Morvan syndrome and related disorders associated with CASPR2 antibodies
Jan. 23, 2023
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POEMS syndrome is a rare multisystem disease with unknown pathogenesis; it is classified as a plasma cell dyscrasia. Although neuropathy is the dominant clinical feature, the syndrome is characterized by a constellation of manifestations, including but not limited to those referred by the acronym: polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes. In this article, the authors discuss the biological basis, clinical presentation, diagnosis, and treatment options, including autologous peripheral blood stem cell transplantation and other emerging therapies.
• POEMS syndrome is a rare multisystem disease caused by an underlying plasma cell dyscrasia.
• The acronym POEMS refers to polyneuropathy (dominant clinical feature), organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes, although many other features may be intermixed.
• The diagnosis is made based on a composite of clinical and lab features. An accurate differential diagnosis should be made to avoid misdiagnosis and improper therapeutic management.
• Treatment targets the underlying plasma cell clone with a risk-adapted therapy.
The first case of what we now know as POEMS syndrome was reported in 1938 by Scheinker (75). Almost 20 years later, Crow described two patients with multiple myeloma and peripheral neuropathy in his paper titled “Peripheral neuritis in myelomatosis.” Both patients presented with peripheral neuropathy and had lytic and sclerotic bone lesions, skin pigmentation, and normal sedimentation rates (14). Twelve years later, other author described a patient with plasmacytoma, polyneuritis, and endocrine abnormalities (81). In 1973, Yodoi described the association of myeloma, polyneuropathy, endocrinopathy, and skin pigmentation and postulated this to be a new syndrome (98). A few years later, Takatsuki and coworkers reviewed 32 patients with polyneuropathy, endocrinopathy, and a plasma cell disorder (86). In 1980, Bardwick and colleagues described similar findings in American patients and coined the term POEMS (polyneuropathy, organomegaly, endocrinopathy, presence of a monoclonal band and skin changes) (07). It has also been referred as Crow-Fukase syndrome, Takatsuki syndrome, PEP syndrome (plasma cell dyscrasia, endocrine disturbances and polyneuropathy), osteosclerotic myeloma, and Japanese multisystem syndrome.
The acronym POEMS refers to polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes. However, many other features may be intermixed, including sclerotic bone lesions, Castleman disease, peripheral edema, papilledema, thrombocytosis, renal disease, and various other systemic manifestations. Each one of these manifestations is described below.
Polyneuropathy. The most common manifestation of POEMS syndrome is peripheral neuropathy, and it is present in all patients with the disease. Symptoms typically start with distal and symmetrical numbness, tingling, prickly pain, or aches in the feet (46), and progress in a "glove and stocking distribution" with motor involvement following the sensory symptoms and leading to progressive weakness. The neuropathy involves small and large fibers equally.
Deep tendon reflexes are lost early. Progression varies among patients, causing some to be bedbound, and ultimately can lead to death. In advanced stages, marked atrophy of distal muscles occurs. Pure motor or pure sensory syndromes have been described. Sphincter dysfunction and cranial nerve involvement are rare.
Electrophysiologic studies reveal demyelinating and axonal features with prolonged distal motor latencies and marked slowing of conduction velocities (from segmental demyelination), reduced motor amplitudes, fibrillations, positive sharp waves, and enlarged, polyphasic motor unit action potentials (from axonal damage). Several electrophysiologic patterns were identified in patients with POEMS syndrome, which are distinct from other types of polyneuropathies. Nerve conduction slowing is typically predominant in the intermediate rather than distal nerve segments, is more severe and frequent in the lower rather than upper limbs, motor rather than sensory fibers are more greatly affected, and conduction block is infrequent (6%) relative to other demyelinating diseases (84; 65).
Cerebrospinal fluid shows a moderate to marked elevation of protein. In 102 patients with POEMS syndrome, 97% had elevated cerebrospinal fluid protein (greater than 50 mg/dL), and 30% had levels greater than 200 mg/dL (69). Similar results were later noted in 109 patients (85).
