Xiaoyu Chai

Fred Hutchinson Cancer Research Center, Seattle, Washington, United States

Are you Xiaoyu Chai?

Claim your profile

Publications (36)188.57 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Failure-free survival, defined as absence of relapse, non-relapse mortality or addition of another systemic therapy, has been proposed as a potential endpoint for clinical trials, but it has only been reported for single center studies. We measured failure free survival in a prospective observational cohort of patients with both newly diagnosed and existing chronic graft-versus-host disease (n=575) from nine centers. Failure was observed in 389 (68%) during the observation period. Median follow up of all patients was 30.9 months, and median failure free survival was 9.8 months (63% at 6 months, 45% at one year, and 29% at two years). Of the variables measured at enrollment, ten were associated with shorter failure free survival: higher NIH 0-3 skin score, higher NIH 0-3 GI score, worse range of motion summary score, lower forced vital capacity (%), bronchiolitis obliterans syndrome, worse quality of life, moderate to severe hepatic dysfunction, absence of treatment for gastric acid, female donor into male patient, and prior grade II-IV acute graft-versus-host disease. Addition of a new systemic treatment, the major cause of failure, was associated with an increased risk of subsequent non-relapse mortality (HR=2.06, 95%CI: 1.29-3.32, p<0.003) and decreased survival (HR=1.51, 95%CI: 1.04-2.18, p<0.03). These results show fewer than half of patients on systemic treatment will be failure-free survivors at one year, and fewer than a third will reach two years without experiencing failure. Better treatments are needed for chronic graft-versus-host disease. Clinicaltrials.gov identifier: NCT00637689. Copyright © 2015, Ferrata Storti Foundation.
    Haematologica 02/2015; DOI:10.3324/haematol.2014.117283 · 5.94 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: To evaluate the treatment, outcome, and prognostic factors in patients with head and neck sarcomas treated in an academic medical center.
    Otolaryngology Head and Neck Surgery 09/2014; DOI:10.1177/0194599814551539 · 1.72 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The National Institutes of Health global score for chronic graft-versus-host disease was devised by experts but was not based on empirical data. We hypothesized that analysis of prospectively collected data would allow derivation of a more accurate model for estimating mortality risk. We analyzed 574 adult patients with chronic graft-versus-host disease enrolled in a multicenter, observational study, using multivariate time-varying analysis accounting for serial changes in severity of eight individual organ sites over time. In the training set, severity of skin, mouth, gastrointestinal tract, liver and lung involvement were independently associated with the risk of nonrelapse mortality. Weighted mortality points were assigned to individual organs based on the hazard ratios and were summed. The population was divided into three risk groups based on the total mortality points. The three new risk groups were validated in an independent validation set, but did not show better discriminative performance than the National Institutes of Health global score. As compared to moderate or mild global score, severe global score was associated with increased risks of nonrelapse and overall mortality across time but not with a decreased risk of recurrent malignancy. The National Institutes of Health global score predicts mortality risk throughout the course of patients with chronic graft-versus-host disease. Further research is required in order to improve outcomes in patients with severe chronic graft-versus-host disease, since their risk of mortality remains elevated.
    Haematologica 07/2014; DOI:10.3324/haematol.2014.109611 · 5.94 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Although older patients undergoing allogeneic hematopoietic stem cell transplantation (HCT) may experience higher morbidity, the impact of chronic graft-versus-host disease (GVHD) on quality of life (QOL) or survival outcomes for older compared to younger patients is currently unknown. We utilized data of patients with moderate or severe chronic GVHD (N=522, 1661 follow-up visits, a total of 2,183 visits) from the Chronic GVHD Consortium, a prospective observational multicenter cohort. We examined the relationship between age group (adolescent and young adult "AYA" 18-40, "middle-aged" 41-59, and "older" ≥ 60 years) and QOL (FACT-BMT), physical functioning (Human Activity Profile (HAP)), functional status (2-minute walk test (2MWT)), non-relapse mortality and overall survival. Because of multiple testing, p-values <0.01 were considered significant. This study included 115 (22%) AYA, 279 (53%) middle-aged, and 128 (25%) older patients with moderate (58%) or severe (42%) chronic GVHD. Despite more physical limitations in older patients as measured by worse functional status [shorter 2MWT (p<0.001) and lower HAP scores (p<0.001)] relative to AYA and middle-aged patients, older patients reported better QOL [FACT-BMT, p=0.004)] compared to middle-aged patients and similar to AYA patients (p=0.99). Non-relapse mortality and overall survival were similar between the age groups. Therefore, despite higher physical and functional limitations, older patients who are selected to undergo HSCT and survive long enough to develop moderate or severe chronic GVHD have preserved QOL and similar overall survival and non-relapse mortality when compared to younger patients. Therefore, we did not find evidence that older age is associated with worse outcomes in patients with moderate or severe chronic GVHD.
    Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 05/2014; 20(9). DOI:10.1016/j.bbmt.2014.05.001 · 3.15 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: To investigate the usefulness of various scales for evaluating joint and fascia manifestations in patients with chronic graft-versus-host disease (GVHD) after allogeneic hematopoietic cell transplantation, and to compare the scales in terms of simplicity of use and ability to yield reliable and clinically meaningful results. In a prospective, multicenter, longitudinal, observational cohort of patients with chronic GVHD (n = 567), we evaluated 3 scales proposed for assessing joint status: the National Institutes of Health (NIH) joint/fascia scale, the Hopkins fascia scale, and the Photographic Range of Motion (P-ROM) scale. Ten other scales were also tested for assessment of symptoms, quality of life, and physical functions. Joint and fascia manifestations were present at study enrollment in 164 (29%) of the patients. Limited range of motion was most frequent at the wrists or fingers. Among the 3 joint assessment scales, changes in the NIH scale correlated with both clinician- and patient-perceived improvement of joint and fascia manifestations, with higher sensitivity than the Hopkins fascia scale. Changes in all 3 scales correlated with clinician- and patient-perceived worsening, but the P-ROM scale was the most sensitive in this regard. Onset of joint and fascia manifestations was not associated with subsequent mortality. Joint and fascia manifestations are common in patients with chronic GVHD and should be assessed carefully in these patients. Our results support the use of the NIH joint/fascia scale and P-ROM scale to assess joint and fascia manifestations. The NIH scale better captures improvement, while the P-ROM scale better captures worsening. The utility of these scales could also be tested in the rheumatic diseases.
    04/2014; 66(4):1044-52. DOI:10.1002/art.38293
  • Cancer Research 03/2014; 73(24 Supplement):P4-01-02-P4-01-02. DOI:10.1158/0008-5472.SABCS13-P4-01-02 · 9.28 Impact Factor
  • Cancer Research 03/2014; 73(24 Supplement):P4-01-03-P4-01-03. DOI:10.1158/0008-5472.SABCS13-P4-01-03 · 9.28 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Retroperitoneal sarcomas (RPS) are rare malignancies, comprising just 10-15 % of all soft-tissue sarcomas. These are challenging tumors to treat, with surgical resection being the only modality capable of providing a cure. This study analyzed the management and survival of patients resected at a large academic institution. A retrospective study of all patients with primary localized RPS referred to the University of Washington between January 2000 and January 2013 was performed. Univariate and multivariate Cox regression models were used to analyze progression-free survival (PFS) and overall survival (OS) by patient, tumor, and treatment variables. The study identified 132 patients. Median follow-up was 31.8 months. Median PFS was 33 months, and median OS was 111 months. Sixty patients (45.5 %) underwent a margin-negative resection (R0), 59 (44.7 %) had a microscopic margin-positive resection (R1), and 7 (5.3 %) had a macroscopic margin-positive resection (R2). Forty (30.3 %) patients received preoperative radiation, 28 (21.2 %) received neoadjuvant chemotherapy, and 7 (5.3 %) received both. Tumor grade and microscopic margin status emerged as statistically significant predictors for both PFS and OS. Tumor size was also found to correlate with PFS. No significant difference in OS or PFS was observed for histologic subtype, neoadjuvant chemotherapy, or neoadjuvant radiation. Complete surgical resection should remain the mainstay of management for RPS, with emphasis on achieving negative microscopic margins. Neither neoadjuvant chemotherapy nor radiation was shown to significantly improve survival, and their unclear role in the management of RPS requires evaluation in a prospective setting.
