Oncologist. The. Symptom Management and Supportive Care

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1 The Oncologist Symptom Management and Supportive Care Does Marital Status Impact Survival and Quality of Life in Patients with Non-Small Cell Lung Cancer? Observations from the Mayo Clinic Lung Cancer Cohort AMINAH JATOI, a PAUL NOVOTNY, b STEPHEN CASSIVI, c MATTHEW M. CLARK, d DAVID MIDTHUN, e CHRISTI A. PATTEN, d JEFF SLOAN, b PING YANG f a Division of Medical Oncology, b Cancer Center Statistics, c Department of Surgery, d Department of Psychiatry and Psychology, e Division of Pulmonary Medicine, and f Division of Epidemiology, Mayo Clinic, Rochester, Minnesota, USA Key Words. Lung cancer Marital status Survival Quality of life Disclosure: No potential conflicts of interest were reported by the authors, planners, reviewers, or staff managers of this article. ABSTRACT Purpose. Previous studies have found that marriage is associated with longer survival and better quality of life among lung cancer patients. The present study used the Mayo Clinic Lung Cancer Cohort to re-examine this issue. Methods. In total, 5,898 non-small cell lung cancer (NSCLC) patients, who had available information on marital status and who had been enrolled in the Mayo Clinic Lung Cancer Cohort (MCLCC), were the focus of this study. Patients had extensive baseline and follow-up data on cancer stage, cancer treatment, and prognostic factors. All patients had been followed within the MCLCC with at least annual confirmation of vital status and patient-reported quality of life (the Lung Cancer Symptom Scale and the Linear Analogue Scales of Assessment). Results. The numbers of patients who were married, single, divorced, and widowed at the time of cancer diagnosis were 4,457 (76%), 265 (4%), 440 (7%), and 736 (12%), respectively. No statistically significant difference in survival was observed among these four groups, even after adjusting for a variety of prognostic factors, such as age, gender, and tumor stage. However, exploratory analyses suggested that widowed and divorced patients received less aggressive cancer therapy, and certain patient subgroups, such as stage IA widowed patients, had a shorter survival. Divorced patients reported greater financial concerns, and married and widowed patients reported greater spirituality and better social support. Conclusion. This study did not observe differences in survival or quality of life based on marital status at the time of diagnosis of NSCLC, but subgroup analyses appear to suggest findings worthy of further exploration. The Oncologist 2007;12: INTRODUCTION Adhering to the vow, Til death do us part, may be healthpromoting. Among individuals who are well and among patients who are suffering a wide array of illnesses, marriage is often associated with longer life and better quality of life [1 3]. Despite the lethality and morbidity of lung cancer, three previous studies suggest that, even with this malignancy, Correspondence: Aminah Jatoi, M.D., Mayo Clinic, 200 First Street SW, Rochester, Minnesota 55905, USA. Telephone: ; Fax: ; jatoi.aminah@mayo.edu Received August 10, 2007; accepted for publication October 16, Alpha- Med Press /2007/$30.00/0 doi: /theoncologist The Oncologist 2007;12:

2 Jatoi, Novotny, Cassivi et al patients derive tangible clinical benefits from marriage. First, a Surveillance Epidemiology and End Results (SEER) study, that comprised 25,871 lung cancer patients, found that the risk for death was significantly higher based on whether patients were single, separated, divorced, or widowed compared with a reference group of married patients [4]. The relative risks for death were 1.18, 1.16, 1.13, and 1.08 in these respective groups. Second, the Norwegian Cancer Registry, consisting of 15,882 male and 3,944 female lung cancer patients, provided similar observations [5]. Female lung cancer patients who were single, divorced/ separated, and widowed manifested a relative risk for death of 1.13, 1.17, and 1.19, respectively, compared with married patients. Similarly, male lung cancer patients manifested relative risks for death of 1.23, 1.17, and 1.12, respectively. Once again, these trends were statistically significant and suggest an important relationship between marriage and survival. Thirdly, Tammemagi et al. [6] examined cancer