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ORIGINAL ARTICLE
Year : 2019  |  Volume : 15  |  Issue : 3  |  Page : 522-527

Dosimetric analysis and clinical outcomes of brachial plexus as an organ-at-risk in head-and-neck cancer patients treated with intensity-modulated radiotherapy


1 Department of Radiotherapy and Oncology, Kasturba Medical College, Manipal University, Manipal, Karnataka, India
2 Department of Medical Physics, Manipal University, Manipal, Karnataka, India

Date of Web Publication29-May-2019

Correspondence Address:
Dr. Prahlad H Yathiraj
Department of Radiotherapy and Oncology, Kasturba Medical College, Manipal University, Karnataka
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jcrt.JCRT_959_17

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 > Abstract 


Objectives: To document the dose received by brachial plexus (BP) in patients treated with intensity-modulated radiotherapy (IMRT) for head-and-neck squamous cell carcinoma (HNSCC) and report the incidence of brachial plexopathy.
Methods: Newly diagnosed patients of HNSCC treated with radical or adjuvant IMRT were included in this retrospective study. No dosimetric constraints were applied for BP maximum dose equivalent dose (EQD2 α/β = 3). Patients with minimum 6-month follow-up were included and patients with suspicion of plexopathy were evaluated further.
Results: Sixty-seven patients were eligible and 127 BP were analyzed. The mean BP maximum dose (BPmax) was 62.4 Gy (+6.9), while mean BP volume was 28.1 cc (+4.1). Proportion of patients receiving BPmax >66 and >70 Gy were 34.7% and 14.2%. The mean BPmax for T4 tumors was significantly higher than T1 tumors (65 vs. 57.5 Gy, P = 0.005) but when adjusted for N-category, T-category was not independently significant in accounting for BPmax >66 or >70 Gy. Mean BPmax for N0 versus N2+ was 59.8 versus 65.6 Gy (P = 0.0001) and N1 versus N2+ was 61.6 versus 65.6 Gy (P = 0.018). After adjusting for T-category, patients with N2+ had a mean 4.2 Gy higher BPmax than N0-N1 (P = 0.0001). Stage III–IV patients had a mean six Gy higher BPmax doses than Stage I–II disease (P = 0.0001). With a median follow-up of 28 months (interquartile range 16–42), no patient had brachial plexopathy.
Conclusion: Clinically significant plexopathy was not seen in spite of majority having over 2-years follow-up and a third of patients having dose above the recommended tolerance. Only nodal category independently influenced dose to the brachial plexii.

Keywords: Brachial plexopathy, clinical outcome, dosimetric analysis, head-and-neck squamous cell carcinoma, intensity-modulated radiotherapy


How to cite this article:
Prakash BB, Yathiraj PH, Sharan T K, Singh A, Reddy AS, Chandraguthi SG, Subramanian RB, Nagesh J, Nair SS, Fernandes DJ, Mamidipudi VS. Dosimetric analysis and clinical outcomes of brachial plexus as an organ-at-risk in head-and-neck cancer patients treated with intensity-modulated radiotherapy. J Can Res Ther 2019;15:522-7

How to cite this URL:
Prakash BB, Yathiraj PH, Sharan T K, Singh A, Reddy AS, Chandraguthi SG, Subramanian RB, Nagesh J, Nair SS, Fernandes DJ, Mamidipudi VS. Dosimetric analysis and clinical outcomes of brachial plexus as an organ-at-risk in head-and-neck cancer patients treated with intensity-modulated radiotherapy. J Can Res Ther [serial online] 2019 [cited 2019 Jun 17];15:522-7. Available from: http://www.cancerjournal.net/text.asp?2019/15/3/522/244488




 > Introduction Top


Radiotherapy is an integral component of the management of head-and -neck cancers with nearly 75% patients requiring RT either in the definitive or adjuvant setting.[1] High rates of local tumor control can be achieved with 5-year survival rates in excess of 80% for Stage I and II and 60%–70% for Stage III and IV tumors.[2] However, acute and long-term sequelae of radiotherapy are highly prevalent which have substantial impact on quality of life.[3],[4] Intensity-modulated radiotherapy (IMRT) has consistently shown to be noninferior in local control rates with significant reduction in acute and late toxicity when compared to three-dimensional conformal radiotherapy.[5],[6]

