Letters COMMENTS AND Annals of Internal Medicine RESPONSES Adjusting for Inflation and Higher Surgery Costs in a Cost-Effectiveness Study of Spinal Surgery TO THE EDITOR: We read with interest the article by Tosteson and colleagues (1) regarding the cost-effectiveness of surgical treatment of spinal stenosis with or without degenerative spondylolisthesis However, the health economic conclusions of the article may be more favorable than suggested by the authors because of the need to adjust the frame of reference to U.S dollars and to adjust for inflation The authors refer to an article by Laupacis and colleagues (2) as a guide to determining whether a health intervention is considered “costly” or not Two factors need to be kept in mind about this reference First, the guidelines by Laupacis and colleagues for interpreting health economic data were calculated in Canadian dollars at a time when the U.S dollar was stronger Second, Laupacis and colleagues’ guidelines were based on the Canadian dollar in 1990, 14 years before the year used by Tosteson and colleagues (2004) to standardize the health costs Inflation over that period means that the value of a dollar in 2004 was not the same as in 1990 Laupacis and colleagues suggest that interventions that cost more than CAN $100 000 per quality-adjusted life-year gained provide “weak evidence for adoption” (that is, are “costly”) On the basis of the exchange rate in mid-1990, this would equate to U.S $85 771 at that time (3) Adjusting for inflation in the United States between mid1990 and mid-2004 increases this to U.S $123 964 (4) On the basis of this standard, both of the interventions studied by Tosteson and colleagues (spinal stenosis surgery and spondylolisthesis surgery) could be considered cost-effective after converting to U.S dollars and accounting for inflation Neil H Shusterman, MD Research Pharmaceutical Services Fort Washington, PA 19034 Haim Erder, PhD Forest Research Institute Jersey City, NJ 07311 Potential Financial Conflicts of Interest: None disclosed References Tosteson AN, Lurie JD, Tosteson TD, Skinner JS, Herkowitz H, Albert T, et al; SPORT Investigators Surgical treatment of spinal stenosis with and without degenerative spondylolisthesis: cost-effectiveness after years Ann Intern Med 2008;149:84553 [PMID: 19075203] Laupacis A, Feeny D, Detsky AS, Tugwell PX How attractive does a new technology have to be to warrant adoption and utilization? Tentative guidelines for using clinical and economic evaluations CMAJ 1992;146:473-81 [PMID: 1306034] FX converter: currency converter for 164 currencies Accessed at www.oanda.com /convert/classic on 24 February 2009 U.S Department of Labor, Bureau of Labor Statistics CPI inflation calculator Accessed at data.bls.gov/cgi-bin/cpicalc.pl on 24 February 2009 TO THE EDITOR: I appreciated the article by Tosteson and col- leagues (1) estimating the cost-effectiveness of back surgery As a retired general internist who treated many patients with back pain at the White River Junction Veterans Affairs Hospital over many years in both short-term and long-term settings (“walk-in” clinic, emergency department, scheduled general medical clinic) and who has some familiarity with Richard Deyo’s seminal work on back pain, several questions come to mind First, the authors mention that most patients were symptomatic for at least to months before study in multidisciplinary spine practices Did each study site allow direct scheduled appointments, unscheduled walk-in evaluations, or emergency department evaluations (that is, direct access) to spine clinics? In other words, did each spine clinic only accept referrals from primary care physicians or emergency department professionals before spine clinic evaluation, and what was the mean time from initial symptom onset to initial spine clinic evaluation and treatment entry (disease duration)? The reason for this interest is to determine whether “referral status” or “spine clinic status” is the better measure of surgical efficacy at years, and to determine whether an increased “delay to surgery” is a predictor of surgical efficacy by allowing operation to only those patients with the most durably symptomatic pain? Is there a duration of pain that might represent an inflection point in the surgical efficacy versus time-to-treatment curve? Second, the authors’ thoroughness in detailing medical costs is impressive However, the largest single-ticket item, and the only truly “discriminating” cost among the treatment groups in Table 2, is “Surgery.” As a general internist, I would be particularly interested in a breakdown of “surgical cost” into “hospital charges: Medicare reimbursable,” “hospital charges: negotiated reduction,” “hospital charges: patient copay,” “hospital charges: patient balance billed,” and “physician charges.” In other words, how well Medicare payment schedules (Part A plus Part B) reflect private insurer costs plus patient costs (total costs) and surgical cost-effectiveness? Is surgical cost-effectiveness in younger, Medicare-ineligible patients better, worse, or similar? Dominic J Balestra, MD Dartmouth College Lebanon, NH 03766 Potential Financial Conflicts of Interest: None disclosed Reference Tosteson AN, Lurie JD, Tosteson TD, Skinner JS, Herkowitz H, Albert T, et al; SPORT Investigators Surgical treatment of spinal stenosis with and without degenerative spondylolisthesis: cost-effectiveness after years Ann Intern Med 2008;149:84553 [PMID: 19075203] IN RESPONSE: We thank Drs Shusterman and Erder for their com- ments, which highlight both the challenges inherent in using any single threshold as a benchmark for ascribing value to health care interventions and the pitfalls in adjusting for inflation and converting between currencies If one first adjusts for the inflation of Canadian dollars from mid-1990 to mid-2004 (an adjustment of 1.319 [1]), then the “costly” $100 000 threshold (2) becomes $131 900 Converting between 2004 Canadian and U.S dollars (1.322 Canadian dollars per U.S dollar as of July 2004 [3]), one achieves a value of $131 900/1.322 ϭ $99 773, or approximately $100 000 in 2004 U.S dollars To overcome relying on a single benchmark, we showed results for the most important sensitivity analyses by using a cost- 652 © 2009 American College of Physicians Downloaded From: http://annals.org/pdfaccess.ashx?url=/data/journals/aim/20181/ by a Fudan University User on 01/15/2017 Letters effectiveness acceptability curve, which graphed the proportion of times the cost per quality-adjusted life-year gained achieved willingness-to-pay thresholds ranging from $20 000 to $300 000 Such graphical presentations should be helpful to those who are skeptical about the use of any particular cost-effectiveness benchmark This methodology was also useful for demonstrating the marked impact that higher surgery costs have on the value of surgery— an issue raised by Dr Balestra’s comment Our costing approach used national standardized Medicare payment amounts as a proxy for actual resource use Thus, the surgery costs in our analysis were lower than what many private insurers pay When the cost of surgery was based on 70% of the amount hospitals billed to Medicare (a higher amount that what Medicare actually pays), the cost per quality-adjusted life-year gained for surgery fell below $100 000 in only a small minority of samples The role that our costing approach had on comparisons between instrumented and noninstrumented fusion surgery warrants comment Our report of no difference in cost between fusion types is largely an artifact of our costing approach, because Medicare payment amounts are minimally different for these surgical alternatives Although no statistically significant differences in health outcome were observed between fusion types over years, further follow-up of SPORT (Spine Patient Outcomes Research Trial) participants by using several approaches to costing will be important for understanding the long-term value of surgery Although the SPORT protocol specified a minimum symptom duration of 12 weeks, we are aware of no referral restrictions at participating centers Previous treatments received by SPORT observational cohort participants have been described (4) and may be indicative of varied referral pathways Our study was not designed to address the optimal symptom duration before surgery Anna N.A Tosteson, ScD James N Weinstein, DO, MS Dartmouth Medical School Hanover, NH 03756 Jonathan S Skinner, PhD Dartmouth College Hanover, NH 03755 Potential Financial Conflicts of Interest: None disclosed References Bank of Canada Inflation Calculator Accessed at www.bankofcanada.ca/en/rates /inflation_calc.html on 24 February 2009 Laupacis A, Feeny D, Detsky AS, Tugwell PX How attractive does a new technology have to be to warrant adoption and utilization? Tentative guidelines for using clinical and economic evaluations CMAJ 1992;146:473-81 [PMID: 1306034] St Louis Federal Reserve Canada/U.S Foreign Exchange Rate Accessed at research Health Effects and Further Consequences of the Train From Golmud to Lhasa TO THE EDITOR: I read with great interest the article by West (1) about the train from Golmud, China, to Lhasa, Tibet; its pathophysiologic aspects; and the approaches taken to address them However, a few more points should be made First, it is important to consider the possible effects of highaltitude travel on travelers who have different kinds of comorbid conditions (for example, diseases