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Fortunately, cancer in children and adolescents is rare, although the overall incidence of childhood cancer has been slowly increasing since 1975. [1] Children and adolescents with cancer should be referred to medical centers that have a multidisciplinary team of cancer specialists with experience treating the cancers that occur during childhood and adolescence. This multidisciplinary team approach is particularly important in the management of retinoblastoma; it incorporates the skills of the following health care professionals and others to ensure that children receive treatment, supportive care, and rehabilitation that will achieve optimal survival and quality of life:
(Refer to the PDQ Supportive and Palliative Care summaries for specific information about supportive care for children and adolescents with cancer.)
Guidelines for pediatric cancer centers and their role in the treatment of pediatric patients with cancer have been outlined by the American Academy of Pediatrics. [2] At these pediatric cancer centers, clinical trials are available for most types of cancer that occur in children and adolescents, and the opportunity to participate in these trials is offered to most patients and their families. Clinical trials for children and adolescents with cancer are generally designed to compare potentially better therapy with therapy that is currently accepted as standard. Most of the progress made in identifying curative therapies for childhood cancers has been achieved through clinical trials. Information about ongoing clinical trials is available from the NCI website.
Dramatic improvements in survival have been achieved for children and adolescents with cancer. [1] [3] [4] Between 1975 and 2010, childhood cancer mortality decreased by more than 50%. [1] [3] [4] Childhood and adolescent cancer survivors require close follow-up because cancer therapy side effects may persist or develop months or years after treatment. (Refer to the PDQ summary on Late Effects of Treatment for Childhood Cancer for specific information about the incidence, type, and monitoring of late effects in childhood and adolescent cancer survivors.)
Retinoblastoma is a rare pediatric cancer that requires a careful integration of multidisciplinary care. Treatment of retinoblastoma aims to save the patient's life and preserve useful vision, and thus, needs to be individualized. The management of intraocular retinoblastoma has evolved to a more risk-adapted approach that aims at minimizing systemic exposure to drugs, optimizing ocular drug delivery, and preserving useful vision. For patients presenting with extraocular retinoblastoma, treatment with intensive chemotherapy is required, including consolidation with high-dose chemotherapy and autologous hematopoietic stem cell rescue. While most patients with orbital disease and a large proportion of patients with systemic extra–central nervous system metastases can be cured, the prognosis for patients with intracranial disease is dismal.
Retinoblastoma is a relatively uncommon tumor of childhood that arises in the retina and accounts for about 3% of the cancers occurring in children younger than 15 years.
Retinoblastoma is a cancer of the very young child; two-thirds of all cases of retinoblastoma are diagnosed before age 2 years, and 95% of cases are diagnosed before age 5 years. [5] Thus, while the estimated annual incidence in the United States is approximately four cases per 1 million children younger than 15 years, the age-adjusted annual incidence in children aged 0 to 4 years is 10 to 14 cases per 1 million (approximately one in 14,000–18,000 live births).
Retinoblastoma arises from the retina, and its growth is usually under the retina and toward the vitreous. Involvement of the ocular coats and optic nerve occurs as a sequence of events as the tumor progresses. Invasion of the choroid is common, although occurrence of massive invasion is usually limited to advanced disease. Following invasion of the choroid, the tumor gains access to systemic circulation and creates the potential for metastases. Further progression through the ocular coats leads to invasion of the sclera and the orbit. Anteriorly, tumor invading the anterior chamber may gain access to systemic circulation through the canal of Schlemm. Progression through the optic nerve and past the lamina cribrosa increases the risk of systemic and central nervous system (CNS) dissemination.
Figure 1. Anatomy of the eye showing the outside and inside of the eye, including the eyelid, pupil, sclera, iris, ciliary body, canal of Schlemm, cornea, lens, vitreous humor, retina, choroid, optic nerve, and lamina cribrosa. The vitreous humor is a gel that fills the center of the eye.
Age at presentation correlates with laterality; patients with bilateral disease present at a younger age, usually in the first 12 months of life. Most cases present with leukocoria, which is occasionally first noticed after a flash photograph is taken. Strabismus is the second most common presenting sign and usually correlates with macular involvement. Very advanced intraocular tumors present with pain, glaucoma, or buphthalmos. As the tumor progresses, patients may present with orbital or metastatic disease. Metastases occur in the CNS or systemically (commonly in the bones, bone marrow, and liver).
The diagnosis of intraocular retinoblastoma is usually made without pathologic confirmation. An examination under anesthesia with a maximally dilated pupil and scleral indentation is required to examine the entire retina. A very detailed documentation of the number, location, and size of tumors, the presence of retinal detachment and subretinal fluid, and the presence of subretinal and vitreous seeds must be performed. Additional imaging studies include bidimensional ocular ultrasound and magnetic resonance imaging (MRI) (preferred over computed tomography [CT] to avoid radiation exposure). These imaging studies are important to evaluate extraocular extension and to differentiate retinoblastoma from other causes of leukocoria.
Evaluation for the presence of metastatic disease also needs to be considered in the subgroup of patients with suspected extraocular extension by imaging or high-risk pathology in the enucleated eye (i.e., massive choroidal invasion or involvement of the sclera or the optic nerve beyond the lamina cribrosa). Patients presenting with these pathological features in the enucleated eye are at high risk of developing metastases. In these cases, bone scintigraphy, bone marrow aspirates and biopsies, and lumbar puncture are performed.
Genetic counseling is recommended for all patients with retinoblastoma.
Retinoblastoma is a tumor that occurs in heritable (25%–30%) and nonheritable (70%–75%) forms. Heritable disease is defined by the presence of a germline mutation of the RB1 gene. This germline mutation may have been inherited from an affected progenitor (25% of cases) or may have occurred in a germ cell before conception or in utero during early embryogenesis in patients with sporadic disease (75% of cases). The presence of positive family history or bilateral or multifocal disease is suggestive of heritable disease.
Heritable retinoblastoma may manifest as unilateral or bilateral disease. The penetrance of the RB1 mutation (laterality, age at diagnosis, and number of tumors) is probably dependent on concurrent genetic modifiers such as MDM2 and MDM4. [6] [7] All children with bilateral disease and approximately 15% of patients with unilateral disease are presumed to have the heritable form, even though only 25% have an affected parent.
In heritable retinoblastoma, tumors tend to be diagnosed at a younger age than in the nonheritable form of the disease. Unilateral retinoblastoma in children younger than 1 year raises concern for heritable disease, whereas older children with a unilateral tumor are more likely to have the nonheritable form of the disease. [8]
The genomic landscape of retinoblastoma is driven by alterations in RB1 that lead to biallelic inactivation. [9] [10] A rare cause of RB1 inactivation is chromothripsis, which may be difficult to detect by conventional methods. [11] Other recurring genomic changes that occur in a small minority of patients include BCOR mutation/deletion, MYCN amplification, and OTX2 amplification. [9] [10] [11] A study of 1,068 unilateral nonfamilial retinoblastoma tumors reported that a small percentage of cases (approximately 3%) lacked evidence of RB1 loss. Approximately one-half of these cases with no evidence of RB1 loss (representing approximately 1.5% of all unilateral nonfamilial retinoblastoma) showed MCYN amplification. [10] A second report confirmed a case of retinoblastoma with wild-type RB1 and RB1 protein expression that showed MYCN amplification. [11]
Children with a germline RB1 mutation may continue to develop new tumors for a few years after diagnosis and treatment; for this reason, they need to be examined frequently. It is common practice for examinations to occur every 2 to 4 months for at least 28 months. [12] The interval between exams is based on the stability of the disease and age of the child (i.e., less frequent visits as the child ages).
A proportion of children who present with unilateral retinoblastoma will eventually develop disease in the opposite eye. Periodic examinations of the unaffected eye are performed until the germline status of the RB1 gene is determined.
Blood and tumor samples can be tested to determine if a patient with retinoblastoma has a mutation in the RB1 gene. Once the patient's genetic mutation has been identified, other family members can be screened directly for the mutation. The RB1 gene is located within the q14 band of chromosome 13. Exon by exon sequencing of the RB1 gene demonstrates germline mutation in 90% of patients with heritable retinoblastoma. [13]
Although a positive finding with current technology confirms susceptibility, a negative finding cannot absolutely rule it out. [14] A multistep assay that includes the following may be performed for a complete genetic evaluation of the RB1 gene: [14]
In cases of somatic mosaicism or cytogenetic abnormalities, the mutations may not be easily detected, and more exhaustive techniques such as karyotyping, multiplex ligation-dependent probe amplification, fluorescence in situ hybridization, and methylation analysis of the RB1 promoter may be needed.
The absence of detectable RB1 mutations in some patients suggests that alternative genetic mechanisms may underlie the development of retinoblastoma. [15] Approximately 3% of unilateral, nonheritable retinoblastoma cases have no somatic RB1 alterations. In half of these cases, high levels of MYCN amplification have been reported; these patients had distinct, aggressive, histologic features and a median age at diagnosis of 4 months. [10] In another small subset of tumors without detectable somatic RB1 mutations, chromothripsis is responsible for inactivating the RB1 gene. [11]
Genetic counseling is an integral part of the management of patients with retinoblastoma and their families, regardless of clinical presentation; counseling assists parents in understanding the genetic consequences of each form of retinoblastoma and in estimating the risk of disease in family members. [13] Genetic counseling, however, is not always straightforward. Approximately 10% of children with retinoblastoma have somatic genetic mosaicism, which contributes to the difficulty of genetic counseling. [16] (Refer to the PDQ summaries on Cancer Genetics Risk Assessment and Counseling and Cancer Genetics Overview for more information.)
Because of the poor prognosis of trilateral retinoblastoma, screening with neuroimaging until age 5 years is a common practice in the follow-up of children with the heritable form of the disease. (Refer to the Trilateral retinoblastoma section of this summary for more information.)
While retinoblastoma is a highly curable disease, the challenge for those who treat retinoblastoma is to preserve life and to prevent the loss of an eye, blindness, and other serious effects of treatment that reduce the patient's life span or the quality of life. With improvements in the diagnosis and management of retinoblastoma over the past several decades, metastatic retinoblastoma is observed less frequently in the United States and other developed nations. As a result, other causes of retinoblastoma-related mortality in the first and subsequent decades of life, such as trilateral retinoblastoma and subsequent neoplasms (SNs), have become significant contributors to retinoblastoma-related mortality. Death from an SN is the most common cause of death and contributes to more than 50% of deaths for patients with bilateral disease. [17] In the United States, before the advent of chemoreduction as a means of treating heritable or bilateral disease, trilateral retinoblastoma contributed to more than 50% of retinoblastoma-related mortality in the first decade after diagnosis. [18]
Trilateral retinoblastoma is a well-recognized syndrome that occurs in 5% to 15% of patients with heritable retinoblastoma and is defined by the development of an intracranial midline neuroblastic tumor, which typically develops between the ages of 20 and 36 months. [19]
Given the poor prognosis of trilateral retinoblastoma and the short interval between the diagnosis of retinoblastoma and the occurrence of trilateral disease, routine neuroimaging could potentially detect most cases within 2 years of first diagnosis. Although it is not clear whether early diagnosis can impact survival, screening with MRI has been recommended as often as every 6 months for 5 years for those suspected of having heritable disease or those with unilateral disease and a positive family history. [19] CT scans are generally avoided for routine screening in these children because of the perceived risk of exposure to ionizing radiation. At the time of diagnosis, patients who are asymptomatic of an intracranial tumor have a better outcome than do patients who are symptomatic. [19]
Approximately 5% to 10% of children with heritable retinoblastoma develop pineal gland cysts detected by MRI; these cyst abnormalities must be distinguished from the pineoblastoma that typically defines trilateral retinoblastoma. [20] [21]
Survivors of retinoblastoma have a high risk of developing SNs. Factors that influence this risk include the following:
