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Originally published as JCO Early Release 10.1200/JCO.2007.13.1870 on January 7 2008 © 2008 American Society of Clinical Oncology.
Moving Research From Bench to Bedside to Community: There Is Still More to Do
RAND, Santa Monica; and David Geffen School of Medicine at University of California, Los Angeles, CA Investment in biomedical research and healthcare in the United States and worldwide has never been greater.1 The substantial return on these investments is seen in the remarkable scientific breakthroughs of the past few decades and the continually accelerating advances in biomedical knowledge that promise to revolutionize health care and significantly improve health.2 Women with breast cancer have benefited from these advances, as the death rate from breast cancer has declined 20% over the last ten years.3-5 This has been attributed both to earlier-stage diagnoses in association with screening and to the early use of systemic adjuvant treatment aimed at eradicating or postponing micrometastases believed responsible for distant disease spread.6 The most recent overview of global trials evaluating adjuvant systemic therapy for early breast cancer, formulated by the Early Breast Cancer Trialists’ Collaborative Group,7 reported that 5 years of treatment with the selective estrogen receptor modulator tamoxifen for women with estrogen receptor (ER) –positive breast cancer translated into a 12% absolute reduction in the likelihood of recurrence at 15 years (33% v 45%), and a 9% reduction in breast cancer–related death (26% v 35%).7,8 The magnitude of mortality reduction was almost three times as great at 15 years as it was at 5 years (9% v 3.6%), while the impact on recurrence was mainly seen in the first 5 years. The absolute difference in recurrence rates between those who used and did not use adjuvant tamoxifen for 5 years was 16% for node-positive and 9% for node-negative disease. Multiple studies have addressed optimal duration of tamoxifen adjuvant treatment, including four trials showing significantly better outcomes for postmenopausal women associated with the use of 5 years compared with 2 years of tamoxifen therapy.9-12 The maturation of follow-up for the Eastern Cooperative Oncology Group trial13 and results of the Adjuvant Tamoxifen Longer Against Shorter and Adjuvant Tamoxifen Treatment Offer More trials,14-18 as well as other ongoing trials, will provide further basis for informing recommendations about treatment duration. The current standard recommendation of 5 years for adjuvant tamoxifen in women with ER-positive early breast cancer has been stable for several years.19 Beyond these advances, new studies have shown improved outcomes for postmenopausal women using aromatase inhibitors as initial adjuvant therapy or in a sequential approach beginning with tamoxifen and changing after 2, 3, or 5 years to an aromatase inhibitor. Across multiple studies of postmenopausal women, anastrozole or letrozole alone or in combination with tamoxifen and anastrozole, letrozole, or exemestane used sequentially after 2 years of tamoxifen have been associated with better outcomes than for women treated with tamoxifen alone or who received no adjuvant therapy. Improved outcomes have been documented in terms of disease-free survival, recurrence, and incidence of contralateral breast cancer, although overall survival benefit from aromatase inhibitors has not been clearly demonstrated to date.20-27 Continuing analyses have suggested outcomes improve even further with continuation of an aromatase inhibitor for up to 5 years after the completion of an initial adjuvant 5 year regimen of tamoxifen.28 Recommendations for initial adjunct treatment now include use of tamoxifen, anastrozole, or letrozole for 5 years’ duration or initial treatment with one of these agents followed by an alternate or with exemestane for 5 or more years of therapy.19 Still, important inquiries regarding the use of adjuvant hormone therapy remain unanswered. Which is the best initial treatment? Is 5 years the optimal duration of adjuvant treatment? Which subsets of patients will benefit from each of the available individual or combinations of adjuvant hormonal regimens? Under what circumstances will sequential treatment be more effective than sustained single-drug treatment? It is gratifying to know that these questions are currently under study. A second important line of inquiry revolves