Xiaoyu Chai

Patient-reported quality of life is associated with severity of chronic graft-versus-host disease as measured by NIH criteria: report on baseline data from the Chronic GVHD Consortium

Quality of life (QOL) after hematopoietic cell transplantation (HCT) is compromised by chronic GVHD. In a prospectively assembled multicenter cohort of adults with chronic GVHD (n = 298), we examined the relationship between chronic GVHD severity defined by National Institutes of Health (NIH) criteria and QOL as measured by the SF-36 and FACT-BMT instruments at time of enrollment. Chronic GVHD severity was independently associated with QOL, adjusting for age. Compared with population normative data, SF-36 scores were more than a SD (10 points) lower on average for the summary physical component score (PCS) and role-physical subscale, and significantly lower (with magnitude 4-10 points) for several other subscales. Patients with moderate and severe cGVHD had PCS scores comparable with scores reported for systemic sclerosis, systemic lupus erythematosus, and multiple sclerosis, and greater impairment compared with common chronic conditions including diabetes, hypertension, and chronic lung disease. Moderate to severe cGVHD as defined by NIH criteria is associated with significant compromise in multiple QOL domains, with PCS scores in the range of other systemic autoimmune diseases. Compromised QOL provides a functional assessment of the effects of chronic GVHD, and may be measured in cGVHD clinical studies using either the SF-36 or the FACT-BMT.

Global and organ-specific chronic graft-versus-host disease severity according to the 2005 NIH Consensus Criteria

In 2005, the National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic GVHD proposed a new scoring system for individual organs and an algorithm for calculating global severity (mild, moderate, severe). The Chronic GVHD Consortium was established to test these new criteria. This report includes the first 298 adult patients enrolled at 5 centers of the Consortium. Patients were assessed every 3-6 months using standardized forms recommended by the Consensus Conference. At the time of study enrollment, global chronic GVHD severity was mild in 10% (n = 32), moderate in 59% (n = 175), and severe in 31% (n = 91). Skin, lung, or eye scores determined the global severity score in the majority of cases, with the other 5 organs determining 16% of the global severity scores. Conventional risk factors predictive for onset of chronic GVHD and nonrelapse mortality in people with chronic GVHD were not associated with NIH global severity scores. Global severity scores at enrollment were associated with nonrelapse mortality (P < .0001) and survival (P < .0001); 2-year overall survival was 62% (severe), 86% (moderate), and 97% (mild). Patients with mild chronic GVHD have a good prognosis, while patients with severe chronic GVHD have a poor prognosis. This study was registered at www.clinicaltrials.gov as no. NCT00637689.

Cisplatin and Radiotherapy With or Without Erlotinib in Locally Advanced Squamous Cell Carcinoma of the Head and Neck: A Randomized Phase II Trial

PURPOSE The 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/m(2) 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. RESULTS Between 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.

Improved diagnostic accuracy of breast MRI through combined apparent diffusion coefficients and dynamic contrast-enhanced kinetics

This study investigated the relationship between apparent diffusion coefficient (ADC) measures and dynamic contrast‐enhanced magnetic resonance imaging (MRI) kinetics in breast lesions and evaluated the relative diagnostic value of each quantitative parameter. Seventy‐seven women with 100 breast lesions (27 malignant and 73 benign) underwent both dynamic contrast‐enhanced MRI and diffusion weighted MRI. Dynamic contrast‐enhanced MRI kinetic parameters included peak initial enhancement, predominant delayed kinetic curve type (persistent, plateau, or washout), and worst delayed kinetic curve type (washout > plateau > persistent). Associations between ADC and dynamic contrast‐enhanced MRI kinetic parameters and predictions of malignancy were evaluated. Results showed that ADC was significantly associated with predominant curve type (ADC was higher for lesions exhibiting predominantly persistent enhancement compared with those exhibiting predominantly washout or plateau, P = 0.006), but was not significantly associated with peak initial enhancement or worst curve type (P > 0.05). Univariate analysis showed significant differences between benign and malignant lesions in both ADC (P < 0.001) and worst curve (P = 0.003). In multivariate analysis, worst curve type and ADC were significant independent predictors of benign versus malignant outcome and in combination produced the highest area under the receiver operating characteristic curve (0.85 and 0.78 with 5‐fold cross validation). Magn Reson Med, 2011.

