Sep. 27, 2023
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Dysembryoplastic neuroepithelial tumors are rare, indolent, low-grade glioneuronal tumors diagnosed predominantly in children and young adults. Most commonly affecting the temporal lobe and its mesial structures, these tumors classically present with seizures before the age of 20 years. Refractory epilepsy is often managed and cured by complete surgical resection of the tumor. Pathology shows glioneuronal elements and so-called floating neurons. Dysembryoplastic neuroepithelial tumors frequently harbor FGFR1 mutations (and not fusions) that ultimately lead to RAS/MAPK pathway activation.
• Dysembryoplastic neuroepithelial tumor is an indolent WHO grade I glioneuronal tumor usually diagnosed in children and young adults.
• This supratentorial tumor most commonly occurs in the temporal lobe and presents with focal seizures.
• Imaging classically shows a (multi)cystic, lobulated, well-circumscribed tumor with expansion of a cortical gyrus.
• Pathology findings are characterized by glioneuronal elements and floating neurons, whereas molecular analysis often reveals an activating mutation of FGFR1.
• Although these tumors are considered benign, surgical resection is recommended for refractory epilepsy.
• Prognosis for seizure control following resection is excellent.
Dysembryoplastic neuroepithelial tumor is a rare but well-recognized tumor of children and young adults that most often results in chronic epilepsy. In 1988, the clinicopathological features were first elucidated by Daumas-Duport and colleagues, who found tumors in 20 patients undergoing epilepsy surgery at St. Anne Hospital in Paris for which existing tumor classification seemed inadequate. These multinodular tumors, composed of both glial and neuronal elements, were remarkably similar to each other and resulted in a distinct clinical picture. Review of the Mayo Clinic Tissue Registry identified 19 additional cases, and the original report of 39 patients remains one of the most thorough and authoritative accounts of this tumor (10). Several other patient series have confirmed the findings of the original report (46; 55; 43), and further study has expanded the histological and molecular recognition and understanding of this tumor (09; 11; 19; 47; 53). Our knowledge of dysembryoplastic neuroepithelial tumor continues to expand due to a growing body of genomic information.
• Dysembryoplastic neuroepithelial tumors are slow-growing glioneuronal tumors occurring in the cerebral cortex, most often involving the temporal lobe.
• Dysembryoplastic neuroepithelial tumors are associated with epilepsy that is often medically refractory.
• Onset of epilepsy typically occurs between childhood and young adulthood.
Dysembryoplastic neuroepithelial tumors are classified under the “Glioneuronal and neuronal tumors” family in the 5th edition of WHO Classification of Tumours, CNS Tumours series published in 2021. These tumors occur almost exclusively in the cerebral cortex. In 10 large series comprising 346 patients, the tumor involved the temporal lobe in about three fourths of patients and the frontal lobe about another 20% (10; 09; 11; 46; 55; 59; 43; 19; 38; 57). Parietal and occipital tumors made up the remainder. Some older series and case reports describe dysembryoplastic neuroepithelial tumors presenting in atypical locations, such as the septum pellucidum, basal ganglia, posterior fossa, and within the ventricles (02; 29; 06; 13; 30). However, given the long list of differential diagnoses and the lack of modern molecular diagnostic techniques, the accurate diagnosis of dysembryoplastic neuroepithelial tumor in these cases should be interpreted with caution. Indeed, molecular analysis confirmed that dysembryoplastic neuroepithelial tumor-like neoplasms of the septum pellucidum have different genomic alterations and distinct methylome profiles from dysembryoplastic neuroepithelial tumors (08).
There is a slight male predominance (55%). The onset of symptoms occurs almost exclusively in childhood or early adulthood, usually between the ages of 1 month and 17 years, with mean age of symptom onset of 9 years (57). Onset of symptoms in adulthood is less common, though in a series of patients who had undergone epilepsy surgery, more than 40% had adult onset of seizures (04).