The brachial plexus (BP) is a network of nerves originating from C5 to T1 nerve roots responsible for the muscular and cutaneous innervations of the chest, shoulder, and upper limbs.[7] The brachial plexii are adjacent to metastatic lymph nodes and high-risk nodal volumes in the neck and is inevitably covered in the radiation portals using conventional techniques and receives 54–70 Gy. Radiation-induced brachial plexopathy (RIBP) is a potentially debilitating complication of radiotherapy, characterized by sensory changes and motor deficits. There may be a gradual evolution of symptoms or a more rapid progression with time, which may on occasion culminate in complete loss of function of the affected arm.[8],[9]

With conventional radiotherapy, inadvertent high dose of radiation was delivered to normal tissues like parotid and healthy oral and pharyngeal mucosa. With the ability to shape high-dose curves around the planning target volume (PTV) in IMRT, structures such as BP and cochlea – which were once not considered critical – have now been brought to the clinician's attention. With this in mind, the primary objective of our study was to report the dose–volume analysis of BP among patients with head-and-neck cancers receiving IMRT and clinically correlate the long-term outcomes of clinical brachial plexopathy.


 > Methods Top


The study was designed to be a retrospective observational study. Patients with a biopsy-proven squamous cell carcinoma of the head-and-neck squamous cell carcinoma (HNSCC) region and planned for radiotherapy using IMRT were included in this study after clearance from the institutional ethics committee. The study included patients aged between 18 and 70 years and ECOG performance status 0–2.[10] Patients with multiple synchronous primaries or with brachytherapy boost after 50 Gy EBRT or those who did not complete planned radiotherapy or those with <6-month follow-up were excluded from the study.

Patients planned for IMRT were immobilized using a 4-clamp thermoplastic mold and a contrast-enhanced simulation CT scan with 3-mm slice thickness was taken. Standard contouring practices were followed as per the published guidelines.[11],[12] Patients planned for IMRT in the definitive setting received one of the two dosing schedules-66 Gy, 60 Gy, and 54 Gy in 30 fractions over 6 weeks or 70 Gy, 63 Gy, and 56 Gy in 35 fractions over 7 weeks to the high-, intermediate-, and low-risk PTV, respectively. Patients planned for postoperative radiotherapy received 60 Gy and 54 Gy over 30 fractions over 6 weeks to the high- and low-risk PTV unless there was an R1 resection or perinodal extension in which case the high-risk disease was planned for 66 Gy over 33 fractions in 6.5 weeks. Concurrent chemotherapy was with cisplatin (either 40 mg/m 2 weekly or 100 mg/m 2 3-weekly) for standard indications. Carboplatin or nimotuzumab was used when the creatinine clearance was <50 mL/min.[13]

The BP were contoured using the guidelines developed by Hall et al.[14] The planning software was Elekta PrecisePLAN (Elekta Inc., Stockholm, Sweden) for first eight cases and then Oncentra v4.1 (Elekta Inc., Stockholm, Sweden) for the rest of the cases. The planning objectives were to cover at least 95% of the volume of the PTV with 95% of the prescription isodose with not more than 1% receiving more than 110% of the planned dose. As the BP were contoured retrospectively, there were no dose constraints used for BP.

The follow-up protocol was 2-monthly for the first 2 years followed by 6-monthly from the 3rd year onward. At each follow-up, the patient was asked for symptoms suggestive of brachial plexopathy. If suggestive of brachial plexopathy, clinical examination and nerve conduction study was performed and dose–volume analysis of BP was performed.

One-way analysis of variance (ANOVA) was performed for correlation of mean maximum BP doses (BPmax) with respect to T-category, N-category, and stage grouping. Two-way ANOVA was performed for T-category while accounting for N-category and vice versa to look for confounding interaction. Statistical analysis was performed using SPSS v16.0 (IBM Corporation, Chicago, IL, USA).