Peripheral nerve biopsies most often show a mixture of axonal degeneration and segmental demyelination. Mononuclear cell infiltration is rarely seen, with case reports of a few scattered mononuclear cells in the endoneurium as well as in the perivascular spaces of the endoneurium and epineurium (89; 90). Immunoglobulin deposits rarely have been described in the endoneurium that have corresponded to the monoclonal antibody in the serum (40; 01). Amyloid deposition is absent. Uncompacted myelin lamellae are highly present in peripheral nerve biopsy specimens of most patients with POEMS syndrome, so their demonstration on a thorough ultrastructural examination can be strongly suggestive of this disease (89; 90).
Ophthalmologic and orbital involvement has included oscillopsia with blurred vision (11), proptosis (31), optic disc drusen, and peripapillary choroidal neovascularization (18). Optical coherence tomography has been used to evaluate and monitor these ophthalmologic findings in POEMS (28).
Organomegaly and Castleman disease. Liver (83%), spleen (24%), and lymph nodes (42%) are the commonly enlarged organs in POEMS syndrome (86; 69; 66). In total, 50% of patients from a large Mayo Clinic series had organomegaly (23). Histologic examination of enlarged lymph nodes may show Castleman disease or reactive changes. Enlargement of other organs, such as kidneys, thyroid, parotid, and heart, has also been reported.
Castleman disease (or angiofollicular lymph node hyperplasia) is a rare lymphoproliferative disorder whose presentation may range from an asymptomatic unifocal mass to multifocal masses with a multitude of symptoms, from B symptoms to autoimmune phenomena or POEMS syndrome.
Endocrinopathy. Endocrine abnormalities vary among reported series, usually due to hormone insufficiency involving the four major endocrine axes (gonadal, thyroid, glucose metabolism, and adrenal). In one large series from the Mayo Clinic, 84% of patients had a recognized endocrinopathy, hypogonadism being the most common (32). Men can develop impotence, gynecomastia, testicular atrophy, and reduced testosterone level as well as elevated estrogen, follicle-stimulating hormone, and luteinizing hormone. Women can experience amenorrhea with decreased luteinizing and follicle-stimulating hormone levels. Diabetes mellitus occurs in nearly 50% of cases. In another series, hypogonadism was followed by hyperprolactinemia (56%), hypothyroidism (54%), abnormal glucose metabolism (24%), adrenal insufficiency (17%; Addison disease), and hypoparathyroidism (09). Hypothyroidism has been associated with inferior survival (96). Spontaneous resolution of endocrine abnormalities can occur, so on-going treatment should remain under review.
Monoclonal plasma cell disorder. According to the new criteria for POEMS syndrome, all patients by definition have a clonal plasmaproliferative disorder (19). In the Mayo Clinic series, a serum or urine monoclonal (M)-protein was found in 88% of patients--usually of small size (median serum M-spike of 11 g/L), the light chain almost always of lambda type, and the associated heavy chain of IgA or IgG isotype (23). However, IgG kappa chains, IgE, and IgM bands have also been reported. In patients without M-protein by immunofixation, clonality can be demonstrated by immunohistochemical staining of bone marrow or sclerotic bone lesions, although bone marrow plasma cell population is usually 10% or less (23). Dao and colleagues studied the bone marrow histopathology in pretreatment samples from 67 patients with POEMS syndrome (16). Based on their findings, the constellation of monotypic (lambda-restricted) plasma cells, lymphoid aggregates rimmed by plasma cells, and megakaryocyte hyperplasia is considered highly suggestive of this diagnosis, especially in the proper clinical context.
Less frequently, POEMS syndrome can be associated with multiple myeloma (usually the osteosclerotic type), plasmacytoma, Waldenström macroglobulinemia, or lymphoproliferative disorders (69; 48). Castleman disease is also clearly associated with POEMS syndrome (11% to 30% of cases), although the nature of the correlation is not well understood (23).
Skin changes. Cutaneous findings are present in 68% of patients and include hyperpigmentation, hypertrichosis, thickened skin, hyperhidrosis, thin white nails (Terry nails), “clubbing,” sclerodermatous changes with Raynaud phenomenon, alopecia, and edema of the skin. Lesions may resemble generalized histiocytomas (17). Glomeruloid hemangiomas, characterized by its histological resemblance to renal glomeruli, are specific cutaneous markers for POEMS syndrome and have immunologic features that differ from traditional hemangiomas and littoral angiomas of the spleen (49; 88). Although rare, histologically proven vasculitic lesions have also been described (78).