of the heart and lung) (2) and the effects of long, high-altitude, and sedentary travel on the blood coagulation profile and other conditions, such as deep venous thrombosis, the antiphospholipid syndrome (3), sickle cell disease, and protein C and protein S deficiency Second, some persons in developing countries, such as Tibet, are infected with tuberculosis, which could be dangerous and infective to other fellow travelers (4) because of the crowded and closed setting of the cabin (necessary to maintain oxygen concentration) Third, the train starts at Golmud (2808 m), reaches a maximum altitude of 5074 m, and travels at an average altitude of 4500 m (Ͼ14 h over 1142 km), finally coming to Lhasa (3658 m) However, trekkers are usually advised to climb high and sleep low above an altitude of 3000 m and acclimatization hiking, which travel on the high-altitude train does not permit Finally, I respect West’s opinion on the political aspect regarding Tibet, the effect of the train, and present scenario of globalization (5) But the article should have mentioned the migration of lowland people (especially Han Chinese) to Tibet (high altitude) and the effect of long-term exposure to chronic hypobaric hypoxia, which are further effects of the railway Matiram Pun, MBBS Tribhuyan University Teaching Hospital Kathmandu, Nepal Potential Financial Conflicts of Interest: None disclosed References West JB A new approach to very-high-altitude land travel: the train to Lhasa, Tibet Ann Intern Med 2008;149:898-900 [PMID: 19075209] Luks AM, Swenson ER Travel to high altitude with pre-existing lung disease Eur Respir J 2007;29:770-92 [PMID: 17400877] Basnyat B, Graham L, Lee SD, Lim Y A language barrier, abdominal pain, and double vision Lancet 2001;357:2022 [PMID: 11438136] Saito M, Pan WK, Gilman RH, Bautista CT, Bamrah S, Martı´n CA, et al Comparison of altitude effect on Mycobacterium tuberculosis infection between rural and urban communities in Peru Am J Trop Med Hyg 2006;75:49-54 [PMID: 16837708] Into thin air: high-altitude train travel on the Qinghai–Lhasa railway; interview with Dr John West, MD, PhD, of the University of California San Diego 16 December 2008 Ann Intern Med 2008;149 Accessed at www.annals.org/podcast/2008-v149 shtml on March 2009 .stlouisfed.org/fred2/data/EXCAUS.txt on 24 February 2009 Cummins J, Lurie JD, Tosteson TD, Hanscom B, Abdu WA, Birkmeyer NJ, et al Descriptive epidemiology and prior healthcare utilization of patients in the Spine Pa- Rejuvenation in Older Adults Receiving Oral Ghrelin tient Outcomes Research Trial’s (SPORT) three observational cohorts: disc herniation, spinal stenosis, and degenerative spondylolisthesis Spine 2006;31:806-14 [PMID: TO THE EDITOR: I read with interest the article by Nass and col- 16582855] leagues (1), which presents clinical evidence of rejuvenation in 65 www.annals.org May 2009 Annals of Internal Medicine Volume 150 • Number 653 Downloaded From: http://annals.org/pdfaccess.ashx?url=/data/journals/aim/20181/ by a Fudan University User on 01/15/2017 Letters healthy older adults (men and women) 60 to 81 years of age after daily administration of oral ghrelin (a secretagogue product) for year Oral administration of MK-677 increased pulsatile growth hormone secretion and serum insulin-like growth factor (IGF)–I (also known as somatomedin C) levels (2) In part, I agree with Nass and colleagues’ findings, because through blood flow, the growth hormone secretagogues (comprising amino acids, some peptides, vitamins, and minerals) may reach the producing hypothalamic nuclei of growth hormone–releasing hormone (3) and, therefore, increase growth hormone secretion from the adenohypophysis However, these treatments may not work in older persons because of atherosclerotic plaques located at the mouths of the collateral branches originating from the supraclinoid carotids and circle of Willis (3, 4) In contrast, revascularization of the arcuate nucleus and surrounding nuclei by means of omental tissue can provoke rejuvenation (3) because the hypothalamus receives an increase in blood flow, oxygen, neurotransmitters, neurotrophic factors, cytokines, and omental stem cells through the omentum (3, 5) For these reasons, I postulate that aging is not a normal biological process but a disease Hernando Rafael, MD Universidad Nacional Auto´noma de Me´xico 03300 Mexico City, Mexico Potential Financial Conflicts of Interest: None disclosed pharmacologic treatment strategies for decreased muscle strength and increased abdominal and intra-abdominal fat must be mentioned when discussing sarcopenia and increased blood glucose levels in elderly persons Markus Gaugg, MD Kaiser Franz Josef Hospital 1100 Vienna, Austria Potential Financial Conflicts