Marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT) lymphoma is an indolent B-cell non-Hodgkin lymphoma arising from the lymphoid tissue at extranodal sites.
Marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT) lymphoma is an indolent B-cell non-Hodgkin lymphoma arising from the lymphoid tissue at extranodal sites. It is genetically characterized by different, usually mutually exclusive, genetic abnormalities that lead to activation of the nuclear factor kappa B (NF-ÎºB) pathway. These lymphomas can arise in any extranodal organ or tissue; however, the stomach-where MALT lymphoma development has been strongly linked to chronic Helicobacter pylori infection-is the most common site. Other microorganisms have been associated with non-gastric MALT lymphomas, but the evidence for such associations is weaker. Treatment aimed at eradicating H pylori infection results in remission of gastric MALT lymphoma in most patients and represents a model of anticancer treatment based on the eradication of the causative factor. Treatment of non-gastric MALT lymphomas is much less well established; either radiotherapy or systemic therapy (with chemotherapy and/or rituximab [Rituxan]) can be effective, while antibiotic therapies (eg, doxycycline in ocular adnexal lymphomas) should still be considered investigational.
According to the fourth edition of the World Health Organization (WHO) classification of tumors of hematopoietic and lymphoid tissues, the group of B-cell marginal zone lymphomas (MZL) comprises three different entities. These are MZL of mucosa-associated lymphoid tissue (MALT), nodal MZL (previously known as monocytoid lymphoma), and splenic MZL (with or without circulating villous lymphocytes).[1-3] While primary splenic and nodal MZLs are quite rare, each comprising approximately 1% to 2% of lymphomas, the extranodal MZL of MALT (currently named MALT lymphoma) is not uncommon, representing approximately 8% of the total number of non-Hodgkin lymphoma cases.
Macroscopically, MALT lymphomas are often indistinguishable from the inflammatory lesion from which the lymphoma arises, but they can also present with obvious tumor masses. These lymphomas are often multifocal, with small, often microscopic clonally identical foci of lymphoma scattered throughout the involved organ. MALT lymphoma is defined as an extranodal lymphoma composed of heterogeneous B cells, including small lymphocytes with round nuclei and clumped chromatin (sometimes centrocyte-like), monocytoid cells, and plasmacytoid cells. One or more cytological features can predominate, or the different types of cells can coexist to various degrees within the same case. Scattered large cells (immunoblast- and centroblast-like) are usually present, but these are in the minority and their prognostic significance is not fully understood. Nevertheless, evaluation for a potential associated large B-cell lymphoma by analysis of extra-follicular components for transformed large B cells is essential because when the blast cells form solid or sheet-like proliferations, a separate diagnosis of a diffuse large B-cell lymphoma should be made. Plasma cell differentiation is often present in MALT lymphomas, as well as a number of non-neoplastic, reactive T cells. Neoplastic B cells can infiltrate and disrupt the mucosal crypts and glands, forming lymphoepithelial lesions. These latter, although highly characteristic of MALT lymphoma, especially gastric lymphoma, are not pathognomonic, nor is their presence essential for the diagnosis, since they can also be detected in some reactive conditions[6,7] and in other lymphoma subtypes.[8,9]
There is no specific immunohistochemical marker for MALT lymphoma at present. The tumor cells typically express IgM, less often IgA or IgG; they are positive for CD20, CD79a, CD21, and CD35, and they are negative for CD5, CD23, CD10, and cyclinD1, recapitulating the immunophenotype of normal marginal zone B cells. Stains for cytokeratin can help in the identification of lymphoepithelial lesions. The immunoglobulin light chain restriction is often difficult to demonstrate in small biopsy specimens.
The demonstration of B-cell monoclonality by polymerase chain reaction (PCR) has been proposed to help differentiate between a florid reactive lymphoid reaction and MALT lymphoma. However, monoclonality can be seen in benign inflammations, such as chronic gastritis,[10-12] and conversely, PCR may fail to detect monoclonality in up to 15% of cases of overt MALT lymphoma, causing false-negative results, due to the presence of a high load of immunoglobulin heavy chain (IGHV) somatic mutations.[13,4]Thus, MALT lymphoma should not be diagnosed in the absence of clear histological evidence.
