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DNA mutations and deficiencies in mitochondrial oxidative phosphorylation in aging skeletal muscle.2 The expression of the peroxisome-proliferator–activated receptor γ coactivator 1α (PGC-1α), nuclear respiratory factor 1, and cytochrome c is substantially lower in the heart and skeletal muscle of old persons.3 An age-associated lack of PGC-1α induction has also been reported in the skeletal muscle of old animals.4 The transgenic overexpression of PGC-1α efficiently prevents sarcopenia in old mice by limiting the degradation of muscle proteasome and apoptosis.5 All these facts highlight the role of most mitochondrial proteins, and probably those involved in mitochondrial fission and fusion, in the loss of muscle mass associated with aging and emphasize the importance of mitochondria as targets for pharmacologic interventions intended to prevent sarcopenia. Fabian Sanchis-Gomar, M.D., Ph.D. University of Valencia Valencia, Spain [email protected]

Frederic Derbré, Ph.D. University Rennes 2 Rennes, France No potential conflict of interest relevant to this letter was reported. 1. Archer SL. Mitochondrial dynamics — mitochondrial fis-

sion and fusion in human diseases. N Engl J Med 2013;369:223651. 2. Viña J, Gomez-Cabrera MC, Borras C, et al. Mitochondrial biogenesis in exercise and in ageing. Adv Drug Deliv Rev 2009;61:1369-74. 3. Dillon LM, Rebelo AP, Moraes CT. The role of PGC-1 coactivators in aging skeletal muscle and heart. IUBMB Life 2012;64:231-41. 4. Derbré F, Gomez-Cabrera MC, Nascimento AL, et al. Age associated low mitochondrial biogenesis may be explained by lack of response of PGC-1α to exercise training. Age (Dordr) 2012;34:669-79. 5. Wenz T, Rossi SG, Rotundo RL, Spiegelman BM, Moraes CT. Increased muscle PGC-1alpha expression protects from sarcope-

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nia and metabolic disease during aging. Proc Natl Acad Sci U S A 2009;106:20405-10. DOI: 10.1056/NEJMc1316254

The Author Replies: Sanchis-Gomar and Derbré correctly note that I failed to discuss the role of mitochondrial dynamics in the atrophy of skeletal muscle (sarcopenia) in my recent article. This omission (and several others) reflects the limitation on the length of the article. Fission and fusion serve a quality-control function, eliminating dysfunctional mitochondria and protecting the aging cell or organism from the accumulation of mitochondria that have mutated DNA and oxidized proteins. Impairment of mitochondrial dynamics contributes to the decline in mitochondrial function with age in muscle, neurons, and other tissues.1 The expression of mitofusin-2 and dynaminrelated protein 1 (DRP1) is reduced in skeletal muscle as we age.2 The resulting fusion–fission imbalance may impair mitochondrial DNA repair and mitochondrial metabolism, promoting muscle atrophy. Both mitofusin-2 and PGC-1α (a transcriptional regulator of mitochondrial biogenesis and a transcriptional coactivator of mitofusin-2) preserve muscle mass; conversely, DRP1 may promote atrophy.1 Stephen L. Archer, M.D. Queen’s University Kingston, ON, Canada [email protected] Since publication of his article, the author reports no further potential conflict of interest. 1. Seo AY, Joseph AM, Dutta D, Hwang JC, Aris JP, Leeuwen-

burgh C. New insights into the role of mitochondria in aging: mitochondrial dynamics and more. J Cell Sci 2010;123:2533-42. 2. Crane JD, Devries MC, Safdar A, Hamadeh MJ, Tarnopolsky MA. The effect of aging on human skeletal muscle mitochondrial and intramyocellular lipid ultrastructure. J Gerontol A Biol Sci Med Sci 2010;65:119-28. DOI: 10.1056/NEJMc1316254

Early Specialty Palliative Care To the Editor: We concur with the Sounding Board article by Parikh et al. (Dec. 12 issue)1 and believe that additional barriers to access to palliative care deserve mention and may or may not be amenable to change in the short term.2 Oncologists may not refer patients because of personal biases. In addition, the palliative care team 1074

itself can sometimes be an obstacle — referrals will continue only if recommendations are thought to be valuable. Furthermore, screening to identify patients who will benefit from palliative care is an issue: oncologists may be aware of the benefits of palliative care and open to referral but lack the ability to identify patients in need of

