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Paraneoplastic disorders or remote effects of cancer can affect any part of the nervous system. Neurologists, oncologists, and ophthalmologists need to be aware that this includes the retina and optic nerve. Retinal neuronal dysfunction and degeneration may occur in association with a number of systemic neoplasms, including--most notably--melanoma and small cell lung carcinoma. For many patients, vision loss is the presenting feature of the associated tumor. Some affected patients have circulating antibodies against retinal antigens; these antibodies serve as diagnostic markers for the condition and may also play a role in causing retinal dysfunction. In this article, the authors summarize the clinical features, autoimmune pathogenesis, and treatment options for patients with paraneoplastic retinal degeneration.
• Paraneoplastic retinopathy is a rare entity associated with a variety of neoplasms, most commonly small cell lung carcinoma or melanoma.
• In most patients with cancer-associated paraneoplastic retinopathy, subacute vision loss is the presenting feature of the malignancy, whereas vision loss develops after the melanoma diagnosis in the majority of patients with melanoma-associated paraneoplastic retinopathy.
• The pattern of vision loss and degree of retinal dysfunction can vary depending on the type of tumor, and a diagnosis is confirmed by widespread retinal dysfunction on electroretinogram (ERG).
• Most patients with paraneoplastic retinopathy have one or more antiretinal autoantibodies with varying immunohistochemical staining patterns and specificity for a number of retinal antigens.
• Immunosuppressive therapy should be offered to patients with vision loss from paraneoplastic retinopathy; early diagnosis may lead to a better outcome.
The first well-documented cases of "photoreceptor degeneration as a remote effect of cancer" were reported in 1976 by Sawyer and colleagues (126). The cases were of 3 female patients with bronchial carcinoma. The term "paraneoplastic autoimmune retinopathy" encompasses patients with heterogeneous tumor associations and clinical features and probably represents more than 1 pathophysiologic mechanism.
In nearly all patients with cancer-associated autoimmune paraneoplastic retinopathy, the visual symptoms are the presenting feature of the tumor, preceding discovery of the tumor by intervals ranging from several months to 2 or more years. The signs and symptoms of paraneoplastic retinopathy nearly always involve both eyes, but asymmetry can be often present, especially early in the course of the disease process. The initial symptoms most frequently entail a progressive, otherwise unexplained vision loss with midperipheral scotomata (missing spots in vision). There may be dimming or blurring of vision; night blindness is common and may be the sole initial complaint. Because the disease causes dysfunction of retinal neurons, many patients report episodic obscurations or photopsias described as distortions, "sparkles," "shimmering," or bizarre images reflecting the dysfunction of damaged photoreceptors (73; 121). Some patients report increased glare or photosensitivity, so-called hemeralopia or day blindness due to cone dysfunction, and many have visual field changes: visual field constriction, midperipheral loss, or central or paracentral scotomata (65; 103; 129). Some patients have central sparing of their visual fields (26; 29). In most patients, the visual symptoms worsen over weeks to months, either in a steady or stepwise fashion. No well-documented cases of spontaneous improvement exist.
The examination of patients with cancer-associated paraneoplastic retinopathy is abnormal. Visual acuity is usually severely impaired and color vision can be affected as well. As a result of widespread, sometimes asymmetric retinal dysfunction, approximately one half of reported patients have afferent pupillary defects. Funduscopic exam shows mild or moderate attenuation of the retinal arterioles in the majority of patients, but is otherwise often unremarkable except for occasional vitreous cells and some instances of optic nerve pallor and mild retinal pigment epithelial changes. Some patients have vascular leakage evident on fluorescein angiography. Chorioretinal atrophy and optic nerve atrophy may eventually be seen later in the disease course (103).
The clinical features of patients in whom retinopathy is associated with melanoma differ somewhat from the clinical features of patients with cancer-associated retinopathy (79; 76; 88). The majority of these patients develop visual symptoms after the diagnosis of melanoma, with intervals of up to 10 years or more. Visual symptoms can lead to the discovery of previously unsuspected systemic metastases (21; 10; 117). Subacute night blindness is a common feature of melanoma-associated retinopathy. Most patients additionally report floaters, shimmering, flickering, or pulsating photopsias early in the course of the disease. Visual acuity, visual fields, color vision, and funduscopic exam can seem unremarkable earlier on; most patients eventually develop decreased visual acuity and visual field abnormalities including generalized constriction, central or paracentral scotomata, or arcuate defects (96; 147; 117; 76). Some patients develop optic disc pallor, retinal vessel attenuation, retinal pigmentary changes, or vitreous cells (76). Uveitis or retinal vasculitis manifesting as leakage around vessels on fluorescein angiography have also been reported (72; 119).