 > Results Top


Between 2010 and 2014, 91 patients were treated with IMRT for HNSCC. Of these, 24 (26%) were excluded from analysis as they did not meet the inclusion criteria [Table 1]. Mean age was 55 years (range: 25–77 years) and 79% were male. The location of primary was oral cavity, oropharynx, and hypopharynx in 37%, 25%, and 19%, respectively. While 55% had T3+ disease, 35% had N2+ status, and correspondingly 80% had Stage III + disease. Definitive RT was used in 56 patients and adjuvant in 11. Concurrent chemotherapy was used in 75% of patients. [Table 2] shows the demographic profile of the patients enrolled in this study.
Table 1: Reason for exclusion from the study (24 patients excluded out of 91 treated with intensity-modulated radiotherapy)

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Table 2: Patient demographics and disease characteristics (n=67)

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The maximum point dose to (BPmax) doses was computed to equivalent dose EQD2 using α/β=3. In total, BP were contoured as an OAR in 61 patients bilaterally (61 × 2 = 122) and in five patients unilaterally. Hence, a total of 127 BP were contoured and their dose-volume parameters and clinical correlation have been reported.

The mean BPmax (adjusted EQD2) is 62.4 ± 6.9, while mean BP volume is 28.1 ± 4.1 cc. The proportion of patients with BPmax doses >55 Gy, >60 Gy, >66 Gy, and >70 Gy were 88.2%, 64.6%, 34.7%, and 14.2%, respectively.

Brachial plexus maximum dose with respect to T-category

One-way ANOVA was performed for comparing mean BPmax doses with respect to T-category, the mean BPmax for T4 tumors was significantly higher than for T1 tumors (65 Gy vs. 57.5 Gy, P = 0.005) as shown in [Figure 1]. When BPmax doses for early (T0-T2) and advanced (T3-T4) tumor categories were compared, the proportion of BP receiving >55 Gy (80% vs. 94.4%, P = 0.024) and >60 Gy (54.5 vs. 72.2%, P = 0.042) was significantly higher among advanced T-category patients. However, proportion of BP receiving >66 Gy was tending toward significance (25.5 vs. 41.7%, P = 0.063) for advanced tumors as compared to early tumors [Table 3].
Figure 1: Mean brachial plexus max dose of individual tumor category

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Table 3: Chi-square analysis with maximum brachial plexus dose at different cutoffs with T-category, N-category, and stage grouping

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When one-way ANOVA was performed without adjusting for nodal category, patients with advanced tumor categories (T3–T4) had a significantly higher probability of having a higher BPmax dose by 3 Gy (P = 0.017) as compared to early tumor categories (T0-T2). However, when accounted for nodal stage by two-way ANOVA, there was no statistical significance with T-category for independently accounting for the proportion of BP having BPmax >55, >60, >66, and >70 Gy.

Brachial plexus maximum dose with respect to N-category

When one-way ANOVA was performed for comparing mean BPmax doses with respect to N-category, there was a significant increase in BPmax dose as nodal category increases – the mean BPmax for N0 versus N2+ (59.8 vs. 65.6 Gy, P = 0.0001) and N1 versus N2+ category (61.6 vs. 65.6 Gy, P = 0.018) as shown in [Figure 2]. When BPmax doses was analyzed for limited (N0-N1) and bulky nodal categories, the proportion of BP receiving >60 Gy (57.3% vs. 77.8%, P = 0.032), >66 Gy (20.7% vs. 60%, P < 0.001), and >70 Gy (5% vs. 31.1%, P < 0.001) were significantly higher in the bulky nodal category as compared to limited nodal category [Table 3].
Figure 2: Mean brachial plexus max dose of individual nodal category

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When two-way ANOVA was performed after adjusting for tumor category, patients with advanced nodal categories (N2+) had a significantly higher probability of having a higher BPmax dose by 4.2 Gy (P = 0.0001).