Almost every patient with dysembryoplastic neuroepithelial tumor presents with seizures. Depending on the location of the lesion, these can be motor or nonmotor focal seizures that may or may not impair awareness. In some cases, the seizure can spread from focal to bilateral tonic clonic. Most patients develop medically refractory epilepsy. Nonepileptic focal neurologic deficits are much less common. Occasionally, there is protrusion of the skull overlying the lesion. One report describes occurrence of this lesion in two (and possibly three) members of a family (16). Rare presentations have been recorded with symptoms such as headache, vomiting, and increased intracranial pressure or hydrocephalus, particularly when the tumor occurs in a periventricular location and obstructs the foramen of Monro (46; 06; 02; 52). Again, however, these nonclassical locations call into question the accurate diagnosis of dysembryoplastic neuroepithelial tumor, particularly with a lack of molecular diagnostics.
The overall prognosis for patients with dysembryoplastic neuroepithelial tumor is favorable, due to the indolent biology of the neoplasm. Radiological surveillance with CT or MRI imaging for periods of 2 to 12 years has shown no change in size (09; 06; 11) or slow growth with tumor doubling time of 10 years. After resection, recurrent tumor is rare, with most studies reporting no recurrence in any patient (46; 55; 11; 19). Two patients who died from other causes 6 to 15 years after resection had no evidence of recurrent tumor at autopsy (10; 19). A minority of patients do experience recurrence, however (43; 38). Malignant transformation of a dysembryoplastic neuroepithelial tumor is quite rare but has been reported in the literature (15; 54).
Seizure prognosis depends on the treatment modality. Tumor-induced epilepsy often requires neurosurgical intervention due to ineffective medical management and the development of treatment refractory epilepsy. Seizure freedom or reduction of antiepileptic medications with good seizure control are realistic expectations following tumor resection. Greater outcomes might be achieved in patients with less than 1-year duration of epilepsy, and in patients who underwent gross-total resection of the lesion (12). Seizures may return months or years after surgery. For example, one study found that although 85% of children were free from disabling seizures at one year after resection, this proportion dropped considerably over the ensuing two years, with only 62% being seizure-free at last follow-up (38). The only factor found to be associated with long-term seizure freedom was complete tumor resection. For tumors in the temporal lobe, temporal lobectomy may be superior to mere lesionectomy. This might be due to the coexisting cortical dysplasia typically found adjacent to these tumors that likely contributes to seizure recurrence postoperatively (07; 58).
A 20-year-old man presented to the emergency department after a seizure. The seizure was described as focal in onset with left arm stiffening and left gaze deviation which progressed to clonic movement of the left arm and face and ended in a generalized convulsion. He reported a prior 3-year history of episodic deja vu and visual hallucinations for which he never sought medical attention. MRI of the brain showed a multicystic-appearing mass in the right temporal lobe extending into the amygdala, hippocampus, and thalamus without enhancement.
Stereotactic biopsy revealed a low-grade glioma. He opted for observation with serial MRI scans and management of his seizures with anticonvulsants. Initially he was treated with levetiracetam but over the next 12 months his seizures increased in frequency and required addition of anticonvulsants including levetiracetam, lacosamide, and oxcarbazepine. Repeat MRI shows a largely unchanged right temporal lobe mass. EEG showed occasional right anterior temporal discharges. He underwent a right anterior temporal lobectomy with an uncomplicated postoperative course. Pathologic examination revealed dysembryoplastic neuroepithelial tumor. He was able to be slowly weaned off several anticonvulsant medications over the following year. At the time of last follow-up he was seizure free on levetiracetam monotherapy and his imaging showed no sign of tumor recurrence.
• The etiology of this tumor is unknown.
• In most cases, these tumors are sporadic, but some data suggest an association with RASopathies.
• Dysembryoplastic neuroepithelial tumors frequently involve the cortical gyrus with a predilection for the temporal lobe.
• Three classic pathologic features have been described: specific glioneuronal elements, glial nodules, and cortical dysplasia.
• In the majority of cases, FGFR1 alterations are driving tumorigenesis.
Dysembryoplastic neuroepithelial tumors appear in situ as enlargement of a cortical gyrus, which exceeds the thickness of the surrounding normal cortex. Macroscopically, the tumor is often contained within the cortical ribbon, with involvement of the underlying subcortical white matter (27; 19; 40). The lesion has a mucinous or semi-liquid consistency with macroscopic nodules and small cysts. The soft consistency of this tumor renders it prone to damage during removal, and great care must be taken in handling the pathologic specimen or diagnosis may be hindered (10). Meningeal involvement occurs occasionally.