The most common SN is sarcoma, specifically osteosarcoma, followed by soft tissue sarcoma and melanoma; these malignancies may occur inside or outside of the radiation field, although most are radiation induced. The carcinogenic effect of radiation therapy is associated with the dose delivered, particularly for subsequent sarcomas, and a step-wise increase is apparent at all dose categories. In irradiated patients, two-thirds of SNs occur within irradiated tissue, and one-third of SNs occur outside the radiation field. [23] [28] [29] [31]
An increased incidence of acute myeloid leukemia in children with heritable retinoblastoma has been suggested; however, no evidence is available to support this suggestion. [36]; [37][Level of evidence: 3iiiA] Of 245 patients who received etoposide, only one patient had acute promyelocytic leukemia after 79 months. [36]
No clear increase in SNs exists in patients without a germline retinoblastoma mutation beyond that associated with the treatment. [28] [38]
Survival from SNs is certainly suboptimal and varies widely across studies. [22] [25] [38] [39] [40] [41] However, with advances in therapy, it is essential that all SNs be treated with curative intent. [42]
As previously discussed, patients with heritable retinoblastoma have an increased incidence of SNs. (Refer to the Subsequent neoplasms section of this summary for more information.) Other late effects that may occur after treatment for retinoblastoma include the following:
One study of visual acuity after treatment with systemic chemotherapy and local ophthalmic therapy was conducted in 54 eyes in 40 children. After a mean follow-up of 68 months, 27 eyes (50%) had a final visual acuity of 20/40 or better, and 36 eyes (67%) had final visual acuity of 20/200 or better. The clinical factors that predicted visual acuity of 20/40 or better were a tumor margin of at least 3 mm from the foveola and optic disc and an absence of subretinal fluid. [45]
Retinoblastoma arises from the photoreceptor elements of the inner layer of the retina. Microscopically, the appearance of retinoblastoma depends on the degree of differentiation. Undifferentiated retinoblastoma is composed of small, round, densely packed cells with hypochromatic nuclei and scant cytoplasm. Several degrees of photoreceptor differentiation have been described and are characterized by distinctive arrangements of tumor cells. The Flexner-Wintersteiner rosettes are specific for retinoblastoma; these structures consist of a cluster of low, columnar cells arranged around a central lumen that is bounded by an eosinophilic membrane analogous to the external membrane of the normal retina. The lumen contains an acid mucopolysaccharide similar to that found around normal rods and cones. These rosettes are seen in 70% of tumors. Homer-Wright rosettes, on the other hand, are composed of irregular circlets of tumor cells arranged around a tangle of fibrils with no lumen or internal-limiting membrane. Horner-Wright rosettes are infrequently seen in retinoblastoma and are most often seen in other neuroblastic tumors, such as neuroblastoma and medulloblastoma.
Retinoblastomas are characterized by marked cell proliferation, as evidenced by high mitosis counts, extremely high MIB-1 labeling indices, and strong diffuse nuclear immunoreactivity for cone-rod homeobox, also known as CRX, a useful marker to discriminate retinoblastoma from other malignant, small, round cell tumors. [1] [2]
Cavitary retinoblastoma, a rare variant of retinoblastoma, has ophthalmoscopically visible lucent cavities within the tumor. The cavitary spaces appear hollow on ultrasonography and hypofluorescent on angiography. Histopathologically, the cavitary spaces have been shown to represent areas of photoreceptor differentiation. [3] These tumors have been associated with minimal visible tumor response to chemotherapy, which is thought to be a sign of tumor differentiation. [4]
The staging of patients with retinoblastoma requires close coordination of radiologists, pediatric oncologists, and ophthalmologists. Several staging and grouping systems have been proposed for retinoblastoma. [1] Overall assessment of retinoblastoma extension is documented by staging systems; intraocular extension, which is relevant for ocular salvage, is documented by grouping systems. For treatment purposes, retinoblastoma is categorized into intraocular and extraocular disease.
Intraocular retinoblastoma is localized to the eye and may be confined to the retina or may extend to involve other structures such as the choroid, ciliary body, anterior chamber, and optic nerve head. Intraocular retinoblastoma, however, does not extend beyond the eye into the tissues around the eye or to other parts of the body.
Extraocular retinoblastoma has extended beyond the eye. It may be confined to the tissues around the eye (orbital retinoblastoma); it may have spread to the central nervous system (CNS); or, it may have spread systemically to the bone marrow or lymph nodes (metastatic retinoblastoma). Magnetic resonance imaging (MRI) can be useful in the evaluation of extrascleral and extraocular disease in children with advanced intraocular retinoblastoma. Optic nerve enhancement by MRI does not necessarily indicate involvement and cautious interpretation is needed. [2] The detection of the synthetase of ganglioside GD2 mRNA by reverse transcriptase-polymerase chain reaction in the cerebrospinal fluid at the time of diagnosis may be a marker for CNS disease. [3]
Several staging systems have been proposed over the years. The AJCC clinical and pathological classifications represent a consensus opinion around which a common language is used.
|Primary tumor cannot be assessed.
|No evidence of primary tumor.
|Tumors no more than 2/3 the volume of the eye with no vitreous or subretinal seeding.
|No tumor in the either eye is greater than 3 mm in largest dimension or located closer than 1.5 mm to the optic nerve or fovea.
|At least one tumor is greater than 3 mm in largest dimension or located closer than 1.5 mm to the optic nerve or fovea. No retinal detachment or subretinal fluid beyond 5 mm from above the base of the tumor.
|At least one tumor is greater than 3 mm in largest dimension or located closer than 1.5 mm to the optic nerve or fovea, with retinal detachment or subretinal fluid beyond 5 mm from the base of the tumor.
|Tumors no more than 2/3 the volume of the eye with vitreous or subretinal seeding. Can have retinal detachment.
|Focal vitreous and/or subretinal seeding of fine aggregates of tumor cells is present, but no large clumps or "snowballs" of tumor cells.
|Massive vitreous and/or subretinal seeding is present, defined as diffuse clumps or "snowballs" of tumor cells.
|Severe intraocular disease.
|Tumor fills more than 2/3 of the eye.
|One or more complications present, which may include tumor-associated neovascular or angle closure glaucoma, tumor extension into the anterior segment, hyphema, vitreous hemorrhage, or orbital cellulitis.
|Extraocular disease detected by imaging studies.
|Invasion of optic nerve.
|Invasion of the orbit.
|Intracranial extension not past chiasm.
|Intracranial extension past chiasm.
|aReprinted with permission from AJCC: Retinoblastoma. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 562–63.
|Regional lymph nodes cannot be assessed.
|No regional lymph node involvement.
|Regional lymph node involvement (preauricular, cervical, submandibular).
|Distant lymph node involvement.
|aReprinted with permission from AJCC: Retinoblastoma. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 562–63.
|No metastasis.
|Systemic metastasis.
|Single lesion to sites other than CNS.
|Multiple lesions to sites other than CNS.
|Prechiasmatic CNS lesion(s).
|Postchiasmatic CNS lesion(s).
|Leptomeningeal and/or CSF involvement.
|CNS = central nervous system; CSF = cerebrospinal fluid.
|aReprinted with permission from AJCC: Retinoblastoma. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 562–63.
|Primary tumor cannot be assessed.
|No evidence of primary tumor.
|Tumor confined to eye with no optic nerve or choroidal invasion.
|Tumor with minimal optic nerve and/or choroidal invasion.
|Tumor superficially invades optic nerve head but does not extend past lamina cribrosa or tumor exhibits focal choroidal invasion.
|Tumor superficially invades optic nerve head but does not extend past lamina cribrosa and exhibits focal choroidal invasion.
|Tumor with significant optic nerve and/or choroidal invasion.
|Tumor invades optic nerve past lamina cribrosa but not to surgical resection line or tumor exhibits massive choroidal invasion.
|Tumor invades optic nerve past lamina cribrosa but not to surgical resection line and exhibits massive choroidal invasion.
|Tumor invades optic nerve to resection line or exhibits extra-ocular extension elsewhere.
|Tumor invades optic nerve to resection line but no extra-ocular extension identified.
|Tumor invades optic nerve to resection line and extra-ocular extension identified.
|aReprinted with permission from AJCC: Retinoblastoma. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 562–63.
|Regional lymph nodes cannot be assessed.
|No regional lymph node involvement.
|Regional lymph node involvement (preauricular, cervical).
|Distant lymph node involvement.
|aReprinted with permission from AJCC: Retinoblastoma. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 562–63.
|No metastasis.
|Metastasis to sites other than CNS.
|Single lesion.
|Multiple lesions.
|CNS metastasis.
|Discrete mass(es) without leptomeningeal and/or CSF involvement.
|Leptomeningeal and/or CSF involvement.
|CNS = central nervous system; CSF = cerebrospinal fluid.
|aReprinted with permission from AJCC: Retinoblastoma. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 562–63.
The more simplified International Retinoblastoma Staging System has been proposed by an international consortium of ophthalmologists and pediatric oncologists. [4] It is more widely used in the clinical setting than the AJCC staging system.
|Stage 0
|Eye has not been enucleated and no dissemination of disease (refer to the International Classification of Retinoblastoma section of this summary for more information).
|Stage I
|Eye enucleated, completely resected histologically
|Stage II
|Eye enucleated, microscopic residual tumor
|Stage III
|Regional extension
|a. Overt orbital disease
|b. Preauricular or cervical lymph node extension
|Stage IV
|Metastatic disease
|a. Hematogenous metastasis (without CNS involvement)
|—Single lesion
|—Multiple lesions
|b. CNS extension (with or without any other site of regional or metastatic disease)
|—Prechiasmatic lesion
|—CNS mass
|—Leptomeningeal and CSF disease
|CNS = central nervous system; CSF = cerebrospinal fluid.
Grouping systems are relevant for assessment of intraocular disease extension and are helpful predictors of ocular salvage.
Reese and Ellsworth developed a classification system for intraocular retinoblastoma that has been shown to have prognostic significance for maintenance of sight and control of local disease at a time when surgery and external-beam radiation therapy (EBRT) were the primary treatment options. However, developments in the conservative management of intraocular retinoblastoma have made the Reese-Ellsworth grouping system less predictive for eye salvage and less helpful in guiding treatment. [5] This grouping system is seldom used.
The new International Classification of Retinoblastoma staging system has been developed with the goal of providing a simpler, more user-friendly classification that is more applicable to current therapies. This new system is based on the extent of tumor seeding within the vitreous cavity and subretinal space, rather than on tumor size and location, and this system seems to be a better predictor of treatment success. [5] [6] [7] [8] This classification system may also help predict high-risk histopathology. In a study of over 500 patients with retinoblastoma, histopathologic evidence of high-risk disease was noted in 17% of Group D and 24% of Group E eyes. Such predication can be helpful in counseling parents regarding the potential need for postoperative systemic therapy. [9]
Treatment planning by a multidisciplinary team of cancer specialists, including a pediatric oncologist, ophthalmologist, and radiation oncologist, who have experience treating ocular tumors of childhood is required to optimize treatment outcomes. [1] Evaluation at specialized treatment centers is highly recommended before the initiation of treatment in order to improve the likelihood of ocular salvage and vision preservation.
The goals of therapy are the following:
Treatment of retinoblastoma is tailored to the intraocular and extraocular disease burden, disease laterality, germline RB1 gene status, and potential for preserving vision. For patients presenting with intraocular disease, particularly those with bilateral eye involvement, a conservative approach consisting of tumor reduction with intravenous or ophthalmic artery chemotherapy, coupled with aggressive local therapy, may result in high ocular salvage rates. Radiation therapy, one of the most effective treatments in retinoblastoma, is usually reserved for cases of intraocular or extraocular disease progression.
A risk-adapted, judicious combination of the following therapeutic options should be considered:
Newer methods of delivering EBRT are being applied in an attempt to reduce adverse long-term effects. This includes intensity-modulated radiation therapy, stereotactic radiation therapy, and proton-beam radiation therapy (charged-particle radiation therapy). [3] [4] [5] [6] Preliminary data suggest that proton radiation therapy is associated with a lower risk of radiation-induced malignancy in survivors of heritable retinoblastoma. In a nonrandomized study that compared two contemporary cohorts of patients with heritable retinoblastoma who were treated with either photon or proton radiation therapy, the 10-year cumulative incidence of radiation-induced SN was significantly different between the two groups (0% for proton radiation vs. 14% for photon radiation, P = .015). [7]
EBRT in infants causes growth failure of the orbital bones and results in cosmetic deformity. It also increases the risk of subsequent neoplasms in children with heritable retinoblastoma.