Osteosclerotic bone lesions. Bone lesions have been described in 50% to 96% of patients with POEMS syndrome as either purely sclerotic or mixed sclerotic and lytic on radiographic bone surveys (85; 69; 23). In a retrospective study, CT assessment demonstrated a high sensitivity in identifying sclerotic lesions (35). In this study, skeletal survey had a false negative rate of 36%, whereas CT showed at least one lesion in all evaluated patients, the most common pattern being multiple small lesions of less than 1 cm; CT also proved to be useful in the response evaluation. Larger lesions had lytic centers with sclerotic margins and used to be 18F-FDG avid by PET. Although only able to detect metabolic active bone lesions, PET has shown to contribute to the diagnosis, evaluation, and monitoring response to treatment in patients with high baseline FDG uptake (02; 82; 35). Finally, a case of POEMS syndrome with destructive polyarthritis and multicentric Castleman disease has been described (10).
Vascular manifestations. Both arterial and venous thromboses have been described, including gangrene, ischemia, ischemic cardiomyopathy (62), vasospastic angina (44), splenic infarcts, and strokes. Cardiomegaly was postulated to have been part of organomegaly in a 51-year-old woman and improved after treatment of the POEMS syndrome (80). Pericarditis leading to tamponade with elevated IL-6 in the pericardial fluid was described in a study (79). Vascular disease may involve infarctions from macroangiopathy (coronary, cerebral, or peripheral nerve) or acute vascular obliteration (56). It has been suggested that vasculopathy might be induced by the overproduction of cytokines and systemic inflammation due to POEMS syndrome (30).
Respiratory manifestations. In a large series of 137 patients with POEMS syndrome from the Mayo Clinic, 28% presented with pulmonary manifestations, including pulmonary hypertension, restrictive lung disease, respiratory muscle weakness, and an isolated diminished diffusing capacity (03). In a series of 154 patients, pulmonary hypertension was identified in 27% and was associated with signs of extravascular volume overload; although reversible with treatment, pulmonary hypertension was associated with worse survival (60). Pleural effusions, pulmonary edema, and chylothorax have also been reported (52; 15).
Extravascular volume overload. Extravascular volume overload is present in approximately one third of patients, mainly as peripheral edema (24% of patients) and less frequently as ascites (7%) or pleural effusion (3%) (23).
Hematologic manifestations. Polycythemia and mainly thrombocytosis are common findings in POEMS syndrome (23). Anemia is unfrequent (hemoglobin lower than 110 g/L in fewer than 5% of patients), and none of the patients in the Mayo Clinic series progressed to overt multiple myeloma (23). There is a well-acknowledged prothrombotic state.
Renal manifestations. Renal involvement is rare, and when present, membranoproliferative glomerulonephritis and endothelial injury are characteristic (97).
Psychiatric involvement. The incidence of depression is reported as 38%, with extent of neuropathy, upper limb function, and ascites reported as significant independent predictors (101).
In the first published series of patients with POEMS syndrome, the mean survival was 33 months in 102 patients (69), and the estimated 5-year survival was 60% in another series with 38 patients (66). In a large series of 291 patients from the Mayo Clinic, a 10-year overall survival of 62% was reported confirming the very good long-term outcomes of patients with this disease (50). On the multivariate analysis, younger age, albumin greater than 32 g/L, and attainment of complete hematologic response were factors associated with superior overall survival (50; 51).
A 43-year-old woman without relevant past medical history complained of paresthesia and neuropathic pain in her legs under her knees leading to progressive difficulty in walking over the previous 6 months.
Electrophysiology demonstrated a demyelinating sensory-motor polyneuropathy, and the patient progressively developed asthenia and dyspnea on exertion. The diagnosis of rheumatic polymyalgia had been suspected, and the patient had received treatment with prednisone and intravenous immunoglobulin without improvement.
On physical examination, she presented with peripheral edema in her legs, moderate hepatomegaly, and skin lesions consisting in telangiectasias and acrocyanosis. Laboratory examinations revealed thrombocytosis of 550 x109/L, a serum IgA-lambda monoclonal spike of 7.5 g/L (Bence Jones protein was negative) with 9% plasma cells in the bone marrow aspirate, and hyperprolactinemia together with a sublinical hypothyroidism. No VEGF was available at that time (in 2001). Radiological skeletal survey showed sclerotic bone lesions in both humeri and proximal left femur.
