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Prognostic factors of ECD
cally significant association between the presence of CNS involvement and sex (P=0.75), year of diagnosis (P=1.0), and existence of bone (P=0.19) and skin lesions (P=0.36), endocrinosis (P=0.12), pulmonary (P=0.20) and digestive organ involvement (P=0.66), or kidney/retroperitoneal dis- ease (P=0.13) was detected.
CRP level and outcome
The CRP level at onset was higher than the upper nor- mal limit in 29 (85.3%) out of 34 patients with sufficient laboratory data, with a median CRP level at onset of 2.61 mg/dL (range: 0.10–14.1). Interestingly, a >3.0 mg/dL CRP level at onset was associated with a worse outcome (median survival, 14.6 vs. 7.4 years; P=0.016; Figure 3A). The cumulative incidence of ECD-related death was also associated with a higher CRP level at onset (P=0.043; Figure 3B). We also compared the CRP level at onset with that after the administration of first-line therapy in 25 patients whose clinical data were available. The results of the Wilcoxon signed-rank test revealed that CRP levels tended to decline following the initial treatment (median at onset and after initial therapy: 2.38 [range, 0.10–14.1] mg/dL and 1.16 [range, 0.01–34.6] mg/dL, respectively; P=0.051; Figure 3C). In addition, patients whose CRP lev- els reduced by more than 2.0 mg/dL after first-line therapy had a better outcome compared with patients whose CRP levels dropped by less than 2.0 mg/dL or increased after first-line treatment (median survival, 11.3 vs. 7.4 years; P=0.045) (Figure 3D).
BRAFV600E mutation
Thirteen patients had available histological samples on
ECD lesions (Online Supplementary Table S3). The genomic DNA was extracted from the samples, which were then subjected to direct sequencing. A BRAFV600E mutation was detected in 11 out of 14 patients (78%). None of the BRAF mutations were detected through Sanger sequenc- ing of the genomic DNA extracted from the peripheral blood or bone marrow samples. Moreover, no correlation between BRAF mutation status and age, CRP level at onset, and other clinical factors were observed.
Discussion
Our nationwide study broadly investigated ECD patients and analyzed the clinical data of 44 patients. ECD is so rare that few reports on multiple ECD patient studies have been published and little evidence about the clinical characteristics or prognostic factors of this disease is avail- able. The study herein is one of the largest in terms of the number of patients with ECD involved in our research.2,6,7,16 In this study, the duration between onset and diagnosis seems to be shorter compared with previ- ous studies, in which many patients were diagnosed sev- eral years after initial onset. It might reflect an increased familiarity with ECD in recent years, although the exact reason is unclear.20 IFN has recently been recommended as first-line therapy, and BRAF inhibitors are also strong can- didates for the treatment of ECD.5,16,21 In our study, IFN was administered to a very small proportion of patients during the clinical course of the disease, and no patients received BRAF inhibitors, which is partially attributed to the Japanese insurance system. Instead, many patients were prescribed corticosteroid, which is believed to tem- porarily alleviate the symptoms, although it is not recom- mended by the consensus guidelines.5 Two patients died from infection (one pneumonia and one invasive pul- monary aspergillosis), possibly due to immunosuppres- sion induced by corticosteroid administration for the treatment of ECD. In our study, the mortality rate was rel- atively high compared with a recent report which showed a five year survival rate of 82.7 %.4 However, the outcome in our cohort was slightly better than that in patients who were not administered IFN in a previous report,16 perhaps due to the improvement of supportive care. To improve the prognosis of patients with ECD, more detailed analy- ses and prospective studies of the pathophysiology of ECD are required. Given that future studies on ECD may not include patients who were not administered with IFN and/or BRAF inhibitors, this study could serve as an important physician’s compass that reveals the baseline clinical behaviors of ECD.
CNS involvement was a significant poor prognostic fac-
Digestive (+) (n=6) P 5–1 0.39
66 (46–68) 0.11 4 (66.6) 1 0 (0) 1
8 (3–11)
5 (83.3) 1 4 (66.7) 0.66 1 (16.7) 1 4 (66.7) 0.67 5 (83.3) 0.19 3 (50.0) 0.68 2 (33.3) 1 3 (50.0) 0.39
Table 4. Digestive involvement and clinical factors. Characteristics
Sex (male–female)
Median age at onset, y (range)
Diagnosed after 2005, no. (%)
Coexistence of LCH, no. (%)
Median number of involved organs (range) Skeletal involvement, no. (%)
CNS involvement, no. (%) Exophthalmos, no. (%)
Cardiovascular involvement, no. (%) Retroperitoneal involvement, no. (%) Endocrine involvement, no. (%) Cutaneous involvement, no. (%) Pulmonary involvement, no. (%)
CRP at onset (mg/dL), median (range)
Digestive (−) (n=38)
23–15
49 (23–76) 27 (71.1) 4 (11.1) 3 (1–7) 33 (91.7) 18 (47.4) 5 (13.2) 19 (50.0) 17 (44.7) 13 (34.2) 16 (42.1) 12 (31.6)
2.52 (0.10–14.1)
0.015
2.70 (0.13–7.46) 0.99
LCH: Langerhans cell histiocytosis; CRP: C-reactive protein; CNS: central nervous system.
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