During the past two decades, systemic chemotherapy to reduce tumor volume (chemoreduction) to facilitate the use of local treatments and to avoid the long-term effects of radiation therapy has been the standard of care. [13] [14]; [15][Level of evidence: 3iiDiii] The success rate for eye salvage varies from center to center, but overall good ocular outcomes are consistently obtained for discrete tumors without vitreous seeding. [13] [14] [16] [17] [18] Chemotherapy may also be continued or initiated with concurrent local control treatments. [19] Eye grouping as defined by the International Classification of Retinoblastoma is the best predictor of ocular salvage using this approach.
Local tumor recurrence is not uncommon in the first few years after treatment [18] and can often be successfully treated with local therapy. [10] Among patients with heritable disease, younger patients and those with a positive family history are more likely to form new tumors. Chemotherapy may treat small, previously undetected lesions by slowing their growth, and this may improve overall salvage with local therapy. [20]
There are data suggesting that the use of systemic chemotherapy may decrease the risk of developing trilateral retinoblastoma. [21]
This modality continues to undergo study at very specialized retinoblastoma treatment centers, but data indicate that this treatment approach results in ocular salvage rates greater than 80% as first-line therapy in patients with intraocular unilateral retinoblastoma, although salvage rates of patients in whom other conservative approaches failed may be less. [22] [25] [26] [27] [28] [29] [30] [31]; [23] [32][Level of evidence: 3iiDiii]; [33] [34][Level of evidence: 3iiDiv]
In a report of 70 eyes in 67 children, globe salvage was achieved in 72% of primary-treated cases and in 62% of secondary-treated cases at 5 years of follow-up. Secondary-treated cases had received intravenous chemotherapy. Primary intra-arterial therapy achieved globe salvage for group B (100%), group C (100%), group D (94%), and group E (36%) eyes. Of all 70 eyes, complete regression was achieved for solid tumor in 48 of 51 eyes (94%), subretinal seeds in 40 of 42 eyes (95%), and vitreous seeds in 34 of 39 eyes (87%). With 3 years of experience, the combined incidence of ophthalmic, retinal, and choroidal vascular ischemia was reduced to 1%. [35][Level of evidence: 3iiD]
Small ocular and body size may pose technical limitations to the use of this modality in very young patients. Intravenous chemotherapy with one or several cycles of single-agent carboplatin has been used to delay the initiation of intra-arterial chemotherapy in neonates and young infants until the child is aged 3 months and weighs 6 kg. [36][Level of evidence: 3iiiDi]
Data also suggest that the cumulative incidence of new tumors in patients with heritable retinoblastoma is lower after intra-arterial chemotherapy than after other ocular salvage treatments. [37][Level of evidence: 3iiDi]
This treatment is not without complications. [22] [27] [38] [39] [40] Retinal and choroidal vasculopathy may occur in 10% to 20% of patients. [30] [41] Vision loss and vascular injury caused by complications of the catheterization or from the high dose of melphalan have been reported, although good vision was maintained. [42]
With the development of new treatments for retinoblastoma, such as intra-arterial and intravitreal delivery of chemotherapy, subtenon chemotherapy is being used less often in the clinical setting.
The issue of balancing long-term tumor control and the consequences of chemotherapy is unresolved. Most patients who receive chemotherapy are exposed to etoposide, which has been associated with secondary leukemia in patients without predisposition to cancer, but at modest rates when compared with the risks associated with EBRT in heritable retinoblastoma. An initial report conducted by informal survey methods described 15 patients who developed acute myeloid leukemia after chemotherapy. Half of the patients also received radiation therapy. [49] This finding has not been substantiated by formal studies. A more recent report of 245 consecutive patients treated with vincristine, carboplatin, and etoposide found a single patient with subsequent acute promyelocytic leukemia. This patient had also undergone EBRT. [50] Additionally, the Surveillance, Epidemiology, and End Result Registry (SEER) calculated standardized incidence rates for secondary hematopoietic malignancies in 34,867 survivors of childhood cancer. The observed-to-expected ratio of secondary acute myeloid leukemia in patients treated for retinoblastoma was zero. [51]
The standard treatment options for intraocular, extraocular, and recurrent retinoblastoma are described in Table 8.
|Treatment Group
|Standard Treatment Options
|Intraocular retinoblastoma:
|Unilateral retinoblastoma
|Enucleation followed by chemotherapy
|Conservative ocular salvage approaches:
|—Chemoreduction with either systemic chemotherapy with subtenon chemotherapy or ophthalmic artery infusion chemotherapy
|—Local treatments including cryotherapy, thermotherapy, and plaque radiation therapy
|Bilateral retinoblastoma
|Enucleation for large intraocular tumors, followed by risk-adapted chemotherapy when the eye and vision cannot be saved
|Conservative ocular salvage approaches when the eye and vision can be saved:
|—Chemoreduction with either systemic chemotherapy with subtenon chemotherapy or ophthalmic artery infusion chemotherapy
|—Local treatments including cryotherapy, thermotherapy, and plaque radiation therapy
|Extraocular retinoblastoma:
|Orbital and locoregional retinoblastoma
|Radiation therapy
|CNS disease
|Systemic chemotherapy and CNS-directed therapy
|Systemic chemotherapy followed by myeloablative chemotherapy and stem cell rescue
|Trilateral retinoblastoma
|Systemic chemotherapy followed by surgery and myeloablative chemotherapy with stem cell rescue
|Systemic chemotherapy followed by surgery and radiation therapy
|Extracranial metastatic retinoblastoma
|Systemic chemotherapy followed by myeloablative chemotherapy with stem cell rescue and radiation therapy
|Progressive or recurrent intraocular retinoblastoma
|Radiation therapy (external-beam or plaque radiation therapy)
|Local treatments (cryotherapy or thermotherapy)
|Salvage chemotherapy (systemic or intra-arterial)
|Intravitreal chemotherapy
|Progressive or recurrent extraocular retinoblastoma
|Systemic chemotherapy and radiation therapy for orbital disease (not a standard treatment)
|Systemic chemotherapy followed by myeloablative chemotherapy with stem cell rescue, and radiation therapy for extraorbital disease (not a standard treatment)
|CNS = central nervous system; EBRT = external-beam radiation therapy.
Standard treatment options for unilateral retinoblastoma include the following:
Because unilateral disease is usually massive and often there is no expectation that useful vision can be preserved, up-front surgery (enucleation) is commonly performed. Careful examination of the enucleated specimen by an experienced pathologist is necessary to determine whether high-risk features for metastatic disease are present. These features include the following: [1] [2] [3] [4] [5]
Pre-enucleation magnetic resonance imaging has low sensitivity and specificity for the detection of high-risk pathology. [6]
Systemic adjuvant therapy with vincristine, doxorubicin, and cyclophosphamide or with vincristine, carboplatin, and etoposide has been used to prevent the development of metastatic disease in patients with certain high-risk features assessed by pathologic review after enucleation. [3] [7] [8]; [9][Level of evidence: 2A]
Conservative ocular salvage approaches, such as chemotherapy and local-control treatments, may be offered in an attempt to save the eye and preserve vision. [10] Ocular salvage rates correlate with intraocular stage. In selected children with unilateral disease, the Reese-Ellsworth (R-E) Group was correlated with ocular outcomes. While the possibility of saving the eye without the use of EBRT was greater than 80% for children with R-E Group II or III disease, the ocular outcomes for children with R-E Group V eyes were poor, with less than 40% ocular salvage rates, even after the use of EBRT. [11]
Caution must be exerted with extended systemic chemotherapy administration and delayed enucleation when tumor control does not appear to be possible, particularly for Group E eyes. Pre-enucleation chemotherapy for eyes with advanced intraocular disease may result in downstaging and underestimate the pathological evidence of extraretinal and extraocular disease, thus increasing the risk of dissemination. [12]
The delivery of chemotherapy via ophthalmic artery cannulation as initial treatment for advanced unilateral retinoblastoma appears to be more effective than does systemic chemotherapy for chemoreduction. In the setting of a multidisciplinary state-of-the-art center, intra-arterial chemotherapy may result in ocular salvage rates greater than 80% for patients with advanced intraocular unilateral retinoblastoma. [13]; [14] [15][Level of evidence: 3iiiDii]; [16][Level of evidence: 3iiiDiv]
Because a proportion of children who present with unilateral retinoblastoma will eventually develop disease in the opposite eye, these children undergo genetic counseling and testing and periodic examinations of the unaffected eye, regardless of the treatment they received. Asynchronous bilateral disease occurs most frequently in patients with affected parents and in children diagnosed during the first months of life.
The management of bilateral disease depends on the extent of the disease in each eye. Systemic therapy is generally chosen based on the eye with more extensive disease. Treatment modality options described for unilateral disease may be applied to one or both affected eyes in patients with bilateral disease. Systemic or intra-arterial chemotherapy (chemoreduction) coupled with aggressive local treatments and very close monitoring is usually the treatment of choice; the goal is ocular and vision preservation and the delay or avoidance of EBRT and enucleation.
Standard treatment options for bilateral retinoblastoma include the following:
Intraocular tumor burden is usually asymmetric, and treatment is dictated by the most advanced eye. While up-front enucleation of an advanced eye and risk-adapted adjuvant chemotherapy may be required, a more conservative approach using primary chemoreduction with close follow-up for response and aggressive local treatment may be indicated. EBRT is now reserved for patients whose eyes do not respond adequately to primary systemic or intra-arterial chemotherapy and local consolidation. [17]
A number of large centers have published trial results that used systemic chemotherapy in conjunction with aggressive local consolidation for patients with bilateral disease. [10] [18] [19] [20] [21] [22] [23] [24] [25] [26] The backbone of the chemoreduction has generally been carboplatin, etoposide, and vincristine. Chemotherapy shrinks the tumors (chemoreduction), allowing greater efficacy of subsequent local therapy. [10] Treatment strategies often differ in terms of chemotherapy regimens and local control measures. Using this approach, the International Classification of Retinoblastoma grouping system has been proven to predict ocular salvage. [27] [28]; [29][Level of evidence: 3iiDiv]
For patients with large intraocular tumor burden with subretinal or vitreous seeds (Groups D eyes), the administration of higher doses of carboplatin, coupled with subtenon carboplatin, and the addition of lower doses of EBRT (36 Gy) for patients with persistent disease has been explored. Using this intensive approach, eye survival may approach a rate of 70% at 60 months. [31][Level of evidence: 2Div]
Delivery of chemotherapy via ophthalmic artery cannulation has also been shown to be feasible and effective in patients with newly diagnosed bilateral disease as tandem administration and in the salvage setting. [14] [15] [32] [33][Level of evidence: 3iiDii] Bilateral administrations increase the risk of systemic toxicity caused by melphalan exposure. [34] In these circumstances, intra-arterial chemotherapy with single-agent carboplatin may be used to treat the less-advanced eye during the tandem procedure. [35] These treatments should only be performed in an experienced center with a state-of-the-art treatment infrastructure and a dedicated multidisciplinary team.
In patients with cavitary retinoblastoma, minimal visual response is seen after intravenous chemotherapy and/or intra-arterial chemotherapy. Despite the blunted clinical response, cavitary retinoblastoma has a favorable long-term outcome with stable tumor regression and globe salvage. Aggressive or prolonged chemotherapy or adjunctive therapies are generally not necessary. In a retrospective series of 26 cavitary retinoblastomas that were treated with intravenous chemoreduction and/or intra-arterial chemotherapy, the mean reduction in tumor base was 22%, and the mean reduction in tumor thickness was 29%. Despite minimal reduction, tumor recurrence was noted in only one eye, globe salvage was achieved in 22 eyes, and there were no cases of metastasis or death during 49 months (range, 6–189 months) of follow-up. [36]
Studies are planned for a variety of patient groups. The International Classification of Retinoblastoma is being utilized for these trials.
The following is an example of a national and/or institutional clinical trial that is currently being conducted. Information about ongoing clinical trials is available from the NCI website.
Check the list of NCI-supported cancer clinical trials that are now accepting patients with intraocular retinoblastoma. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
General information about clinical trials is also available from the NCI website.
In high-income countries, few patients with retinoblastoma present with extraocular disease. Extraocular disease may be localized to the soft tissues surrounding the eye or to the optic nerve beyond the margin of resection. However, further extension may progress into the brain and meninges with subsequent seeding of the spinal fluid and as distant metastatic disease involving the lungs, bones, and bone marrow.
Standard treatment options for extraocular retinoblastoma (orbital and locoregional) include the following:
Orbital retinoblastoma occurs as a result of progression of the tumor through the emissary vessels and sclera. For this reason, transscleral disease is considered to be extraocular and should be treated as such. Orbital retinoblastoma is isolated in 60% to 70% of cases.