of Interest: None disclosed References Nass R, Pezzoli SS, Oliveri MC, Patrie JT, Harrell FE Jr, Clasey JL, et al Effects of an oral ghrelin mimetic on body composition and clinical outcomes in healthy older adults: a randomized trial Ann Intern Med 2008;149:60111 [PMID: 18981485] Cironi L, Riggi N, Provero P, Wolf N, Suva` ML, Suva` D, et al IGF1 is a common target gene of Ewing’s sarcoma fusion proteins in mesenchymal progenitor cells PLoS ONE 2008;3:e2634 [PMID: 18648544] Jungwirth A, Schally AV, Pinski J, Groot K, Armatis P, Halmos G Growth hormone-releasing hormone antagonist MZ-4-71 inhibits in vivo proliferation of Caki-I renal adenocarcinoma Proc Natl Acad Sci U S A 1997;94:5810-3 [PMID: 9159156] Simmons JG, Ling Y, Wilkins H, Fuller CR, D’Ercole AJ, Fagin J, et al Cellspecific effects of insulin receptor substrate-1 deficiency on normal and IGF-I-mediated colon growth Am J Physiol Gastrointest Liver Physiol 2007;293:G995-1003 [PMID: 17823215] References Nass R, Pezzoli SS, Oliveri MC, Patrie JT, Harrell FE Jr, Clasey JL, et al Effects of an oral ghrelin mimetic on body composition and clinical outcomes in healthy older adults: a randomized trial Ann Intern Med 2008;149:601-11 [PMID: 18981485] Chapman IM, Bach MA, Van Cauter E, Farmer M, Krupa D, Taylor AM, et al Stimulation of the growth hormone (GH)-insulin-like growth factor I axis by daily oral administration of a GH secretogogue (MK-677) in healthy elderly subjects J Clin Endocrinol Metab 1996;81:4249-57 [PMID: 8954023] Rafael H Rejuvenation after omental transplantation on the optic chiasma and carotid bifurcation Case Rep Clin Pract Rev 2006;7:48-51 Rafael H Hypothalamic ischemia and premature aging [Letter] Med Sci Monit 2007;13:LE9-10 [PMID: 17599033] Garcı´a-Go´mez I, Goldsmith HS, Angulo J, Prados A, Lo´pez-Herva´s P, Cuevas B, et al Angiogenic capacity of human omental stem cells Neurol Res 2005;27:807-11 [PMID: 16354540] TO THE EDITOR: I read with interest the study by Nass and colleagues (1) I would like to address some critical issues, with particular reference to adverse events First, growing evidence suggests that IGF-I is a cytokine involved in promotion and induction of oncogenesis in different types of tumors, such as Ewing sarcoma (2), renal cell carcinoma (3), and adenocarcinoma of the gastrointestinal tract (for example, colorectal carcinoma [4] and cholangiocellular carcinoma) Why didn’t the authors report the results of screening methods (fecal occult blood test, abdominal ultrasonography, colonoscopy) or staging of reported adverse events? Second, magnetic resonance imaging and biopsy of skeletal muscle in relation to the observed effects would have been of interest in context with a clinical trial designed to prove a concept Finally, the study did not seem to focus on adverse events or economic issues, which was part of the stated objective I wish the authors had included a detailed discussion of the observed adverse events Non- TO THE EDITOR: The study by Nass and colleagues (1) elegantly reinforces the prevalent health strategy first proposed by Juan Ponce de Leon in 1513 (2): Simply find the magic fountain, or the right pill, and perpetual youth and perhaps even immortality will be yours, without breaking a sweat, and oh, don’t worry about the cost A contrasting approach would cite the impressive data confirming the benefits of lifestyle changes, especially exercise, in preventing and reversing frailty (3), which as a bonus reduces obesity, prevents falls, and may even improve mental status All this without decreasing insulin sensitivity or other potential long-term side effects, such as diabetes Perhaps future studies testing ghrelin mimetic should include a “control group” of participants performing an aerobic and weightresistance exercise program combined with a diet intervention One might reasonably predict that this latter group would outperform the pharmacologically enhanced cohort by a wide margin The control group would also feel better and have lower costs while expending only sweat equity Jim Webster, MD, MS Northwestern University, Feinberg School of Medicine Chicago, IL 60611 Potential Financial Conflicts of Interest: None disclosed References Nass R, Pezzoli SS, Oliveri MC, Patrie JT, Harrell FE Jr, Clasey JL, et al Effects of an oral ghrelin mimetic on body composition and clinical outcomes in healthy older adults: a randomized trial Ann Intern Med 2008;149:601-11 [PMID: 18981485] Olschki L Ponce de Leon’s fountain of youth: History of a geographical myth Hispanic American Historical Review 1941;26:361-85 654 May 2009 Annals of Internal Medicine Volume 150 • Number Downloaded From: http://annals.org/pdfaccess.ashx?url=/data/journals/aim/20181/ by a Fudan