infiltration and extravascular granulomas; the presence of asthma and ANCA positivity with a perinuclear pattern is also often present. Lanham et al. [2] showed that these criteria often do not coexist temporally or spatially and may only be found at the same time in a minority of cases. Churg-Strauss syndrome rarely involves the prostate and then presents with allergic/eosinophilic granulomatous prostatitis. Only 12 patients are reported to have had such prostatitis with asthma, of whom only five had significant blood CASE REPORTA 60-year-old man presented with poor urinary flow, hesitancy and nocturia over 1 month. He had chronic urinary retention with a 1 L residual on catheterization. A peripheral blood count showed a raised white cell count with an eosinophilia of 8.0 ¥ 10 9 (reference range 0.1-0.4 ¥ 10 9 ). Renal ultrasonography showed bilateral hydronephrosis with cortical preservation, and his urea and electrolytes were normal. He underwent TURP and was discharged without a catheter. Histology showed fibromuscular hyperplasia and florid eosinophilic prostatitis; granulomata and vasculitis were specifically noted to be absent (Fig. 1). Two weeks after discharge he was admitted as an emergency with a rash affecting both ankles and legs. A clinical diagnosis of nodular vasculitis consistent with incipient infarction was made, and a biopsy showed a leukocytoclastic vasculitis (Fig. 2). Asthma of recent onset was also noted. Investigations now showed a urea of 9.5 mmol/L, creatinine 209 m mol/L, a white cell count of 18.4 ¥ 10 9 , an eosinophil count of 10.1 ¥ 10 9 /L, an ESR of 87 mm/h, and perinuclear antineutrophil cytoplasmic antibody (ANCA) was positive. There was proteinuria and microscopic haematuria; a chest X-ray showed old pleural calcification of the left lung. The clinical and laboratory findings suggested Churg-Strauss syndrome with cutaneous, prostatic and possibly renal involvement. He was treated with pulsed intravenous methyl prednisolone, oral azathioprine and prednisolone, and his rash settled within 48 h. He developed a bronchopneumonia, which resolved after antibiotics, secondary to immunosuppression. At the time of discharge his electrolytes and eosinophil count had returned to normal. At a urological review 5 months after TURP he was voiding well with a maximum flow rate of 35 mL/s and no residual volume after voiding. COMMENTChurg-Strauss syndrome was originally described in 1951 [1]. The diagnostic criteria include peripheral blood eosinophilia, necrotizing vasculitis with eosinophilic tissue FIG. 1. The histology of the prostate, showing diffuse infiltration of the muscle and glands by an eosinophilic rich infiltrate. Haematoxylin and eosin, ¥ 25, inset ¥ 400. FIG. 2. Small-vessel vasculitis with perivascular fibrin and eosinophils. MSB stain ¥ 100, inset ¥ 400.
Background: Liquid biopsy is a promising technology that can offer various advantages for molecular testing over tissue-based approaches. Most studies trying to address the utility of liquid biopsy in thyroid cancer have failed so far to achieve satisfactory rates of detection of relevant mutations. In this study, we examined a newly developed approach for ultrasensitive detection of oncogenic mutations in thyroid cancer using BRAF mutation as a proof-of-concept. In an exploratory analysis, we also correlated our findings with clinical outcomes and with levels of standard of care biomarkers. Methods: We included a group of patients with metastatic thyroid carcinoma. Cell free DNA (cfDNA) was isolated from an average of 2 ml of plasma and from matched formaldehyde fixed paraffin tissue blocks (FFPB) that were obtained from prior surgery. Extracted DNA was subject to preamplification of mutant copies using Q5 High-Fidelity PCR kit. Digital droplet PCR was performed on pre-amplified purified DNA where BRAF mutated allele frequencies (AF) were measured using BioRad ddPCR Qx200. Results: Thirty-three patients were included in our study with a median age at diagnosis of 62. Our method achieved a sensitivity of detection of 47.6% and a specificity of 80%. Mutant BRAF V600E was detected in cfDNA of 54.5% of patients (n=18) compared to 80.8% in isolated DNA from matched FFPB. Median overall survival (OS) was shorter in patients with wild type (WT) BRAF in both ctDNA and tissue (127m vs 218m, p=0.015; 116m vs 223m, p=0.004). Thyroglobulin (Tg) levels did not correlate with BRAF mutations either quantitatively or qualitatively. In the papillary thyroid carcinoma-classic variant cohort (n=20), however, patients with cfDNA mutant BRAF were more likely to have elevated Tg (90.9% versus 44.4% respectively, p=0.05). Conclusions: Our study provided a proof of concept for a newly developed technique to provide high sensitivity of mutation detection in thyroid cancer. The achieved sensitivity of detection is the highest to date using liquid biopsy in this tumor type. While we addressed only BRAF mutations in our study, the same approach can potentially be used for other mutations as well, likely changing the paradigm for use of liquid biopsy in thyroid cancer.
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