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referral. As we3,4 and others5 have shown, application of screening guidelines6 with little lead time in both the outpatient and inpatient settings may have an effect. Finally, we have piloted application of the “bundles” concept to palliative care referrals in the intensive care unit. By using ventilator withdrawal as the trigger for a consult, we increased the number of earlier referrals. Such screening tools may enable the busy yet caring oncologist to quickly identify patients who might benefit from palliative care services. Paul Glare, M.D. Andrew S. Epstein, M.D. Stephen M. Pastores, M.D. Memorial Sloan-Kettering Cancer Center New York, NY [email protected] No potential conflict of interest relevant to this letter was reported. 1. Parikh RB, Kirch RA, Smith TJ, Temel JS. Early specialty pal-

liative care — translating data in oncology into practice. N Engl J Med 2013;369:2347-51. 2. Meier DE, Sieger CE. A guide to building a hospital based palliative care program. New York: Center to Advance Palliative Care, 2004. 3. Glare PA, Semple D, Stabler SM, Saltz LB. Palliative care in the outpatient oncology setting: evaluation of a practical set of referral criteria. J Oncol Pract 2011;7:366-70. 4. Glare P, Plakovic K, Schloms A, et al. Study using the NCCN guidelines for palliative care to screen patients for palliative care needs and referral to palliative care specialists. J Natl Compr Canc Netw 2013;11:1087-96. 5. Weissman DE, Meier DE. Identifying patients in need of a palliative care assessment in the hospital setting: a consensus report from the Center to Advance Palliative Care. J Palliat Med 2011;14:17-23. 6. Levy MH, Back A, Benedetti C, et al. NCCN clinical practice guidelines in oncology: palliative care. J Natl Compr Canc Netw 2009;7:436-73. DOI: 10.1056/NEJMc1400243

To the Editor: Several clinical trials have shown the benefit of early specialty palliative care in advanced cancer, with improved symptom control, satisfaction with care, quality of life, and possibly survival at reduced cost.1-3 Parikh and colleagues highlight the commonly held misperception that palliative care is synonymous with end-of-life care as a key barrier to the implementation of an integrated palliative care–oncology pathway. Although oncologists agree that early referral to palliative care is ideal, studies consistently show that patients continue to be referred late, often close to the end of life, and only after all anticancer treatments have been exhausted.4 Palliative care training for medical oncologists has the potential to improve this trend. Since 2003, the European So-

ciety for Medical Oncology has been leading the way by formally accrediting centers of integrated oncology and palliative care. A similar initiative by the American Society of Clinical Oncology would serve as a catalyst for the implementation of the more optimum care outlined in the Sounding Board article. Jodie E. Battley, M.B., B.Ch. Louise C. Connell, M.B., B.Ch. Seamus O’Reilly, M.D., Ph.D. Cork University Hospital Cork, Ireland [email protected] No potential conflict of interest relevant to this letter was reported. 1. Temel JS, Greer JA, Muzikansky A, et al. Early palliative care

for patients with metastatic non–small-cell lung cancer. N Engl J Med 2010;363:733-42. 2. Greer JA, Jackson VA, Meier DE, Temel JS. Early integration of palliative care services with standard oncology care for patients with advanced cancer. CA Cancer J Clin 2013;63:349-63. 3. Zimmermann C, Swami N, Rodin G, et al. Cluster-randomized trial of early palliative care for patients with metastatic cancer. Presented at the 2012 American Society for Clinical Oncology Annual Meeting, Chicago, June 1–5, 2012. abstract. 4. Ramchandran K, Von Roenn JH. Palliative care always. Oncology (Williston Park) 2013;27:13-6, 27-30, 32-4. DOI: 10.1056/NEJMc1400243

The authors reply: As Glare et al. note, screening1 and practice2 guidelines for oncologists to identify patients in need of referral to specialty palliative care do exist. Such guidelines have proved to be successful in identifying seriously ill patients who are at high risk for early death and who should be a priority for earlier palliative care.3 These measures may be useful to reduce the staggering rates of late referrals for palliative care, as described by Battley et al. However, although practice changes and education may reduce practitioners’ resistance to early palliative care, these advances must be accompanied by system-level changes. For example, reimbursement structures should provide incentives for advance care planning and palliative care consultations early in the course of illness. Some institutions have even implemented quality-improvement initiatives that tie evidence-based palliative care screening to pay-for-performance reimbursement.4 These initiatives have tripled the rates of early palliative care consultation in target populations. Only through such a coordinated strategy can we ensure that the benefits of early specialty palliative care are fully realized in tomorrow’s health care system.