University User on 01/15/2017 www.annals.org Letters Hall WJ Centenarians: metaphor becomes reality [Editorial] Arch Intern Med 2008;168:262-3 [PMID: 18268165] IN RESPONSE: We appreciate the thoughtful comments in response to our article and offer some clarifications We believe that aging is not a disease but a complex multisystem decline that occurs over decades It is likely that MK-677 acts at multiple sites, including the hypothalamus, the pituitary, and the periphery We have no evidence that atherosclerosis impairs its action We did not perform other cancer screening in these healthy older adults Women were carefully monitored with Papanicolaou smears and mammography, and prostate-specific antigen was monitored in men Adverse effects were reported in the Results section A study of this size cannot assess cancer risk; however, as of 20 July 2007, more than 600 adults had been exposed to MK-677 for to 12 months The combined incidence rate for malignant conditions in any MK-677 treatment group was similar to the incidence rate in the placebo groups in these studies (Papanicolaou DA Personal communication.) The cancer risk of growth hormone and IGF-I administration is controversial and has been extensively reviewed (1) As Dr Webster points out, the benefits of exercise are well established and should always be recommended However, physiologic studies show that the effects of resistance training on intramuscular metabolic changes achieved in elderly persons, as well as muscle growth response, are significantly less than those in younger study samples (2, 3) Additional data suggest that in men older than 80 years of age, the capacity to gain strength with resistance training is decreased because of limited myocellular adaptive response (4) Furthermore, some elderly adults cannot exercise because of substantial muscle loss and frailty Interventions that prevent or delay a decline in muscle mass would be desirable, given the expected demographic shift in the aging population Our observations support a role for ghrelin mimetics to enhance growth hormone secretion; this resulted in both arrest of muscle mass loss as well as an increase in muscle mass The increase in appetite also may be important Recent data from the Health ABC (Dynamics of Health, Aging and Body Composition) Study demonstrate a significant association between change in lean mass in elderly persons and dietary protein intake (5) Long-term studies comparing the effects of exercise with a ghrelin mimetic alone or in combination with exercise are certainly needed in elderly patients who are physically able to exercise We emphasized that ours was a “proof-of-concept” study, and now definitive studies need to be designed and performed Ralf M Nass, MD Mary Lee Vance, MD Michael O Thorner, MBBS, DSc University of Virginia Health System Charlottesville, VA 22908 Potential Financial Conflicts of Interest: None disclosed References Critical evaluation of the safety of recombinant human growth hormone administration: statement from the Growth Hormone Research Society J Clin Endocrinol www.annals.org Metab 2001;86:1868-70 [PMID: 11344173] Kosek DJ, Kim JS, Petrella JK, Cross JM, Bamman MM Efficacy of days/wk resistance training on myofiber hypertrophy and myogenic mechanisms in young vs older adults J Appl Physiol 2006;101:531-44 [PMID: 16614355] Welle S, Thornton C, Statt M Myofibrillar protein synthesis in young and old human subjects after three months of resistance training Am J Physiol 1995;268: E422-7 [PMID: 7900788] Slivka D, Raue U, Hollon C, Minchev K, Trappe S Single muscle fiber adaptations to resistance training in old (Ͼ80 yr) men: evidence for limited skeletal muscle plasticity Am J Physiol Regul Integr Comp Physiol 2008;295:R273-80 [PMID: 18448613] Houston DK, Nicklas BJ, Ding J, Harris TB, Tylavsky FA, Newman AB, et al; Health ABC Study Dietary protein intake is associated with lean mass change in older, community-dwelling adults: the Health, Aging, and Body Composition (Health ABC) Study Am J Clin Nutr 2008;87:150-5 [PMID: 18175749] CLINICAL OBSERVATIONS Hepatitis B Virus Reactivation in a Patient With Resolved Hepatitis B Virus Infection Receiving Maintenance Rituximab for Malignant B-Cell Lymphoma Background: The risk for hepatitis B virus (HBV) reactivation in patients with seemingly resolved infection who are undergoing treatment for cancer remains controversial Objective: To report a case of HBV reactivation in a patient with seemingly resolved infection who was undergoing lymphoma treatment Case Report: A 71-year-old man with mantle cell lymphoma had previously resolved hepatitis B virus (HBV) infection, defined as negative HBV surface antigen (HBsAg) with detectable antibody to HBV core antigen (anti-HBc) He had no detectable antibody to HBsAg (anti-HBsAg) Full staging investigations showed multiple enlarged lymph nodes An excision biopsy of the right axillary lymph node was performed, and immunohistochemistry highlighted a nodular lymphoid infiltrate of CD20ϩ B cells with strong nuclear cyclin D1 expression The patient was treated with cycles of rituximab, cyclophosphamide, vincristine, doxorubicin, and prednisolone (R-CHOP) chemotherapy without prophylactic lamivudine during or after chemotherapy Three months after chemotherapy, he began receiving maintenance rituximab at a dose of 375 mg/m2 once every months (1) Liver enzyme levels before each cycle of maintenance rituximab were normal (Table) One month after the third dose of maintenance rituximab, he reported increasing lethargy His bilirubin and serum aminotransferase levels were elevated (Table) On repeated testing, he had detectable levels of serum HBsAg, anti-HBc IgM, hepatitis B e antigen, and HBV DNA (HBV DNA level, 2.3 ϫ 106 copies/mL or 8.1 pg/mL) Discussion: This case demonstrates seeming reactivation of HBV infection in a patient undergoing treatment for lymphoma, including rituximab therapy We cannot exclude the possibility that the patient became reinfected with HBV, but we believe that reactivation of latent infection is more likely The risk for HBV reactivation in patients with resolved HBV who are receiving chemoimmunotherapy remains controversial Yeo and colleagues (2) reported the risk to be as high as 24%, suggesting that prophylactic lamivudine may be indicated, but May 2009 Annals of Internal Medicine Volume 150 • Number 655 Downloaded From: http://annals.org/pdfaccess.ashx?url=/data/journals/aim/20181/ by a Fudan University User on 01/15/2017 Letters Table Development of Elevated Aminotransferase Levels During Maintenance Rituximab Therapy Variable At Baseline Before Sixth Cycle of R-CHOP Before First Cycle of Maintenance Rituximab Before Second Cycle of Maintenance Rituximab Before Third Cycle of Maintenance Rituximab Month After Third Cycle of Maintenance Rituximab Time point Bilirubin level* mg/L mol/L ALT level, U/L* AST level, U/L* November 2007 March 2008 June 2008 August 2008 December 2008 January 2009 0.47 (0.018) (0.3) 20 (0.6) 20 (0.6) 0.35 (0.018) (0.3) 24 (0.7) 21 (0.6) 0.47 (0.018) (0.3) 23 (0.6) 19 (0.5) 0.53 (0.023) (0.4) 19 (0.5) 20 (0.6) 0.58 (0.023) 10 (0.4) 34 (0.9) 29 (0.8) 12.5 (0.52) 214 (8.9) 1450 (40.3) 1090 (30.3) ALT ϭ alanine aminotransferase; AST ϭ aspartate aminotransferase; R-CHOP ϭ rituximab, cyclophosphamide, vincristine, doxorubicin, and prednisolone * Numbers in parentheses are how many times greater than the upper limit of normal the given value is larger studies (3, 4) found the risk for reactivation to be less than 2% In all studies, the prevalence of resolved HBV was relatively high (30% to 40%) Absence of anti-HBsAg is a proposed risk factor for reactivation (2) in patients with lymphoma and resolved HBV infection who are undergoing chemoimmunotherapy Indeed, our patient had undetectable levels of anti-HBsAg at diagnosis However, we recently identified an anti-HBsAg–positive patient with resolved HBV infection in our institution who had reactivation 10 months after completing R-CHOP chemotherapy; therefore, we believe that presence of anti-HBsAg may not confer protection against reactivation Another important observation is that our patient had HBV reactivation while receiving maintenance rituximab, which is typically given for years after chemotherapy No data are available on the risk for HBV reactivation in patients with resolved HBV infection who are undergoing maintenance rituximab therapy One study showed that rituximab, a chimeric anti-CD20 monoclonal antibody used in B-cell lymphomas, suppresses B lymphocytes, impairs their function, and may be associated with HBV reactivation (5) Prolonged use of rituximab would make antiviral prophylaxis challenging because it is clearly not feasible to continue antiviral prophylaxis indefinitely Furthermore, withdrawal of lamivudine after long-term prophylaxis could precipitate reactivation Because maintenance rituximab is increasingly incorporated into the management of patients with lymphoma, the question of risk for reactivation and the role of antiviral prophylaxis will grow in importance Conclusion: Seemingly resolved HBV infection may reactivate in patients undergoing chemotherapy or rituximab treatment Further studies are required to define the role of prophylaxis in this population Yu Xuan Koo Yong Loo Lin School of Medicine, National University of Singapore Singapore 117597 Daniel S.W Tan, MBBS Iain B Tan, MBBS Miriam Tao, MBBS Soon Thye Lim, MBBS National Cancer Centre Singapore Singapore 