Echocardiography suggested a severe pulmonary hypertension that was confirmed by hemodynamic studies, and lung function test showed a severe restrictive lung disease. She also presented a papilledema by funduscopy. A CT scan found homogeneous liver enlargement without lymphadenopathy.
This patient fulfilled both mandatory major criteria (polyneuropathy and monoclonal gammopathy), one additional major criterion (sclerotic bone lesions), and at least five minor criteria for POEMS syndrome as well as associated pulmonary hypertension.
Given her poor performance status at presentation, she was considered not to be a good transplant candidate and received cyclophosphamide and prednisone together with supportive therapy (diuretics and anticoagulation). Clinical improvement was evident after two cycles of chemotherapy, and she was eventually able to receive high-dose melphalan and stem cell rescue. After transplant, the patient achieved a complete hematologic response and mild improvement of polyneuropathy as well as a significant clinical improvement of the remaining clinical features of the disease. This response lasted for 12 years.
Although the underlying plasma cell dyscrasia in POEMS syndrome suggests an antibody-mediated etiopathogenesis, the features of the disease are not explained by immune-mediated processes alone. Pathologic review of affected organs does not support paraprotein deposition as a mechanism of disease (69; 89; 90) even though the association between monoclonal plasma cells and activity of the disease is well established (45). Overproduction of proinflammatory cytokines and angiogenic growth factors, mainly vascular endothelial growth factor, are believed to play an important pathogenic role (95). However, there is no unifying explanation for all the features of POEMS syndrome, and the pathogenesis remains unknown.
Regarding VEGF, significantly elevated serum levels have been found in POEMS syndrome (92), higher than in other monoclonal gammopathies (92) and other neurologic diseases (93), and decreased levels in correlation with response to conventional therapy have been described (93; 74). VEGF is secreted by platelets during platelet aggregation (36) and possibly by plasma cells (93). Aggregation of platelets on vascular walls could lead to elevated local VEGF concentration, promoting vascular permeability, angiogenesis, and monocyte and macrophage migration. These mechanisms could explain the arterial obliteration, microthrombosis, edema, organomegaly, pulmonary hypertension, skin changes, and neuropathy. Overexpression of VEGF is thought to affect peripheral nerves by causing endoneurial edema and microangiopathy of endoneurial vessels (74). Glomeruloid hemangiomas, thought to be highly specific for POEMS syndrome, are believed to be a reactive endothelial proliferation in response to angiogenic stimuli (88). However, the cause of VEGF overproduction remains to be elucidated. Agents that specifically reduce VEGF levels, such as ticlopidine (63) and bevacizumab (06), have been reported to improve disease symptoms, but the response appears to be inconsistent (76), suggesting that other angiogenic growth factors might be playing a role (95).
Overproduction of proinflammatory cytokines, such as tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), and interleukin-6 (IL-6), have also been involved in the pathogenesis of the disease (34). Elevated levels of matrix metalloproteinases and tissue inhibitors of metalloproteinases have been described (64). Human herpesvirus-8 (HHV-8) has been identified in POEMS disease associated with Castleman disease, and a homologue to human IL-6 is present in the HHV-8 genome (04). Although the pathogenesis of the endocrine disturbance remains unexplained, one patient showed serum antibody activity against pituitary tissue, suggesting an autoimmune basis (71).
Nagao and colleagues performed a comprehensive genetic analysis of plasma cells from 20 patients with POEMS syndrome, including whole exome sequencing, targeted sequencing, and RNA sequencing (68). They identified 20 mutations in seven recurrently mutated genes (not including any of the driver gene mutations frequently found in multiple myeloma) as well as a specific transcription profile. In contrast, Chen and colleagues performed a similar analysis and revealed heterogeneous genomic profiles of bone marrow plasma cells that might share similarities to other plasma cell disorders (12).
