Prognostic factors in solitary plasmacytoma of the bone: a multicenter Rare Cancer Network study
- David Knobel†1,
- Abderrahim Zouhair†1,
- Richard W Tsang2,
- Philip Poortmans3,
- Yazid Belkacémi4, 8,
- Michel Bolla5,
- Fazilet Dinçbas Oner6,
- Christine Landmann7,
- Bernard Castelain8,
- Mahmut Ozsahin1Email author and
- for the Rare Cancer Network
© Knobel et al; licensee BioMed Central Ltd. 2006
Received: 08 February 2006
Accepted: 05 May 2006
Published: 05 May 2006
Solitary plasmacytoma (SP) of the bone is a rare plasma-cell neoplasm. There are no conclusive data in the literature on the optimal radiation therapy (RT) dose in SP. Therefore, in this large retrospective study, we wanted to assess the outcome, prognostic factors, and the optimal RT dose in patients with SP.
Data from 206 patients with bone SP without evidence of multiple myeloma (MM) were collected. Histopathological diagnosis was obtained for all patients. The majority (n = 169) of the patients received RT alone; 32 chemotherapy and RT, and 5 surgery. Median follow-up was 54 months (7–245).
Five-year overall survival, disease-free survival (DFS), and local control was 70%, 46%, and 88%; respectively. Median time to MM development was 21 months (2–135) with a 5-year probability of 51%. In multivariate analyses, favorable factors were younger age and tumor size < 5 cm for survival; younger age for DFS; anatomic localization (vertebra vs. other) for local control. Older age was the only predictor for MM. There was no dose-response relationship for doses 30 Gy or higher, even for larger tumors.
Younger patients, especially those with vertebral localization have the best outcome when treated with moderate-dose RT. Progression to MM remains the main problem. Further investigation should focus on adjuvant chemotherapy and/or novel therapeutic agents.
Solitary plasmacytoma (SP) is a rare plasma-cell neoplasm . There are two separate entities, dependent on the location of the lesion originating in either bone or extramedullary soft tissue . It is defined as a proliferation of monoclonal plasma cells without evidence of significant bone-marrow plasma-cell infiltration . Bone SP is characterized by a unique lesion involving any part of the squeleton, most commonly in the spine.
Recommendations for the choice of treatment modalities in this radiosensitive disease  are based mainly on data from retrospective studies often considering relatively small numbers of patients, with a limited ability to make any robust conclusions [4, 5], and only one prospective study including 53 patients .
Definitive radiation therapy (RT) is the treatment of choice for solitary plasmacytoma giving adequate local control. However, with respect to long-term outcome, it is known that bone plasmacytoma progresses more frequently to multiple myeloma (MM) than soft-tissue plasmacytoma [7–9].
There are no conclusive data in the literature on the optimal RT dose in SP. Many authors reported a wide range of doses varying from 30–66 Gy [10–12]. Most centers use 50 Gy or more to treat SP, without any strong evidence whether doses higher than 30 Gy are needed.
We report herein the results of a retrospective multicenter study of a large cohort of patients with bone SP from European and North American centers, assessing treatment approaches, radiation dose-response effects and different prognostic factors for survival, myeloma progression, and patterns of local failure.
Characteristics of 206 patients with bone plasmacytoma
Number of patients
Site of lesion
Surgery alone (+CT in one)
All but 5 patients received RT. Surgical treatment was implemented in 69 (33%) patients (partial resection in 66, and complete excision in 3). Chemotherapy was given in 32 (16%) patients. The planning RT volume included the radiologically visible gross tumor volume with a sufficient margin. For vertebral SP, the planning RT volume included one vertebra above and below the involved vertebra. No attempt was made to cover regional lymph nodes. Median dose was 40 Gy (range: 20–64); median number of fractions was 20 (range: 4–33) using a median dose of 2 Gy per fraction (range: 1.25–5). To facilitate the comparison of the different fractionation schedules used by different centers, we computed the 2-Gy per fraction biologically effective dose (BED) according to the linear-quadratic model: BED = nd(1+ [d÷α/β]); where α/β = 10 for plasmacytoma; n = number of fractions; and d = dose per fraction . Median BED was 40.00 Gy (range: 18.75–66.00).