169610 Potential Financial Conflicts of Interest: None disclosed References Kahl BS, Longo WL, Eickhoff JC, Zehnder J, Jones C, Blank J, et al; Wisconsin Oncology Network Maintenance rituximab following induction chemoimmunotherapy may prolong progression-free survival in mantle cell lymphoma: a pilot study from the Wisconsin Oncology Network Ann Oncol 2006;17:1418-23 [PMID: 16766582] Yeo W, Chan TC, Leung NW, Lam WY, Mo FK, Chu MT, et al Hepatitis B virus reactivation in lymphoma patients with prior resolved hepatitis B undergoing anticancer therapy with or without rituximab J Clin Oncol 2009;27:605-11 [PMID: 19075267] Koo YX, Tan SW, Tan BH, Quek R, Tao M, Chow WC, et al Risk of hepatitis B virus (HBV) reactivation and role of anti-viral prophylaxis in lymphoma patients with past HBV infection (HBV antigen negative but anti-hepatitis B core antibody positive) receiving chemo-immunotherapy blood [Abstract] ASH Annual Meeting Abstracts 2008;112:3768 Targhetta C, Cabras MG, Mamusa AM, Mascia G, Angelucci E Hepatitis B virusrelated liver disease in isolated anti-hepatitis B-core positive lymphoma patients receiving chemo- or chemo-immune therapy [Letter] Haematologica 2008;93:951-2 [PMID: 18515881] Sera T, Hiasa Y, Michitaka K, Konishi I, Matsuura K, Tokumoto Y, et al AntiHBs-positive liver failure due to hepatitis B virus reactivation induced by rituximab Intern Med 2006;45:721-4 [PMID: 16819252] The Immune Inflammatory Reconstitution Syndrome and Central Nervous System Toxoplasmosis Background: The immune inflammatory reconstitution syndrome (IRIS) is a paradoxical worsening of an opportunistic infection as CD4 cells proliferate because highly active antiretroviral therapy (HAART) engages antigenic epitopes and triggers an overshooting inflammatory response A weak link exists between IRIS and the most frequent neurologic complication of AIDS, central nervous system (CNS) toxoplasmosis Objective: To show that IRIS can also occur in CNS toxoplasmosis and to share our approach to the problem Case Report: In early September 2008, we admitted a 30-yearold woman with headaches, imbalance, and left-sided weakness for week She had untreated HIV-1 infection diagnosed months before admission On examination, she had fever (38.9 °C) and oral thrush Her mental status was normal, no papilledema was present, and she had left hemiparesis with the Babinski sign Relevant laboratory tests were a positive HIV-1 test result, a CD4 cell count of 14 ϫ 109 cells/L, and Toxoplasma gondii IgG level of 267 U/mL Brain magnetic resonance imaging showed a ring- 656 May 2009 Annals of Internal Medicine Volume 150 • Number Downloaded From: http://annals.org/pdfaccess.ashx?url=/data/journals/aim/20181/ by a Fudan University User on 01/15/2017 www.annals.org Letters enhancing mass in the right basal nuclei (Figure, A) We began treatment with intravenous trimethoprim–sulfamethoxazole, mg/kg every hours; dexamethasone, mg twice daily; and HAART with a 3-in-1 formulation (efavirenz, 600 mg; emtricitabine, 200 mg; and tenofovir, 300 mg, once daily) She was discharged days later after clinical and radiographic improvement (Figure, B) Her oral outpatient regimen was fluconazole; azithromycin; trimethoprim–sulfamethoxazole; and prednisone, 40 mg/d, weaning by 10 mg weekly The patient was readmitted on 20 October 2008 with left hemiparesis for 48 hours and headaches for weeks She was still receiving prednisone, 10 mg/d The mass in the left basal nuclei persisted, with more vasogenic edema and new, bilateral but smaller contrastenhancing lesions (Figure, C) Her CD4 cell count was 137 ϫ 109 cells/L After a literature search and review of her magnetic resonance imaging studies, we decided to perform a biopsy with primary CNS lymphoma in the differential diagnosis On immunohistochemical analysis, we saw abundant tachyzoites (Figure, D), confirming that this woman had IRIS We continued the same treatment, tapering the steroid dose over weeks instead of month She only had slower alternating movements in the left hand when she came for an office visit in December 2008 The immune inflammatory reconstitution syndrome, a wellrecognized complication of HAART, is the transient exacerbation of an opportunistic infection as the CD4 cell count increases and HIV-1 RNA copies decrease with antiretroviral treatment (1) About 10% to 30% of patients beginning HAART develop IRIS; the pa- tients at highest risk are HAART-naive and young and start treatment during a recent diagnosis of an opportunistic infection (2) In the CNS, Mycobacterium tuberculosis and Cryptococcus neoformans, but not T gondii, have been clearly and consistently linked to IRIS (2, 3) We learned from this experience that patients with AIDS who present with