Brachial plexus maximum dose with respect to stage grouping

When one-way ANOVA was performed for comparing mean BPmax doses with respect to individual stage category, there was a significant increase in BPmax dose as stage group increases – the mean BPmax for Stage I versus Stage III (54.6 vs. 61.7 Gy, P = 0.029), Stage I versus Stage IV (54.6 vs. 65.0 Gy, P = 0.001), and Stage II versus Stage IV (59.1 vs. 65.0 Gy, P = 0.037).

When two-way ANOVA was performed between patients with advanced stage (Stage III and IV) had a significantly higher probability of having a higher BPmax dose by 6 Gy (P = 0.0001). Similarly, when BPmax doses was analyzed for early stages (I and II) and advanced stages (III and IV), the proportion of BP receiving >55 Gy (69.6% vs. 92.3%, P = 0.006), >60 Gy (43.5% vs. 69.2%, P = 0.029), and >66 Gy (4.3% vs. 41.3%, P < 0.001) within these groups were significantly higher in the advanced stages as compared to limited early stages [Table 3].

Brachial plexii – clinical outcomes

With 52 patients having a follow-up of 24 months including 28 of them who had received a BPmax dose >66 Gy, none had symptoms related to brachial plexopathy as per the physician based neurological examination based on patient's symptomatology. Two patients (both having BPmax <66 Gy) complained of shoulder movement problems. Both were evaluated with a magnetic resonance imaging of the shoulder which showed adhesive capsulitis of the rotator cuff and diagnosed as frozen shoulder secondary to long standing diabetes mellitus.


 > Discussion Top


IMRT is commonly used in HNSCC for Stage I–II disease as an attempt to reduce the late toxicity where long-term control rates can be upward of 80%.[15] However, IMRT also has a significant role to play in advanced tumors, where adequate tumor coverage would not be possible without unacceptable toxicity. In our study, Stages III–IV constituted 80% of the population, a finding similar to a prospective study evaluating brachial plexopathy where 75% of patients had Stage IV disease.[16] Although BP has been recognized as an organ at risk of long-term toxicity and in spite of a lucid contouring guideline published nearly a decade ago, there are only a handful of studies reporting dose–volume analysis with IMRT and clinical outcomes of brachial plexopathy.[16],[17],[18],[19],[20]

In our study, the BP has been contoured based on the radiation therapy oncology (RTOG) guidelines after the completion of treatment – similar to three other papers published previously.[18],[19],[20] This is justifiable for two reasons – (a) BP is almost never given a priority while planning IMRT and there are no tolerance doses as prescribed in the quantitative analyses of normal tissue effects in the clinic recommendations and (b) the incidence of brachial plexopathy is comparable when BP was contoured prospectively vis-à -vis retrospectively (82% Vs. 81%, P = 0.52).[21] While most RTOG protocols in prospective studies in HNSCC keep BPmax doses to <60 or 66 Gy, nearly 70% and 30% of the patients of HNSCC receive doses >66 Gy and 70 Gy, respectively.[14],[18]

When one-way ANOVA was performed for comparing mean BPmax doses with respect to T-category, the mean BPmax for T4 tumors was significantly higher than for T1 tumors (65 Gy vs. 57.5 Gy, P = 0.005). These results are similar to the study done by Turong et al., where BP max dose was analyzed with tumor category and patients with T4 category had higher BP max dose by 5 Gy when compared with T0–T3 category (63.4 Gy vs. 58.4 Gy) for pharyngeal tumors but was not significant for nasopharynx or oral cavity cancers.[16] However, when we accounted for nodal stage, there was no statistical significance with T-category in independently accounting for maximum doses received by the plexii. Locally advanced primary tumors are more likely to harbor node metastases, which could have confounded the relationship between dose to the BP and the primary tumor size, preventing it from being an independent predictor of higher doses to the plexii.

