Oral Symptom Intensity, Health-Related Quality of Life, and Correlative ...

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assessed oral cGVHD by the OMRS scale (mean score, 18.38 6 12.99; range, 2-46). Oral dryness (in ... edge of the appropriate supportive care needs impedes.
Oral Symptom Intensity, Health-Related Quality of Life, and Correlative Salivary Cytokines in Adult Survivors of Hematopoietic Stem Cell Transplantation with Oral Chronic Graft-versus-Host Disease Jane M. Fall-Dickson,1 Sandra A. Mitchell,2 Susan Marden,3 Edward S. Ramsay,4 Jean-Pierre Guadagnini,5 Tianxia Wu,6 Lena St. John,1 Steven Z. Pavletic7 for the National Institutes of Health Chronic Graft-versus-Host Disease Study Group Oral chronic graft-versus-host disease (cGVHD) is a frequent, clinically significant sequela of allogeneic hematopoietic stem cell transplantation (HSCT). This study was designed to elucidate relationships among clinical characteristics of oral cGVHD and related oral pain and oral dryness, salivary proinflammatory cytokine interleukin (IL)-6 and IL-1a concentrations, and health-related quality of life (HRQL). An understanding of the characteristics and correlates of oral cGVHD manifestations and related symptoms, such as oral dryness, is fundamental to the development of therapeutic interventions. Oral cGVHD severity was assessed with the Oral Mucositis Rating Scale (OMRS). Oral pain and perceived intensity of oral dryness were self-reported via a visual analog scale and a numeric rating scale, respectively. HRQL was assessed with the Functional Assessment of Cancer Therapy-General (FACT-G). Salivary IL-1a and IL-6 concentrations were measured by enzyme-linked immunosorbent assay. All 42 adult subjects (59% males) had clinicianassessed oral cGVHD by the OMRS scale (mean score, 18.38 6 12.99; range, 2-46). Oral dryness (in 43% of subjects; mean OMRS score, 2.56 6 3.45; range, 0-10) was more prevalent than oral pain (8%; mean score, 0.13 6 0.47). Salivary IL-6 was associated with oral cGVHD severity (r 5 0.49; P \.01), oral ulceration (r 5 0.38; P 5 .04), and erythema (r 5 0.63; P \.01). FACT-G total score and physical and emotional well-being subscale scores were meaningfully lower than U.S. population normative values. Participants with more severe oral cGVHD manifestations had significantly inferior social/family well being (r 5 -0.49; P \.01). Oral dryness was associated with higher salivary IL-1a (r 5 0.41; P 5 .04) and, controlling for cGVHD severity, with lower HRQL (r 5 -0.41; P 5 .03). Subjects with moderate to severe oral dryness tended to report the poorest overall HRQL. This study provides preliminary evidence of the relationship between oral dryness and HRQL, the contribution of oral cGVHD to inferior HRQL, and the association between IL-6 and oral cGVHD severity, ulceration, and erythema. The high prevalence of oral dryness and its relationship to HRQL in a sample of subjects with oral cGVHD underscores the importance of improving our evaluation and management of this symptom in long-term survivors of allogeneic HSCT. The positive associations between IL-6 and oral cGVHD severity and erythema, as well as the positive trend with oral ulceration, warrant further exploration of this cytokine as a potential biomarker of active oral cGVHD. Biol Blood Marrow Transplant 16: 948-956 (2010) Published by Elsevier Inc.

KEY WORDS: Oral chronic graft-versus-host disease, Quality of life, Symptoms

From the 1Mucosal Injury Unit, Symptom Management Branch, National Institute of Nursing Research; 2Nursing Research and Translational Science, Clinical Center; 3Office of Extramural Programs, National Institute of Nursing Research; 4Symptom Management Branch, National Institute of Nursing Research; 5Dental Service, National Institute of Dental and Craniofacial Research; 6Center for Information Technology; and 7Experimental Transplantation and Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland. The opinions expressed herein are those of the authors and do not represent the official position of The National Institutes of Health or the U.S. Government.