around the prevention and treatment of side effects related to the use of selective estrogen receptor modulators and aromatase inhibitors. With tamoxifen, side effects include early onset of hot flashes and vaginal discharge and later onset of risk for thromboembolic events, endometrial cancer, and uterine sarcomas.7,29-35 With the aromatase inhibitors, prevalent side effects include milder hot flashes, anorexia, myalgias, arthralgias, bone loss, and fractures.21,22,36 The Multicenter Breast International Group Study is currently evaluating the effectiveness and morbidity profile of patients treated with tamoxifen, letrozole, and combinations of these.22 Further scientific inquiry into the prevention and treatment of morbidities in association with adjuvant treatment should be pursued. For many women receiving tamoxifen, symptoms persist either undetected or unmanaged.37-40 The same problem is emerging in relation to problem detection and management for postmenopausal women using aromatase inhibitors. For example, studies are in progress regarding how often diagnoses of osteopenia and osteoporosis should be sought with bone density studies in women using adjunct therapies. Should the threshold for initiating pharmacologic intervention to treat osteopenia or osteoporosis differ for women receiving and not receiving aromatase inhibitors? Despite the need to systematically address these queries, multiple trials have shown that treatment with oral adjuvant hormone agents for at least 5 years after initial treatment improves patient outcomes. In this context, two new studies published in this issue of the Journal of Clinical Oncology41,42 demonstrate substantial gaps between how biomedical and clinical scientists and clinicians intend adjuvant therapy to be used, and how it is used by patients in community settings. Owusu et al41 report that 49% of women at least 65 years of age with stage I-IIB ER-positive or indeterminate breast cancer who had initiated adjuvant tamoxifen therapy discontinued the drug earlier than 5 years after initiation. Partridge et al42 report that 12 months after treatment initiation, 12% to 19% of women were not taking the aromatase inhibitor as prescribed. The proportion of women not using the treatment as prescribed continued to increase annually, with lack of adherence noted for 21% to 38% of women 3 years after initiation of the treatment. These findings illustrate that women with breast cancer are not receiving evidence-based care recommended by their physicians. Although tamoxifen or anastrozole therapy can be recommended for fewer than 5 years when used in conjunction with another agent, these investigators evaluated rates of adherence to prescribed medication, not a change in the physician's prescription. The influence on outcomes of the many possible patterns of lack of compliance with recommended treatment is not known. The extent to which expected outcomes would be hampered by patients using the drug intermittently or by cutting the daily, weekly, or monthly dose is not known. For many diseases, the presence of side effects reduces the use of medications prescribed to prevent future complications.43 Several studies have documented side effects as the most important reason for women discontinuing their adjuvant hormone therapy.38,44-46 This suggests the importance of clinicians tracking the incidence, prevalence, and severity of treatment-associated side effects.47 Clinicians or their designated support staff should become experts in learning from patients their concerns about their diseases and also about symptoms and signs developed in association with treatments.39,43,48 Clinicians or their support personnel should systematically query patients to understand the extent to which patients are using prescribed treatments. When evidence suggests adjuvant treatments are not being used as recommended, clinicians should nonjudgmentally engage with the patient to understand the reasons for under-, mis-, or overuse and to discuss with their patients the challenges associated with long-term medication use.43 Other strategies for improving adherence to medication regimens are worth considering,43,49 including those developed for specific diseases, such as HIV infection,50,51 hypertension,52 and psychiatric illnesses.53,54 When symptoms cannot be prevented or treated, we now have a variety of alternate adjuvant hormone regimens that can be implemented to improve patient's