Six cycles (range: 1–12) of chemotherapy consisting of melphalan and prednisone (n = 23; 72%), vincristine, doxorubicin and dexamethasone (VAD) (n = 7; 22%), and other combinations (n = 2; 6%) were administered in 32 (16%) patients.
Overall survival (OS), disease-free survival (DFS), local control, and time to MM progression were estimated using the product-limit method . Time to any event was measured from the date of histological diagnosis. The events were death (all causes) for OS, and death (all causes) or relapse and/or progression to MM for DFS. For the local control rate, the event consisted of local failure, censoring patients without local relapse. For progression to MM, all patients without MM progression were censored. Confidence intervals (CI) were calculated from standard errors. Differences between groups were assessed using the log rank test . Multivariate analyses were done using the Cox stepwise-regression analysis to determine the independent contribution of each prognostic factor .
Distribution of local relapses according to biologically effective radiation dose*
All patients (n = 206)
Tumors ≥ 5 cm (n = 59)
Radiation dose (Gy)
Number of patients
Local relapse (%)
Number of patients
Local relapse (%)
≥ 30 – <40
≥ 40 – <50
Univariate analyses (logrank test)
10-yr. OS (%)
%95 CI (%)
10-yr. DFS (%)
%95 CI (%)
10-yr. LC (%)
%95 CI (%)
10-yr. MM (%)
%95 CI (%)
Site of plasmacytoma
Largest tumor dimension (cm)
Type of treatment
CT + RT 100
2 Gy/fr equivalent RT dose (Gy) a
≥ 40 and <50
≥ 30 and <40
Progression to multiple myeloma
At the time of analysis, 135 patients were alive (50 with disease), and 71 had died (54 died of disease including 2 with unknown causes, 16 related to intercurrent disease, and 1 from cardiopulmonary disease probably related to mediastinal RT).
In all patients, the 5- and 10-year probability of OS were 70% (95% CI: 63–77) and 50% (95% CI: 40–60), respectively; and for 5- and 10-year DFS, 46% (95% CI: 38–54) and 25% (95% CI: 16–34), respectively.
In univariate analyses, statistically significant best factors influencing the OS were younger age (60 years or younger), and tumor size (< 5 cm). Ten-year probabilities of OS and DFS according to different prognostic factors are shown in Table 3.
Multivariate analyses revealed that the best independent factors predicting the outcome were: younger age (RR = 0.59; p < 0.00001) and tumors less than 5 cm (RR = 0.56; p = 0.0007) for OS; younger age (RR = 0.79; p = 0.02) for DFS; and vertebra localization (RR = 0.63; p = 0.04) for local control. Older age (RR = 0.78; p = 0.01) was the only independent predictor for MM development.
Early side effects according to CTC v2.0 depended on the irradiated anatomical regions . Grade 1 toxicity was observed in 46 patients (22%), grade 2 in 14 (7%), and grade 3 in 4 (2%).
According to the RTOG/EORTC late effect scoring system , grade 1 toxicity was observed in one patient (asymptomatic bone necrosis), no grade 2 toxicity, and grade 3 toxicity in 2 (femoral head necrosis in one, and xerostomia in the other). Grade 4 pulmonary toxicity was observed in one patient who died from cardiopulmonary disease probably related to mediastinal RT toxicity.
We recently reported our experience on a series of 258 patients including bone and extramedullary SP . In the present study, we wanted to specifically assess different treatment approaches, radiation dose-response effects; and different prognostic factors in patients with bone plasmacytoma. Several factors are reported to influence the outcome of SP in the literature [2, 8, 10, 12, 20–24].
Despite good local control with RT, patients with bone SP progresses to MM more frequently than those with extramedullary SP [7, 10]. Many questions remain unanswered about prognostic factors influencing the outcome and radiation dose-response, probably due to the limited number of patients included in reported series [9, 12, 24]. This may be related to the lack of routine use of MRI to exclude occult lesions at initial diagnosis [25, 26]. MRI was done in only 33% of our patients (Table 1). Staging using MRI to exclude multiple lesions has contributed in recent years to more accurate diagnosis of SP, since only the patients with truly solitary involvement are eligible for curative RT [25, 26]. This may also help radiation oncologists to define target radiation volumes with higher precision . Unfortunately, in this study, whether MRI examination was done or not did not result in an improved ability to predict progression to MM. However, it was not clear how often MRI was done to define the local extent of disease, rather than for the detection of occult disease in other bony sites such as the spine and pelvis. Nevertheless, in our patients who had an MRI examination, no occult asymptomatic MM lesions were detected.