symptoms in 1,154 lung cancer patients and observed that marital status provided an independent correlate of symptoms. The odds ratio of a spouseless patient having adverse symptoms at diagnosis was 1.79 with a 95% confidence interval (95% CI) of Thus, both in terms of survival and quality of life, marriage appears to confer benefits to lung cancer patients. How might marriage do this? This question has not been fully explored in lung cancer patients, but, in other clinical settings, marriage appears to improve survival by increasing the likelihood of patients receiving aggressive cancer treatment [7, 8]. In effect, marriage may perhaps provide better social support mechanisms and better financial resources that permit patients to accept more aggressive therapy. It is important to recognize that the SEER database and the Norwegian Cancer Registry do not provide much detail on cancer therapy [4, 5]. Nor do these databases provide information on smoking status, nutrition, and a host of other factors that have previously been shown to be associated with superior clinical outcomes and that must be adjusted for to understand the influence of marriage [9 11]. Thus, in effect, we can only speculate on what might actually contribute to the observed clinical benefits of marriage in lung cancer patients. The present study used the Mayo Clinic Lung Cancer Cohort (MCLCC) in order to provide an in-depth assessment of the association between marital status and clinical outcomes in patients with non-small cell lung cancer (NSCLC). The purpose of this study was (a) to determine whether marital status at the time of cancer diagnosis did in fact predict survival and quality of life among patients within the MCLCC after a diagnosis of NSCLC and (b) to assess what types of cancer treatment and what prognostic factors might be associated with marital status. This study was therefore designed to be one of the first to explore in great detail how marital status might influence clinical outcomes in lung cancer patients. METHODS Overview of the MCLCC The MCLCC is an ever-expanding database established at the Mayo Clinic in Rochester, Minnesota in All patients in the cohort either have been diagnosed and treated at the Mayo Clinic in Rochester, Minnesota, or have joined the MCLCC upon seeking consultation at this institution. In the present study, all NSCLC patients with available information on marital status were included. The MCLCC has undergone review and approval by the Mayo Clinic Institutional Review Board at least once a year since its inception. All patients provided informed, written consent prior to enrollment. Specifics on ongoing patient recruitment, baseline data retrieval, and patient follow-up have been previously described and are again briefly summarized below [12]. Upon enrollment into the MCLCC, all patients completed baseline health-related surveys at 6 and 12 months, and they were mailed similar surveys every 12 months. In addition, trained personnel reviewed their medical records at enrollment. Information on demographics, previous or concurrent illnesses, tobacco exposure, tumor staging, nutritional habits, and cancer therapy were abstracted and entered into the database. The Revised Tumor Node Metastasis Staging System of NSCLC was used [13]. Of note, all cancer treatment decisions were deferred to the individual patients health care providers, and enrollment into the MCLCC in no way influenced clinical decision making. Marital Status In the present study, information on marital status was assessed at the time of cancer diagnosis or was derived from the patient survey data routinely included in the MCLCC. It was decided to focus specifically on marital status at the time of cancer diagnosis, as this is a pivotal time at which major cancer treatment decisions are made. Marital status within the MCLCC was retrieved from the clinical medical record, in which such information is available by means of an electronically scanned, handwritten document that is completed by the patient. Using such resources, the study team was thereby able to classify the majority of patients within the MCLCC as married, single, divorced, or widowed at the time of their NSCLC diagnosis. These classifications were included as general demographic information for each patient at the time the MCLCC was established.