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Financial disclosure: See Acknowledgments on page 955. Correspondence and reprint requests: Jane M. Fall-Dickson, PhD, RN, AOCN, Mucosal Injury Unit, Symptom Management Branch, National Institute of Nursing Research, National Institutes of Health, 10 Clinical Research Center, Room 2NE-1339, 10 Center Drive, Bethesda, MD 20892-1203 (e-mail: dicksonj@ mail.nih.gov). Received October 6, 2009; accepted January 28, 2010 Published by Elsevier Inc. 1083-8791/$36.00 doi:10.1016/j.bbmt.2010.01.017

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Oral Chronic GVHD Related Symptoms, Quality of Life, and Cytokines

INTRODUCTION Chronic graft-versus-host disease (cGVHD) is a major complication of allogeneic hematopoietic stem cell transplantation (HSCT) resulting from an exaggerated inflammatory mechanism as donor lymphocytes encounter foreign antigens on host cells and mount an inflammatory reaction [1-4]. Approximately 50% of patients who undergo allogeneic HSCT develop cGVHD [5], with increasing incidence related to lower treatment-related mortality and changing HSCT utilization patterns [1]. Approximately 45% of patients with cGVHD live with these late treatment effects for a prolonged period [1], and our limited knowledge of the appropriate supportive care needs impedes the delivery of quality care. Animal and human models suggest that the underlying immunologic mechanisms of cGVHD include donor-derived alloreactive T lymphocytes; autoreactive T-lymphocytes that evade thymic deletion [6,7]; alterations in absolute numbers, ratios, or kinetics of lymphocyte subpopulations [8,9], such as regulatory T lymphocytes [10-14]; and dysregulation of cytokine expression [15-17]. Elevated levels of interleukin (IL)-6, IL-1b, IL-1a, IL-1 receptor antagonist, tumor necrosis factor alpha (TNF-a), soluble TNF-receptor II, monocyte chemoattractant protein 1, and soluble B cell activating factor are associated with autoimmune or chronic inflammatory diseases that clinically parallel cGVHD [18-25]. Several of these immune activity mediators are candidate biomarkers of cGVHD activity [15,16]. Approximately 80% of patients with cGVHD have oral involvement, including tissue atrophy and edema, erythema, lichenoid changes, and oral ulcerations

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(Figure 1). Xerostomia, immunosuppressant side effects, and viral or fungal infection can exacerbate the severity of discomfort because of oral cGVHD [4,26,27]. Patients with cGVHD have significantly reduced stimulated submandibular and sublingual gland saliva flow rates [28]. This decreased salivary volume results in decreased salivary immunoglobulin secretion (IgA, IgG, and EGF) [28], possibly increasing the risk of infection. cGVHD-related oral pain is prevalent [4,27] and may occur in association with oral ulceration(s). cGVHD-related xerostomia, oropharyngeal pain, and heightened oral sensitivity also may contribute to decreased nutritional intake and weight loss [29]. Although candidate serum biomarkers of cGVHD are currently being explored [17], little is known about cytokine expression in oral tissues involved with cGVHD. Exploration of the oral tissue cytokine milieu might yield important insight into the pathobiology of oral cGVHD and inform the rational development of targeted interventions. Observational studies have demonstrated that patients with cGVHD experience impaired health status and health-related quality of life (HRQL) [1,30,31]. The extent to which oral cGVHD contributes to these impairments is unknown. Xerostomia induced by radiation therapy has a significantly negative impact on HRQL in patients with head and neck cancer [3234] and lymphoma [35,36]. The relationship between oral cGVHD-related symptoms and HRQL has not yet been examined, however. Patients with oral cGVHD may live the remaining years of their lives with the disease, making effective management essential. In this descriptive study, we examined the oral symptom experience, HRQL, and salivary

Figure 1. Erythema and ulceration/pseudomembrane in a subject with oral cGVHD.