Treatment includes systemic chemotherapy and radiation therapy; with this approach, 60% to 85% of patients can be cured. Because most recurrences occur in the central nervous system (CNS), regimens using drugs with well-documented CNS penetration are used. Different chemotherapy regimens have proven to be effective, including vincristine, cyclophosphamide, and doxorubicin and platinum- and epipodophyllotoxin-based regimens, or a combination of both. [1] [2] [3]
For patients with macroscopic orbital disease, delay of surgery until response to chemotherapy is achieved (usually two or three courses of treatment) has been effective. Patients then undergo enucleation and receive an additional four to six courses of chemotherapy. Next, local control is consolidated with orbital irradiation (40 Gy to 45 Gy). Using this approach, orbital exenteration is not indicated. [3]
Patients with isolated involvement of the optic nerve at the transsection level are considered to have extraocular disease and are treated using systemic therapy, similar to that used for macroscopic orbital disease, and irradiation of the entire orbit (36 Gy) with 10 Gy boost to the chiasm (total of 46 Gy). [2]
Standard treatment options for extraocular retinoblastoma (CNS disease) include the following:
Intracranial dissemination occurs by direct extension through the optic nerve, and its prognosis is dismal. Treatment for these patients includes platinum-based intensive systemic chemotherapy and CNS-directed therapy. Although intrathecal chemotherapy has been used traditionally, there is no preclinical or clinical evidence to support its use. The administration of radiation therapy to these patients is controversial. Responses have been observed with craniospinal radiation using 25 Gy to 35 Gy to the entire craniospinal axis and a boost (10 Gy) to sites of measurable disease.
Therapeutic intensification with high-dose, marrow-ablative chemotherapy and autologous hematopoietic progenitor cell rescue has been explored, but its role is not yet clear. [4][Level of evidence: 3iiA]
Standard treatment options for trilateral retinoblastoma include the following:
Trilateral retinoblastoma is usually associated with a pineal lesion or, less commonly, as a suprasellar lesion. [5] [6] [7] In patients with the heritable form of retinoblastoma, CNS disease is less likely the result of metastatic or regional spread than of a primary intracranial focus, such as a pineal tumor. Trilateral retinoblastoma has been the principal cause of death from retinoblastoma in the United States during the first decade of life. [7] The prognosis for patients with trilateral retinoblastoma is very poor; most patients die of disseminated neuraxis disease in less than 9 months. [8] [9] However, with increased surveillance and aggressive therapy, there has been improvement in survival, from 6% (patients treated before 1995) to 44% (patients treated after 1996). [10]
While pineoblastomas occurring in older patients are sensitive to radiation therapy, current strategies are directed towards avoiding irradiation by using intensive chemotherapy followed by consolidation with myeloablative chemotherapy and autologous hematopoietic progenitor cell rescue, an approach similar to those being used in the treatment of brain tumors in infants. [11]
Because of the poor prognosis of trilateral retinoblastoma and the apparent improved survival with early detection and aggressive treatment, screening with neuroimaging is a common practice in the monitoring of children with the heritable form of the disease. [10] Routine baseline brain magnetic resonance imaging (MRI) is recommended at diagnosis because it may detect trilateral retinoblastoma at a subclinical stage. In a small series of patients, the 5-year overall survival was 67% for those detected at baseline, compared with 11% for the group with a delayed diagnosis. [5] The value of screening with MRI for those suspected of having heritable disease or those with unilateral disease and a positive family history is not determined. MRI screening may be needed as often as every 6 months until the child is age 5 years. Given the short interval between the diagnosis of retinoblastoma and the occurrence of trilateral retinoblastoma, routine screening might detect most cases within 2 years.
Computed tomography scans are avoided for routine screening in these children to minimize exposure to ionizing radiation.
Standard treatment options for extracranial metastatic retinoblastoma include the following:
Hematogenous metastases may develop in the bones, bone marrow, and less frequently, in the liver. Although long-term survivors have been reported with conventional chemotherapy, these reports should be considered anecdotal; metastatic retinoblastoma is not curable with conventional chemotherapy. In recent years, however, studies of small series of patients have shown that metastatic retinoblastoma can be cured using high-dose, marrow-ablative chemotherapy and autologous hematopoietic stem cell rescue. [12] [13] [14] [15] [16] [17] [18]; [19][Level of evidence: 3iiA]
Check the list of NCI-supported cancer clinical trials that are now accepting patients with extraocular retinoblastoma. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
General information about clinical trials is also available from the NCI website.
The prognosis for a patient with progressive or recurrent retinoblastoma depends on the site and extent of the progression or recurrence and previous treatment received. Intraocular and extraocular recurrence have very different prognoses and are treated in distinctly different ways.
Treatment options for progressive or recurrent intraocular retinoblastoma include the following:
Treatment options for progressive or recurrent extraocular retinoblastoma include the following:
New intraocular tumors can arise in patients with the heritable form of disease, whose eyes have been treated with local control measures only, because every cell in the retina carries the RB1 mutation; this should not be considered a recurrence. Even with previous treatment consisting of chemoreduction and local control measures in very young patients with heritable retinoblastoma, surveillance may detect new tumors at an early stage and additional local control therapy, including plaque brachytherapy, can be successful in eradicating tumor. [3] [4] [5] [6] [7]
When the recurrence or progression of retinoblastoma is confined to the eye and is small, the prognosis for sight and survival may be excellent with local therapy only. [8][Level of evidence: 3iiDiv] If the recurrence or progression is confined to the eye but is extensive, the prognosis for sight is poor; however, survival remains excellent. Intra-arterial chemotherapy into the ophthalmic artery has been effective in patients who relapse after systemic chemotherapy and radiation therapy. [9] Radiation therapy should be considered for patients that have not been previously irradiated. Finally, enucleation may be required in cases of progressive disease after all eye-salvaging treatments have failed.
Recurrence in the orbit after enucleation is treated with aggressive chemotherapy in addition to local radiation therapy because of the high risk of metastatic disease. [10][Level of evidence: 3iiA]
If the recurrence or progression is extraocular, the chance of survival is poor. [11] However, the use of intensive systemic chemotherapy and consolidation with high-dose chemotherapy and autologous hematopoietic stem cell rescue may improve the chance of cure, particularly for patients with extracranial recurrence (refer to the Treatment Options for Extraocular Retinoblastoma section of this summary for more information). For patients recurring after those intensive approaches, clinical trials may be considered.
Check the list of NCI-supported cancer clinical trials that are now accepting patients with recurrent retinoblastoma. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
General information about clinical trials is also available from the NCI website.
The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.
General Information About Retinoblastoma
Added text to state that the genomic landscape of retinoblastoma is driven by genomic alterations in RB1 that lead to biallelic inactivation (cited Zhang et al. as reference 9). Also added that a rare cause of RB1 inactivation is chromothripsis, which may be difficult to detect by conventional methods. Added text about two studies with cases of retinoblastoma with wild-type RB1 and RB1 protein expression that showed MYCN amplification.
This summary is written and maintained by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® - NCI's Comprehensive Cancer Database pages.
This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of retinoblastoma. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.
This summary is reviewed regularly and updated as necessary by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).
Board members review recently published articles each month to determine whether an article should:
Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.
The lead reviewers for Retinoblastoma Treatment are:
Any comments or questions about the summary content should be submitted to Cancer.gov through the NCI website's Email Us. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.
Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Pediatric Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.
PDQ is a registered trademark. Although the content of PDQ documents can be used freely as text, it cannot be identified as an NCI PDQ cancer information summary unless it is presented in its entirety and is regularly updated. However, an author would be permitted to write a sentence such as "NCI's PDQ cancer information summary about breast cancer prevention states the risks succinctly: [include excerpt from the summary]."
The preferred citation for this PDQ summary is:
PDQ® Pediatric Treatment Editorial Board. PDQ Retinoblastoma Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: http://www.cancer.gov/types/retinoblastoma/hp/retinoblastoma-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389442]
Images in this summary are used with permission of the author(s), artist, and/or publisher for use within the PDQ summaries only. Permission to use images outside the context of PDQ information must be obtained from the owner(s) and cannot be granted by the National Cancer Institute. Information about using the illustrations in this summary, along with many other cancer-related images, is available in Visuals Online, a collection of over 2,000 scientific images.
Based on the strength of the available evidence, treatment options may be described as either "standard" or "under clinical evaluation." These classifications should not be used as a basis for insurance reimbursement determinations. More information on insurance coverage is available on Cancer.gov on the Managing Cancer Care page.
More information about contacting us or receiving help with the Cancer.gov website can be found on our Contact Us for Help page. Questions can also be submitted to Cancer.gov through the website's Email Us.
Date last modified: 2016-05-26
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Margaret Frame graduated with a first class honours BSc in Biochemistry, followed by a PhD from the Medical Faculty, both at the University of Glasgow. She worked for a brief period in industry, and then joined the MRC Virology Unit in Glasgow as a post-doctoral scientist until 1987. After time off for family, she returned to work at the Beatson Institute for Cancer Research in 1991, first as a post-doc and then subsequently as a group leader. In 1995, she was jointly appointed as Professor of Cancer Research in the Faculty of Biological Sciences at the University of Glasgow and the Beatson Institute, where she became Deputy Director in 2002. She was awarded the Tenovus Medal in 1999 for her work on Src family kinases, was elected a Fellow of the Royal Society of Edinburgh in 2002, an EMBO Member in 2008 and a Fellow of the Academy of Medical Sciences in 2010.
Margaret Frame's long-held research interests are in cancer invasion and metastasis, and the role of tyrosine kinases in controlling tumour cell spread. She has had several CR-UK funded programs of research to work on understanding cancer invasion and metastasis, the key hallmarks of malignancy, and was recently awarded an ERC Advanced Investigator grant to build a novel cancer discovery platform. Her major goal is to work with clinicians treating cancers of unmet need, to determine whether, and if so how, targeting the invasive and metastatic processes may be therapeutically beneficial, and may be monitored in the preclinical and clinical settings by novel imaging techniques.
Margaret Frame joined the new MRC-University of Edinburgh Institute of Genetics and Molecular Medicine in October 2007. She co-directs the Edinburgh Cancer Research Centre in Edinburgh University's College of Medicine and Veterinary Medicine, with the role of Science Director in the recently established Cancer Research UK Centre (from January 2010). The vision of the Edinburgh Cancer Research Centre she directs is to develop novel and emerging technologies for the development of innovative cancer discovery and translational science. Together with close colleagues, she has recently formed the Edinburgh Cancer Discovery Unit (http://www.ecrc.ed.ac.uk/edinburgh-cancer-discovery-unit/edinburgh-cancer-discovery-unit), increasingly funding via several pharmaceutical company alliances, Edinburgh BioQuarter and CR-UK Drug Discovery Office; the vision is to generate evidence-led tests for cancer therapeutics and combinations that will predict clinical efficacy.
Margaret Frame also recently became Director of Research in the College of Medicine and Veterinary Medicine at the University of Edinburgh. She is a former Chair (or member) of several funding panels; Association of International Cancer Research, NCI Animal Models of Cancer, Welcome Trust Genes, Molecules and Cells, CR-UK Science Project and Program Funding, and is the current Chair of Cancer Research UK's Career Development Panel and Training Board, and serves on several Advisory Boards in the UK and across Europe, including Department of BioMedizin, University of Basel and the Marseilles Institute of Biology.