POEMS syndrome is a rare disease with unknown exact incidence. Most initial cases were reported from Japan. An estimated frequency of 20 cases per year has been described in Germany (08). A study from Taiwan of 10,974 patients evaluated for monoclonal proteins found that 2.6% had monoclonal bands, and 2.8% of them (8 patients) fulfilled criteria for POEMS syndrome (55). Patients usually present around 50 years of age. In four separate studies, the median ages were 46 years (69), 51 years (66), 55.3 years (26), and 51 years (23).
No preventive measures to reduce the risk of POEMS have been identified.
The differential diagnosis of POEMS syndrome includes other causes of peripheral neuropathy (such as chronic inflammatory demyelinating polyneuropathy); other monoclonal gammopathies (both asymptomatic and symptomatic); various skeletal abnormalities; and other diseases, including diabetes, porphyria, heavy metal toxicity, sarcoidosis, paraneoplastic disorders, and hereditary demyelinating states. Regarding skeletal abnormalities, the differential diagnosis of osteosclerotic lesions includes osteosclerotic myeloma; Paget disease; and osteoblastic solid tumors, such as prostate metastasis, lymphoma, or systemic mastocytosis. On the other hand, other conditions with osteolytic lesions (although less frequently seen in POEMS) are osteolytic myeloma, osseous metastasis, histiocytosis X, solitary plasmacytoma, and lymphoma. Finally, lymphadenopathy alone or associated with other enlarged organs may represent neoplastic lesions, such as those seen with Castleman disease or other lymphomas. Organomegaly may also occur from infiltrative diseases, such as sarcoidosis, and from metastatic neoplastic disease.
The diagnosis of POEMS syndrome is based on a combination of clinical and laboratory features and requires a good history and physical examination, including a whole skin evaluation. The following studies should be performed in a patient with clinical suspicion of POEMS syndrome (22; 21).
• Blood test with a complete blood count, sedimentation rate, electrolytes, urea, creatinine, liver function tests, and serum and urine immunoglobulin electrophoresis and immunofixation.
• Serum VEGF measurement.
• Endocrine screening, including testing for diabetes and pituitary and thyroid dysfunction as well as assessment of bone metabolism.
• In the presence of a monoclonal band and a neuropathy, bone marrow aspiration is required to search for a plasma cell malignancy.
• If no serum or urine monoclonal protein is detected and the clinical suspicion for POEMS syndrome is high, immunohistochemical staining of biopsy specimens from skeletal lesions or bone marrow is indicated.
• Electromyography is needed to determine the nature of the polyneuropathy.
• A skeletal survey for osteolytic or osteosclerotic lesions should be undertaken in all patients. CT imaging and PET/CT should be considered.
• Enlarged lymph nodes should be biopsied to diagnose lymphoproliferative disorders and neoplastic conditions. In this sense, 18F-FDG PET/CT may be useful in detecting and selecting bone lesions and lymph nodes for biopsy (02).
New criteria for the diagnosis of POEMS syndrome were proposed from a retrospective study of 99 patients (23). Clinical features were divided into mandatory major, major, and minor criteria (Table 1). Both mandatory major criteria, together with at least one of three major and one of the six minor criteria are necessary for the diagnosis.
Mandatory major criteria
• Sclerotic bone lesions
• Organomegaly (splenomegaly, hepatomegaly, or lymphadenopathy)
Other known associations
* Diabetes mellitus and thyroid abnormalities are not sufficient alone to meet the minor criterion due to their high prevalence.
Due to the low frequency of this disease, few controlled clinical trials and even fewer randomized trials have been conducted. Consequently, there is no consensus regarding standard therapeutic regimens for POEMS syndrome. Most of the recommendations for treatment have been derived from small numbers of cases and experienced groups (20; 21; 54). A systematic review of the most commonly used therapies for POEMS syndrome has also been published (29). In order to choose the appropriate treatment, bone marrow involvement and the number of osteosclerotic bone lesions should be taken into account (41; 21). Evaluation of response after treatment should consider clinical symptoms, hematologic response, VEGF levels, and PET/CT scan (27).
Patients with a limited number (up to three) of osteosclerotic bone lesions and those with multiple lesions in a limited area without disseminated bone marrow involvement can be treated by radiation therapy with doses of 40 Gy or more (39). More than half of patients have significant symptom improvement and durable responses, with time to response of neurologic symptoms being about 3 to 6 months after treatment, whereas nonneurologic manifestations tend to respond more quickly (39).