3 1458 Marital Status Impact in NSCLC Patients Vital Status Information from patient- or next of kin completed 6-month surveys has been included in the MCLCC since Vital status has also been included and updated within the database. Vital status has been continuously checked and verified annually for each patient by means of the following resources: the Mayo Clinic registration clinical database, next-of-kin reports, death certificates, documentation of death in the clinical medical record, the Mayo Clinic Tumor Registry, and the Social Security Death Index Website. Quality of Life Measurement Quality of life was measured by the Lung Cancer Symptom Scale (LCSS) and the Linear Analogue Self Assessment (LASA) scales. Consisting of nine items, each on a 100-cm horizontal visual analogue scale, the LCSS has been validated and was designed to evaluate symptoms in lung cancer patients [14, 15]. For this study, the distance from the patient s vertical mark that intersects the horizontal line to the leftmost end of the horizontal line was measured and transformed to a 100-point scale. Total scores were calculated by adding the nine individual scores, which were then transformed to allow for higher scores to indicate a better quality of life. The LASA is a series of items that require that patients rate their responses on a 0 10 point scale with 0 being as bad as it can be and 10 being as good as it can be. The last-completed set of quality of life surveys was used in the analyses for this study. Analyses The primary outcome of this study was survival from the time of lung cancer diagnosis, and patients were compared based on their marital status at the time of the NSCLC diagnosis. Patients who were alive at last contact were censored. A log-rank test was used to assess the statistical significance of survival differences among groups (married, single, divorced, or widowed). A Cox proportional hazards model was developed to assess the impact of other clinical variables on the survival endpoint. Variables in this model include age, gender, cancer stage, tumor histology, tumor grade, cancer treatment, patient age, vitamin use, and pack-years of cigarette use, all of which have been shown to carry prognostic significance [9 11]. Quality of life was a secondary endpoint. Total LCSS and LASA scores, derived from the last survey completed, were directly compared among the marital status groups. In addition, a linear regression model was developed to estimate the mean difference in quality of life scores among marital status groups. The same variables described earlier were also included in this model. Other secondary endpoints included health habits, such as smoking status at lung cancer diagnosis, and cancer treatment prescribed. Health habits and treatment type (surgery, radiation, chemotherapy as single or multimodality therapy) were included within a series of categorical variables, and direct comparisons of the proportion of patients in each group were undertaken based on marital status. Statistical analyses were performed using a SAS software package, Version 8.2 (SAS Institute, Inc., Cary, NC). Descriptive statistics that include the reporting of means, standard deviations (SDs), and 95% CIs are provided as appropriate. A p-value.05 is viewed as statistically significant. RESULTS Overview In total, 7,902 newly diagnosed NSCLC patients were within the MCLCC at the end of 2006, and 5,898 are included in this study. The remaining 2,004 patients had no information on marital status at the time of their cancer diagnosis. Within this group of 5,898 patients, 59% were men. The numbers of patients who were married, single, divorced, and widowed at the time of cancer diagnosis were 4,457 (76%), 265 (4%), 440 (7%), and 736 (12%), respectively. Widowed patients were older than patients in the other three groups. Among patients who were widowed, a greater proportion were women (67%), and among patients who were married, a greater proportion were men (64%) (Table 1). Patients general health habits differed based on marital status. Among married, single, divorced, and widowed patients, rates of never having smoked at diagnosis were 12%, 13%, 6%, and 15%, respectively (p.0001, for the differences among all smoking categories). Of note, widowed patients had the highest percentage of neversmokers. Similarly, at diagnosis, 58% of divorced patients smoked, 47% of single patients smoked, and 42% of widowed patients smoked, compared with only 38% of married patients (p.001). There were no statistically significant differences among groups in the use of vitamin and mineral supplements at the time of last report (Table 1). In terms of ethnicity, the percentages of married, single, divorced, and widowed patients who reported being white were 87%, 86%, 84%, and 84%, respectively. The percentages who reported being Alaskan or Native American were 2.4%, 1.6%, 3.5%, and 2.7%, respectively. Finally, the percentages who reported themselves as African American were 0.9%, 2.4%, 1.9%, and 0.8%, respectively. All other racial categories were either consistently 1% among all categories of marital status or were not reported.