subset: commoncrawl


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Enter Exit Lists for Interstate Highways
This project received 24 bids from talented freelancers with an average bid price of $73 USD.Get free quotes for a project like this
Skills Required
Project Budget$30 - $100 USD
Total Bids24
Project Description
1. Online Maps like Expedia to see interstate highway exit numbers
2. Data Entry Form on our web site.
3. It is helpful to have a recent road atlas to avoid having to zoom in and out to see the town names on Expedia. Any book store or many big-box stores will have USA 2006 road atlases.
1. Find exit number on an online map like Expedia or Mapquest. Enter this information as the "Item" example "Exit 123". Each exit is listed twice on the maps (one for each direction), but only include the exit once on the [url removed, login to view] form.
2. Enter in summary field the following if present: Junctions of highways, towns within approximately 10 kilometers.
If it is a city say "City of ". For smaller places use "Community of" since we don't know if it is a town, or village) Always note the state name after the community name.
Examples: "Access to Highway US 123", "Access to Communities of Apple, Texas; City of Dallas, Texas;"
3. Occasionally there is a state park, historical site, or national forest shown on the map, include this information. If the parks have a campground, place the word "campground" after the name of the park;
Example: "Big Rock State Park Campground; Historic Site: Battle of Little Bear;
It is helpful to have a recent road atlas to avoid having to zoom in and out to see the town names. Any book store or many big-box stores will have these.
We'll start you off with one interstate that has about 150 exits to do, then if we're both happy with the results, we can do some more.
Looking to make some money?
- Set your budget and the timeframe
- Outline your proposal
- Get paid for your work
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- Times Online