There is limited information in the literature regarding the outcome of elderly patients with myeloma. Some series indicate that advanced age is clearly associated with poor survival whereas others do not . In our series older age (>60 years) was found to be a bad prognostic factor, either in univariate or multivariate analyses, in terms of OS, DFS, or progression to MM. This difference may be related to several reasons. In terms of survival, older patients who develop MM are possibly treated with "less aggressive" treatments, or not included in prospective trials compared to younger patients . However, it is difficult to find an explanation why our patients older than 60 years develop MM more frequently than the younger ones.
Multivariate analysis* (Cox model) in 201 irradiated patients
≤ 60 years better
Localization (vertebra vs.other)
Tumor size (cm) (<5 vs. ≥5)
<5 cm better
Progression to MM has been reported to be less frequent in younger patients, whose survival is also better [10, 24, 30, 31]. Our study confirmed these reports, with progression to MM seen more frequently in older patients, and improved survival in younger patients (Fig. 3, Table 3). However, local failure did not depend on age.
Baseline immunoglobulin (M protein) levels are reported to be a predictive factor of occult disseminated disease, and almost all experts agree that an M protein level of 20 g/l is crucial for the definition of SP [11, 13]. In our series, only 18 patients had an M protein level above 20 g/l, and no difference in terms of MM development was observed between patients with M protein levels above and below 20 g/l. Furthermore, patients showing persistent M protein levels for more than one year after RT are prone to progress to MM [30, 32]. This factor could not be assessed in our series because we did not have adequate data on M protein level responses to treatment, and the correlation of progression to MM with M protein persistence.
Tumor size is reported to be an important prognostic factor in terms of local control. Tsang et al  reported a better outcome for lesions less than 5 cm, while other studies did not find tumor size to be a factor . In our series, local control was higher for plasmacytomas measuring less than 5 cm (91%) than for those 5 cm or higher (73%). It is important to note that size was not reported for 112 (43%) of the patients in our study (Table 3).
In a large review of over 400 publications from 1905 to 1997, Alexiou et al  reported evidence that surgery alone gave the best results for extramedullary bone plasmacytoma when clear surgical margins were obtained. In the present series, 94 patients were treated by surgery with (n = 86) or without RT (n = 8). Nine (3%) had a complete resection with negative margins; of these, only one received adjuvant RT, and seven relapsed. This finding argues against proposing surgery alone, even in cases where complete resection is achieved.
While radiation therapy is the treatment of choice for solitary plasmacytoma, the evidence of its efficacy is solely based on small retrospective studies . There is no clear RT dose-response relationship in the literature. The analysis performed by Mendenhall et al  suggested a minimum dose of 40 Gy for optimal local control. Despite little evidence for a dose-response relationship above 30–40 Gy [8, 21, 24], some authors propose doses between 40 and 50 Gy for small lesions, and higher doses for larger tumors [23, 26, 34]. While Tsang et al  reported that there was no convincing dose-response relationship above 35 Gy for small lesions, they concluded that local control was related to the size of the lesion and suggested giving higher doses or combined modality treatment for bulky tumors. This has also been proposed by other groups .
Our data showed no correlation between local failure and radiation dose, even for large tumors (Fig. 1, Table 2). Due to its retrospective nature, these results should be interpreted with caution. However, it included a large number of patients treated with a wide spectrum of RT doses, with the finding that 30 Gy in 2-Gy fractions, or a biologically equivalent regimen was sufficient. It appears from this study that administering a higher radiation dose may be unable to overcome the negative prognostic impact of a bulky tumor on local control, in comparison with smaller tumors (Table 2). In addition to size, it is possible that other poorly documented factors (e.g. local invasiveness, proliferation rate, or morphologic grade) also impact on the risk of local relapse, and are confounding factors in a dose-response analysis.
Chemotherapy, which is not considered as a standard of care in patients with SP, has been proposed by some investigators in the initial management of bone plasmacytoma. Only one prospective study reported a benefit with combined chemotherapy and RT compared to RT alone . The chemotherapy used consisted of melphalan-prednisone given every six weeks for three years. Although a limited number of patients was included (n = 53), this study concluded that combined radiochemotherapy seems to increase remission and survival duration.