A Treatment Algorithm for Localized Gastric MALT Lymphoma
MALT lymphoma usually arises in mucosal sites where lymphocytes are not normally present and where MALT is acquired in response to either chronic infectious conditions or autoimmune processes, such as Hashimoto thyroiditis or Sjgren syndrome. Helicobacter pylori gastritis is the best studied condition, but other infectious agents have been implicated in the pathogenesis of MALT lymphomas arising in the skin (Borrelia burgdorferi), in the ocular adnexa (Chlamydophila psittaci), and in the small intestine (Campylobacter jejuni).
MALT lymphoma presents with somatically mutated IGHV genes in all cases. IGHV sequence analysis shows a pattern of somatic hypermutation and rearrangement suggesting that the tumor cell has undergone antigen selection in germinal centers.[15,16] The presence of so-called ongoing mutations (intraclonal variation) and the biased usage of some IGHV segments (eg, 1-69 in salivary glands) indicate that the expansion of lymphoma cells could still be antigen-driven. Also, the antibodies expressed by MALT lymphoma cells often have specificity for self-antigens.[18-20] In the context of this continual antigenic stimulation, abnormal B-cell clones that acquire successive genetic abnormalities can progressively replace the normal B-cell population of the inflammatory tissue, thereby giving rise to the lymphoma.
MALT lymphomas present with a series of recurrent genomic lesions, including chromosomal translocations and unbalanced genomic aberrations (Table 1).[21-31]
The t(11;18)(q21;q21) translocation is the most common translocation, and it results in the reciprocal fusion of BIRC3-previously named cellular inhibitor of apoptosis protein 2 (cIAP2)-on 11q21 with MALT1 on 18q21.[20,31] The presence of t(11;18) is associated with a low probability of response to antibiotics and with H pylori negativity in primary gastric MALT lymphoma; it is also associated with more advanced disease.[33-35] However, MALT lymphomas with this translocation present a lower risk of transformation to diffuse large B-cell lymphoma (DLBCL).
The t(14;18)(q32;q21) translocation is cytogenetically identical to the t(14;18)(q32;q21) translocation involving BCL2 in follicular lymphoma or DLBCL; here, however, it juxtaposes the MALT1 gene to the promoter region of the IGHV genes, with subsequent MALT1 deregulation.
The t(1;14)(p22;q32) translocation causes overexpression of the BCL10 gene due to the juxtaposition of the IGHV genes and the promoter region. BCL10 is highly expressed in the nuclei of the neoplastic cells of MALT lymphomas carrying this translocation, and a high nuclear expression is also detected in t(11;18)-positive cases and in other patients as well.[34,35,37,38]
The t(3;14)(p13;q32) translocation induces the juxtaposition of the gene coding for the transcription factor FOXP1 and the enhancer region of the IGHV genes.[24,31] Unlike t(11;18) and t(14;18), t(3;14) is not strictly specific for MALT lymphomas; it can also be detected in DLBCL. Indeed, a high expression of FOXP1 seems to correlate with a poor outcome in both MALT lymphomas and DLBCL, and high expression of this transcription factor may be associated with a risk of transformation to high-grade tumors.[39,40]
Other recurrent translocations, such as the t(9;14)(9p24;q32) translocation juxtaposing the JMJD2C gene and the IGHV promoter regions, have been reported; however, their role in MALT lymphomas is uncharacterized. JMJD2C is a histone demethylase, recently shown to be deregulated by DNA amplification in primary mediastinal B-cell lymphoma and in Hodgkin lymphoma.
MALT lymphomas, together with the splenic and nodal MZLs, present gains of chromosomes 3/3q and 18/18q at a frequency higher than that seen in other B-cell tumors.[26,43-45] A new recurrent 6q23.3 deletion has been described, which, together with somatic mutations, inactivates the TNFAIP3/A20 gene.[44,46-48] The presence of gains affecting chromosomes 3 and 18 and the lack of other lesions-such as deletions at 7q31 (common in splenic MZL), at 13q14.3 (common in chronic lymphocytic leukemia), or at 11q22 (common in chronic lymphocytic leukemia or mantle cell lymphoma)-can help distinguish MALT lymphomas from other indolent lymphoid neoplasms.