Microscopically, dysembryoplastic neuroepithelial tumors display specific pathologic features. The most specific for this tumor type are the multinodular intracortical growth pattern and the so-called "specific glioneuronal elements," which are formed by bundles of axons and columns of monotonous, small, round cells with little cytoplasm that resemble oligodendrocytes (09; 55).
These columns are oriented perpendicular to the cortical surface and typically form an alveolar pattern, with the interstitial spaces filled with pale, mucinous fluid. Thin capillaries run through these columns, and cytologically normal neurons give the appearance of floating within the fluid matrix (“floating neurons”). Mitotic figures are rare. These small round cells stain positively for S-100 (an oligodendroglial marker), and the majority of tumors showed staining with myelin oligodendrocyte glycoprotein, a marker for mature oligodendrocytes (14). These cells stain only rarely with GFAP (an astrocytic marker); however, multiple reports also demonstrate that in 7% to 40% of cases, small fractions of these cells stain positively for neurofilament protein, synaptophysin, neuron-specific enolase, or class III beta-tubulin, suggesting early neuronal differentiation. In addition, electron microscopy has demonstrated dense-core granules (a characteristic of neuronal differentiation) in a few of these cells and occasional synapse formation involving them (18; 29; 55; 43). This evidence suggests origin from an early glioneuronal precursor rather than from an oligodendroglial cell.
The simple form of dysembryoplastic neuroepithelial tumors contains these specific glioneuronal elements.
The complex form of dysembryoplastic neuroepithelial tumor consists of glial nodules in addition to the specific glioneuronal elements. The sharply demarcated regions of glial nodules are most often situated at the edge of the specific glioneuronal element, bordering the white matter. They are composed variously of astrocytes (usually pilocytic, but sometimes fibrillary or even anaplastic), small round oligodendrocyte-like cells, and mature neurons, with astrocytic nodules being most common. Occasionally, nodules may be composed of cells of glioneuronal lineage that cannot be further characterized (10). Calcified vessels might be visible and can be the source of hemorrhage.
Some distinguish a diffuse/nonspecific form of dysembryoplastic neuroepithelial tumors that lack the specific glioneuronal elements. This form remains controversial without clear and specific histopathological features.
Other than the distinct histological features, the different forms of dysembryoplastic neuroepithelial tumors carry no clinical significance.
Focal cortical dysplasia might be present in a graded fashion at the edges of the specific glioneuronal element, shading off into normal cortex at either end. Neurons in this area do not demonstrate any cytologic atypia. Focal cortical dysplasia type 3b has been reported but remains controversial (09; 57).
The most likely cellular origin of this tumor is the subpial granular layer of the cortex, one of the secondary germinal layers of the nervous system. These cells are believed to migrate into the cerebral cortex in the middle-to-late stages of gestation, and subsequently mature into cortical glial cells (09). Thinning of the inner table of the skull, a frequent radiologic finding in this tumor, and the surrounding cortical dysplasia seen histologically also attest to its development in the earliest stages of life. This hypothesis does not explain the remarkable stability of this lesion; it has been proposed that early control of the abnormal growth by embryonic tissues may be responsible (10). Others have suggested that this lesion is actually a complex hamartoma, with overgrowth of what may represent normal embryonic nervous system tissue, rather than true neoplastic cells (42; 18). However, given the clinical and cytologic characteristics of the lesion, most authors consider this growth to be a benign tumor, and the low rate of recurrence or growth of the lesion support this (10; 55). The reason for the slight male predominance of this lesion is not known.
Proliferative indices seen in dysembryoplastic neuroepithelial tumor range from no labeling (about 25% to 40% of cases) to slight or intermediate labeling of less than 1% of nuclei (50% to 65% of cases) to a high labeling index that may reach the level of cell division seen in high-grade gliomas (10% to 20% of cases) (09; 55; 59; 43; 11; 19). The oligodendrocytic cells of the specific glioneuronal element are rarely labeled. The labeling index of the nodules does not correspond to the aggressiveness of their histologic appearance, nor does the clinical course of highly labeled tumors deviate from the usual indolence that is a constant feature of this entity, suggesting that cell loss keeps up with cell proliferation in these cases.