    Annals of Surgical Oncology 03/2014; 21(7). DOI:10.1245/s10434-014-3616-7 · 3.94 Impact Factor
  • Biology of Blood and Marrow Transplantation 02/2014; 20(2):S65. DOI:10.1016/j.bbmt.2013.12.074 · 3.35 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: There are no validated biomarkers for chronic GVHD (cGVHD). We used a protein microarray and subsequent sequential ELISA to compare 17 patients with treatment-refractory de novo onset cGVHD and 18 time-matched control patients without acute or chronic GVHD to identify five candidate proteins that distinguished cGVHD from no cGVHD: CXCL9, IL2Rα, Elafin, CD13 and BAFF. We then assessed the discriminatory value of each protein individually and in composite panels in a validation cohort (n=109). CXCL9 was found to have the highest discriminatory value with an area under the receiver operating characteristic curve of 0.83 (95% confidence interval, 0.74-0.91). CXCL9 plasma concentrations above the median were associated with a higher frequency of cGVHD even after adjustment for other factors related to developing cGVHD including age, diagnosis, donor source and degree of HLA matching (71% vs. 20%, p<0.001). A separate validation cohort from a different transplant center (n=211) confirmed that CXCL9 plasma concentrations above the median were associated with more frequent newly diagnosed cGVHD after adjusting for the aforementioned factors (84% vs. 60%; p=0.001). Our results confirm that CXCL9 is elevated in patients with newly diagnosed cGVHD.
    Blood 12/2013; 123(5). DOI:10.1182/blood-2013-08-520072 · 9.78 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The 2005 NIH Consensus Conference recommended assessment of lung function in patients with chronic graft-versus-host disease (GVHD) by both pulmonary function tests (PFTs) and assessment of pulmonary symptoms. We tested whether pulmonary measures were associated with non-relapse mortality (NRM), overall survival (OS) and patient reported outcomes (PRO). Clinician and patient-reported data were collected serially in a prospective, multicenter observational study. Available PFT data were abstracted. Cox regression models were fit for outcomes using a time-varying covariate model for lung function measures and adjusting for patient and transplant characteristics and non-lung chronic GVHD severity. A total of 1591 visits (496 patients) were used in this analysis. The NIH symptom-based lung score was associated with NRM (p=0.02), overall survival (p=0.02), patient-reported symptoms (p<0.001) and functional status (p<0.001). Worsening of NIH symptom-based lung score over time was associated with higher NRM and lower survival. All other measures were not associated with OS or NRM, although some were associated with patient-reported lung symptoms. In conclusion, the NIH symptom-based lung symptom score of 0-3 is associated with NRM, OS, and PRO measures in patients with chronic GVHD. Worsening of the NIH symptom-based lung score was associated with increased mortality.
    Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 12/2013; DOI:10.1016/j.bbmt.2013.11.025 · 3.15 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Background:Cisplatin-radiotherapy is a preferred standard for locally advanced, head and neck squamous cell carcinoma (HNSCC). However, the cisplatin-attributable survival benefit is small and toxicity substantial. A biomarker of cisplatin resistance could guide treatment selection and spare morbidity. The ERCC1-XPF nuclease is critical to DNA repair pathways resolving cisplatin-induced lesions.Methods:In a phase II trial, patients with untreated Stage III-IVb HNSCC were randomised to cisplatin-radiotherapy with/without erlotinib. Archived primary tumours were available from 90 of 204 patients for this planned substudy. Semi-quantitative ERCC1 protein expression (H-score) was determined using the FL297, 4F9, and 8F1 antibodies. The primary analysis evaluated the relationship between continuous ERCC1 protein expression and progression-free survival (PFS). Secondary analyses included two pre-specified ERCC1 cutpoints and performance in HPV-associated disease.Results:Higher ERCC1 expression was associated with inferior PFS, as measured by the specific antibodies FL297 (HR=2.5, 95% CI=1.1-5.9, P=0.03) and 4F9 (HR=3.0, 95% CI=1.2-7.8, P=0.02). Patients with increased vs decreased/normal ERCC1 expression experienced inferior PFS (HR=4.8 for FL297, P=0.003; HR=5.5 for 4F9, P=0.007). This threshold remained prognostic in HPV-associated disease.Conclusion:ERCC1-XPF protein expression by the specific FL297 and 4F9 antibodies is prognostic in patients undergoing definitive cisplatin-radiotherapy for HNSCC, irrespective of HPV status.British Journal of Cancer advance online publication, 24 September 2013; doi:10.1038/bjc.2013.576 www.bjcancer.com.
    British Journal of Cancer 09/2013; DOI:10.1038/bjc.2013.576 · 5.08 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Hand grip strength (HGS) and the 2-minute walk test (2MWT) have been proposed as elements of chronic graft-versus-host disease (GVHD) assessment in clinical trials. Using all available data (n = 584 enrollment visits, 1689 follow-up visits, total of 2273 visits) from a prospective observational cohort study, we explored the relationship between HGS and 2MWT and patient-reported measures (Lee symptom scale, MOS 36-Item Short-Form Health Survey [SF-36], and Functional Assessment of Cancer Therapy [FACT]-Bone Marrow Transplantation quality of life instruments and Human Activity Profile [HAP]), chronic GVHD global severity (National Institutes of Health global score, clinician global score, and patient-reported global score), calculated and clinician-reported chronic GVHD response, and mortality (overall survival, nonrelapse mortality, and failure-free survival) in multivariable analyses adjusted for significant covariates. 2MWT was significantly associated with intuitive domains of the Lee Symptom Scale (overall, skin, lung, energy), SF-36 domain and summary scores, FACT summary and domain scores, and HAP scores (all P < .001). Fewer associations were detected with the HGS. The 2MWT and HGS both had significant association with global chronic GVHD severity. In multivariable analysis, 2MWT was significantly associated with overall survival, nonrelapse mortality, and failure-free survival, whereas no association was found for HGS. 2MWT and HGS were not sensitive to National Institutes of Health or clinician-reported response. Based on independent association with mortality, these data support the importance of the 2MWT for identification of high-risk chronic GVHD patients. However, change in 2MWT is not sensitive to chronic GVHD response, limiting its usefulness in clinical trials.
    Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 06/2013; 19(6):967–972. DOI:10.1016/j.bbmt.2013.03.014 · 3.15 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Chronic GVHD (cGVHD) is associated with mortality, disability and impaired quality of life. Understanding the role of comorbidity in patients with cGVHD is important both for prognostication and potentially for tailoring treatments based on mortality risks. In a prospective cohort study of patients with cGVHD (n=239), we examined the performance of two comorbidity scales, the Functional Comorbidity Index (FCI) and the Hematopoietic Cell Transplantation-specific Comorbidity Index (HCT-CI). Both scales detected a higher number of comorbidities at cGVHD cohort enrollment than pre-hematopoietic cell transplant (HCT) (P<0.001). Higher HCT-CI scores at the time of cGVHD cohort enrollment were associated with higher non-relapse mortality (HR: 1.21:1.04-1.42, P=0.01). For overall mortality, we detected an interaction with platelet count. Higher HCT-CI scores at enrollment were associated with an increased risk of overall mortality when the platelet count was 100 000/μL (HR: 2.01:1.20-3.35, P=0.01), but not when it was >100 000/μL (HR: 1.05:0.90-1.22, P=0.53). Comorbidity scoring may help better to predict survival outcomes in patients with cGVHD. Further studies to understand vulnerability unrelated to cGVHD activity in this patient population are needed.Bone Marrow Transplantation advance online publication, 13 May 2013; doi:10.1038/bmt.2013.70.