Most Common Lesions Detected in MALT Lymphomas
Importantly, the result of at least four of the recurrent lesions (TNFAIP3 loss, BIRC3-MALT1, IGHV-BCL10, IGHV-MALT1) is the activation of the nuclear factor kappa B (NF-ÎºB) pathway, which is central in regulating immunity, inflammation, and apoptosis, and which represents a possible therapeutic target for MALT lymphomas. Interestingly, while direct TNFAIP3 inactivation is caused by similar lesions in different lymphoma subtypes (ie, deletions and/or somatic mutations),[44,47,48,50,51] different mechanisms seem to activate BIRC3 in different MZL subtypes, as shown by a recent study reporting recurrent somatic mutations in splenic MZL that disrupt the same RING domain that is removed by t(11;18) in MALT lymphomas.
Lastly, it is worth mentioning that the chromosomal translocations are mutually exclusive, and that, unlike 3/3q and 18/18q gains and 6q23 deletions, they show a different anatomical distribution.[25,29,30]
MALT lymphoma is a neoplasm of adults with a median age at presentation of about 60 years; a slightly higher proportion of females than males are affected. Pediatric cases are exceedingly rare. The presenting symptoms are essentially related to the primary location. Very few patients present with elevated lactate dehydrogenase (LDH) or beta-2 microglobulin levels, and constitutional B symptoms are extremely uncommon. MALT lymphoma usually remains localized for a prolonged period within the tissue of origin, but dissemination to multiple sites is not uncommon, with either synchronous or metachronous involvement of multiple mucosal sites or non-mucosal sites such as the bone marrow, the spleen, or the liver. Regional lymph nodes can also be involved. Bone marrow involvement is reported in up to 20% of cases.
The stomach is the most common site of localization, accounting for about one-third of cases. Other typical presentation sites include the salivary glands, the ocular adnexa, the thyroid, and the lung.
Advanced disease at diagnosis appears to be more common in MALT lymphomas that arise outside the gastrointestinal (GI) tract. Up to one quarter of patients with gastric lymphoma-but nearly half of those with non-GI lymphoma-present with disseminated disease.[52,53]
Within the stomach, MALT lymphoma is often multifocal, possibly explaining the reports of relapses in the gastric stump after surgical excision. Gastric MALT lymphoma can often disseminate to the small intestine
and to the splenic marginal zone. Concomitant GI and non-GI involvement can be detected in approximately 10% of cases.[52,53]
MALT lymphoma usually has a favorable outcome, with overall survival at 5 years higher than 85% in most series. Patients with lymph node or bone marrow involvement at presentation, but not those with involvement of multiple mucosal sites, may have a worse prognosis. If initially localized, the disease is generally slow to disseminate. Recurrences may involve either extranodal or nodal sites. The median time to progression has been reported to be better for GI than for non-GI lymphomas, but with no significant differences in overall survival between the two groups. In fact, non-GI MALT lymphomas, despite presenting more often as stage IV disease, usually have a quite indolent course, regardless of treatment type. Nonetheless, they are significantly more prone to relapse (most often at other mucosal sites) than primary gastric cases. Localization may have prognostic relevance because of organ-specific clinical problems that determine particular management strategies, but also because of specific local pathogenetic mechanisms, as suggested by the reports of different frequencies of different chromosomal translocations at distinct anatomic locations.
In a radiotherapy study from Toronto, gastric and thyroid MALT lymphomas had the best outcome, whereas distant failures were more common for other sites.[55,56] In a multicenter series from the International Extranodal Lymphoma Study Group (IELSG), those patients who initially presented with disease in the upper airways appeared to have a slightly poorer outcome, but their small number prevented any definitive conclusion. In general, despite frequent relapses, MALT lymphomas most often maintain an indolent course. Histological transformation to large-cell lymphoma is reported in about 10% of cases (apparently a lower rate than in other indolent lymphomas), and usually occurs late during the course of the disease and independently from dissemination.[57-59] It is unknown whether the incidence of transformation differs among sites.
The most common presenting symptoms of gastric MALT lymphoma are nonspecific upper GI complaints, often leading to endoscopy that usually reveals nonspecific gastritis or peptic ulcer, with mass lesions being unusual. Diagnosis is based on the histological evaluation of the gastric biopsy specimens.