The molecular features of dysembryoplastic neuroepithelial tumors have become better elucidated. The most characteristic genomic alteration involves mutations in FGFR1 (39). The BRAFV600E mutation, notably found in both high- and low-grade primary brain tumors, has also been reported in approximately 3% of dysembryoplastic neuroepithelial tumors (01). If there is mutation of IDH or homozygous 1p/19q co-deletion is detected, it is not a dysembryoplastic neuroepithelial tumor.
As is the case for other causes of refractory epilepsy, it is not entirely understood why the seizures produced by this entity often appear to be drug resistant. Some evidence suggests that the same multidrug transporter proteins that may produce resistance to chemotherapy in tumors (such as p-glycoprotein, multidrug resistance-associated protein 1, and major vault protein) and that are present in other causes of refractory epilepsy (such as hippocampal sclerosis) are likewise present in dysembryoplastic neuroepithelial tumors and might contribute to their antiepileptic drug resistance (50; 51). A transcriptomic study of nonneoplastic epileptogenic cortical tissues resected from patients with dysembryoplastic neuroepithelial tumors demonstrated enrichment of genes belonging to glutamatergic synapse, as well as altered expression of GABRB1 (synapse formation), SLIT2 (axonal growth), and PROKR2 (neuron migration). These genes/pathways could serve as potential links to epileptogenesis (24).
• Dysembryoplastic neuroepithelial tumors are rare, with an incidence of 0.033 per 100,000 person-years.
• Dysembryoplastic neuroepithelial tumors often present with chronic or medically refractory epilepsy.
Data from the Surveillance, Epidemiology, and End Results (SEER) database from 2004 to 2013 demonstrated the incidence of dysembryoplastic neuroepithelial tumor to be 0.033 per 100,000 person years (37). Within the population of patients with chronic epilepsy seen at tertiary referral centers, the incidence of brain tumors is 15%; 6% of these tumors are dysembryoplastic neuroepithelial tumors, yielding an overall incidence of 0.9% in this patient group (36). This is clearly influenced by selection bias. Two more case series, however, using expanded diagnostic criteria for the tumor, found that 18% to 19% of patients undergoing temporal lobe resection for refractory epilepsy had a dysembryoplastic neuroepithelial tumor (11; 19). It is unclear if these numbers hold up in contemporary times after decades of experience in surgical management of epilepsy.
• No means of preventing these tumors is available.
• Some data suggest association of dysembryoplastic neuroepithelial tumors with RASopathies. As a result, patients with a germline NF1 or FGFR1 mutations, as well as with Noonan syndrome, might have an increased risk for development of dysembryoplastic neuroepithelial tumors (28; 03; 47; 49).
The differential diagnosis for this lesion consists of:
• Glial tumors (both infiltrating and circumscribed) including pilocytic astrocytoma, astrocytomas, oligodendroglioma, and pleomorphic xanthoastrocytoma
• Glioneuronal tumors including ganglioglioma, neurocytoma, myxoid glioneuronal tumor, multinodular and vacuolating neuronal tumor
• Cortical dysplasia
• BRAF-mutant tumors
Complete resection of dysembryoplastic neuroepithelial tumors has clinical and diagnostic benefit. The soft consistency of this tumor renders it prone to damage during removal, and great care must be taken in handling the pathologic specimen or diagnosis may be hindered (10). Histologically, the specific glioneuronal element may be mistaken for that of an oligodendroglioma due to the appearance of the predominant cell type. The nodules may be mistaken for astrocytoma. Biopsy may yield only one of the components, leading to the potential for misdiagnosis.
Pleomorphic xanthoastrocytoma and ganglioglioma usually appear as cystic lesions with enhancing mural nodules on imaging, but lack the hallmark histopathological features of dysembryoplastic neuroepithelial tumors, such as the specific glioneuronal elements and floating neurons. Gangliogliomas contain dysplastic ganglion cells, eosinophilic granular bodies, and perivascular lymphocytic infiltration; these are features that are missing in dysembryoplastic neuroepithelial tumors. Oligodendroglial tumors are often calcified and demonstrate strong cytoplasmic staining for IDH R132H (or IDH mutation noted on sequencing) along with 1p/19q co-deletion on molecular analysis. Astrocytomas also have positive staining for IDH mutation or proof of IDH mutation by gene sequencing. Hamartoma must also be considered in the differential diagnosis.
