STAT1 mutations in autosomal dominant chronic mucocutaneous candidiasis.

BACKGROUND: Chronic mucocutaneous candidiasis (CMC) is characterized by susceptibility to candida infection of skin, nails, and mucous membranes. Patients with recessive CMC and autoimmunity have mutations in the autoimmune regulator AIRE. The cause of autosomal dominant CMC is unknown. METHODS: We evaluated 14 patients from five families with autosomal dominant CMC. We incubated their peripheral-blood mononuclear cells with different combinations of stimuli to test the integrity of pathways that mediate immunity, which led to the selection of 100 genes that were most likely to contain the genetic defect. We used an array-based sequence-capture assay, followed by next-generation sequencing, to identify mutations. RESULTS: The mononuclear cells from the affected patients were characterized by poor production of interferon-γ, interleukin-17, and interleukin-22, suggesting that the defect lay within the interleukin-12 receptor and interleukin-23 receptor signaling pathways. We identified heterozygous missense mutations in the DNA sequence encoding the coiled-coil (CC) domain of signal transducer and activator of transcription 1 (STAT1) in the patients. These mutations lead to defective responses in type 1 and type 17 helper T cells (Th1 and Th17). The interferon-γ receptor pathway was intact in these patients. CONCLUSIONS: Mutations in the CC domain of STAT1 underlie autosomal dominant CMC and lead to defective Th1 and Th17 responses, which may explain the increased susceptibility to fungal infection. (Funded by the Netherlands Organization for Scientific Research and others.).

Timeliness of lung cancer diagnosis and treatment in a rapid outpatient diagnostic program with combined 18FDG-PET and contrast enhanced CT scanning.

INTRODUCTION: Delays in the diagnosis of lung cancer are under debate and may affect outcome. The objectives of this study were to compare various delays in a rapid outpatient diagnostic program (RODP) for suspected lung cancer patients with those described in literature and with guideline recommendations, to investigate the effects of referral route and symptoms on delays, and to establish whether delays were related to disease stage and outcome. METHODS: A retrospective chart study was conducted of all patients with suspected lung cancer, referred to the RODP of our tertiary care university clinic between 1999 and 2009. Patient characteristics, tumor stage and different delays were analyzed. RESULTS: Medical charts of 565 patients were retrieved. 290 patients (51.3%) were diagnosed with lung cancer, 48 (8.5%) with another type of malignancy, and in 111 patients (19.6%) the radiological anomaly was diagnosed as non-malignant. In 112 (19.8%) no immediate definite diagnosis was obtained, however in 82 of these cases (73.2%) the proposed follow-up strategy confirmed a benign outcome. The median first line delay was 54 days, IQR (interquartile range) 20-104 days, median patient delay 19 days (IQR 4-52 days), median referral delay was 7 days (IQR 5-9 days), median diagnostic delay 2 days (IQR 1-19 days). In 87% a diagnosis was obtained within 3 weeks after visiting a chest physician and 52.5% started curative therapy within 2 weeks after diagnosis. Patients presenting with hemoptysis had shorter first line delays. The RODP care was generally far more timely compared to literature and published guidelines, except for both referral and palliative therapeutic delay. No specific delay was significantly related to disease stage or survival. CONCLUSIONS: An RODP results in a timely diagnosis well within guideline recommendations. Patient and first line delay account for most of total patient delay. Within the limitations of this retrospective study, we found no association with disease stage or survival.