 DD in some cases.

The malignant choroidal melanoma, in contrast, appears as a mottled, often significantly elevated lesion, ranging in coloration from white to greenish-gray. As it grows, it may break through Bruch's membrane, taking on a mushroom-like appearance. Serous retinal detachments are commonly associated with this presentation. You may also observe overlying orange pigmentation known as lipofuscin. Most malignant melanomas are over 10 DD in size at the time of diagnosis. Most patients with choroidal melanomas are asymptomatic. However, should a significantly large lesion occur in proximity to the macula, the patient may present with metamorphopsia, acuity loss, visual field deficit and/or a hyperopic refractive shift.

PATHOPHYSIOLOGY

A choroidal melanoma represents a focal accumulation of melanocytes at the level of the uvea. In a choroidal nevus, these melanocytes are normal in both form and function. In malignant melanoma, the cells undergo neoplasia, reproducing at a faster rate than usual and resulting in a dysfunctional tumor mass. This tumor is capable of not only local extension but also of distant metastasis. While choroidal nevi do not typically lead to this type of damage, it is believed that they can convert to malignancy; the rate of malignant transformation over a 10-year period is estimated at 21 in 100,000.

Choroidal Nevus

MANAGEMENT

Nevi of 2 DD or less are harmless. Document the presentation with photography and, when possible, perform a B-scan and follow-up annually. Nevi between 2 and 5 DD are more suspicious. Either perform or refer for angiography to help differentiate the mass, and follow-up regularly at six-month intervals.

When the lesion is greater than 5 DD, consider it a malignant melanoma until proven otherwise. It may not require immediate treatment if relatively small and demonstrates no growth. But if the presentation suddenly changes dramatically or if sight is threatened, refer to a retinal specialist for treatment.

CLINICAL PEARLS

• While a nevus is of little concern, malignant melanoma presents a potentially life-threatening situation because of its propensity toward metastasis. These tumors have been known to spread to the liver, lungs, skin and gastrointestinal tract.

• Refer patients with newly detected malignant melanomas to a primary care physician for testing, which may include liver enzymes, carcinoembryonic antigen (CEA), neuroimaging, and chest CT.