Another recognized variant of melanoma-associated retinopathy is "paraneoplastic vitelliform retinopathy" (67; 22; 15). Patients present with mild loss of visual acuity and frequently have night blindness and photopsias. Funduscopic exam shows multiple serous detachments of the retinal pigment epithelium and neurosensory retina.
The clinical course of cancer-associated paraneoplastic retinopathy is usually one of deterioration over the course of weeks to months, in a gradual or stepwise fashion, to a level of severe visual impairment. No well-documented instances of significant spontaneous improvement are known.
A 64-year-old man with a past medical history notable for a 40-pack-a-year history of cigarette smoking developed painless blurring and dimming of the central field of vision in his left eye, with associated light sensitivity, especially when outside. Three weeks later, similar symptoms developed in his right eye, and the vision in both eyes progressively deteriorated. He also noted intermittent, colorful "sparkles" or halos around objects. Examination 6 weeks after the onset of symptoms demonstrated visual acuities of 20/400 in the right eye and 20/200 in the left eye with severe dyschromatopsia. Both pupils were minimally reactive to light, and there was no relative afferent pupillary defect. Ophthalmoscopy was normal except for attenuation of the retinal arterioles. Visual fields were severely constricted bilaterally with a ring scotoma evident in the right eye. Electroretinogram showed near absence of the cone response in both eyes. Brain MRI with and without contrast was within normal limits. Chest x-ray showed suspicious mediastinal widening, and chest CT scan showed hilar adenopathy. Bronchoscopy was diagnostic for small cell lung carcinoma. Staging workup showed no metastatic tumor. Serum was found to contain antirecoverin antibodies. The patient was placed on prednisone 60 mg/day (1 mg/kg) and chemotherapy with cisplatin and etoposide. After 1 month of prednisone and 1 cycle of chemotherapy, the patient's visual acuity and visual fields remained essentially stable. Steroids were tapered and discontinued, and a complete tumor remission was attained after 4 cycles of chemotherapy. The patient's vision deteriorated but returned to its previous baseline again after 3 weeks of prednisone (60 mg/day).
As with other neurologic paraneoplastic disorders, the leading theory of the pathogenesis of paraneoplastic retinopathy is that an autoimmune response initially directed against tumor cell antigens subsequently "spills over" to attack photoreceptor cells and other retinal neurons (34). The mechanism by which these antibodies cross the blood-retinal barrier is less clear (85).
The most common histopathologic features of paraneoplastic retinopathy associated with small cell lung carcinoma (cancer-associated retinopathy) are severe; sometimes there is total loss of the inner and outer segments of rods and cones, and widespread degeneration of the outer nuclear layer (126; 26; 121; 05). Some eyes show patchy, mild infiltration of mononuclear cells around retinal arterioles. Varying changes in ganglion and bipolar cells as well as photoreceptor cells may be present (53). A proposed mechanism of photoreceptor loss is that autoantibodies anchor to the photoreceptors and activate the complement pathway, leading to cell lysis. It remains unclear why photoreceptors often degenerate whereas the retinal pigment epithelium does not (35).
A few reported autopsies of patients with melanoma-associated retinopathy showed preservation of the photoreceptor cell layers but marked depletion of cell nuclei in the inner nuclear and bipolar layers (50). A single autopsied case of paraneoplastic vitelliform retinopathy showed multifocal retinal edema as well as atrophy affecting mainly the inner nuclear layer, outer plexiform layer, and outer nuclear layers (15).
Most patients with paraneoplastic retinopathy have circulating antiretinal autoantibodies. As with other neurologic paraneoplastic disorders (34; 52; 123), the autoantibody specificities among patients with paraneoplastic retinopathy are heterogeneous (08; 01). The most prevalent antiretinal antibodies are polyclonal IgG antibodies against the 23 kd calcium-binding protein recoverin. The majority of patients with paraneoplastic retinopathy and antirecoverin antibodies have small cell lung carcinoma (65; 115; 08). Antirecoverin antibodies may also be present in patients with gynecologic or other carcinomas (141; 40; 103; 08; 125). Antirecoverin antibodies stain the inner and outer segment layers, the outer nuclear layer of the retina, and to a lesser degree the inner nuclear layer of the retina (140; 115; 75).