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I've modded a control into an arcade stick, but the left analog stick likes to dance around the place...
Is there a way to replace it something else? is gonna be used for emulators, so no need to keep it or replace it for a functional part.
Using this diagram
Hot To Remove The Analog Sticks From S Controller?
Started by bidrug , Jun 24 2011 10:38 PM
3 replies to this topic
Posted 24 June 2011 - 10:38 PM
Posted 25 June 2011 - 05:37 AM
get a soldering iron and solder sucker and desolder the stick assemblies from the board. As a replacement for the sticks I'd suggest leaving the microswitches attatched to the stick assemblies on the board and fill the holes where the sticks were with buttons which will press down on those microswitches.
Posted 25 June 2011 - 06:08 AM
did u ever get the a button unjammed?
Posted 25 June 2011 - 12:18 PM
did u ever get the a button unjammed?
Never ever, this is a different controller with a different approach, for the very same mod, I don-t really get it, the button never got back, so i-m unsoldering all the work done...
I remember some kind of resistor being used for the analog stick (for a replacement), of course, you have to take in count, i'm using a salvaged controller for the very same mod, but the left stick is dancing like insanely crazy, unleashX unable to use, gotta use remote.
any help will be appreciated.
Edited by bidrug, 25 June 2011 - 12:23 PM.
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Accepting new patients
Accepting new patients
2211 Whitehorse Mercerville Rd
Trenton, NJ 08619 Phone number & directions
Trenton, NJ 08619 Phone number & directions
License & Identifications
A medical license is required for a doctor to practice medicine in a particular state. Requirements vary by state but most require, at a minimum, post-graduate training in the doctor's specific specialty. An NPI number is a national identifier unique to an individual health care provider and is managed by the Center for Medicare & Medicaid Services (CMS).
Learn more about Dr. George Loutfi:
View the full profile to get information on:
- Qualifications
- What's important to you
View full profile
Patient Reviews
Have you visited Dr. Loutfi? Share your experience.
Write a Review
Write a Review
Specialties & Research
- He has special expertise in 1 area:
- Bridges and Crowns
Education & Awards
Dr. Loutfi graduated from University of Pennsylvania , Philadelphia.
Home > Find a Dentist > NJ > Trenton Dentists > Dr. George Loutfi, DDS, DMD
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- Additional Information
- Dr. George Loutfi DDS and DMD is a male dentist and practices in Family Dentistry.
- Where does Dr. George Loutfi practice?
- Dr. George Loutfi has 1 office location.
Dr. George Loutfi practices Family Dentistry near Trenton, NJ.
See Trenton Dentists.


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Love it!
I was a little worried about whether or not this SSD would work in my ancient Compaq V2401CL laptop circa 2001. That laptop has only been used as a backup for many years and basically has been collecting dust. When I replaced my HD on my MacBook with an SSD I thought what about this paper weight, can I revive this as well? The install was simple, the only modification that I made to the drive was moving the jumper to "MASTER" so my laptop would recognize it. The drive has the chart on the drive itself to show where the jumper belongs. I connected it, booted in my Linux Mint 15 DVD and made a fresh install which only took around 10 minutes to complete because of the speed of the drive. Now, my 12 year old laptop has a 2013 operating system with an SSD that boots to the desktop in 20 seconds. It's not a new MacBook Air or Ultrabook but this upgrade has revived it into a functional piece of equipment again.
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Plans for Conneaut Township bridge replacement to be displayed
ALBION -- Plans to replace the Route 6N bridge over Marsh Run in Conneaut Township will be on display at the township building beginning Monday.
The road will be closed at the bridge during construction, which is expected to begin next summer, Pennsylvania Department of Transportation spokesman Jim Carroll said.
A 4-mile detour will be posted until construction is completed, in about six weeks.
Plans for the project will be displayed at the Conneaut Township Building, 12500 Route 6N, through June 20. Call township supervisors at (814) 756-4301 to see them.
The 13-foot bridge is over Marsh Run, west of Albion, between Barney Road and Route 215. The bridge, built in 1923, is rated as structurally deficient.


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"bringing back the songs and comedy of old Las Vegas"
MARIO ROSALES, who's passion is entertaining, is a singer, stand-up comedian / impressionist, actor and voice-over artist.
Mario Rosales will be performing one of his last shows in the Ozarks for us. Mario will soon be moving to Las Vegas.
We wish him all the success in the world!
Laugh along with the world's greatest Rodney Dangerfield impressionist. Reminisce to a wide variety of music. With singer, stand-up comedian / impressionist, actor and voice-over artist Mario Rosales... It's all about fun!
Born and raised in Southern California, Mario was one of eleven children in a very musical family. He began playing piano and violin at the age of five and later learned to play the clarinet, saxophone and guitar.
Mario spent most of his adult life as an actor, voice-over artist and stand-up comedian in Hollywood, California. Later in life, he worked in radio as a talk show host. In 2004 he began singing as his main career path which eventually led him to his current home in "the live entertainment capitol of the world" Branson, Missouri.
Although Mario performs mainly in Branson, he also travels frequently to the west coast and South Texas. You may find him doing casino shows or an occasional cruise ship performance.
His shows frequently include his amazing impression of the late, great, comedian Rodney Dangerfield along with music encompassing several musical genres.
Mario's musical range is extensive and eclectic. From Hank Williams Classic Country to Frank Sinatra.
His easy style pleases audiences everywhere!
Branson's Own - Mario Rosales is sure to be a thoroughly enjoyable evening of entertainment.


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This event has expired. This may be a recurring event, so please check the calendar in the future for updated occurrences.
Shawano Folk Music Festival
The 38th annual festival features concerts on Fri & Sat evenings, plus daytime workshops, performances, children's program, quilt raffle and crafts. Enjoy a mix of ethnic and contemporary folk music and dance.
Fair/Festival Type
- Arts & Crafts
- Music


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Top Definition
a box or pan used in rolf. this is comparable to the hole in real golf or basket in disc golf.
The box spiggler was in a very precarious position! If Cody didn't throw the spiffler just right the box spiggler would be out reach by normal humans.
بواسطة the rolfer سبتمبر/أيلول 6, 2006
Trending Now
Can you define these popular missing words?


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Vintage Baby Names for Boys
Simon is pure and simple (not in the nursery rhyme sense), and an appealingly genuine Old and New Testament name that's not overused -- making Simon a stylish choice.
In the Bible,... Read More
Spencer is a name that has everything: it's both distinguished sounding and accessible, dignified but Spencer Tracy-like friendly. Picked by several celebrities (a couple of times even for a... Read More
Many modern parents use Theo as the short form for Theodore rather than the dated Ted--including some celebs, such as Dallas Bryce Howard-- but others bypass the Grandpa name Theodore entirely and... Read More
Tobias is one of a number of s-ending boys' names that are riding a wave of popularity. It rose to its highest-ever position, Number 316, in 2015, and looks to climb even higher.
With... Read More
Tristan -- known through medieval legend and Wagnerian opera -- has a slightly wistful, touching air. This, combined with the name's popular "an" ending, makes Tristan very appealing to parents... Read More
Zachary, a Top 20 name for over 10 years, is now dropping steadily in the ratings, slumping to its lowest point in decades. But with its ancient roots and modern feel, you can understand why... Read More
Recent User Lists
- Cowboy / Western Names (BOYS)
- Skyrim Girl Names
- Boys Names that Sound Both Strong and Smart
- Classic, but Uncommon Names
- my top Hyphen girl Names
You might also like these lists:
- Cool Girl Names from Ancient Cultures Includes: Aurelia
- Baby Names That Mean Luck Includes: Asher
- Space Baby Names Includes: Aurora
- Italian Word Names Includes: Aurora
- Names Girls Love Having Includes: Ariel
- 1900s Baby Names Includes: Arthur
- Belles of the Ball Includes: Annabel, Arabella
- Unisex Baby Names Includes: Avery
- Antique Baby Names Ready for Restoration Includes: Adeline, Amos, Atticus
- Literary Names for Girls Includes: Arabella, Aurora


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With national signing day less than 48 hours away, the UCLA Bruins are putting the final touches on what will be considered an exceptional recruiting class.
As it currently stands, the Bruins are ranked by multiple recruiting services as having a top-10 class nationally. Scout has the Bruins' class ranked sixth nationally, while Rivals has UCLA as the ninth-best class in the land.
However, those rankings could shoot up by the time Wednesday rolls around. The Bruins are heavily involved with four elite prospects (Eddie Vanderdoes, Kylie Fitts, Asiantii Woulard, Isaac Savaiinaea), and it wouldn't be a shock to see UCLA land the entire quartet.
Of the prospects currently committed, here's a look at who could potentially start next season as true freshmen.