Validation of measurement scales in ocular graft-versus-host disease

PURPOSE To validate measurement scales for rating ocular chronic graft-versus-host disease (GVHD) after allogeneic hematopoietic cell transplantation. Candidate scales were recommended for use in clinical trials by the National Institutes of Health (NIH) Chronic GVHD Consensus Conference or have been previously validated in dry eye syndromes. DESIGN Prospective follow-up study. PARTICIPANTS Between August 2007 and June 2010, the study enrolled 387 patients with chronic GVHD in a multicenter, prospective, observational cohort. METHODS Using anchor-based methods, we compared clinician or patient-reported changes in eye symptoms (8-point scale) with calculated changes in 5 candidate scales: The NIH eye score, patient-reported global rating of eye symptoms, Lee eye subscale, Ocular Surface Disease Index, and Schirmer test. Change was examined for 333 follow-up visits where both clinician and patient reported eye involvement at the previous visit. Linear mixed models were used to account for within-patient correlation. MAIN OUTCOME MEASURES An 8-point scale of clinician or patient-reported symptom change was used as an anchor to measure symptom changes at the follow-up visits. RESULTS In serial evaluations, agreement regarding improvement, stability, or worsening between the clinician and patient was fair (weighted kappa = 0.34). Despite only fair agreement between evaluators, all scales except the Schirmer test correlated with both clinician-reported and patient-reported changes in ocular GVHD activity. Among all scales, changes in the NIH eye scores showed the greatest sensitivity to symptom change reported by clinicians or patients. CONCLUSIONS Our results support the use of the NIH eye score as a sensitive measure of eye symptom changes in clinical trials assessing treatment of chronic GVHD.

Overlap subtype of chronic graft-versus-host disease is associated with an adverse prognosis, functional impairment, and inferior patient-reported outcomes: a Chronic Graft-versus-Host Disease Consortium study

Background The National Institutes of Health Consensus Conference proposed the term “overlap” graft-versus-host disease to describe the situation when both acute and chronic graft-versus-host disease are present. Design and Methods We examined whether the overlap subtype of graft-versus-host disease was associated with a different prognosis, functional limitations, or patient-reported outcomes compared to “classic” chronic graft-versus-host disease without any acute features. Results Prospective data were collected from 427 patients from nine centers. Patients were classified as having overlap (n=352) or classic chronic (n=75) graft-versus-host disease based on reported organ involvement. Overlap cases had a significantly shorter median time from transplantation to cohort enrollment (P=0.01), were more likely to be incident cases (P<0.001), and had a lower platelet count at onset of the graft-versus-host disease (P<0.001). Patients with overlap graft-versus-host disease had significantly greater functional impairment measured by a 2-minute walk test, higher symptom burden and lower Human Activity Profile scores. Quality of life was similar, except patients with overlap graft-versus-host disease had worse social functioning, assessed by the Short Form-36. Multivariable analysis utilizing time-varying covariates demonstrated that the overlap subtype of graft-versus-host disease was associated with worse overall survival (HR 2.1, 95% CI 1.1–4.7; P=0.03) and higher non-relapse mortality (HR 2.8, 95% CI 1.2–8.3; P=0.02) than classic chronic graft-versus-host disease. Conclusions These findings suggest that the presence of acute features in patients with chronic graft-versus-host disease is a marker of adverse prognosis, greater functional impairment, and higher symptom burden.

Plasma CXCL9 elevations correlate with chronic GVHD diagnosis

There are no validated biomarkers for chronic GVHD (cGVHD). We used a protein microarray and subsequent sequential enzyme-linked immunosorbent assay to compare 17 patients with treatment-refractory de novo-onset cGVHD and 18 time-matched control patients without acute or chronic GVHD to identify 5 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 < .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 = .001). Our results confirm that CXCL9 is elevated in patients with newly diagnosed cGVHD.

Pulmonary symptoms measured by the National Institutes of Health lung score predict overall survival, nonrelapse mortality, and patient-reported outcomes in chronic graft-versus-host disease

The 2005 National Institutes of Health (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 nonrelapse 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 transplantation characteristics and nonlung 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 = .02), OS (P = .02), patient-reported symptoms (P < .001) and functional status (P < .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 to 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.

Association between serial dynamic contrast‐enhanced MRI and dynamic 18F‐FDG PET measures in patients undergoing neoadjuvant chemotherapy for locally advanced breast cancer

To investigate the relationship between changes in vascularity and metabolic activity measured by dynamic contrast‐enhanced magnetic resonance imaging (DCE‐MRI) and dynamic 18F‐FDG‐positron emission tomography (PET) in breast tumors undergoing neoadjuvant chemotherapy.

ERCC1 is a prognostic biomarker in locally advanced head and neck cancer: results from a randomised, phase II trial.

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.