Recoverin is expressed by retinal rods, cones, and bipolar cells. It functions in the phototransduction cascade by modulating the phosphorylation of rhodopsin (20). Recoverin is expressed by the majority of small cell lung carcinomas (92; 93; 19). Patients' antirecoverin antibodies exert a cytotoxic effect and induce apoptosis in rat retinal cells in vitro (06; 28; 27; 131; 09). Intravitreous injection of antirecoverin antibodies into rats produces abnormal electroretinograms and thinning of the inner and outer nuclear retinal layers (101; 93). These effects are enhanced when antibodies against heat-shock protein are injected into the vitreous together with antirecoverin antibodies. Rats or mice immunized with purified recoverin develop antirecoverin antibodies, uveoretinitis with cellular infiltrates, and degeneration of photoreceptors (07; 91; 87). These same histopathologic changes can be reproduced by passive transfer of stimulated lymphocytes from rats immunized with recoverin into naive animals.
Some patients with retinopathy associated with small cell lung carcinoma or other carcinomas have no identifiable antiretinal antibodies, have autoantibodies that react with retinal target antigens distinct from recoverin (74), or have antibodies against recoverin plus antibodies against one or more other retinal antigens (60). Other identified retinal target antigens include a 65 kd heat shock protein (102; 150; 103); retinal enolase (03; 55; 08; 148); neurofilament triplet proteins (54; 134); the 48 kd retinal S-antigen (121; 105; 136); carbonic anhydrase (57); a photoreceptor cell nuclear receptor (39); a 78 kd retinal protein that belongs to the "tubby" gene family (77); 35 and 40 kd photoreceptor membrane proteins (109; 107); and antibodies against 1 or more as yet unidentified retinal proteins (104; 99; 127; 143; 103; 128; 86; 44; 94). Anti-aldolase autoantibodies have been proposed as a possible biomarker associated with colon cancer–associated retinopathy, anti-carbonic anhydrase II with prostate cancer–associated retinopathy, and anti-arrestin in melanoma–associated retinopathy (04).
The immunoreactivity of autoantibodies from patients with melanoma-associated retinopathy is also heterogeneous. Sera from some patients with melanoma-associated retinopathy stain a subset of approximately 30% of retinal bipolar cells, and, to a lesser degree, outer rod segments (96; 147; 72; 119; 23). There is a single reported patient with retinal degeneration and antibipolar cell antibodies associated with colon carcinoma (64). The molecular target(s) of antibipolar cell antibodies have not been well characterized (58). One of the known targets is TRPM1 (transient receptor potential cation channel, subfamily M, member 1), a cation channel that mediates the light response in bipolar cells (32; 81; 38; 144; 37; 78). Three isoforms of TRPM1 have been identified in melanoma-associated retinopathy patients (146). There is a single reported case of anti-TRPM1 antibodies in a patient with retinopathy and small cell lung carcinoma (81).
Other patients with melanoma-associated retinopathy have autoantibodies distinct from the "typical" antibipolar cell antibodies. Retinal antigens reacting with these antibodies include the photoreceptor proteins rhodopsin or transducin (116; 58), recoverin, enolase, S-arrestin, heat shock protein, and aldolase (88). Reported patients with melanoma-associated paraneoplastic vitelliform retinopathy also have varied antiretinal antibodies, including antibodies against bipolar cells, or against 1 of a number of identified proteins including alpha-enolase or carbonic anhydrase II, or other as yet unidentified autoantibodies (22; 15).
Injection of IgG from patients with melanoma-associated retinopathy into the vitreous of monkeys produces electroretinographic changes similar to those seen in human patients (83). Adoptive transfer of splenocytes from transgenic melanoma-bearing mice into wild-type mice produced retinopathy in some recipients (18).