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proinflammatory cytokines in a sequentially accrued cohort of patients (n 5 42) with oral cGVHD. The specific aims of this study were to describe (1) clinical characteristics of oral cGVHD, (2) cGVHD-related perceived oral dryness and oral pain intensity, (3) HRQL, (4) concentrations of salivary IL-6 and IL-1a, and (5) associations among characteristics of oral cGVHD, oral dryness, HRQL, and salivary cytokine expression. Elucidating components of the symptom experience of patients with oral cGVHD, as well as their associations with HRQL and the cytokine milieu, is a preliminary step in designing studies to test novel treatments and supportive care strategies for this oral disease [37]. MATERIALS AND METHODS This study analyzed cross-sectional data from a sequentially accrued subsample of patients with oral cGVHD who were enrolled in the National Cancer Institute (NCI)- sponsored cGVHD Natural History Protocol, ‘‘Prospective Assessment of Clinical and Biological Factors Determining Outcomes in Patients with cGVHD’’ (clinicaltrials.gov #NCT00331968). The study was approved by the NCI’s Institutional Review Board, National Institutes of Health (NIH). Patients were referred by their primary transplantation physician for evaluation by the NIH cGVHD Study Group. Written informed consent was obtained from all participants. The study dentist (J-P G) performed oral examinations to confirm the clinical diagnosis of oral cGVHD, and recorded data on self-reported oral pain and oral dryness during one protocol visit in the Dental Clinic, Clinical Center, NIH. Stimulated submandibular/sublingual saliva samples were obtained during this protocol visit. Submandibular/sublingual saliva samples also were obtained from a comparison sample of healthy adult volunteers (mean age, 43.74 years; range, 21-72 years; 57% males; n 5 31). Using standardized criteria, a summative cGVHD severity score was derived based on a clinical and diagnostic evaluation of multiple organ systems, including the skin, mouth, eyes, liver, lungs, and gastrointestinal systems, as well as functional capacity, and also gynecologic disease manifestations in women [38]. Measurement of HRQL was completed within 6 48 hours of the Dental Clinic visit. Research Instruments Oral cGVHD Characteristics The Oral Mucositis Rating Scale (OMRS), constructed through selection of clinical descriptors of oral mucosal changes following bone marrow transplantation [39], has been found to be reliable and valid in classifying oral changes related to cGVHD

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[27]. The tool divides the oral cavity into 7 distinct anatomic areas: lips (upper and lower), labial mucosa (upper and lower), buccal mucosa (right and left), tongue (dorsal, lateral, and ventral), floor of mouth, palate (hard and soft), and attached gingiva. These 13 oral cavity areas are clinician-assessed for erythema, atrophy, hyperkeratosis, lichenoid changes, and edema, and these oral tissue changes are rated on a scale of 0-3, as compared with normal oral tissue (0, normal/no change; 1, mild change; 2, moderate change; and 3, severe change). The extent of ulceration/pseudomembrane is estimated based on the surface area involved (0, none; 1, .0 but #1 cm2; 2, .1 cm2 but #2 cm2; and 3, .2 cm2). The total score is the sum of all OMRS items, with a possible range of 0-273. Oral Symptom Intensity Current oral pain intensity was reported by subjects using a 10-cm visual analog scale (VAS) ranging from 0 (‘‘no pain’’) to 10 (‘‘worst possible pain’’) [40]. Studies have demonstrated high testretest reliability for VASs [40]. Current oral dryness intensity was measured using a verbally administered 10-cm numeric rating scale consisting of a 1-item, 11-point scale with the anchors representing extremes of the oral dryness continuum, from 0 (‘‘no dryness’’) to 10 (‘‘worst possible dryness’’). A written numeric rating scale has been shown to be valid in the measurement of dyspnea [41] and has demonstrated evidence of reliability, validity, and responsiveness for pain assessment [42]. Health-Related Quality of Life HRQL was measured with FACT-G version 4 [43]. The 27 items evaluate aspects of physical, social/family, emotional, and functional well being on a scale of 0 (‘‘not at all’’) to 4 (‘‘very much’’). Scores are summed for a total FACT-G score, with a possible range of 0-108. The FACT-G includes 4 subscales: physical well being (PWB), social/family well being (SWB), emotional well being (EWB), and functional well being (FWB). Higher total FACT-G and subscale scores indicate better HRQL and greater well being within these domains. Normative values for the general U.S. population and for adults with cancer are available to aid interpretation [44]. A 2-point difference in the FACT-G subscale scores and a 5-point difference in the FACT-G total score represent the minimum clinically important difference [44]. More than 50% of the items on the FACT-G assess symptoms, underscoring the importance of symptoms in the HRQL experience. Evidence of reliability and construct validity for the FACT-G has been demonstrated across a wide range of chronically ill populations [43,45,46].