Systemic therapy targeting the underlying plasma cell clone is necessary if the patient has extensive bone marrow involvement or more than three bone lesions. Radiation therapy can be considered as adjuvant therapy in cases of large, bony lesions with a significant lytic component, but no earlier than 6 months after completing systemic therapy. Corticosteroids alone or in combination with alkylator-based therapies with melphalan or cyclophosphamide (23; 61) as well as immunosuppressant agents, such as cyclosporine or azathioprine with prednisone (23), have been of limited benefit. The first therapeutic approach to show dramatic responses in this disease was high-dose chemotherapy with autologous stem cell transplant (ASCT) (38; 72; 43). Dispenzieri and colleagues reported responses in 14 of 16 patients who received this treatment, with neuropathy improvement in all of them, although with significant morbidity and transplant-related mortality in one patient (25). An update of this series with 59 patients who received an ASCT at the Mayo Clinic and a median follow-up of 45 months showed a hematologic response rate of 78% (including 57% complete responses) and clinical improvement in 92% of patients (27). In this series, the 5-year progression-free survival and overall survival were 75% and 94%, respectively, with younger age (below 50 years), IgG-lambda isotype, presence of PET-avid lesions at baseline, and lack of hematologic response being significant risk factors for progression (27). Similar results were reported in a large series of patients from the EBMT registry (13). No differences were observed between cyclophosphamide plus G-CSF versus G-CSF alone as a mobilization regimen of peripheral blood progenitors in a retrospective Italian study (05). Induction chemotherapy before ASCT is not mandatory, but it might help to obtain a rapid response, allowing some patients to undergo transplant in a better condition (41). However, ASCT can be complicated by engraftment syndrome in up to 50% of cases (24), so the use of G-CSF after transplant should be avoided, and graft failure can occur in up 10% of them (stem cell backup recommended according to personal experience). Moreover, pulmonary complications requiring mechanical ventilation occurred in a third of patients in one series, with transplant-related mortality up to 7.5%, so an accurate pulmonary evaluation before ASCT is necessary (25; 53).
For those patients who are not candidates for radiation therapy nor for high-dose chemotherapy and ASCT, there is no consensus on the best treatment option. VEGF responses were reported with thalidomide plus dexamethasone, but it is not recommended as first-line therapy due to potential neurotoxicity (67). Promising responses have been published with lenalidomide plus dexamethasone becoming a safe and effective treatment option even in the setting of newly diagnosed disease (73; 42; 99; 57; 70; 59) and in thalidomide-refractory patients (83). Thrombotic risk associated with this regimen and the disease itself should be taken into account, and the type of prophylaxis should be individualized according to the risk of falls (21). The role of bortezomib to treat POEMS syndrome as a single agent, in combination with dexamethasone, or with cyclophosphamide and dexamethasone has also been supported by a number of case reports and a small series of patients with no significant neurologic worsening (91; 100; 37). The investigation of newer agents, such as pomalidomide, daratumumab (47; 33; 58; 77; 87), or even CAR-T cell therapy (94), is warranted.
Supportive therapy and a multidisciplinary approach, including physical and occupational therapy, are essential given the common significant physical limitations and complex nature of the disease. Dialysis may be needed for renal disease, antiplatelet agents in cases of thrombocytosis, phlebotomy for polyglobulia, and endocrine interventions for the specific disturbances. Intravenous immunoglobulin and plasmapheresis are not effective.
All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.
Joan Blade MD PhD
Dr. Blade of Hospital Clinic of Barcelona received honorariums for educational lectures from Janssen and Celgene/BMS.See Profile
M Teresa Cibeira MD PhD
Dr. Cibeira of Hospital Clinic of Barcelona received honorariums as guest speaker and advisory board member from Akcea Therapeutics, Amgen, Janssen, and Sanofi.See Profile
Francesc Graus MD PhD
Dr. Graus, Emeritus Professor, Laboratory Clinical and Experimental Neuroimmunology, Institut D’Investigacions Biomédiques August Pi I Sunyer, Hospital Clinic, Spain, has no relevant financial relationships to disclose.See Profile
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