More than 75% of reported patients with paraneoplastic retinopathy have a single tumor type: small cell lung carcinoma. A unique feature of paraneoplastic retinopathy compared to other paraneoplastic syndromes is that the second most common tumor association is with melanoma (10; 12; 96; 79; 147; 88). Also existing are case reports of patients with nonsmall cell lung carcinoma (141; 134; 55; 103), breast carcinoma (80; 06), ovarian carcinoma (115; 57), endometrial carcinoma (100), prostate carcinoma (06; 109; 103; 51), gastric carcinoma (102), colon carcinoma, pancreatic cancer (48), uterine tumors (73; 29; 40; 104; 02; 127), teratoma (136), lymphoma (143), thymoma (71; 150; 103), and Waldenstrom macroglobulinemia (128).
The only known risk factors are the strong association between cigarette smoking and small cell lung carcinoma, and the association between sun exposure and melanoma.
The differential diagnosis of vision loss in cancer patients includes direct tumor spread, adverse effects of treatment, and remote effects of tumors on the visual system. MR scanning should rule out infiltration or compression of the optic nerve or chiasm by metastatic tumor. Many patients with leptomeningeal metastases from solid tumors develop vision loss during the course of their illness, either from papilledema or from direct tumor cell infiltration in and around the optic nerves (124). In some of these patients, vision loss is the presenting complaint.
Radiation-induced retinal damage may occur following focal cobalt plaque radiotherapy for choroidal melanoma or following external beam radiotherapy for orbital tumors, usually when the doses are in excess of 50 Gy (25; 118). The peak time of onset of vision loss is 14 to 18 months after radiotherapy. Funduscopic exam shows “cotton wool spots,” telangiectasias, neovascularization, and in some patients, hemorrhages with neovascular glaucoma. Fluorescein angiography shows areas of retinal capillary nonperfusion.
Radiation-induced optic neuropathy most commonly occurs after fractionated radiotherapy for tumors of the orbit, paranasal sinus, nasopharynx, pituitary adenoma, or craniopharyngioma, or less commonly, following whole-brain radiotherapy for primary or metastatic brain tumors (122). Optic neuropathy may also occur after stereotactic radiosurgery for pituitary adenoma or meningioma (49). The peak incidence of radiation optic neuropathy is 12 to 18 months following completion of radiation. Patients present with painless unilateral or bilateral subacute loss of visual acuity, central scotoma, and afferent pupillary defects. Funduscopic exam may show swollen discs, telangiectasias, exudates, and retinal arteriolar narrowing. MRI scanning shows patchy contrast enhancement of one or both optic nerves, and occasionally of the optic chiasm. Microvascular injury is thought to be the underlying mechanism.
Several antineoplastic agents can, in rare instances, damage the retina or optic nerve and cause vision loss. Toxic retinopathy has been reported following use of cisplatin, carboplatin, nitrosoureas, procarbazine, tamoxifen, and interferon (62; 11). Optic neuritis or optic atrophy may occur following use of cisplatin, vincristine, fludarabine, methotrexate, nitrosoureas, procarbazine, paclitaxel, and 5-fluorouracil (90). The risk of retinal or optic nerve toxicity from chemotherapy is greatly increased when the agents (particularly cisplatin or carmustine) are administered via the internal carotid artery for treatment of brain tumors.
Paraneoplastic optic neuritis is a rare complication of breast carcinoma, small cell lung carcinoma, thymoma, or other tumors. Nothing is clinically distinctive about the optic neuritis in these patients, who have decreased visual acuity, afferent pupillary defects, cecocentral scotomata, and disc edema. Paraneoplastic optic neuritis may occur in isolation (84; 130; 14) or in conjunction with retinopathy (30; 44). Some patients with optic neuritis also have cerebellar ataxia (95; 31; 89; 139), multifocal encephalomyelitis (30), or a syndrome resembling Devic disease (neuromyelitis optica) (30; 13; 36; 114). Some patients have serum collapsin response-mediator protein-5 (CRMP5) antibodies, which can be associated with a variety of malignancies including small cell lung cancer, renal cell carcinoma, and thyroid papillary carcinoma, among others (151; 17; 98; 68). CRMP5 paraneoplastic processes can present with multiple neurologic and visual symptoms such as cognitive dysfunction, imbalance, and blurred vision. Other patients may have anti-CV2 antibodies (31; 139; 30; 130; 14), antiaquaporin-4 antibodies (114), or other antineuronal antibodies (84; 13; 132).