Targeting the mechanisms that control angiogenesis, which has an integral role in the pathophysiology of hematologic malignancies, could be an innovative therapeutic approach in the treatment of SP. Kumar et al  reported high-grade angiogenesis in 64% of tumors in their series of 25 bone SP patients, and found that angiogenesis is highly correlated with progression to MM. Therefore, antiangiogenic compounds such as thalidomide, vascular-endothelial growth-factor, or proteasome inhibitors may be promising in this disease.
Overall, the results obtained in this study, to our knowledge the largest series in the literature, are in accordance with other published series [4, 5, 8, 9, 12, 21, 23, 24]. Although high rates of local control were obtained, survival was disappointing because of progression to MM. Only a large prospective study conducted by collaborative groups could answer the unresolved questions in this relatively rare disease. Following a complete staging work-up, which may include very sensitive imaging tools such as positron-emission tomography [36, 37], current evidence supports the use of involved-field moderate-dose radiation therapy. Future investigation in phase II or III prospective trials should focus on the use of adjuvant chemotherapy and/or novel therapeutic agents.
biologically effective dose
common toxicity criteria
Radiation Therapy Oncology Group
European Organisation for Research and Treatment of Cancer
The authors thank Ms. Frances Godson for her excellent secretarial assistance.
- Knowling MA, Harwood AR, Bergsagel DE: Comparison of extramedullary plasmacytomas with solitary and multiple plasma cell tumors of bone. J Clin Oncol. 1983, 1: 255-262.PubMedGoogle Scholar
- Galieni P, Cavo M, Avvisati G, Pulsoni A, Falbo R, Bonelli MA, Russo D, Petrucci MT, Bucalossi A, Tura S: Solitary plasmacytoma of bone and extramedullary plasmacytoma: two different entities?. Ann Oncol. 1995, 6: 687-691.PubMedGoogle Scholar
- Jyothirmayi R, Gangadharan VP, Nair MK, Rajan B: Radiotherapy in the treatment of solitary plasmacytoma. Br J Radiol. 1997, 70: 511-516.View ArticlePubMedGoogle Scholar
- Brinch L, Hannisdal E, Abrahamsen AF, Kvaloy S, Langholm R: Extramedullary plasmacytomas and solitary plasma cell tumours of bone. Eur J Haematol. 1990, 44: 131-134.Google Scholar
- Shih LY, Dunn P, Leung WM, Chen WJ, Wang PN: Localised plasmacytomas in Taiwan: comparison between extramedullary plasmacytoma and solitary plasmacytoma of bone. Br J Cancer. 1995, 71: 128-133.View ArticlePubMedPubMed CentralGoogle Scholar
- Aviles A, Huerta-Guzman J, Delgado S, Fernadez A, Diaz-Maqueo JC: Improved outcome in solitary bone plasmacytoma with combined therapy. Hematol Oncol. 1996, 14: 111-117. 10.1002/(SICI)1099-1069(199609)14:3<111::AID-HON575>3.0.CO;2-G.View ArticlePubMedGoogle Scholar
- Dimopoulos MA, Moulopoulos LA, Maniatis A, Alexanian R: Solitary plasmacytoma of bone and asymptomatic multiple myeloma. Blood. 2000, 96: 2037-2044.PubMedGoogle Scholar
- Mayr NA, Wen BC, Hussey DH, Burns CP, Staples JJ, Doornbos JF, Vigliotti AP: The role of radiation therapy in the treatment of solitary plasmacytomas. Radiother Oncol. 1990, 17: 293-303. 10.1016/0167-8140(90)90003-F.View ArticlePubMedGoogle Scholar
- Liebross RH, Ha CS, Cox JD, Weber D, Delasalle K, Alexanian R: Clinical course of solitary plasmacytoma. Radiother Oncol. 1999, 52: 245-249. 10.1016/S0167-8140(99)00114-0.View ArticlePubMedGoogle Scholar