The best staging system is still controversial. The Ann Arbor staging system, routinely used for non-Hodgkin lymphoma, was developed for Hodgkin disease and is not adequate for the specific problems posed by GI-tract lymphomas. A variety of alternative systems have therefore been proposed. We have primarily used a modification of the Blackledge system known as the ‘‘Lugano’’ staging system. However, this system was proposed before the advent of endoscopic ultrasound examination and does not accurately describe the depth of infiltration in the gastric wall, a parameter that is highly predictive of the MALT lymphoma response to anti-Helicobacter therapy. There is a general consensus that initial staging procedures should include gastro-duodenal endoscopy, with multiple biopsies from each region of the stomach, duodenum, and gastro-esophageal junction, as well as from any abnormal-appearing site. Fresh biopsy and washing material should be available for cytogenetic studies in addition to routine histology and immunohistochemistry. FISH analysis or a molecular assay for the detection of t(11;18) is recommended for identifying disease that is unlikely to respond to antibiotic therapy. The presence of active infection must be determined by histochemistry and breath test; serology studies are recommended when the results of histology are negative. Endoscopic ultrasound is recommended at the initial follow-up for evaluation of depth of infiltration and presence of perigastric lymph nodes.
Although the disease usually remains localized to the stomach, systemic dissemination and bone marrow involvement should be excluded at presentation. Staging should include complete blood cell counts; basic biochemical studies; CT of the chest, abdomen and pelvis; and a bone marrow biopsy.[61,62]
A major change in the management of gastric MALT lymphoma occurred following the identification of H pylori as its etiologic agent. Surgical resection, often followed by postoperative radiotherapy or chemotherapy, was standard up to the early 1990s. After the initial report by Wotherspoon et al in 1993, several groups have now confirmed the achievement of durable lymphoma remissions in 60% to 100% of patients with localized (ie, confined to the gastric wall) H pylori–positive gastric MALT lymphoma treated with antibiotics. Differences in the response criteria used in individual studies to evaluate the lymphoma eradication after antibiotic therapy may explain the wide range of reported remission rates. Unfortunately, the interpretation of residual lymphoid infiltrate in post-treatment gastric biopsy specimens can be very difficult, and there are no uniform criteria in the literature defining histological remission.[63,64] Copie-Bergmann et al have proposed a new histological grading system with the aim of providing information that is useful to clinicians.[64,65] This system, summarized in Table 2, may become a useful tool if its reproducibility can be confirmed in larger series. Histological remission can usually be documented within 6 months following H pylori eradication, but sometimes the period required is more prolonged and the therapeutic response may be delayed for more than a year.
GELA Histological Grading System to Define the Gastric MALT Lymphoma Response After
Several effective programs are available for the treatment of H pylori infection.[66-68] The choice should be based on the epidemiology of the infection in the patient’s country of residence, taking into account the locally expected antibiotic resistance. The most commonly used regimen is triple therapy: a proton pump inhibitor (eg, omeprazole, lansoprazole [Prevacid], pantoprazole [Protonix], or esomeprazole [Nexium]) in association with amoxicillin and clarithromycin. Metronidazole can be substituted for amoxicillin in penicillin-allergic individuals. Other regimens that use bismuth or H2-receptor antagonists with antibiotics are also effective.
The role of additional chemotherapy after antibiotics was investigated in a randomized study (whose power, however, was limited due to its not having reached the planned accrual). In this study, chlorambucil (Leukeran) conferred no benefit, with progression-free survival and overall survival rates similar for observed-only and chlorambucil-treated patients.
Antibiotic therapy may also be of benefit in some cases of gastric DLBCL, since in the subset of cases that may have been derived from a lymphoma of the MALT type, antibiotics may eliminate the persistent antigen stimulation that could be responsible for tumor recurrence. Cases of regression of gastric DLBCL after anti-Helicobacter therapy have been reported. However, relying solely on antibiotic therapy for gastric large-cell lymphomas cannot be advised outside clinical trials until large-scale prospective studies have validated its use as first-line therapy, and at present we recommend treating gastric large-cell lymphomas as localized DLBCL.