CNS toxoplasmosis and begin HAART may also be at risk for IRIS; this is important because the main differential diagnosis is primary CNS lymphoma, a condition that is sometimes difficult to differentiate from CNS toxoplasmosis If IRIS is suspected in a patient with HIV-1 infection and CNS toxoplasmosis, close observation for to 15 days, a higher steroid dose to control IRIS (4), uninterrupted HAART, and ongoing treatment for toxoplasmosis can resolve the problem without biopsy Ivo W Tremont-Lukats, MD University of Texas M.D Anderson Cancer Center Houston, TX 77030 Pedro Garciarena, MD Rube´n Juarbe, MD Rima N El-Abassi, MD Louisiana State University New Orleans, LA 70119 Acknowledgment: The authors thank Marc K Rosenblum, MD, who provided panel D of the Figure Potential Financial Conflicts of Interest: None disclosed Figure The immune inflammatory reconstitution syndrome in a patient infected with HIV-1 who had central nervous system toxoplasmosis References Dhasmana DJ, Dheda K, Ravn P, Wilkinson RJ, Meintjes G Immune reconstitution inflammatory syndrome in HIV-infected patients receiving antiretroviral therapy: pathogenesis, clinical manifestations and management Drugs 2008;68:191-208 [PMID: 18197725] Shelburne SA, Visnegarwala F, Darcourt J, Graviss EA, Giordano TP, White AC Jr, et al Incidence and risk factors for immune reconstitution inflammatory syndrome during highly active antiretroviral therapy AIDS 2005;19:399-406 [PMID: 15750393] Riedel DJ, Pardo CA, McArthur J, Nath A Therapy Insight: CNS manifestations of HIV-associated immune reconstitution inflammatory syndrome Nat Clin Pract Neurol 2006;2:557-65 [PMID: 16990829] Venkataramana A, Pardo CA, McArthur JC, Kerr DA, Irani DN, Griffin JW, et al Immune reconstitution inflammatory syndrome in the CNS of HIV-infected patients Neurology 2006;67:383-8 [PMID: 16894096] CORRECTION Correction: The Effect of Preventive Lamivudine on Hepatitis B Reactivation During Chemotherapy A Pretreatment brain magnetic resonance imaging B Improvement 15 days after highly active antiretroviral therapy and antimicrobial therapy C On readmission 40 days after start of treatment D Toxoplasma gondii tachyzoites stained with immunolabeled antitoxoplasma IgG (magnification, ϫ400) www.annals.org In Table of the recent systematic review by Loomba and colleagues (1), patients from the studies of Lau and colleagues (2) and Hsu and colleagues (3) were both erroneously labeled as respectively not receiving and not reported to be receiving corticosteroids In Table and the figures, the study by Hsu and colleagues (3) was inadvertently misclassified as a prospective study with historical con5 May 2009 Annals of Internal Medicine Volume 150 • Number 657 Downloaded From: http://annals.org/pdfaccess.ashx?url=/data/journals/aim/20181/ by a Fudan University User on 01/15/2017 Letters trols rather than a randomized, controlled trial with a deferred lamivudine control group Lau GK, Yiu HH, Fong DY, Cheng HC, Au WY, Lai LS, et al Early is superior to deferred preemptive lamivudine therapy for hepatitis B patients undergoing chemotherapy Gastroenterology 2003;125:1742-9 [PMID: 14724827] References Hsu C, Sur IJ, Hwang WS, Wang MC, Lin SF, Lin TH, et al A prospective Loomba R, Rowley A, Wesley R, Liang TJ, Hoofnagle JH, Pucino F, et al System- comparative study of prophylactic or therapeutic use of lamivudine for chemotherapy- atic review: the effect of preventive lamivudine on hepatitis B reactivation during associated hepatitis B (HBV) reactivation in non-Hodgkin’s lymphoma patients [Ab- chemotherapy Ann Intern Med 2008;148:519-28 [PMID: 18378948] stract] Gastroenterology 2006;131:S297 READERS’ COMMENTS Readers wishing to comment on published articles should use the “Send comment/rapid response letter” option at www.annals.org While this service is free to Annals subscribers, readers without subscriptions who wish to comment on articles may purchase temporary access 658 May 2009 Annals of Internal Medicine Volume 150 • Number Downloaded From: http://annals.org/pdfaccess.ashx?url=/data/journals/aim/20181/ by a Fudan University User on 01/15/2017 www.annals.org ... utilization of patients in the Spine Pa- Rejuvenation in Older Adults Receiving Oral Ghrelin tient Outcomes Research Trial’s (SPORT) three observational cohorts: disc herniation, spinal stenosis, and... change in lean mass in elderly persons and dietary protein intake (5) Long-term studies comparing the effects of exercise with a ghrelin mimetic alone or in combination with exercise are certainly... cytokine involved in promotion and induction of oncogenesis in different types of tumors, such as Ewing sarcoma (2), renal cell carcinoma (3), and adenocarcinoma of the gastrointestinal tract