4 Jatoi, Novotny, Cassivi et al Table 1. Baseline patient demographics Married (n 4,457) Tumor Characteristics and Cancer Treatment In terms of cancer stage and grade, there were also notable differences based on marital status. The percentages of married, single, divorced, and widowed patients with stage IV disease were 37%, 38%, 39%, and 30%, respectively (p.013 across all tumor stages). Widowed patients also had a higher rate of malignant lymph node involvement (44%). Widowed patients had lower grade tumors. The percentages of patients with grade I cancer within these four marital groups were 13%, 16%, 10%, and 18%, respectively (p.006 across all tumor grades) (Table 2). In addition, cancer treatment differed based on marital status. The percentages of patients who were married, single, divorced, and widowed who received no cancer treatment were 30%, 33%, 38%, and 39%, respectively (p.0001). The percentages of patients who underwent surgery based on marital status were 41%, 39%, 35%, and 41% (p.08). Of note, differences in radiation administration were apparent: 27%, 26%, 24%, and 17%, respectively (p.0001), with widowed patients once again having the lowest rate of radiation administration. Similar findings were observed in prescribing chemotherapy: 34%, 27%, 31%, and 19%, respectively (p.0001). As noted, once again, widowed patients had the very lowest rate of chemotherapy administration (Table 2). Survival and Quality of Life First, in terms of survival, a univariate analysis showed no differences among groups based on marital status. Even after introducing other variables of prognostic significance, such as age, tumor stage, tumor grade, smoking status at diagnosis, gender, and vitamin use as part of a multivariate analysis with a Cox model, there were still no statistically Single (n 265) Divorced (n 440) Widowed (n 736) p-value Age in years at diagnosis, mean 65 (10) 62 (13) 62 (10) 73 (9).0001 (standard deviation) Gender (%) Male 2,861 (64) 158 (60) 214 (49) 242 (33).0001 Female 1,596 (36) 107 (40) 226 (51) 494 (67) Smoking (%) Never 528 (12) 34 (13) 27 (6) 113 (15) Former 2,019 (46) 89 (34) 137 (31) 286 (39).0001 Current 1,682 (38) 123 (47) 252 (58) 307 (42) Occasional current smoking 213 (5) 17 (7) 22 (5) 27 (4) Vitamin/mineral supplement use (%) 1,106 (68) 52 (67) 82 (71) 135 (66).81 Not all percentages add up to 100% because of rounding. significant differences in survival among groups [9, 10, 11] (Fig. 1). Similar survival analyses were performed based on whether patients were married or not with a collapse of other marital status categories, and no statistically significant difference in survival was observed between these two groups either. However, exploratory subgroup analyses do suggest specific differences in survival based on marital status, and cancer stage. Widowed patients with stage IA lung cancer manifested an inferior survival, with a median survival time (95% CI) for married, widowed, and divorced patients of 7.1 ( ) years, 5.9 ( ) years, and 6.9 years (4.3 years to unable to be calculated), with single patients being too few to enable survival estimates. Similarly, widowed and divorced patients with stage IIB cancers also had inferior survival, with median survival times (95% CI) among widowed, divorced, married, and single patients of 1.3 ( ) years, 1.7 ( ) years, 2.7 ( ) years, and 6.4( ) years. Finally, widowed and single patients with IIIB cancers did not live as long as patients in the other two groups: 0.8 ( ) years, 0.8 ( ) years, 1.1 ( ) years, 1.0 ( ) years in widowed, single, divorced, and married patients, respectively (Figs. 2 4). Second, in terms of quality of life, some interesting findings were observed. Overall quality of life scores were no different among the four marital status groups. There were differences within specific quality of life domains, although it is difficult to know if these differences are truly clinically significant. Nonetheless, widowed and married patients scored more favorably on overall spiritual well-being at the time of last follow-up. Spiri-