Rarely, progressive bilateral vision loss may be caused by diffuse uveal melanocytic proliferation occurring as a remote effect of ovarian, lung, breast, gastrointestinal, or other genitourinary carcinomas (47; 24; 33; 145). In most reported patients, vision loss was the presenting feature of an otherwise occult tumor. Fundoscopy classically reveals a pattern of multiple, round, red subretinal patches that are hyperfluorescent on fluorescein angiography. Additionally, patients have multiple pigmented and nonpigmented uveal melanocytic tumors, exudative retinal detachment, and cataracts. Other retinopathies such as acute exudative polymorphous vitelliform maculopathy and autosomal recessive bestrophinopathy can resemble fundoscopic findings in paraneoplastic retinopathy as well (16). It is also important to remember that there are numerous other etiologies of bilateral vision loss, independent of cancer history, such as retinitis pigmentosa, cone dystrophy, toxic retinopathies, toxic and nutritional optic neuropathies, and hereditary optic neuropathies, among many others; working closely with ophthalmology (often neuro-ophthalmology, uveitis, and retina subspecialists) becomes critical to ensuring all possible etiologies are explored.
The finding of serum antirecoverin antibodies in patients with vision loss is a highly suggestive, but not absolute, indicator of the presence of an underlying tumor, especially small cell lung carcinoma. When antirecoverin antibodies were first characterized they were believed to be absolutely specific for paraneoplastic retinal degeneration (74). Antirecoverin antibodies have been detected in several patients presenting with retinal degeneration in whom no associated tumor was even detected, even after long periods of follow-up (149; 59). Positive serologic testing should also not exclude other possible inflammatory or autoimmune etiologies such as birdshot chorioretinopathy or acute zonal occult outer retinopathy (138; 129).
Nonparaneoplastic autoimmune retinopathy. There is increasing recognition of autoimmune retinopathy occurring in persons without an associated neoplasm (60; 46; 137). The clinical features of nonparaneoplastic autoimmune retinopathy do not reliably differ from those of cancer-associated retinopathy (also present with photopsias or blind spots and have rapid vision changes). The consensus statement on this entity concluded that essential diagnostic criteria include: ERG abnormalities, an absence of fundus lesions or retinal dystrophy or other clear cause of vision loss, along with an absence of significant ocular inflammation and the presence of antiretinal antibodies on serologic testing (46). Some patients with nonparaneoplastic autoimmune retinopathy have serum autoantibodies against 1 or more retinal antigens, including antienolase antibodies (08; 148), or autoantibodies reacting with antigens other than recoverin or enolase (97; 110; 111; 112). Still, there remain limitations with testing for serum antiretinal antibodies as there remains no standardization or validation of testing approaches to date (45).
The antibipolar cell antibodies associated with melanoma and retinopathy have not been reported in patients with other conditions, except for a single reported patient in whom no melanoma or other tumor was detected after several years of follow-up.
The electroretinogram (ERG) in almost all patients with cancer-associated paraneoplastic retinopathy shows reduced amplitude of the a-wave, and it may be nearly flat, reflecting diffuse dysfunction of both rod and cone photoreceptor cells (141; 65). The ERG can be severely abnormal in the face of relatively preserved visual acuity and normal ophthalmoscopic exam. The ERG in patients with melanoma-associated retinopathy usually shows a marked reduction in the amplitude of the dark-adapted b-wave and a normal dark-adapted a-wave (21; 10; 12; 79; 147; 72; 76; 69). This resembles the abnormalities in patients with "congenital stationary night blindness" and indicates dysfunction of retinal bipolar cells. In some melanoma patients the ERG a-wave is reduced, reflecting photoreceptor cell degeneration (76). ERG of a small number of reported patients with melanoma-associated vitelliform retinopathy suggests involvement of both rods and cones (15).
Other retinal studies, including fluorescein angiography, fundus autofluorescence, and optical coherence tomography (OCT) are also important ancillary tests to rule out other retinal pathology and have demonstrated varied patterns of abnormalities in these patients (22; 113; 94; 106).
In the small number of reported patients tested, cerebrospinal fluid was normal, except for slightly elevated protein or a mild lymphocytic pleocytosis in a few patients (82; 65).