experiences.19,55,56 Physicians and patients should consider the option of switching the adjuvant hormone regimen as an alternative to patients’ discontinuing adjuvant treatment altogether. Efficient care in this regard will require physicians to track how patients are tolerating adjunct medications. Serial assessments of patient symptoms and signs and documentation of patients’ use of prescribed medications will allow clinicians to identify patients at risk for discontinuing medications and to potentially avoid that outcome. Analyses categorizing outcomes for patients who switch adjuvant regimens—as an alternative to stopping treatment in patients with refractory symptoms—would be a welcome addition to the knowledge base of clinicians. In 1993, DiMatteo et al57 showed provider characteristics influence patient's adherence to medical treatments. Recently, one observational study indicated that demographics, other than age, contributed little to predicting long-term compliance with tamoxifen use. Symptoms were the most important predictor of discontinuing long-term use.38 However, even after adjustment for symptom onset and intensity, patient-centered care was the most important predictor of ongoing adjunct tamoxifen use in the setting of new onset breast cancer. When financial strain associated with the cost of adjuvant medications is an issue, patients can be referred to Partnership for Assistance, a national program supported by America's pharmaceutical companies. Doctors, other health care providers, patient advocacy organizations, and community groups can help qualifying patients who lack prescription coverage obtain the medicines they need through public or private programs.58,59 Several catalogues of interventions shown in randomized trials to increase long-term adherence to medications have been documented.43,49,60 Haynes et al60 noted the complexity of the successful interventions typically involving combinations of more convenient care, information, reminders, self-monitoring, reinforcement, counseling, family therapy, psychologic therapy crisis intervention, manual telephone follow-up, and supportive care. In contrast to the many trials evaluating the efficacy of various adjuvant drug regimens that have been completed or underway, trials evaluating the effectiveness of adjuvant treatment in community settings and trials evaluating the effectiveness of interventions to increase compliance with recommended long-term treatment regimens are rare. This is surprising because medication adherence may be the most mutable predictor of patient outcomes for patients with chronic disease and for risk of recurrence in treated diseases such as breast cancer.42,61 As the evidence accumulates to show that prescriptions for ongoing adjunct cancer treatments in community settings are not being implemented for substantial numbers of patients, it is important to conceptualize, implement, and study the effectiveness of interventions designed to assure that evidence-based interventions are used. Recent research in community venues have revealed important problems that threaten the usefulness of the extraordinary advances in basic and clinical science made in recent decades.62,63 If treatments known to extend the quality and quantity of life are not used, they will not be effective. Now is the time to move research into the real world of community settings that include the heterogeneous sets of patients who represent our population and are cared for by a diverse set of providers in a rich mix of settings. When we do this, a new set of queries will reveal themselves. Who is prescribing the initial set of adjuvant treatments for patients? For how long does that physician follow the patient? Which physician specialty does the patient see most often and for the longest duration? Is there one configuration of the patient's team of providers that is most effective in supporting patient's ongoing use of adjuvant treatment? Does this change for patients with complex health care situations, including those with multiple medications, comorbidities, providers, settings, or venues of care? When patients have multiple physicians, how are decisions made regarding which one is responsible for systematically evaluating signs or symptoms in association with the treatment? Who monitors compliance? Who should? Is there a taxonomy of reasons for discontinuation that providers could readily use to categorize risk for medication discontinuation