5 1460 Marital Status Impact in NSCLC Patients Table 2. Tumor characteristics and treatment Married Single Divorced Widowed p-value Cancer stage (%) a IA 606 (14) 29 (11) 63 (15) 120 (17) IB 481 (11) 34 (13) 35 (8) 110 (16) IIA 69 (2) 3 (1) 10 (2) 14 (2) IIB 262 (6) 19 (7) 23 (5) 47 (7).013 IIIA 637 (15) 38 (15) 62 (15) 91 (13) IIIB 661 (15) 40 (15) 65 (15) 111 (16) IV 1,612 (37) 99 (38) 165 (39) 216 (31) Histology (%) Adenocarcinoma/bronchioalveolar 2,412 (54) 151 (57) 218 (49) 390 (53).16 Squamous 831 (19) 69 (26) 85 (19) 120 (16) Other 1,214 (27) 45 (17) 137 (31) 226 (31) Grade (%) a (13) 41 (16) 45 (10) 127 (18) ,811 (41) 108 (42) 176 (41) 298 (42) 3 1,695 (39) 96 (37) 180 (42) 241 (34) (7) 14 (5) 33 (8) 52 (7) No treatment (%) 1,331 (30) 86 (33) 165 (38) 289 (39).0001 Treatment Surgery alone (%) 1,237 (28) 79 (30) 109 (25) 237 (32) Radiation alone (%) 244 (6) 21 (8) 19 (4) 49 (7) Chemotherapy alone (%) 474 (11) 22 (8) 42 (10) 57 (8).001 Multimodality therapy (%) Surgery radiation 129 (3) 7 (3) 10 (2) 25 (3) Surgery chemotherapy 210 (5) 9 (3) 18 (4) 25 (3) Radiation chemotherapy 581 (13) 33 (13) 61 (14) 39 (5) Surgery, radiation, chemotherapy 251 (6) 8 (3) 16 (4) 15 (2) a Information on stage and grade was unavailable in 176 and 108 patients, respectively. Figure 1. Survival was not significantly different among groups based on marital status, even after adjustment for multiple factors of prognostic significance (p.0967). tual well-being mean (SD) scores among married, single, divorced, and widowed patients were 8.1 (2.1), 7.1 (2.6), 7.5 (2.6), and 8.4 (2.0), respectively (p.02). Widowed and married patients also had more favorable mean scores to suggest better support from family and friends. Mean (SD) scores for this domain were 8.9 (1.7), 8.3 (2.1), 8.2 (2.3), and 8.9 (1.8), respectively (p.04). These two groups of widowed and married patients also had more favorable overall symptom scores as assessed within this domain of the LCSS with mean (SD) scores of 75 (26), 71 (29), 69 (23), and 79 (26), respectively (p.02). Finally, divorced patients had greater financial concerns than patients within the other groups, and widowed patients had fewer such concerns. Mean (SD) scores within this domain among married, single, divorced, and widowed patients were 7.7 (2.7), 7.1 (3.0), 6.3 (3.4), and 8.4 (2.3), respectively (p.001) (Table 3).

6 Jatoi, Novotny, Cassivi et al Figure 2. Widowed patients with stage IA lung cancer manifested inferior survival. Median survival times (95% confidence interval) for widowed, married, and divorced patients were 5.9 ( ) years, 7.1 ( ) years, and 6.9 years (4.3 years to unable to be calculated), with single patients being too few to enable survival estimates (p.9955). Figure 3. Widowed and divorced patients with stage IIB cancers also had inferior survival. Median survival times (95% confidence interval) among widowed, divorced, married, and single patients were 1.3 ( ) years, 1.7 ( ) years, 2.7 ( ) years, and 6.4 ( ) years (p.1136). DISCUSSION This MCLCC study was undertaken to assess the impact of marital status on clinical outcomes in patients with NSCLC. Survival was the primary endpoint, and this study found no survival difference based on marital status, even after adjusting for variables of prognostic significance. Previous studies have shown that marital status is linked to clinical outcomes, and, in this respect, the primary survival data derived from this study are at odds with prior reports [1 8]. There are perhaps three reasons why this study did not show the same survival advantages as earlier studies. First, the MCLCC includes only those patients who have received a medical opinion at the Mayo Clinic, a major tertiary care Figure 4. Widowed and single patients with IIIB cancers did not live as long as patients in the other two groups. Median survival times (95% confidence interval) were 0.8 ( ) years, 0.8 ( ) years, 1.1 ( ) years, and 1.0 ( ) years in widowed, single, divorced, and married patients, respectively (p.0022). medical center in the U.S. It is plausible that referral patterns may have resulted in some degree of bias in favor of patients endowed with strong social support and family ties and favorable socioeconomic status, all of which enabled them to seek care at a tertiary medical center and perhaps may have overridden the previously reported benefits of marriage. Second, the categories of marital status used in this study did not distinguish between patients who were separated and those who were married or between patients who were single and those in a committed relationship. Such patients may conceivably manifest very different outcomes compared with the other patients within their assigned designation. Hence, clinical outcomes based on the four marital status categories used in this study may differ from what has been reported earlier. Future studies that focus on the impact of marital status may choose to modify their study design based on this issue. Third, the present study carries some limitations. There is no information available on socioeconomic status. Conceivably, however, if the cohort largely consisted of patients with a relatively high socioeconomic status, this factor might have obscured differences based on marital status. Moreover, slightly over 2,000 patients within the cohort did not have information on marital status. Although we are unable to discern what impact such missing data might have had on our findings, this limitation of the data set should be noted. Nonetheless, this study did provide some interesting observations. First, although the study s primary endpoint was not achieved, subgroup analyses did suggest that marital status may nonetheless affect survival. When survival was assessed stage by stage based on marital status, widowed