- Tsang RW, Gospodarowicz MK, Pintilie M, Bezjak A, Wells W, Hodgson DC, Stewart AK: Solitary plasmacytoma treated with radiotherapy: impactof tumor size on outcome. Int J Radiat Oncol Biol Phys. 2001, 50: 113-120. 10.1016/S0360-3016(00)01572-8.View ArticlePubMedGoogle Scholar
- Dimopoulos MA, Hamilos G: Solitary bone plasmacytoma and extramedullary plasmacytoma. Current Treatment Options Oncol. 2002, 3: 255-259.View ArticleGoogle Scholar
- Bolek TW, Marcus RB, Mendenhall NP: Solitary plasmacytoma of bone and soft tissue. Int J Radiat Oncol Biol Phys. 1996, 36: 329-333. 10.1016/S0360-3016(96)00334-3.View ArticlePubMedGoogle Scholar
- The International Myeloma Working Group: Criteria for the classification monoclonal gammopathies, multiple myeloma and related disorders: a report of the International Myeloma Working Group. Br J Haematol. 2003, 121: 749-757. 10.1046/j.1365-2141.2003.04355.x.View ArticleGoogle Scholar
- Hall EJ: Time, dose, and fractionation in radiotherapy. Radiobiology for the Radiologist. Edited by: Hall EJ. 1994, Philadelphia: Lippincott, 211-229.Google Scholar
- Kaplan EL, Meier P: Nonparametric estimation from incomplete observations. J Am Stat Assoc. 1958, 53: 457-481. 10.2307/2281868.View ArticleGoogle Scholar
- Peto P, Pike MC, Armitage P, Breslow NE, Cox DR, Howard SV, Mantel N, McPherson K, Peto J, Smith PG: Design and analysis of randomised clinical trials requiring prolonged observation of each patient: part II. Br J Cancer. 1977, 35: 1-39.View ArticlePubMedPubMed CentralGoogle Scholar
- Cox DR: Regression models and life tables. J Roy Stat Soc. 1972, 34: 187-220.Google Scholar
- Trotti A, Byhardt R, Stetz J, Gwede C, Corn B, Fu K, Gunderson L, McCormick B, Morrisintegral M, Rich T, Shipley W, Curran W: Common toxicity criteria: version 2.0. An improved reference for grading the acute effects of cancer treatment: impact on radiotherapy. Int J Radiat Oncol Biol Phys. 2000, 47: 13-47. 10.1016/S0360-3016(99)00559-3.View ArticlePubMedGoogle Scholar
- Cox JD, Stetz J, Pajak TF: Toxicity criteria of the Radiation Therapy Oncology Group (RTOG) and the European Organization for Research and Treatment of Cancer (EORTC). Int J Radiat Oncol Biol Phys. 1995, 31: 1341-1346. 10.1016/0360-3016(95)00060-C.View ArticlePubMedGoogle Scholar
- Ozsahin M, Tsang RW, Poortmans P, Belkacemi Y, Bolla M, Oner Dincbas F, Landmann C, Castelain B, Buijsen J, Curschmann J, Kadish SP, Kowalczyk A, Anacak Y, Hammer J, Nguyen TD, Studer G, Cooper R, Sengoz M, Scandolaro L, Zouhair A: Outcomes and patterns of failure in solitary plasmacytoma: a multicenter Rare Cancer Network study of 258 patients. Int J Radiat Oncol Biol Phys. 2006, 64: 210-217. 10.1016/j.ijrobp.2005.06.039.View ArticlePubMedGoogle Scholar
- Soutar R, Lucraft H, Jackson G, Reece A, Bird J, Low E, Samson D: Guidelines on the diagnosis and management of solitary plasmacytoma of bone and solitary extramedulary plasmacytoma. Br J Haematol. 2004, 124: 717-726. 10.1111/j.1365-2141.2004.04834.x.View ArticlePubMedGoogle Scholar
- Liebross RH, Ha CS, Cox JD, Weber D, Delasalle K, Alexanian R: Solitary bone plasmacytoma: outcome and prognostic factors following radiotherapy. Int J Radiat Oncol Biol Phys. 1998, 41: 1063-1067. 10.1016/S0360-3016(98)00186-2.View ArticlePubMedGoogle Scholar
- Mendenhall CM, Thar TL, Million RR: Solitary plasmacytoma of bone and soft tissue. Int J Radiat Oncol Biol Phys. 1980, 6: 1497-1501.View ArticlePubMedGoogle Scholar