Given the increased usage of molecular testing, the differential for dysembryoplastic neuroepithelial tumors could also include other CNS tumors with mutations in BRAF. The BRAFV600E mutation is found in epithelioid glioblastoma, pleomorphic xanthoastrocytoma, anaplastic pleomorphic xanthoastrocytoma, ganglioglioma, anaplastic ganglioglioma, astroblastoma, desmoplastic infantile astrocytoma, subependymal giant cell astrocytoma, diffuse astrocytoma, and pilocytic astrocytoma (01).
Although our understanding of the biology of dysembryoplastic neuroepithelial tumors is still evolving, it is critical to combine the clinical, radiological, histopathological, and molecular findings to arrive at an integrated diagnosis. Proper diagnosis of this entity is crucial for patient care, as the treatment is different than that for low-grade astrocytomas.
• MRI of the brain with and without contrast typically shows a (multi)cystic, lobulated, T2 hyperintense lesion without cerebral edema or mass effect and with or without enhancement on T1 post-contrast images.
• EEG may be obtained for epilepsy localization and to rule out other epileptic foci.
Because most patients present with childhood epilepsy, they will likely undergo radiological imaging and EEG. On computed tomography imaging, dysembryoplastic neuroepithelial tumors appear as hypodense lesions, with calcification in about 25% of patients and contrast enhancement in 15% (10; 09; 46; 25; 55). Perhaps 5% of cases are CT occult. Thinning of the overlying skull is apparent on CT in approximately one-third of cases, particularly when the tumor has a superficial location. In early studies, cystic appearance was reported in 28% to 50% of cases with CT or MRI (10; 11; 46; 55). However, a series using MRI noted small cysts, sometimes separated from the main tumor mass, in 100% of 37 cases and found that these “pseudocysts” actually corresponded pathologically to the specific glioneuronal element (05).
MRI reveals the lesion to have hyperintense signal on T2-weighted images and hypointense signal on T1-weighted images in the large majority of cases. The intracortical location of the tumor is seen much more clearly on MRI than on CT. Neither mass effect nor edema is seen. Contrast enhancement, generally focal or punctate in appearance, was seen in about 30% of cases in early series and might be related to the presence of focal cortical dysplasia (09; 46; 25; 55; 05). Thick gyriform or nodular configuration, often with well-demarcated tumor lobules, appears to be highly specific for dysembryoplastic neuroepithelial tumor (25). Angiography is often normal but may show neovascularization or an avascular mass with shift of normal structures. 11C-methionine positron emission tomography (PET) can also be helpful in narrowing a differential diagnosis, as dysembryoplastic neuroepithelial tumors exhibit low metabolism compared to gangliogliomas which are often hypermetabolic (41).
Two studies have shown that patients with these tumors frequently have discordant or bilateral interictal epileptiform activity on EEG. However, this does not correlate with seizure outcomes after surgery (46; 26). It remains to be seen if new advances in epilepsy surgery (such as brain mapping) will provide better guidance for clinical management, specifically to delineate the optimal area of surgical resection.
Surgical resection is recommended for confirmatory pathologic diagnosis and to rule out other conditions. Tumor resection may be curative for associated epilepsy. However, the presence of satellite lesions is a poor prognostic factor for long-term seizure control (58).
Genomic analysis of the tumor tissue is recommended to identify somatic mutations and potentially suggest underlying germline mutations. Dysembryoplastic neuroepithelial tumors frequently harbor FGFR1 kinase domain tandem duplication or hotspot missense mutations at codons p.N546 or p.K656. BRAF mutations are also described in dysembryoplastic neuroepithelial tumors. As we learn more about the molecular background of these tumors, a new classification system based on biology might be expected in the future.
• Tumor-associated epilepsy is common with dysembryoplastic neuroepithelial tumors and medical management with anticonvulsants is recommended.
• Given the indolent and benign nature of these tumors, surgical resection is only recommended for patients with medically refractory epilepsy.
• There is no rule for radiotherapy or chemotherapy in the upfront treatment of dysembryoplastic neuroepithelial tumors.
Although patients with dysembryoplastic neuroepithelial tumor are unlikely to die as a consequence of neoplastic growth, active management is often indicated to treat tumor symptoms, particularly epilepsy. A substantial portion of patients with this tumor have epilepsy that is refractory to anticonvulsant medication (though there may be some ascertainment bias, with resection and diagnosis occurring more often in patients with intractable seizures). No studies examine the use of particular anticonvulsant agents in this population.