7 1462 Marital Status Impact in NSCLC Patients Table 3. Select quality of life scores at last follow-up Married Single Divorced Widowed p-value Shortness of breath (n 842) 4.6 (2.8) 5.0 (2.7) 4.2 (2.7) 4.8 (2.8).55 Spiritual well-being (n 828) 8.1 (2.1) 7.1 (2.6) 7.5 (2.6) 8.4 (2.0).02 Support from family/friends (n 839) 8.9 (1.7) 8.3 (2.1) 8.2 (2.3) 8.9 (1.8).04 Social activity (n 838) 7.0 (2.5) 5.9 (3.0) 6.8 (2.7) 7.3 (2.4).12 Legal concerns (n 835) 8.4 (2.5) 7.7 (2.7) 8.4 (2.6) 8.5 (2.4).24 Financial concerns (n 836) 7.7 (2.7) 7.1 (3.0) 6.3 (3.4) 8.4 (2.3).001 Coughing (n 1,630) a 72 (26) 68 (29) 68 (26) 72 (25).34 Fatigue (n 1,639) a 52 (25) 48 (27) 53 (27) 50 (25).56 Pain (n 1,630) a 77 (25) 70 (28) 73 (27) 77 (27).19 Appetite (n 803) a 69 (25) 66 (30) 67 (24) 67 (26).90 Blood in sputum (n 799) a 94 (13) 97 (5) 96 (11) 95 (13).71 Lung cancer symptoms (n 783) a 75 (26) 71 (29) 69 (23) 79 (26).02 Scores represent mean (standard deviation) values; higher scores indicate more favorable quality of life outcomes in all the domains listed, regardless of how the domain is phrased. a Category included from the Lung Cancer Symptom Scale. patients with stage IA lung cancer had a saliently compromised survival; widowed and divorced patients with stage IIB cancers also had compromised survival; and widowed and single patients with IIIB cancers also did poorly. Thus, even in this study, such exploratory observations suggest that marital status carries a prognostic effect. Second, marital status was clearly associated with certain specific characteristics directly relevant to patients and their malignancies. Despite their poor survival with early-stage disease, widowed patients surprisingly had lower grade tumors and tended to be nonsmokers. Ironically, although widowed patients had such favorable characteristics, they also had the highest rates of no cancer therapy. These observations once again point out that marital status does appear to exert an influence on various clinical factors and outcomes. Thirdly, quality of life seems to be influenced by marital status. Widowed and married patients reported more favorable quality of life outcomes. These two groups scored better on the domains of spirituality, support of family and friends, and overall lung cancer symptoms. Moreover, divorced patients were fraught with financial concerns. Thus, although this study did not demonstrate survival differences among groups, it nonetheless did provide some preliminary interesting evidence that marital status is associated with some clinical outcomes in patients with NSCLC. Finally, it is important to comment on the message from the several other studies that preceded this one: human bonds appear to influence the type of cancer treatment that patients receive. It is true that this study did not achieve its primary aim of demonstrating differences in survival based on marital status. Nonetheless, marital status at times appeared to have influenced whether or not a patient received certain types of cancer therapy. Moreover, spirituality and social support data appear to be stronger among married and widowed lung cancer patients. Thus, health care providers should continue to remain sensitive to the importance of human bonds as they care for patients with NSCLC. ACKNOWLEDGMENTS The authors acknowledge the important contributions of Ms. Shawn Stoddard and Mr. Joel Worra. This work was supported by R01CA80127, R01CA84354, and CA awarded to PY and by funding from the Centers for Disease Control and Prevention awarded to AJ. REFERENCES 1 Sorlie PD, Backlund E, Keller JB. US mortality by economic, demographic, and social characteristics: The National Longitudinal Mortality Study. Am J Public Health 1995;85: Rohrbaugh MJ, Shoham V, Coyne JC. Effect of marital quality on eight-year survival of patients with heart failure. Am J Cardiol 2006;98: Gore JL, Kwan L, Saigal CS et al. Marriage and mortality in bladder carcinoma. Cancer 2005;104: Lai H, Lai S, Krongrad A et al. The effect of marital status on survival in late-stage cancer patients: An analysis based on Surveillance, Epidemiology, and End Results (SEER) Data in the United States. Int J Behav Med 1999;6: Kravdal O. The impact of marital status on cancer survival. Soc Sci Med 2001;52:

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