or to motivate interventions to sustain adherence? Because many patients with breast cancer receive most of their follow-up care from cancer physicians other than the first treating physician or from noncancer physicians, studying medication adherence in a community setting may generate results applicable to the largest cohort of patients with breast cancer eligible for long-term use of oral adjunct therapies. The empirical data presented in two well-performed studies41,42 in this issue of the Journal of Clinical Oncology demonstrate that brilliant laboratory and clinical breakthroughs are only the beginning of the journey toward improved population health. To complete the translation of the basic and clinical sciences to improve health for breast cancer survivors who populate the communities of America and beyond, we need to understand the types of structure and processes of care that best support the initiation of evidence-based interventions.43,60,61 To improve outcomes for breast cancer, we also need to understand the structure and processes that are most effective in helping patients to continue long-term use of oral adjunct medications. With so many multifaceted biomedical advances in recent decades, this is not a problem unique to breast cancer. However, with the solid foundation of so many trials across so many years in this disease, breast cancer experts, in collaboration with population and health care delivery scientists, can lead the way toward a new breakthrough that will better align scientific advances and improvements in population health. AUTHOR'S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest. NOTES published online ahead of print at www.jco.org on January 7, 2008 REFERENCES 1. Mathieu MP: PAREXEL's Pharmaceutical R&D Statistical Sourcebook 2005/2006. Waltham, MA, Barnett Educational Services, 2005 2. Sung NS, Crowley WF, Genel M: Central challenges facing the national clinical research enterprise. JAMA 289:1278-1287, 2003 3. Jemal A, Ward E, Thun MJ: Recent trends in breast cancer incidence rates by age and tumor characteristics among U.S. women. Breast Cancer Res 9:R28, 2007[CrossRef][Medline] 4. Surveillance, Epidemiology and End Results (SEER) program: National Cancer Institute DCCPS Surveillance Research Program, Cancer Statistics Branch. http://www.seer.cancer.gov 5. Chu KC, Tarone RE, Kessler LG, et al: Recent trends in U.S. breast cancer incidence, survival, and mortality rates. J Natl Cancer Inst 88:1571-1579, 1996 6. Berry DA, Cronin KA, Plevritis SK, et al: Effect of screening and adjuvant therapy on mortality from breast cancer. N Engl J Med 353:1784-1792, 2005 7. Early Breast Cancer Trialists’ Collaborative Group: Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: An overview of the randomised trials. Lancet 365:1687-1717, 2005[CrossRef][Medline] 8. Powles T, Eeles R, Ashley S, et al: Interim analysis of the incidence of breast cancer in the Royal Marsden Hospital tamoxifen randomised chemoprevention trial. Lancet 352:98-101, 1998[Medline] 9. Stewart HJ, Prescott RJ, Forrest AP: Scottish adjuvant tamoxifen trial: A randomized study updated to 15 years. J Natl Cancer Inst 93:456-462, 2001 10. Delozier T, Spielmann M, Mace-Lesec'h J, et al: Tamoxifen adjuvant treatment duration in early breast cancer: Initial results of a randomized study comparing short-term treatment with long-term treatment—Federation Nationale des Centres de Lutte Contre le Cancer Breast Group. J Clin Oncol 18:3507-3512, 2000 11. Randomized trial of two versus five years of adjuvant tamoxifen for postmenopausal early stage breast cancer: Swedish Breast Cancer Cooperative Group. J Natl Cancer Inst 88:1543-1549, 1996 12. Belfiglio M, Valentini M, Pellegrini F, et al: Twelve-year mortality results of a randomized trial of 2 versus 5 years of adjuvant tamoxifen for postmenopausal early-stage breast carcinoma patients (SITAM 01). Cancer 104:2334-2339, 2005[CrossRef][Medline] 13. Tormey DC, Gray R, Falkson HC: Postchemotherapy adjuvant tamoxifen therapy beyond five years in patients with lymph node-positive breast cancer: Eastern Cooperative Oncology Group. J Natl Cancer Inst 88:1828-1833, 1996 14. Bryant J, Fisher B, Dignam J: Duration of adjuvant tamoxifen therapy. J Natl Cancer Inst Monogr 56-61, 2001 15. Davies C, Nomura Y, Ohashi Y: [Adjuvant tamoxifen duration: More large-scale randomized evidence is needed]. Gan To Kagaku Ryoho 24:1203-1209, 1997[Medline] 16. Fisher B, Costantino JP, Wickerham