Endoscopic ultrasound can be useful for predicting a lymphoma's response to H pylori eradication. There is a significant difference between the response rates of lymphomas restricted to the gastric mucosa and rates in less superficial lesions. The response rate is highest for mucosa-confined lymphomas (approximately 70% to 90%) and then decreases markedly and progressively for tumors infiltrating the submucosa, the muscularis propria, and the serosa.[71-75] In cases with documented nodal involvement, response is highly unlikely.[73-75] Almost no gastric lymphomas with the t(11;18) translocation will respond to H pylori eradication therapy. A French study indicates that the t(11;18) translocation can also-to some extent-predict the therapeutic response of gastric MALT lymphoma to chlorambucil, but this is not necessarily true for responses to other therapeutic approaches, such as chemotherapy or immunotherapy.[77,78] Moreover, the cases that carry this translocation rarely undergo high-grade transformation and have been reported to have a significantly longer relapse-free survival irrespective of treatment modality.
A number of molecular follow-up studies have shown that post-antibiotic histological and endoscopic remission does not necessarily translate to a cure. Long-term persistence of monoclonal B cells after histological regression of the lymphoma has been reported in about half of cases, suggesting that H pylori eradication suppresses but does not eradicate the lymphoma clones. Transient histological and molecular relapses have been reported during long-term follow-up of antibiotic-treated patients; however, without the stimulus from H pylori such a relapse usually remains a self-limiting event and does not imply frank clinical progression. The clinical relevance of the detection of monoclonal B cells by molecular methods remains unclear. In the long-term follow-up of some cases with minimal residual disease, neither clinical growth of the lymphoma nor histological transformation was documented despite persistent clonality, suggesting that a watch-and-wait policy could be feasible and safe, at least for patients who are amenable to frequent endoscopies and who do not necessarily require additional treatment.[59,61,62,79,80]
Several cases of synchronous or metachronous gastric adenocarcinomas in patients with gastric MALT lymphomas have been documented. Indeed, a tumor-registry study has shown an increased risk (six times higher) for gastric adenocarcinoma in patients with gastric MALT lymphomas compared with the general population. This supports a policy of strict follow-up even in patients with lymphoma regression after H pylori eradication. Histological evaluation of repeated biopsies is the basic follow-up procedure.
No definite guidelines exist for the management of H pylori–negative or antibiotic-resistant cases or for patients with non-gastric lymphoma. In retrospective series, no significant difference in survival was apparent between patients who received different initial treatments (including chemotherapy alone, surgery alone, surgery with additional chemotherapy or radiation therapy, or antibiotics against H pylori).[52,54,57,82]
A modest dose of involved-field radiotherapy (25 to 35 Gy) gives excellent disease control; this may be the treatment of choice for patients with stage I–II MALT lymphoma of the stomach without evidence of H pylori infection, or for those with persistent lymphoma after antibiotics, as well as for most non-gastric localized presentations. Effective radiotherapy is frequently possible for both common and rare presentations of the disease. Side effects of radiotherapy are mild and reversible. For patients with localized non-gastric MALT lymphoma, given its unique biologic behavior (a tendency to relapse in MALT tissues and an indolent course), radiotherapy is often the first-line treatment of choice. The emerging literature on localized MALT lymphomas confirms a high rate of local control, with a high proportion of patients likely to be cured of the disease. The moderate doses of radiation required for cure are generally associated with a low risk of long-term toxicity, although special considerations are needed for particular sites of localization, such as the eye or the lung.[55,56,83,84] In spite of the excellent results of radiotherapy, there is no clear consensus as to whether radiation or systemic therapy is more effective in MALT lymphomas at different locations; thus, the choice is often based on the experience of the treating center and the patient’s preferences with respect to adverse effects.
Radiotherapy can also be an effective therapy that can provide local disease control for some patients with stage III or IV disease; however, its use for the optimal management of disseminated MALT lymphomas is less clearly defined.
Because no curative treatment exists, expectant observation can be an adequate initial policy in most patients. In general, the treatment should be ‘‘patient-tailored,’’ taking into account the site and the stage of the disease, and the clinical characteristics of the individual patient. When systemic treatment is needed, enrollment in controlled clinical trials is advisable. Indeed, in the presence of disseminated or advanced disease, chemotherapy (and/or immunotherapy with anti-CD20 monoclonal antibodies) is an obvious choice, but only a few compounds and regimens have been tested specifically in MALT lymphomas.