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Oral Chronic GVHD Related Symptoms, Quality of Life, and Cytokines

Saliva Sample Collection, Processing, and Analysis

RESULTS

Submandibular/sublingual saliva was stimulated by the bilateral application of 2% citric acid to the tongue using a cotton-tipped swab. Once the parotid gland was isolated with cotton gauze, saliva was suctioned from the sublingual area for a total of 1 minute, with 30-second intervals between applications. The saliva was put into 1.5-mL polypropylene microcentrifuge tubes on ice and transported to the research laboratory. The saliva was aliquoted to 300mL samples in 0.6 mL tubes, which were stored at 280 C. For analysis, samples were thawed to room temperature and then centrifuged at 4000 rpm for 10 minutes at 4 C; the supernatant was retained. Salivary concentrations of IL-1a and IL-6 in both subjects and healthy volunteers were measured by enzymelinked immunosorbent assay (ELISA) (R&D Systems, Minneapolis, MN).

Demographic Characteristics

Statistical Analysis Descriptive statistics were used to characterize the demographic and clinical profiles of the samples. The strength and direction of linear relationships between total OMRS score and clinical characteristics, oral dryness intensity, FACT-G and subscale scores, and salivary cytokine concentrations were assessed using Pearson product moment correlations. Significance of the correlation between oral dryness and FACT-G was tested controlling for the overall severity of cGVHD. Significance was established as P \ .01 to accommodate an adjustment for multiple comparisons. Wilcoxon’s exact 2-sample test was used to test for differences in oral dryness and HRQL between subjects with and without opioid use. Scatterplots were used to evaluate oral dryness and HRQL data by symptom intensity for linear and nonlinear trends (Figure 2). Data analysis was done using SAS version 9.1.3 (SAS Institute, Cary, NC) [47].

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Subjects (n 5 42) ranged in age from 22 to 61 years, with a median age of 48.5 years (Table 1). The majority were male (60%) and White (90%). The subjects had a median of 36.9 months (range, 5-201 months) from peripheral blood stem cell (79%) or bone marrow (19%) transplantation, used primarily to treat a hematologic malignancy (Table 1). A median of 11 months (range, 1-196 months) had elapsed since the subjects’ cGVHD was diagnosed (Table 2). The subjects had predominantly moderate (48%) or severe (50%) cGVHD as assessed by the NIH’s cGVHD Global Rating, with a median of 3 organ systems involved (range, 1-6 systems) (Table 2). Approximately two-thirds of the subjects were receiving moderate or high levels of systemic immunosuppression (Table 2). Nineteen subjects were receiving one or more systemic opioids; drugs included oxycodone (n 5 13), oxycontin (n 5 4), methadone (n 5 2), percocet (n 5 1), morphine (n 5 1), transcutaneous fentanyl (n 5 1), acetaminophen with codeine (n 5 1), and dilaudid (n 5 1).