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Ravi B. Parikh, A.B. Harvard Medical School Boston, MA

Jennifer S. Temel, M.D. Massachusetts General Hospital Boston, MA [email protected] Since publication of their article, the authors report no further potential conflict of interest. 1. Weissman DE, Meier DE. Identifying patients in need of a

palliative care assessment in the hospital setting: a consensus

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report from the Center to Advance Palliative Care. J Palliat Med 2011;14:17-23. 2. Levy MH, Back A, Benedetti C, et al. NCCN clinical practice guidelines in oncology: palliative care. J Natl Compr Canc Netw 2009;7:436-73. 3. Moss AH, Ganjoo J, Sharma S, et al. Utility of the “surprise” question to identify dialysis patients with high mortality. Clin J Am Soc Nephrol 2008;3:1379-84. 4. Bernacki RE, Ko DN, Higgins P, et al. Improving access to palliative care through an innovative quality improvement initiative: an opportunity for pay-for-performance. J Palliat Med 2012;15:192-9. DOI: 10.1056/NEJMc1400243

Case 38-2013: A Man with Fever and Lymphadenopathy To the Editor: In the Case Record, Ray et al. (Dec. 12 issue)1 provide no data about serologic analysis for parvovirus B19. Although the patient had no rash or any affliction of the joints, it would be important to rule out parvovirus B19 infection because of the low reticulocyte count (which has to be corrected for its true estimation) and the dramatic drop in hemoglobin levels (a decrease of approximately 15% in the hematocrit in just 5 days), especially in view of the patient’s hemoglobinopathy (homozygous hemoglobin D disease).2 Parvovirus remains a notorious and usual culprit of aplastic crisis in patients with hemoglobinopathies.3 The patient’s hemoglobinopathy per se is not a sufficient explanation for the abrupt worsening of anemia reported in the case. In addition to afflicting a patient with hemoglobinopathy, infection with parvovirus B19 may lead to hospital outbreaks.4 Petros I. Rafailidis, M.D. 12 Mourganas St. Koropi, Greece [email protected] No potential conflict of interest relevant to this letter was reported. 1. Case Records of the Massachusetts General Hospital (Case

38-2013). N Engl J Med 2013;369:2333-43.

2. Mohanty D, Colah RB, Gorakshakar AC, et al. Prevalence of

β-thalassemia and other haemoglobinopathies in six cities in India: a multicentre study. J Community Genet 2013;4:33-42. 3. Young NS, Brown KE. Parvovirus B19. N Engl J Med 2004; 350:586-97. 4. Bell LM, Naides SJ, Stoffman P, Hodinka RL, Plotkin SA. Human parvovirus B19 infection among hospital staff members after contact with infected patients. N Engl J Med 1989;321:48591. DOI: 10.1056/NEJMc1400186

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To the Editor: Ray et al. state that serologic testing for systemic lupus erythematosus (SLE) is recommended for all patients with biopsy results suggestive of Kikuchi–Fujimoto disease. However, such testing (e.g., for antinuclear antibodies) should be indicated on the basis of clinical characteristics of individual patients with Kikuchi– Fujimoto disease. In Japan, we commonly see many patients with this disease, which is mostly self-limited and is usually treated conservatively. After the illness has resolved, follow-up advice is provided if any symptoms develop. But serologic testing for SLE is not routinely performed in patients with Kikuchi–Fujimoto disease unless they have other manifestations suggestive of SLE, such as skin lesions.1 SLE developed in only 2 of 108 patients with Kikuchi–Fujimoto disease (2%) in a U.S. cohort2 and in 2 of 195 (1%) in a Taiwan cohort.3 In such patients with positive results on antinuclear antibody testing but no symptoms or signs of SLE, there are no measures to prevent SLE, so the positive test result would make little change in our clinical practice. Yasuharu Tokuda, M.D., M.P.H. University of Tsukuba Mito City, Japan [email protected] No potential conflict of interest relevant to this letter was reported. 1. Kim SK, Kang MS, Yoon BY, et al. Histiocytic necrotizing

lymphadenitis in the context of systemic lupus erythematosus (SLE): is histiocytic necrotizing lymphadenitis in SLE associated with skin lesions? Lupus 2011;20:809-19. 2. Dorfman RF, Berry GJ. Kikuchi’s histiocytic necrotizing lymphadenitis: an analysis of 108 cases with emphasis on differential diagnosis. Semin Diagn Pathol 1988;5:329-45.

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Early specialty palliative care.

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