When BPmax dose was analyzed for variation with the extent of node involvement, we identified that 78% of patients receiving >70 Gy had N2 or N3 disease. Using any dose cutoff ranging from 55 Gy to 70 Gy, the proportion of BP receiving more dose was significantly higher in the bulky nodal category as compared to limited nodal category. After accounting for T-category, the patients who had advanced nodal disease received on an average of 4.2 Gy higher dose to the plexii compared to limited node disease. This outcome is probably due to the proximity of clinically enlarged cervical nodes, especially lower deep cervical and posterior triangle lymph nodes to the plexii. In patients who have node-positive disease, high-risk PTV may overlap over BP, leading to high doses. Similar results were reported in the study by Truong et al., and the mean of BP max dose increased by 8.1 Gy for patients with N2–N3 category as against N0-N1 category (52.8 Gy vs. 60.1 Gy).[16] They also reported that the BP max dose was significantly higher in advanced nodal disease patients even after adjusting for BP volume, tumor size, and site of primary.

Brachial plexopathy has consistently been reported being absent in head-and-neck cancer patients on follow-up barring the one study by Chen et al. where the 3- and 5-year incidence was 5% and 8% after confirmation by electrophysiological studies.[21] However, authors have commented that the contribution of cisplatin cannot be ruled out as it mimics radiation-induced neuropathic changes. Even in their study, high nodal burden (N3 category) was shown to be predictive of plexopathy both in patient-reported and electrophysiologically confirmed cases. In our study, none of the patients presented with RIBP with a median follow-up of 24 months, notwithstanding 14% of cases having a BPmax dose >70 Gy. In head-and-neck cancers, V70 <10% and V74 <4% of BP volume have been recommended as the tolerance doses for RIBP.[21]

Drawbacks of the present study are that the median follow-up of 24 months might be inadequate as nerve toxicity worsen with time and may manifest several years after treatment. Second, a questionnaire was not used to identify subtle plexopathy and the symptoms of neuropathy were mere recorded as present or absent and were only investigated if there was suspicion of RIBP.


 > Conclusion Top


We report no clinically relevant brachial plexopathy among our patients with a median follow-up of 24 months who were treated with IMRT for HNSCCs. This is in spite of a majority of patients presenting in the advanced stage and around 14% of BP receiving a maximum dose of 70 Gy or more. While advanced T-category, site of the primary and stage of the disease influence doses to the BP but not independently. Only N-category independently influences doses to BP. From our analysis, it appears safe to prioritize PTV over the maximum doses to BP even if the tolerance doses are exceeding 66 Gy.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
 > References Top

1.
Barton MB, Jacob S, Shafiq J, Wong K, Thompson SR, Hanna TP, et al. Estimating the demand for radiotherapy from the evidence: A review of changes from 2003 to 2012. Radiother Oncol 2014;112:140-4.  Back to cited text no. 1
    
2.
Pignon JP, le Maître A, Maillard E, Bourhis J; MACH-NC Collaborative Group. Meta-analysis of chemotherapy in head and neck cancer (MACH-NC): An update on 93 randomised trials and 17,346 patients. Radiother Oncol 2009;92:4-14.  Back to cited text no. 2
    
3.
Langendijk JA, Doornaert P, Verdonck-de Leeuw IM, Leemans CR, Aaronson NK, Slotman BJ. Impact of late treatment-related toxicity on quality of life among patients with head and neck cancer treated with radiotherapy. J Clin Oncol 2008;26:3770-6.  Back to cited text no. 3
    
4.
Laskar SG, Yathiraj PH. Acute radiation toxicity in head and neck and lung malignancies. South Asian J Cancer 2014;3:5-7.  Back to cited text no. 4
[PUBMED]  [Full text]  
5.
Gupta T, Agarwal J, Jain S, Phurailatpam R, Kannan S, Ghosh-Laskar S, et al. Three-dimensional conformal radiotherapy (3D-CRT) versus intensity modulated radiation therapy (IMRT) in squamous cell carcinoma of the head and neck: A randomized controlled trial. Radiother Oncol 2012;104:343-8.  Back to cited text no. 5
    
6.
Ghosh-Laskar S, Yathiraj PH, Dutta D, Rangarajan V, Purandare N, Gupta T, et al. Prospective randomized controlled trial to compare 3-dimensional conformal radiotherapy to intensity-modulated radiotherapy in head and neck squamous cell carcinoma: Long-term results. Head Neck 2016;38 Suppl 1:E1481-7.  Back to cited text no. 6
    