Oral cGVHD, Oral Symptoms, and HRQL Our sample with oral cGVHD had erythema (91%), lichenoid changes (72%), and ulceration (56%) (Table 3). Oral dryness (43%; mean OMRS score, 2.56 6 3.45; range, 0-10) was more prevalent than oral pain (8%; mean score, 0.13 6 0.47) (Table 3). Previous acute GVHD had little association with oral dryness (r 5 0.16; P 5 .03). Subjects receiving opioids did not have significantly greater oral dryness (Wilcoxon’s exact 2-sample test; P 5 .71) or more impairment in HRQL (P 5 .85) compared with those who were not receiving these agents. No other demographic factors were associated with oral dryness. FACT-G scores and all subscale scores except SWB score were below the US norm data (Table 3).

Figure 2. Scatterplots of individual scores of the (A) FACT-G total version 4 and (B) FACT-G PWB, EWB, SWB, and FWB subscales by oral dryness, classified as none (0), mild (1-3), moderate (4-6), or severe (7-10); n 5 29. Higher FACT-G total score (range, 0-108) and higher PWB, SWB, FWB (range 0-28), and EWB (range, 0-24) scores represent better HRQL.

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Table 1. Clinical and Demographic Characteristics of the Sample (n 5 42) n Age, years Sex Male Female Race Caucasian Non-Caucasian Marital status Single Married Divorced/widowed/separated Diagnosis Acute leukemia/myelodysplastic syndrome Chronic leukemia/lymphoma Multiple myeloma Other Conditioning Myeloablative Reduced intensity Donor type Related Unrelated Stem cell source Bone marrow Peripheral blood Unspecified Karnofsky Performance Scale score 80.1, PWB score >22.7, SWB score >19.1, EWB score >19.9, and FWB score >18.5 are interpreted as exceeding the general US adult population norm data (n ~1600) [49]. FACT-G score >80.9, PWB score >21.3, SWB score >22.1, EWB score >18.7, and FWB score >18.9 are interpreted as exceeding the US adult cancer patient norm data (n 5 2226) [49].

Salivary Cytokine Concentrations Despite the presence of oral dryness, 31 subjects (73%) were able to produce an adequate amount ($400 mL) of stimulated submandibular/sublingual saliva for ELISA analysis. In submandibular/sublingual saliva, mean IL-1a concentration was 85.2 pg/mL (median, 68 pg/mL; range, 13-250 pg/mL; n 5 29), and mean IL-6 concentration was 2.48 pg/mL (median, 1.29 pg/mL; range, 0.100-10 pg/mL; n 5 29). In submandibular/sublingual saliva of healthy volunteers, mean IL-1a concentration was 31.97 pg/ mL (range, 6-48.7 pg/mL; n 5 23), with 20 of 23 values below the assay detection limit of 3.9 pg/mL. Mean IL6 concentration in submandibular/sublingual saliva of healthy volunteers was 0.93 pg/mL (range, 0.08-5.14 pg/mL), with 11 of 23 values below the assay’s detection limit of 0.156 pg/mL. When salivary IL-6 or the IL-1a levels were not detectable by the ELISA assay kit, the lowest detectable level was used. There were statistically significant differences between the subjects’ and healthy volunteers’ submandibular/sublingual saliva IL-1a concentrations (P \ .05) and IL-6 concentrations (P \ .001). Associations Among Oral cGVHD, Oral Dryness, HRQL, and Salivary Cytokines Total OMRS score had a low negative association with the FACT-G SWB subscale (r 5 -0.49; P #.01) (Table 4). IL-6 had a low positive association with OMRS score (r 5 0.49; P \ .01) and a moderate positive association with erythema (r 5 0.63, P \ .01), and a positive trend was seen with oral ulceration (r 5 0.38; P 5 .04). However, no association was found between clinician-assessed erythema, lichenoid, or ulcerative cGVHD manifestations and FACT-G total or subscale scores. Oral pain was not included in the

association analysis, because only 3 subjects had oral pain exceeding 0. Oral dryness had a low positive association with IL-1a (r 5 0.41; P 5 .04). Oral dryness also was associated with lower total FACT-G score (r 5 -0.41; P 5 .03) and with lower PWB score (r 5-0.42; P 5 .03) and lower SWB score (r 5 -0.40; P 5 .04), at trend levels. Scatterplots (Figure 2) showed that subjects with moderate to severe oral dryness tended to report the lowest HRQL. The association between oral dryness and impaired HRQL remained when cGVHD severity was controlled for in the analysis (P 5 .03).