Oral alkylating agents (either cyclophosphamide or chlorambucil, with median treatment duration of 1 year) can result in a high rate of disease control. Phase II studies have demonstrated some anti-tumor activity for the purine analogs fludarabine (Fludara) and cladribine, although these may be associated with an increased risk of a secondary myelodysplastic syndrome. A polychemotherapy regimen (chlorambucil/mitoxantrone/prednisone) has also shown anti-tumor activity. Aggressive anthracycline-containing chemotherapy should be reserved for patients with high tumor burden (bulky masses, unfavorable international prognostic index). The activity of the anti-CD20 monoclonal antibody rituximab (Rituxan) has also been demonstrated in a phase II study (with a response rate of about 70%), and this may represent an additional option for the treatment of systemic disease. The efficacy of the combination of rituximab with chlorambucil has been explored in a randomized study by the IELSG in gastric MALT lymphomas that had failed antibiotics and in non-gastric MALT lymphomas (IELSG19, NCT00210353). In a preliminary report of this trial, at a median follow-up time of 62 months, the 5-year event-free survival was significantly better for the patients treated with chlorambucil plus rituximab (68% vs 50%), who also achieved a higher complete remission rate than did those treated with chlorambucil alone (78% vs 65%, P = .025); however, 5-year overall survival was identical (88%) in both groups.
In principle, antibiotic treatment in non-gastric lymphomas should be regarded as investigational. The finding that C psittaci (the etiologic agent of psittacosis) has a potential pathogenic role in the development of MALT lymphoma of the ocular adnexa and has been detected in about 80% of Italian patients may provide the rationale for antibiotic treatment of localized lesions. However, the treatment of ocular adnexal MALT lymphoma remains a controversial issue.
The prevalence of C psittaci infection in ocular adnexal lymphoma varies among countries and among different regions within the same country, being higher in Italy, Austria, Korea, and Germany, and virtually absent in Japan, France, and China. With respect to the United States, one study reported the presence of C psittaci in 6 of 17 cases (35%) from various East Coast regions, but the micro-organism was not detected in any of 112 cases included in four other North American series (incorporating patients from Miami, Chicago, Rochester, NY, and Cleveland).[89,90] Following the initial demonstration that doxycycline treatment may cause tumor regression in patients with C psittaci –associated lesions, subsequent reports on the efficacy of antibiotic therapy in ocular adnexa lymphoma produced conflicting data and apparent geographic variations. A prospective phase II study was then launched by the IELSG (IELSG 27, NCT01010295), and this has recently provided preliminary but encouraging results, showing lymphoma regression in more than 60% of patients after front-line treatment with doxycycline. Of interest, lymphoma regression after doxycycline treatment has been observed in some lymphomas with no evidence of C psittaci as well as in cases in which this treatment failed to eradicate the C psittaci infection. These results contrast with results in the better studied gastric MALT lymphoma (where H pylori–negative patients are generally unresponsive to the antibiotic treatment) and might suggest that other doxycycline-sensitive microorganisms are linked with the lymphoma. Therefore, further investigations are warranted to identify other potential infective agents and to improve antibiotic efficacy.
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Extraordinary progress has been made in the past two decades in understanding the etiology and the critical cellular and molecular pathological events in MALT lymphomas-as well as in identifying easily treatable causative bacterial agents. H pylori–associated gastric MALT lymphoma has become a model of antigen-driven lymphomagenesis and is currently treated with antibiotics aimed at eradicating H pylori. However, no consensus has yet been reached regarding the initial management of non-gastric tumors. Modern radiotherapy techniques have been shown to be effective in eradicating MALT lymphoma in sites that are unlikely to respond, or that have failed to respond, to antibiotics, allowing organ preservation and the forgoing of surgery. Moreover, the availability of effective chemotherapy agents and anti-CD20 monoclonal antibodies has expanded our treatment options in these settings. In the absence of randomized trials, either immunochemotherapy or radiotherapy is currently used. The establishment of national and international groups has advanced our clinical understanding; however, there is a continued need for such groups in order to better define our treatment strategy and expand our therapeutic options in the years to come.
Financial Disclosure:The authors have no conflicts of interest that are relevant to the subject matter under consideration in this article. In particular, they have no significant financial interests to be disclosed or other relationships with the manufacturers of any products or providers of any service mentioned in the article.
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