7.
Schierle C, Winograd JM. Radiation-induced brachial plexopathy: Review. Complication without a cure. J Reconstr Microsurg 2004;20:149-52.  Back to cited text no. 7
    
8.
Bowen BC, Verma A, Brandon AH, Fiedler JA. Radiation-induced brachial plexopathy: MR and clinical findings. AJNR Am J Neuroradiol 1996;17:1932-6.  Back to cited text no. 8
    
9.
Amini A, Yang J, Williamson R, McBurney ML, Erasmus J Jr., Allen PK, et al. Dose constraints to prevent radiation-induced brachial plexopathy in patients treated for lung cancer. Int J Radiat Oncol Biol Phys 2012;82:e391-8.  Back to cited text no. 9
    
10.
Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, et al. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 1982;5:649-55.  Back to cited text no. 10
    
11.
Grégoire V, Levendag P, Ang KK, Bernier J, Braaksma M, Budach V, et al. CT-based delineation of lymph node levels and related CTVs in the node-negative neck: DAHANCA, EORTC, GORTEC, NCIC, RTOG consensus guidelines. Radiother Oncol 2003;69:227-36.  Back to cited text no. 11
    
12.
Grégoire V, Eisbruch A, Hamoir M, Levendag P. Proposal for the delineation of the nodal CTV in the node-positive and the post-operative neck. Radiother Oncol 2006;79:15-20.  Back to cited text no. 12
    
13.
National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology. Head and Neck Cancers. Version 2. 2018. National Comprehensive Cancer; 01 January, 2010. Available from: https://www.nccn.org/professionals/physician_gls/pdf/head-and-neck.pdf. [Last accessed on 2018 Jul].  Back to cited text no. 13
    
14.
Hall WH, Guiou M, Lee NY, Dublin A, Narayan S, Vijayakumar S, et al. Development and validation of a standardized method for contouring the brachial plexus: Preliminary dosimetric analysis among patients treated with IMRT for head-and-neck cancer. Int J Radiat Oncol Biol Phys 2008;72:1362-7.  Back to cited text no. 14
    
15.
Pulte D, Brenner H. Changes in survival in head and neck cancers in the late 20th and early 21st century: A period analysis. Oncologist 2010;15:994-1001.  Back to cited text no. 15
    
16.
Truong MT, Romesser PB, Qureshi MM, Kovalchuk N, Orlina L, Willins J. Radiation dose to the brachial plexus in head-and-neck intensity-modulated radiation therapy and its relationship to tumor and nodal stage. Int J Radiat Oncol Biol Phys 2012;84:158-64.  Back to cited text no. 16
    
17.
Chen AM, Hall WH, Li J, Beckett L, Farwell DG, Lau DH, et al. Brachial plexus-associated neuropathy after high-dose radiation therapy for head-and-neck cancer. Int J Radiat Oncol Biol Phys 2012;84:165-9.  Back to cited text no. 17
    
18.
Platteaux N, Dirix P, Hermans R, Nuyts S. Brachial plexopathy after chemoradiotherapy for head and neck squamous cell carcinoma. Strahlenther Onkol 2010;186:517-20.  Back to cited text no. 18
    
19.
Chen AM, Hall WH, Li BQ, Guiou M, Wright C, Mathai M, et al. Intensity-modulated radiotherapy increases dose to the brachial plexus compared with conventional radiotherapy for head and neck cancer. Br J Radiol 2011;84:58-63.  Back to cited text no. 19
    
20.
Thomas TO, Refaat T, Choi M, Bacchus I, Sachdev S, Rademaker AW, et al. Brachial plexus dose tolerance in head and neck cancer patients treated with sequential intensity modulated radiation therapy. Radiat Oncol 2015;10:94.  Back to cited text no. 20
    
21.
Chen AM, Wang PC, Daly ME, Cui J, Hall WH, Vijayakumar S, et al. Dose – Volume modeling of brachial plexus-associated neuropathy after radiation therapy for head-and-neck cancer: Findings from a prospective screening protocol. Int J Radiat Oncol Biol Phys 2014;88:771-7.  Back to cited text no. 21
    


    Figures

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