DISCUSSION This study explored the clinical characteristics and severity of oral cGVHD, prevalence and intensity of related oral pain and oral dryness, salivary IL-6 and IL-1a concentrations, HRQL, and examined associations among these findings in a sample of adult patients diagnosed with oral cGVHD. Clinician-assessed oral cGVHD characteristics and patient-reported symptoms were studied separately, as recommended by the NIH’s cGVHD Study Group Response Criteria Working Group [48]. Accurate assessment of oral cGVHD lesions is critical in both clinical research and practice settings because these lesions may be the only observed indicator of cGVHD, and they are a highly predictive index of the presence of systemic cGVHD [49]. The low association between oral cGVHD severity and oral dryness in our sample underscores the importance of objective clinical evaluation of oral cGVHD clinical characteristics. Although more than 50% of our subjects had oral ulcers, only 2 subjects with oral ulcers reported oral pain. Possible explanations for these results include

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IL-laS indicates IL-la concentration in submandibular/sublingual saliva; cGVHD, chronic graft-versus-host disease; OMRS, Oral Mucositis Rating Scale; FACT-G, Functional Assessment of Cancer Therapy-General; VAS, visual analog scale; PWB, physical well being; EWB, emotional well being; FWB, functional well being; SWB, social well being; HRQL, health-related quality of life; IL-6S, IL-6 concentration in submandibular/ sublingual saliva. *.01 # P < .05; **P < .01; ***P < .001; probability > jrj under H0: rho 5 0.

0.267128 20.30822 20.15849 20.21075 20.10633 20.2007 0.034808 20.02881 0.4087* 20.24163 0.043233 20.16786 0.17447 20.36535 20.26923 0.00009 0.345739 0.49221** 20.17345 20.31585 20.30228 20.3998* 20.13323 20.16336 0.20507 0.021231 0.053615 0.01839 0.296871 20.4207* 20.24574 0.077317 0.357699 20.30353 20.07682 20.20068 0.009007 20.4114* 2.18558 20.03401 0.223991 0.494027** 0.195994 0.628402** 0.378025* 0.305972 0.333071 1 20.06659 0.126738 20.34064 0.279536 20.02234 0.407659* 1 20.35519 0.190347 0.060984 0.18994 0.259602 1 0.083346 0.61427** 0.507305** 0.545079** 1 0.148605 0.52971** 1 20.08425 1 Age OMRS Lichenoid Erythema Ulceration Oral dryness IL-1aS IL-6S

20.00897 0.92127*** 0.360538* 1

Lichenoid OMRS Variable

Erythema

Ulceration

Oral Dryness

IL-1aS

IL-6S

FACT-G

PWB

SWB

EWB

FWB

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Table 4. Associations Among Oral cGVHD Severity, HRQL, and Salivary Cytokine Concentrations (n 5 30)