A reasonable starting workup for patients with suspected paraneoplastic retinopathy includes MR imaging of the brain and orbits with contrast with attention to the optic pathways, ERG, and serum assay for antiretinal antibodies (or paraneoplastic panel that includes this antibody). Screening for serum antirecoverin antibodies can be done by a number of commercial or research laboratories. It should be noted that a negative assay for antirecoverin or other antiretinal antibodies does not rule out paraneoplastic retinopathy or the presence of an underlying tumor, and that a few patients with antiretinal antibodies never develop an identifiable associated neoplasm. Similarly, the presence of these antibodies is not in itself diagnostic and there remain difficulties with antibody detection and consistency in results among different laboratories (51; 133). A study by Faez and colleagues demonstrated a concordance rate of any antiretinal antibody around 60% and noted a poor interobserver agreement on lab detection and measurement (42). Clinical correlation remains of paramount importance.
For patients with suspected paraneoplastic retinopathy, with or without identifiable antiretinal antibodies, a complete oncologic work-up should be pursued, including CT chest/abdomen/pelvis or equivalent MRI. Whole-body FDG-PET scanning may reveal a tumor in the lung or elsewhere that was not clearly imaged by other techniques (108; 56). PET scanning does have some false positives and negatives. It is not uncommon for patients’ initial evaluations for an occult tumor to be unrevealing; in these patients, the workup should be repeated every several months.
Empiric antitumor treatment without a histologic cancer diagnosis in patients with suspected paraneoplastic retinopathy is not recommended. When the tumor is diagnosed, it should be treated with the appropriate surgical, chemotherapeutic, or radiation measures, with the realization that progressive visual loss often occurs despite successful antitumor treatment. In conjunction with treatment of the tumor, patients with paraneoplastic retinopathy should receive a trial of prednisone 60 to 80 mg per day, with or without a preceding "pulse" of methylprednisolone. Local therapy with intravitreal or sub-Tenon triamcinolone and, most recently, intravitreal long-acting steroid implants have been utilized as well (70; 120). Prednisone should also be offered to patients with a clinical diagnosis of retinopathy and positive serum antirecoverin antibodies or other antiretinal antibodies, but no detectable neoplasm. In 1 series the majority of patients with antibody-associated carcinoma-associated retinopathy or nonparaneoplastic autoimmune retinopathy showed improved visual acuity and visual fields after treatment with a regimen of prednisone, azathioprine, and cyclosporin (43). Reports exist of patients whose vision improved with intravenous immunoglobulin (55; 135) or with rituximab, a monoclonal antibody against CD20-expressing B lymphocytes (106); some of these patients failed to respond to prior corticosteroids. There is a single reported case of significant visual improvement after treatment with the monoclonal antibody alemtuzumab, which causes depletion of T lymphocytes and B lymphocytes bearing the CD52 cell surface antigen (41).
Patients treated with immunosuppression therapy may show initial improvement in visual acuity, even before discovery of the underlying neoplasm, but generally disease stabilization is the best outcome (73; 80; 121; 105; 40; 61). Improvement in outer retinal structures including the photoreceptor layer has been demonstrated in a case report following chemotherapy as well as topical steroid drops; such structural improvement has also been demonstrated with rituximab therapy (63). There does not seem to be a difference in the response to prednisone between patients with antirecoverin antibodies and patients with other antiretinal antibodies or no antibodies. No definite reports mention visual improvement following surgery or chemotherapy of small cell lung cancer without concomitant corticosteroid therapy.
Patients with melanoma-associated retinopathy generally suffer progressive vision loss despite tumor treatment or immunomodulatory therapy. Some patients do, however, have visual improvement after cytoreductive tumor surgery, corticosteroids, or intravenous immunoglobulin (10; 96; 72; 119; 23; 76; 66; 125; 142).
Nicholas J Volpe MD
Dr. Volpe of Northwestern University and Northwestern Memorial Hospital is an equity owner in Opticent Inc., has research support from Quark, Inc and has consulted for Opthotech.See Profile
Shira S Simon MD MBA
Dr. Simon of Northwestern University and Northwestern Memorial Hospital has received research support from Quark, Inc.See Profile
Rimas V Lukas MD
Dr. Lukas of Northwestern University Feinberg School of Medicine received honorariums from Novocure for speaking engagements, honorariums from Novocure and Merck for advisory board membership, and research support from BMS as principal investigator.See Profile
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