- Frassica D, Frassica FJ, Schray MF, Sim FH, Kyle RA: Solitary plasmacytoma of bone: Mayo clinic experience. Int J Radiat Oncol Biol Phys. 1989, 16: 43-48.View ArticlePubMedGoogle Scholar
- Moulopoulos LA, Dimopoulos MA, Weber D, Fuller L, Libshitz HI, Alexanian R: Magnetic resonance imaging in the staging of solitary plasmacytoma of bone. J Clin Oncol. 1993, 11: 1311-1315.PubMedGoogle Scholar
- Vogl TJ, Steger W, Grevers G, Balzer J, Mack M, Felix R: MR characteristics of primary extramedullary plasmacytoma in the head and neck. Am J Neuroradiol. 1996, 17: 1349-1354.PubMedGoogle Scholar
- Susnerwala SS, Shanks JH, Banerjee SS, Scarffe JH, Farrington WT, Slevin NJ: Extramedullary plasmacytoma of the head and neck region: clinicopathological correlation in 25 cases. Br J Cancer. 1997, 75: 921-927.View ArticlePubMedPubMed CentralGoogle Scholar
- Anagnostopoulos A, Gika D, Symeonidis A, Zervas K, Pouli A, Repoussis P, Grigoraki V, Anagnostopoulos N, Economopoulos T, Maniatis A, Dimopoulos MA: Multiple myeloma in elderly patients: prognostic factors and outcome. Eur J Haematol. 2005, 75: 370-375. 10.1111/j.1600-0609.2005.00532.x.View ArticlePubMedGoogle Scholar
- Hjorth M, Holmberg E, Rodjer S, Turesson I, Westin J, Wisloff F: Survival in conventionally treated younger (<60 years) multiple myeloma patients: no improvement during two decades. Eur J Haematol. 1999, 62: 271-277.View ArticlePubMedGoogle Scholar
- Bataille R, Sany J: Solitary myeloma: clinical and prognostic features of a review of 114 cases. Cancer. 1981, 48: 845-851.View ArticlePubMedGoogle Scholar
- Chak LY, Cox RS, Bostwick DG, Hoppe RT: Solitary plamacytoma of bone: treatment, progression, and survival. J Clin Oncol. 1987, 5: 1811-1815.PubMedGoogle Scholar
- Wilder RB, Ha CS, Cox JD, Weber D, Delasalle K, Alexanian R: Persistance of myeloma protein for more than one year after radiotherapy is an adverse prognostic factor in solitary plasmacytoma of bone. Cancer. 2002, 94: 1532-1537. 10.1002/cncr.10366.View ArticlePubMedGoogle Scholar
- Alexiou C, Kau RJ, Dietzfelbinger H, Kremer M, Spiess JC, Schratzenstaller B, Arnold W: Extramedullary plasmacytoma: tumor occurrence and therapeutic concepts. Cancer. 1999, 85: 2305-2314. 10.1002/(SICI)1097-0142(19990601)85:11<2305::AID-CNCR2>3.0.CO;2-3.View ArticlePubMedGoogle Scholar
- Hu K, Yahalom J: Radiotherapy in the management of plasma cell tumors. Oncology. 2000, 14: 101-111.PubMedGoogle Scholar
- Kumar S, Fonseca R, Dispenzieri A, Lacy MQ, Lust JA, Wellik L, Witzig TE, Gertz MA, Kyle RA, Greipp PR, Rajkumar SV: Prognostic value of angiogenesis in solitary bone plasmacytoma. Blood. 2003, 101: 1715-1717. 10.1182/blood-2002-08-2441.View ArticlePubMedGoogle Scholar
- Orchard K, Barrington S, Buscombe J, Hilson A, Prentice HG, Mehta A: Fluoro-deoxyglucose positron emission tomography imaging for the detection of occult disease in multiple myeloma. Br J Haematol. 2002, 117: 133-135. 10.1046/j.1365-2141.2002.03407.x.View ArticlePubMedGoogle Scholar
- Schirrmeister H, Buck AK, Bergmann L, Reske SN, Bommer M: Positron emission tomography (PET) for staging of solitary plasmacytoma. Cancer Biother Radiopharm. 2003, 18: 841-845. 10.1089/108497803770418382.View ArticlePubMedGoogle Scholar
- The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2407/6/118/prepub
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