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cross-sectional assessment of oral pain without swallowing, accommodation to the symptom experience in chronically ill patients, and use of opioids. Oral sensitivity was not assessed in this study, and this would be a useful addition to future symptom research in patients with oral cGVHD. Although prescribed medications may have contributed to perceived oral dryness in this sample, subjects receiving opioids did not have significantly greater perceived oral dryness than those not receiving opioids. Oral dryness is accompanied by a decrease in factors that act to protect the oral mucosa [28] and maintain oral cavity homeostasis [50]. The negative trends between oral dryness and overall HRQL, physical well being, and social/family well being, as well as the trend of an association between oral dryness and higher salivary IL-1a concentration, merit exploration in a larger sample. Cytokines play a dynamic role in regulating and modulating immunologic and inflammatory processes [51] via cooperative networks that control normal physiological activity and disease-related threats to homeostasis. The positive association between erythema and salivary IL-6, an essential mediator of inflammatory response to localized mucosal inflammation [51,52], should be evaluated empirically as a potential biomarker of oral cGVHD activity and severity. Associations between oral cGVHD severity and IL-6 gene polymorphisms have been reported [53]. Significant redundant functionality and temporality exist with cytokines, such that no single cytokine is likely responsible for controlling a specific cellular function or physiological process [51]. Therefore, exploration of the cytokine pathways and crosstalk involved in the pathogenesis of oral cGVHD is needed to better elucidate the pathogenesis of oral cGVHD and molecular mechanisms of related symptoms [53,54,55]. To date, few studies have examined candidate biomarkers of organ-specific disease activity in cGVHD, including disease activity in the oral cavity. Saliva is easy to procure during clinic visits, and salivary cytokine profiles also may provide a marker of overall cGVHD activity, because oral manifestations are often associated with systemic cGVHD presenting in the eye, liver, and skin [17]. Although previous studies have described HRQL in HSCT survivors without cGVHD [56], the impact of cGVHD on HRQL is not well characterized in the literature [57]. Our sample reported FACT-G scores and PWB subscale scores below both general U.S. adult and adult cancer population normative values, and EWB subscale scores below U.S. norm data [44] (Table 3). The fact that these differences exceeded the threshold of the minimally important differences of 2 points on the subscale scores and 5 points on the FACT-G [44] suggests that these differences may be clinically meaningful.

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Oral Chronic GVHD Related Symptoms, Quality of Life, and Cytokines

Although the generalizability of our results is limited by the small sample size drawn from a single institution, the high prevalence of oral dryness (43%) observed in our sample is in accordance with previous research. Our finding of a negative association between oral cGVHD severity and social/family well being, and the trends observed between oral dryness and inferior physical well being and social/family well being, merit further exploration in larger, prospective samples. The fact that the association between oral dryness and inferior HRQL remained even when overall cGVHD severity was controlled for suggests that oral cGVHD and its symptoms may contribute to impaired HRQL. This hypothesis should be empirically tested using a longitudinal or comparative study design. This study also elucidates the association between the immunobiology of oral cGVHD and the subject’s symptom experience. Examining relationships among clinician-assessed characteristics of oral cGVHD, related oral symptoms, HRQL, and the local proinflammatory cytokine milieu is critical to improving our understanding of the pathobiology and sequelae of this oral disease. Although candidate serum biomarkers of cGVHD are being actively explored [17], continued study of the oral tissue cytokine milieu and its association with clinician-assessed and patient reported features of oral cGVHD is needed to inform the rational development of targeted interventions to test in clinical trials. ACKNOWLEDGMENTS The authors thank Dr. Mary E. Kerr, National Institute of Nursing Research, and Dr. Joan K. Austin, Indiana University School of Nursing, for useful discussions regarding manuscript development. They also thank Dr. Matin Imanguli, DDS, formerly of the Experimental Transplantation and Immunology Branch, National Cancer Institute (NCI) for saliva sample acquisition; Sherri Gollins, BS and Sharon Mitchell, National Institute of Dental and Craniofacial Research (NIDCR), for assistance with the saliva collection; and Dr Gabor Illei, NIDCR, for submandibular/sublingual saliva sample acquisition from healthy volunteers. We also acknowledge with gratitude the subjects in the NCI-sponsored Chronic Graft-versus-Host Disease Natural History Protocol (clinicaltrials.gov #NCT00331968). Financial disclosure: The authors have nothing to disclose. REFERENCES 1. Shlomchik WD, Lee SJ, Couriel D, et al. Transplantation’s greatest challenges: advances in chronic graft-versus-host-disease. Biol Blood Marrow Transplant. 2007;13:2-10.

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