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Wall Street Decline Takes Its Toll...
LC-MS Gains Favor Due To the...
Expanding Use of NGS Has Largely...
Quadruple Helices Appear To Have Role...
Researchers from the joint biomedical engineering program at North Carolina State University and the University of North Carolina at Chapel Hill report the development of daisy-shaped, nanoscale structures that are made predominantly of anticancer drugs. The scientists say their novel delivery system is capable of introducing a cocktail of multiple drugs into cancer cells.
"We found that this technique was much better than conventional drug delivery techniques at inhibiting the growth of lung cancer tumors in mice," explained Zhen Gu, Ph.D., an assistant professor in the joint biomedical engineering program. "And based on in vitro tests in nine different cell lines, the technique is also promising for use against leukemia, breast, prostate, liver, ovarian, and brain cancers."
To make the nanodaisies, the researchers begin with a solution that contains polyethylene glycol (PEG), which forms long strands that have much shorter strands branching off to either side. Researchers directly link the anticancer drug camptothecin (CPT) onto the shorter strands and introduce the anticancer drug doxorubicin (Dox) into the solution.
PEG is hydrophilic while CPT and Dox are hydrophobic. As a result, the CPT and Dox cluster together in the solution, wrapping the PEG around themselves. This results in a daisy-shaped drug cocktail, only 50 nanometers in diameter, which can be injected into a cancer patient.
Once injected, the nanodaisies float through the bloodstream until they are absorbed by cancer cells. In fact, one of the reasons the researchers chose to use PEG is because it has chemical properties that prolong the life of the drugs in the bloodstream. The scientists published their study ("Folding graft copolymer with pendant drug segments for co-delivery of anticancer drugs") in Biomaterials.
Once in a cancer cell, the drugs are released. "Both drugs attack the cell's nucleus, but via different mechanisms," says Wanyi Tai, Ph.D., a former postdoctoral researcher in Dr. Gu's lab.
"Equipped with a PEG shell, the nanocarriers displayed good stability and can be internalized by a variety of cancer cell lines via the lipid raft and clathrin-mediated endocytotic pathway without premature leakage, which showed a high synergetic activity of CPT and Dox toward various cancer cells," wrote the investigators. "In vivo study validated that the nanocarriers exhibited strong accumulation in tumor sites and showed a prominent anticancer activity against the lung cancer xenograft mice model compared with free drugs."
"Combined, the drugs are more effective than either drug is by itself," noted Dr. Gu. "We are very optimistic about this technique and are hoping to begin preclinical testing in the near future."
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Massachusetts Automobile Insurance Plan (MAIP)
From this page, you can access all of the information and forms you need to process Massachusetts Automobile Insurance Plan (MAIP) business with Integon National Insurance Company, a National General company.
MAIP/ Integon National Homeland Insurance Contact Information
Mail New Business Applications and deposit premium checks to:
National General Companies
550 Essjay Rd
Williamsville, NY 14221
Fax endorsement requests and cancellations to: 212-655-1040
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Second requests - please email: firstname.lastname@example.com
Claims - 1-888-856-5522
MAIP Supplemental Application - You must answer additional questions in order to complete National General's automobile policy application process. Please submit this supplemental application along with the standard MAIP Application and deposit.
Category Rating Rule and Scoring Variables - Use these rules to assign all policies to the appropriate rating category.
Installment Plan for Premium Payment - New and renewal MAIP policyholders can choose from different options for paying their premiums. For maximum convenience, they can pay their premiums electronically via electronic funds transfer. Nothing could be easier - no paperwork, no checks, no stamps, no envelopes and nothing to remember to mail. For further information regarding EFT or if you have any billing questions, please contact our billing customer service representatives at 1-888-452-0374.


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Lone Wolf® "Sit & Climb" Combo II Climbing Tree Stand, Regular
Item # WX2-215768SOLD OUT
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Lone Wolf® "Sit & Climb" Combo II Climbing Tree Stand. Comfort meets convenience.
And without sacrificing an ounce of performance. The treestands pivoting "Sit & Climb" bar provides easy climbing. The 2-panel contoured foam seat pad makes that all-day sit a cinch. Tree stand features a full-size 30 x 19 1/2" one-piece platform.
This feature-filled Climber Tree Stand packs down to a slim 4" profile. Just grab it and GO. You'll soon learn why the Sit & Climb Tree Stand is a favorite of both gun and bow hunters. 17 1/4" wide seat .Feature:
- Huge 30 x 19 1/2" one-piece cast aluminum platform
- Comfortable 2-panel, contoured foam seat pad
- Tree stands bow holder accommodates most parallel limb bows
- Pivoting "Sit & Climb" bar
- Backpack straps, 1 bungee strap and stabilizing straps included
- Distinctive 3-D camo platform design
- Fits trees 6"-19" in diameter
- 350-pound treestand weight rating
- Just 20 pounds
- Includes TMA approved 6-pt Fall Arrest System.
Order ONLINE Today!


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The clip being human from Seed of Chucky (2004) with Jennifer Tilly, Brad Dourif Chucky, it's time. Give m...
The clip being human from Seed of Chucky (2004) with Jennifer Tilly, Brad Dourif Chucky, it's time. Give me the power, I beg of you. Hold it! Hold it. Chucky. First he has to choose. I beg your pardon? Sorry, she has to choose. We don't have time for this shit. Wait Chucky! We have a son and a daughter. Glen and Glenda. Don't you get it? Maybe they don't have to choose. Help! Hurry Chucky, do the chant! Somebody help! Chucky, do it now! Help! Help us! We won't get another chance. What are you waiting for, Chucky? Help! Do it! Do it! Everybody shut up! I've had it! That's it! There's a limit to how much I can take. What are you talking about? Look around you, Tiff. This is nuts! And I have a very high tolerance for nuts. If this is what it takes to be human... then I'd rather take my chances as a supernaturally possessed doll... it's less complicated. You can't be serious. As a heart attack. Think about it. What's so great about being human anyway? You get sick, you get old, you can't get it up anymore. I'm not looking forward to that. Honey, I wanna be Jennifer Tilly. I wanna be a star. And I don't wanna be your chauffer. As a doll, I'm fucking infamous! I'm one of the most notorious slashers in history. And I don't wanna give that up! I'm Chucky, the Killer Doll! And I dig it!


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A proven business leader and strategist, Mark A. Ascolese was named president and CEO of Active Power in September 2013. Ascolese is an electrical infrastructure and energy management expert with more than 40 years of experience serving a variety of mission critical and energy markets including data centers.
Prior to joining Active Power, Ascolese first served as CEO and then as board chairman of Power Analytics, an electrical infrastructure enterprise software firm. He served as president at Powerware Corporation (now part of Eaton Corp.) and in senior management positions at General Electric.
From 2000-2002, Ascolese served as senior vice president of Business Development at Active Power during the company's initial public offering. In this role, he led the efforts in securing multimillion dollar distribution and development agreements with key market players.
Ascolese earned a bachelor's of Science in Commerce from the University of Louisville.
A certified public accountant, Jay Powers is an accomplished finance leader with broad and deep experience at both domestic and international organizations in a variety of industries including manufacturing, power quality, and energy storage.
Powers brings more than 30 years of finance, accounting, and operations experience to Active Power with a proven record of protecting assets, implementing new processes that lead to operational improvements, and succeeding in fast paced, change driven environments.
Powers most recently served as senior vice president of Finance of the U.S. Windows and Doors division of PlyGem Industries. He has also served in executive finance and accounting roles at large multinational companies including Xerium Technologies, Invensys PLC (Powerware), and ABB.
Powers received a bachelor's of Science in Accounting from the State of University of New York at Albany.
Ron Landis is an accomplished electronic and mechanical design and systems engineer with more than 26 years of experience in designing single and three phase uninterruptible power supply (UPS) systems. He has a proven track record of building and leading high functioning engineering teams that successfully bring products to full production.
Prior to joining Active Power in 2000, Landis served more than 12 years in various senior engineering roles at Powerware, a global provider of power quality and backup power management products, which is now a part of Eaton Corp. As senior design engineer, he led a team in the release of a new UPS product family overseeing mechanical design documentation for fabrication and assembly through first article testing.
Landis earned a bachelor's of Science in Electrical Engineering from DeVry Institute of Technology in Phoenix, Arizona.
Todd Kiehn brings a broad and deep skill set in leading marketing and technology strategies with more than 15 years of experience in the critical power infrastructure and telecommunications markets. At Active Power, Kiehn leads all marketing, positioning, and product development efforts in the mission critical, modular infrastructure, and energy storage markets and aligns strategy across the company's organizations and products.
Prior to Active Power, Kiehn held numerous marketing and product management roles in the telecommunications industry. Kiehn earned a master's in Business Administration from the Haas School of Business at the University of California at Berkeley and a bachelor's degree in Government from Georgetown University.
Kevin Carter brings more than 25 years of experience in field service operations and technical support worldwide for a variety of three phase UPS products including rotary, static, and diesel hybrid systems. His strong technical acumen combined with proven leadership has enabled Carter to successfully build and lead service teams on a global scale.
Since joining Active Power in 2007, Carter has rapidly been promoted to roles of increasingly responsibility currently serving as director of Global Service. In this role, he leads an international team of more than 40 service professionals responsible for startup, maintenance, and servicing of UPS and associated ancillary equipment.
Prior to Active Power, Carter spent nearly 20 years as a field service technician at Piller Power Systems. He also served as a sonar technician in the U.S. Navy and earned qualifications on three distinct classes of nuclear submarines. During his naval service, Carter led teams responsible for maintenance and repairs to sonar suites on multiple platforms.
Dawn Chyten has more than 20 years of senior leadership experience in various aspects of HR including recruiting and sourcing, training and development, organizational design, and workforce planning. She is a motivational team leader that has demonstrated success in mentoring, training, and managing employees to optimize teams.
Prior to Active Power, Chyten led all HR and recruiting processes at Massachusetts based Eliza Corp., a provider of healthcare communications services, as senior director of HR. She successfully expanded the organization from 50 employees to more than 200 during her four year tenure and retained more than $500,000 in cost through consolidation of recruiting efforts.
Chyten has served in a number of senior HR roles for large manufacturing and IT organizations including Ultra Electronics and Sierra Systems. She also launched a HR and recruiting consulting firm representing marquee clients including Vignette, Dell, and IXC Communications.
Scott J. Depta has more than 15 years of experience in leading strategic and tactical legal initiatives, advising on business transactions, securities laws, corporate governance, and regulatory compliance matters.
Prior to Active Power, Depta served in various leadership roles at Dell for more than 11 years. In these roles, he had responsibility for general corporate matters including mergers and acquisitions, corporate finance, and securities law compliance and disclosure. At Dell, Depta advised the Finance and Treasury organizations, Enterprise Solutions Group, Worldwide Procurement, and global IT organization in a variety of legal matters.
Depta also served as assistant general counsel at Wingcast, LLC, a Ford and QUALCOMM joint venture based in San Diego, Calif. He began his legal career at Cravath, Swaine & Moore in New York and then at Latham & Watkins in San Diego.
Depta earned bachelor's degrees in Economics and Anthropology and a juris doctor from the University of Pennsylvania.