Refractory epilepsy can be debilitating, particularly in the adolescent population. These patients experience deleterious effects on their learning and behavior in school, as well as negative impacts on their emotional and physical wellbeing (21). Up to 50% of young patients with epilepsy have difficulties with attention, concentration, and memory; a study found that adolescents hospitalized with epilepsy were shown to have a three-times higher risk of not achieving minimum standards for mathematics and reading (45; 23; 32). Thus, effective treatment of these patients is paramount to minimize potential long-term cognitive, social, and emotional sequelae.
The mainstay of management of this tumor is surgical resection (48). Surgery is usually indicated to obtain tissue diagnosis. Surgical resection tends to be safe, and a review of 185 pediatric patients with dysembryoplastic neuroepithelial tumor who underwent surgical resection showed a 12% rate of postoperative complications (44).
Early surgical intervention, younger age, and less than one year of seizure duration are good prognostic indicators for seizure control. As a result, surgery is recommended once medical management of seizure has failed. The negative effect of a surgical intervention on neurodevelopment needs to be accounted when risks and benefits of the treatment options are considered.
Radiation therapy and systemic therapies have limited utility in the initial treatment of these tumors. Patients who have received radiation for dysembryoplastic neuroepithelial tumor have been shown to have worse outcomes and decreased overall survival (37). This may be driven, in part, by more aggressive tumors receiving radiation and/or adjuvant radiation use for subtotal resections. Radiation therapy may also lead to radiation induced side effects (eg, neurocognitive decline, radiation necrosis, alopecia), malignant transformation of the tumor, and the potential development of a second cancer, which is especially poignant in this age group.
There are no consensus guidelines regarding follow up recommendations following gross total resection with adequate seizure control. Repeat imaging would be warranted should a patient present with seizure recurrence or other new onset neurologic changes. MRI surveillance is recommended following subtotal resection due to the possibility of tumor recurrence and/or malignant transformation, particularly for extra-temporal complex forms (31).
• Seizure freedom is associated with extent of neurosurgical tumor resection.
• Early surgical intervention, younger age, and less than 1 year of seizure duration are good prognostic indicators for seizure control.
The overall prognosis for patients with dysembryoplastic neuroepithelial tumor is favorable due to the indolent biology of the neoplasm.
Improvement in tumor-induced epilepsy can be achieved either with medical management or with tumor resection. Total or subtotal resection resulted in elimination of seizures at follow-up of 1 year in about 80% of the patients (10; 11; 46; 43; 04). However, seizure-free rates decline measurably over years 2 and 3 to around 60% (38). Complete tumor resection plays a critical role for long-term seizure freedom, with results far better in the patients having complete resection than in those with residual tumor (40% seizure-free vs. 88% seizure-free, respectively). Longer duration of epilepsy has been associated with worse seizure outcomes in dysembryoplastic neuroepithelial tumor patients (20; 33). It is possible that this is due to the cortical dysplasia that frequently abuts this tumor and may suggest that tumor resection should be accomplished with an ample margin to remove such dysplastic regions (58). MRI may help in the identification of patients who benefit from larger surgical resection.
Positive prognostic factors for improved seizure control following tumor resection include younger age at diagnosis, earlier diagnosis, focal onset seizures at presentation, and larger extent of tumor resection (34).
In very rare cases, malignant transformation of dysembryoplastic neuroepithelial tumor can be seen. Risk factors for malignant transformation include complex-type histologic features, location outside the temporal lobe, and subtotal resection (35; 17).
In light of the presence of FGFR abnormalities in these tumors, targeted therapies may be considered; however, at this time clinical data are limited (22).
No information is available regarding the effects of pregnancy on this tumor, or vice versa (56). Pregnant patients might need closer follow up with an epileptologist.
No information is available regarding the use of specific anesthetic agents in patients with dysembryoplastic neuroepithelial tumor.
All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.
Rimas V Lukas MD
Dr. Lukas of Northwestern University Feinberg School of Medicine received honorariums from Novocure for speaking engagements, honorariums from Cardinal Health, Novocure, and Merck for advisory board membership, and research support from BMS as principal investigator.See Profile
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