DL, et al: Tamoxifen for the prevention of breast cancer: Current status of the National Surgical Adjuvant Breast and Bowel Project P-1 study. J Natl Cancer Inst 97:1652-1662, 2005 17. Wapnir IL, Anderson SJ, Mamounas EP, et al: Prognosis after ipsilateral breast tumor recurrence and locoregional recurrences in five National Surgical Adjuvant Breast and Bowel Project node-positive adjuvant breast cancer trials. J Clin Oncol 24:2028-2037, 2006 18. Clinical Trial Service Unit: Adjuvant tamoxifen longer against shorter (ATLAS), Protocol, April 1995: ATLAS Office. Oxford, England, Radcliffe Infirmary, 1995 19. Winer EP, Hudis C, Burstein HJ, et al: American Society of Clinical Oncology technology assessment on the use of aromatase inhibitors as adjuvant therapy for postmenopausal women with hormone receptor-positive breast cancer: Status report 2004. J Clin Oncol 23:619-629, 2005 20. Baum M, Buzdar A, Cuzick J, et al: Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of postmenopausal women with early-stage breast cancer: Results of the ATAC (Arimidex, Tamoxifen Alone or in Combination) trial efficacy and safety update analyses. Cancer 98:1802-1810, 2003[CrossRef][Medline] 21. Howell A, Cuzick J, Baum M, et al: Results of the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial after completion of 5 years’ adjuvant treatment for breast cancer. Lancet 365:60-62, 2005[CrossRef][Medline] 22. Thürlimann B, Keshaviah A, Coates AS, et al: A comparison of letrozole and tamoxifen in postmenopausal women with early breast cancer. N Engl J Med 353:2747-2757, 2005 23. Goss PE, Ingle JN, Martino S, et al: A randomized trial of letrozole in postmenopausal women after five years of tamoxifen therapy for early-stage breast cancer. N Engl J Med 349:1793-1802, 2003 24. Boccardo F, Rubagotti A, Puntoni M, et al: Switching to anastrozole versus continued tamoxifen treatment of early breast cancer: Preliminary results of the Italian Tamoxifen Anastrozole Trial. J Clin Oncol 23:5138-5147, 2005 25. Jakesz R, Jonat W, Gnant M, et al: Switching of postmenopausal women with endocrine-responsive early breast cancer to anastrozole after 2 years’ adjuvant tamoxifen: Combined results of ABCSG trial 8 and ARNO 95 trial. Lancet 366:455-462, 2005[CrossRef][Medline] 26. Coombes RC, Kilburn LS, Snowdon CF, et al: Survival and safety of exemestane versus tamoxifen after 2-3 years’ tamoxifen treatment (Intergroup Exemestane Study): A randomised controlled trial. Lancet 369:559-570, 2007[CrossRef][Medline] 27. Dowsett M, Cuzick J, Wale C, et al: Retrospective analysis of time to recurrence in the ATAC trial according to hormone receptor status: An hypothesis-generating study. J Clin Oncol 23:7512-7517, 2005 28. Ingle JN, Tu D, Pater JL, et al: Duration of letrozole treatment and outcomes in the placebo-controlled NCIC CTG MA 17 extended adjuvant therapy trial. Breast Cancer Res Treat 99:295-300, 2006[CrossRef][Medline] 29. Osborne CK: Tamoxifen in the treatment of breast cancer. N Engl J Med 339:1609-1618, 1998 30. Fisher B, Costantino JP, Redmond CK, et al: Endometrial cancer in tamoxifen-treated breast cancer patients: Findings from the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-14. J Natl Cancer Inst 86:527-537, 1994 31. Chalas E, Costantino JP, Wickerham DL, et al: Benign gynecologic conditions among participants in the Breast Cancer Prevention Trial. Am J Obstet Gynecol 192:1230-1237, 2005[CrossRef][Medline] 32. Kedar RP, Bourne TH, Powles TJ, et al: Effects of tamoxifen on uterus and ovaries of postmenopausal women in a randomised breast cancer prevention trial. Lancet 343:1318-1321, 1994[CrossRef][Medline] 33. Lahti E, Blanco G, Kauppila A, et al: Endometrial changes in postmenopausal breast cancer patients receiving tamoxifen. Obstet Gynecol 81:660-664, 1993[Medline] 34. Swerdlow AJ, Jones ME: Tamoxifen treatment for breast cancer and risk of endometrial cancer: A case-control study. J Natl Cancer Inst 97:375-384, 2005 35. Braithwaite RS, Chlebowski RT, Lau J, et al: Meta-analysis of vascular and neoplastic events associated with tamoxifen. J Gen Intern Med 18:937-947, 2003[CrossRef][Medline] 36. Lønning PE, Geisler J, Krag LE, et al: Effects of exemestane administered for 2 years versus placebo on bone mineral density, bone biomarkers, and plasma lipids in patients with surgically resected early breast cancer. J Clin Oncol 23:5126-5137, 2005 37. Grunfeld EA, Hunter MS, Sikka P, et al: Adherence beliefs among breast