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You missed it This great deal for 876 Cafe is over. But don't despair, we've got more great deals every day.
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876 Cafe
$10 to Spend on Online Ordering in Van Ness
With LivingSocial's Takeout & Delivery, online ordering is easy: Browse menus from local restaurants, place your order on our platform, and pay with your LivingSocial account—no need to pick up the phone or scramble to find cash!
Today, pay $5 and you'll get $10 to spend on online food and drink orders from 876 Cafe. When fixin' for rice and peas, let this eatery woo you with all kinds of Caribbean eats. Opposing flavors collide right out of the gates with the spinach and pear salad, teeming with blue cheese and citrus vinaigrette and the sweet-and-spicy shrimp app, painted with mango-tomato salsa. Curried crab po' boys and the jerk chicken wrap definitely make the winner's circle, beside the pan-roasted black bass fillet.
PAID VALUE EXPIRES ON September 27, 2021
PROMOTIONAL VALUE EXPIRES ON April 16, 2013


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Dunkin Donuts
1580 Dorchester Ave
Dorchester, MA 02122
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(617) 288-3302
Cuisine: Donuts
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4 of 5.0 from 3 reviews
price range:Less than $10
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Micky Ward to make appearance at Mohegan Sun for 30 minute Q&A on Thursday
For those of you in New England. Micky Ward will be making an appearance at Mohegan Sun on Thursday night for a 30 minute Q&A with local sports radio analyst Jason Page, formerly of ESPN 1410. Not sure on the exact time yet, but it will be located near the shops at Mohegan.
I would imagine Ward will also be doing autographs.
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Joseph D Castleberry Photographer
Jonavae ZontayeModel Female Los Angeles, California, US
My Website: Jonavae
Mayhem # 1851473
About MeI am a very outgoing woman. I enjoy laughter and making others laugh. Besides modeling I enjoy acting, singing, babysitting, and kickboxing. I am an extremely determined girl. My goal is to continue to be a part of the entertainment industry as my career.
Have you worked with Jonavae Zontaye? Add Credits for Jonavae Zontaye! >>
Credit Notes*THEATER*
The Best Christmas Pageant ever: The Des Moines Playhouse-2002
Thesius and the Minitar: Harding Middle School-2003
Sound of Music: Grace United Methodist Church-2004
South Pacific: Roosevelt High School-2004"Un-cool": Roosevelt High School (One Act-Iowa High School Speech Association)-2005
Arkansas Bear: North High School-2006
Fiddler on the Roof: North High School-2006
MGTV: North High School-2007
The Love Doctor: North High School-2007
Ensemble Acting: Eternal Sunshine of the Spotless Mind: Clementine-2007
What A character Iowa lead Disney/cartoon Performer-2008-2010
Member for 8 years; The Iowa Youth Chorus (Silver Medalists at the 2004 Choir Olympics in Germany)
The National Anthem singer; 2002 FX Tough man Boxing Match
Des Moines Teen Idol contest winner 2003 & 2004
Soloist in TALENT CONNECTIONS Variety Show-2005
Des Moines Symphony singer: Lord of the Rings Concert: Civic Center-2005Thresholds Native Ameican festival singer with: Buffy Sante Marie-2007
Vocal coach for lead vocalist of Punk Band Albino Spiders: 2008-current
Green Death music video-2013
Ellie Goulding music video-2015
*T. V/ Radio/Feature Film*
Training workshops and performance: BRAVO ON WITH THE SHOW: Bravo Network- TV special: improvisation, acting, dance & singing-2003
Radio News Broadcasting: Iowa High School Speech Association: All State competitor-2007(superior ratings)
The Crazies: Jekyll Productions-2010
Janie Jones: Absurda Entertainment-2011
Dead Awake: September Productions-2010
Smitty: Tri Coast Productions-2011
Fertile Grounds: After Dark Films-2011
Last Vegas: Four Fellas Productions-2012
Best Western Hotel radio commercial for Kiss FM and The Bus-2010
Deichmann shoe commercial-2013
House of Lies-2013
Naked Vegas: SyFy television show-2013
Toby Keith Short Film-2014
Mall Cop Blart 2: Columbia Pictures-2014
Pawnography: ( 2 episodes)-2014
Top Chef Late Night-2014
Sin City Saints-2014
Late Night Chef Fight-2014
Anybody Can Dance 2-2014
Monopoly Millionaire's Club: Proxy-2015
Late Night Chef Fight-2015
EDC promo video shoot-2015
Formerly signed to Look Talent in San Francisco: local print, commercials and runway jobs
Modeled in 2005 Talent Connections in Des Moines
'Hairy Tail' Runway Fashion show- La James international salon & designers: Des Moines-2006
Fashion/Hair Runway Show- Convention Center (Cache Clothing, Sage Tree Hair Salon): Dsm-2007
Vogue Vision Runway Show- (Sahars clothing & hair): Dsm-2008
Possibilities Runway Show(Fabrik,Velvet Coat, Sahars clothing/hair) - Liars Club: Dsm-2008
Aaron Stigger Photography brochure: Los Angeles; 2006-on going(2009)
1980s Hair Clothing Model Nova Awards Print Ad:Trilix Marketing group-2009
Vitae Runway Fashion Review Show: Liars Club-Dsm, IA-2009
Fangs For Nothing Clothing: catalog shoot-2009
Vogue Vision Photoshoot: Catalog/print shoot-2009
Aveda Fashion Show: runway show-2009
Aveda and Salon W: hair model-2010
Promo model: Mentos-Iowa Speedway-2012
PRomo Model: ABC network-2012
Promo Model: Schick Hydro SIlk-2012
RAW Runway SHow-2012
Raw Fashion Show: Las Vegas-2012
WPPI convention-promo model-2013
Raw Runway Show: Green Tease-2013
Emerge Arts Magazine spread: Las Vegas-2013
Music Through the Lens: Las Vegas Print Model-2014
Russtick Knitt Bullet Jewerly: Print Model-2014
Heineken Light: Promo Model-2014
CES promo model-2015
The Bullet Studio print model-2015
Promo model T-mobile international VIP launch-2015
Improvisation training/workshops, Vocal training 8+ years, dance 5yrs (gymnastics, hip hop, jazz, modern),
Model Boot Camp, Drama classes7+years, Advanced Drama classes
Special Skills: basketball, singing, yoga, kickboxing, volleyball, Tae Kwan Do, violin, guitar, painting, photography, show choir, cooking, roller blading, horse back riding, great with animals and children
Joseph D Castleberry Photographer
Jennifer Gerstner Makeup Artist
AaronStigg... Photographer
Travis Lee Ferguson Model
Holli Milosevic Model
MDunn Photography Photographer
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South Metro Rose Show is May 17-18
The South Metro Rose Society will be holding its 29th annual Rose Show on May 17-18 at Fayetteville Church of Christ fellowship hall at 870 Redwine Rd.
Local rose growers are invited to enter their roses into competition. Ribbons and prizes will be awarded. Members of the society will advise newcomers on entering their roses by calling the number below. Entries must be made at the show site by 9:30 a.m. on May 17 for judging. The show is free to the public from 1-4 p.m. on both days to view, smell, and photograph the exhibited roses.
Hundreds of roses and rose arrangements will be displayed. Rose bouquets will be sold and there will be an Information Table where questions will be answered by ARS Consulting Rosarians. Items to be raffled include a silver plated rose from R. DuBose Jewelers, Georgia Aquarium tickets, Georgia Shrimp gift certificates, Pike's and Autumn Hill Nursery gift certificates, miniature and large rose bushes, and more.
South Metro Rose Society is affiliated with the American Rose Society located in Shreveport, LA. SMRS meets on the 4th Monday of Jan-Apr and Aug-Oct at The Heritage Bank at 440 N. Jeff Davis Dr. in Fayetteville. All rose enthusiasts, especially novices, are invited to visit the meetings at no charge. For more information call 770-631-3885.


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International Encyclopaedia for Migration Law
Editor: Prof. Dr. Dirk Vanheule More about the editors
The International Encyclopaedia for Migration Law deals with international and national rules on immigration and right of residence of non-nationals. It contains national monographs on the migration law applicable in each country. This information is completed by monographs on the legal instruments on migration law adopted by supranational, international and regional organisations. The national...
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