    Bone marrow transplantation 05/2013; DOI:10.1038/bmt.2013.70 · 3.00 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: PURPOSEThe combination of cisplatin and radiotherapy is a standard treatment for patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN). Cetuximab-radiotherapy is superior to radiotherapy alone in this population, validating epidermal growth factor receptor (EGFR) as a target. Erlotinib is a small-molecule inhibitor of EGFR. Adding EGFR inhibition to standard cisplatin-radiotherapy may improve efficacy. PATIENTS AND METHODS Patients with locally advanced SCCHN were randomly assigned to receive cisplatin 100 mg/m2 on days 1, 22, and 43 combined with 70 Gy of radiotherapy (arm A) or the same chemoradiotherapy with erlotinib 150 mg per day, starting 1 week before radiotherapy and continued to its completion (arm B). The primary end point was complete response rate (CRR), evaluated by central review. The secondary end point was progression-free survival (PFS). Available tumors were tested for p16 and EGFR by fluorescent in situ hybridization.ResultsBetween December 2006 and October 2011, 204 patients were randomly assigned. Arms were well balanced for all patient characteristics including p16, with the exception of more women on arm A. Patients on arm B had more rash, but treatment arms did not differ regarding rates of other grade 3 or 4 toxicities. Arm A had a CRR of 40% and arm B had a CRR of 52% (P = .08) when evaluated by central review. With a median follow-up time of 26 months and 54 progression events, there was no difference in PFS (hazard ratio, 0.9; P = .71). CONCLUSION Erlotinib did not increase the toxicity of cisplatin and radiotherapy in patients with locally advanced HNSCC but failed to significantly increase CRR or PFS.
    Journal of Clinical Oncology 03/2013; 31(11). DOI:10.1200/JCO.2012.46.3299 · 17.88 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: While data support adverse prognosis of overlap subtype of chronic GVHD, the importance of site of gastrointestinal (GI) and type of hepatic involvement is not known. Using data from the Chronic GVHD Consortium observational cohort study (n=567, total of 2115 visits), we examined whether the site of GI (esophageal, upper GI, lower GI) and type of hepatic (bilirubin, alkaline phosphatase (AP), alanine aminotransferase (ALT)) involvement are associated with overall survival (OS)and non-relapse mortality (NRM), symptoms, quality of life (QOL) and functional status measures. In multivariate analysis utilizing data from enrollment visits only, lower GI involvement (HR 1.67, p=0.05) and elevated bilirubin (HR 2.46, p=0.001) were associated with OS; both were also associated with NRM. In multivariable analysis using all visits (time-dependent covariates), GI score greater than zero (HR 1.69, p=0.02) and elevated bilirubin (HR 3.73, p<0.001) were associated with OS; results were similar for NRM. Any esophageal involvement and GI score greater than zero were associated with both symptoms and QOL while elevated bilirubin was associated with QOL. We found no consistent evidence that upper GI involvement, AP, ALT, or NIH liver score add prognostic value for survival, overall symptom burden, or quality of life. These data support important differences in patient-reported outcomes according to GI and hepatic involvement among chronic GVHD affected patients, and identify those with elevated bilirubin or higher GI score at any time, or lower GI involvement at cohort enrollment, as patients at greater risk for mortality under current treatment approaches.
    Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 02/2013; DOI:10.1016/j.bbmt.2013.02.001 · 3.15 Impact Factor
  • Biology of Blood and Marrow Transplantation 02/2013; 19(2):S338. DOI:10.1016/j.bbmt.2012.11.516 · 3.35 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Oral chronic GVHD (cGVHD) is a serious complication of alloSCT. Scales and instruments to measure oral cGVHD activity and severity have not been prospectively validated. The objective of this study was to describe the characteristics of oral cGVHD and determine the measures most sensitive to change. Patients enrolled in the cGVHD Consortium with oral involvement were included. Clinicians scored oral changes according to the National Institutes of Health (NIH) criteria, and patients completed symptom and quality-of-life measures at each visit. Both rated change on an eight-point scale. Of the 458 participants, 72% (n=331) had objective oral involvement at enrollment. Lichenoid change was the most common feature (n=293; 89%). At visits where oral change could be assessed, 50% of clinicians and 56% of patients reported improvement, with worsening reported in 4-5% for both the groups (weighted kappa=0.41). Multivariable regression modeling suggested that the measurement changes most predictive of perceived change by clinicians and patients were erythema and lichenoid, NIH severity and symptom scores. Oral cGVHD is common and associated with a range of signs and symptoms. Measurement of erythema and lichenoid changes and symptoms may adequately capture the activity of oral cGVHD in clinical trials but require prospective validation.Bone Marrow Transplantation advance online publication, 28 January 2013; doi:10.1038/bmt.2012.285.
    Bone marrow transplantation 01/2013; 48(8). DOI:10.1038/bmt.2012.285 · 3.00 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: PURPOSE Diffusion-weighted imaging (DWI) with MRI shows promise for detecting and characterizing breast cancers. Due to higher cellularity, malignancies typically appear hyperintense on DWI and hypointense on apparent diffusion coefficient (ADC) maps. Further information about DWI at 3T is warranted, particularly given interest in DWI for non-contrast screening. We evaluated the performance of DWI at 3 Tesla (T) for the detection and characterization of mammographically and clinically occult breast malignancies. METHOD AND MATERIALS Participants were recruited prior to biopsy of BI-RADS 4 or 5 lesions that were mammographically and clinically occult and detected on dynamic contrast enhanced (DCE) MRI. DWI (b=0, 800 s/mm2) sequences were obtained with clinical DCE examinations on a 3T MRI scanner (Philips Achieva). Mean ADC values of benign versus malignant lesions were calculated and compared. ADC diagnostic performance was assessed by area under the receiver operating characteristic curve (AUC) and threshold ADC value. For malignancies, DWI conspicuity was assessed by contrast-to-noise ratio (CNR: comparing signal intensity of lesion to normal parenchyma). Influence of lesion size on ADC and CNR was evaluated by generalized estimating equations. RESULTS 98 lesions (38 malignant, 60 benign) were evaluated in 78 women enrolled from 10/2010 to 10/2011. Mean ADC was lower in malignancies than benign lesions (1.13±0.32 vs. 1.60±0.30 x10-3mm2/s; p<0.0001), with AUC=0.84. An ADC threshold of 1.6x10-3 mm2/s predicted malignancy with 89% sensitivity, 53% specificity, 55% PPV, 89% NPV. Larger lesion size was associated with higher ADC (p=0.03). Most malignancies were hyperintense on DWI (mean CNR: 1.8±2.6); 28/36 (78%) had CNR>0. CNR was not associated with lesion size (p=0.22). However, all 8 hypointense malignancies (CNR≤0) had size <14 mm. CONCLUSION DWI ADC at 3T discriminates between benign and malignant suspicious lesions detected with DCE MRI. Use of an ADC threshold could improve the specificity and PPV over DCE alone. The majority of malignancies show hyperintensity on DWI, a useful feature for lesion detection given interest in DWI as an MRI screening tool. CLINICAL RELEVANCE/APPLICATION DWI at 3T shows promise as an adjunct to DCE MRI for lesion characterization, and as a non-contrast MRI screening tool for detection of otherwise occult breast cancer.
    Radiological Society of North America 2012 Scientific Assembly and Annual Meeting; 11/2012
  • Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 10/2012; DOI:10.1038/leu.2012.292 · 10.16 Impact Factor

Publication Stats

260 Citations
188.57 Total Impact Points


  • 2010–2015
    • Fred Hutchinson Cancer Research Center
      • Division of Clinical Research
      Seattle, Washington, United States
  • 2011
    • Moffitt Cancer Center
      • Program in Blood and Marrow Transplantation
      Tampa, FL, United States
    • Kagoshima University
      • Graduate School of Medical and Dental Sciences
      Kagosima, Kagoshima, Japan