cancer patients taking tamoxifen. Patient Educ Couns 59:97-102, 2005[CrossRef][Medline] 38. Kahn KL, Schneider EC, Malin JL, et al: Patient centered experiences in breast cancer: Predicting long-term adherence to tamoxifen use. Med Care 45:431-439, 2007[CrossRef][Medline] 39. Yoon J, Malin JL, Tao ML, et al: Symptoms after breast cancer treatment: Are they influenced by patient characteristics? Breast Cancer Res Treat 2007 40. Day R, Ganz PA, Costantino JP, et al: Health-related quality of life and tamoxifen in breast cancer prevention: A report from the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J Clin Oncol 17:2659-2669, 1999 41. Owusu C, Buist DS, Field TS, et al: Predictors of tamoxifen discontinuation among older women with estrogen-receptor positive breast cancer. J Clin Oncol doi: 10.1200/JCO.2006.10.1022 42. Partridge AH, LaFountain A, Mayer E, et al: Adherence to initial adjuvant anastozole therapy among women with early stage breast cancer. J Clin Oncol 26:556-562, 2008 43. Osterberg L, Blaschke T: Adherence to medication. N Engl J Med 353:487-497, 2005 44. Demissie S, Silliman RA, Lash TL: Adjuvant tamoxifen: Predictors of use, side effects, and discontinuation in older women. J Clin Oncol 19:322-328, 2001 45. Lash TL, Fox MP, Westrup JL, et al: Adherence to tamoxifen over the five-year course. Breast Cancer Res Treat 99:215-220, 2006[CrossRef][Medline] 46. Atkins L, Fallowfield L: Intentional and non-intentional non-adherence to medication amongst breast cancer patients. Eur J Cancer 42:2271-2276, 2006[CrossRef][Medline] 47. Morisky DE, Green LW, Levine DM: Concurrent and predictive validity of a self-reported measure of medication adherence. Med Care 24:67-74, 1986[Medline] 48. Yoon J, Malin JL, Tisnado DM, et al: Symptom management after breast cancer treatment: Is it influenced by patient characteristics? Breast Cancer Res Treat [epub ahead of print on July 19, 2007] 49. Haynes RB, McDonald HP, Garg AX: Helping patients follow prescribed treatment: Clinical applications. JAMA 288:2880-2883, 2002 50. Simoni JM, Frick PA, Pantalone DW, et al: Antiretroviral adherence interventions: A review of current literature and ongoing studies. Top HIV Med 11:185-198, 2003[Medline] 51. Tuldrà A, Fumaz CR, Ferrer MJ, et al: Prospective randomized two-arm controlled study to determine the efficacy of a specific intervention to improve long-term adherence to highly active antiretroviral therapy. J Acquir Immune Defic Syndr 25:221-228, 2000[CrossRef][Medline] 52. Feldman R, Bacher M, Campbell N, et al: Adherence to pharmacologic management of hypertension. Can J Public Health 89:I16-I18, 1998[Medline] 53. Ran MS, Xiang MZ, Chan CL, et al: Effectiveness of psychoeducational intervention for rural Chinese families experiencing schizophrenia: A randomised controlled trial. Soc Psychiatry Psychiatr Epidemiol 38:69-75, 2003[CrossRef][Medline] 54. Zygmunt A, Olfson M, Boyer CA, et al: Interventions to improve medication adherence in schizophrenia. Am J Psychiatry 159:1653-1664, 2002 55. National Comprehensive Cancer Network (NCCN) Breast Cancer (version IX) Clinical Practice Guidelines in Oncology. http://www.nccn.org 56. Goldhirsch A, Glick J, Gelber R, et al: Meeting highlights: International consensus panel on the treatment of primary breast cancer. J Natl Cancer Inst 1601-1608, 1998 57. DiMatteo MR, Sherbourne CD, Hays RD, et al: Physicians’ characteristics influence patients’ adherence to medical treatment: Results from the Medical Outcomes Study. Health Psychol 12:93-102, 1993[CrossRef][Medline] 58. PPA: Partnership for Prescription Assistance Program 2007. http://www.pparx.org/ 59. RXHelpForCalifornians: RX Help for Californians 2007. http://www.rxhelpforca.org 60. Haynes R, Yan X, Degani A, et al: Interventions for Enhancing Medication Adherence (Review). Cochrane Database Syst Rev 4:CD000011, 2005[Medline] 61. Sabate E: Adherence to Long Term Therapies: Evidence for Action. Geneva, Switzerland, World Health Organization, 2003 62. Malin JL, Schneider EC, Epstein AM, et al: Results of the National Initiative for Cancer Care Quality: How can we improve the quality of cancer care in the United States? J Clin Oncol 24:626-634, 2006 63. McGlynn EA, Asch SM, Adams J, et al: The quality of health care delivered to adults in the United States. 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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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