Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract. GISTs express KIT and have KIT mutations. Majority of these mutations cluster in the 5' end of the KIT juxtamembrane domain. Little is known about the clinicopathological profile of GIST carrying internal tandem duplications in the 3' end of KIT juxtamembrane domain (ITDs in the 3' KIT-JM). In this study, 500 immunohistochemically KIT-positive GISTs were screened for this type of mutation, and 18 cases were identified (3.6%). The majority of the ITDs consisted of 1 to 18 codon duplications, with Tyr(578), Asp(579), and Leu(576) being the most commonly duplicated codons. There were 14 gastric (78%), 2 small intestinal (11%), and 2 anal (11%) primary tumors diagnosed in 12 females and 6 males with median age of 71 years. The frequency of IDTs in gastric GISTs was 6.5% and was only 0.5% in intestinal GISTs. There was a strong female predominance (79%) among the patients with gastric tumors. Histologically, 16 GISTs were spindle cell, and 2 had epithelioid morphology. The sizes of primary tumors varied from 1 to >20 cm. Based on the combination of tumor size and mitotic activity, six tumors were classified as benign or probably benign, eight as having uncertain malignant potential, and only four as malignant. Follow-up data available in 17 patients confirmed the malignant course of disease in 3 cases. Only one of the tumors classified as potentially malignant metastasized, although the follow-up was limited in some cases. In summary, the great majority of GISTs with ITDs in the 3' KIT-JM were mitotically inactive tumors occurring predominantly in the stomach and that seemed to have a favorable course. This suggests that presence of these IDTs may define a clinicopathologically favorable subset of GISTs. The consequence of these mutations to KIT signaling should be investigated.
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Background: Several registries of idiopathic pulmonary fibrosis (IPF) have been established to better understand its natural history, though their size and duration of follow-up are limited. Here, we describe the large European MultiPartner IPF Registry (EMPIRE) and validate predictors of long-term survival in IPF. Methods: The multinational prospective EMPIRE registry enrolled IPF patients from 48 sites in 10 Central and Eastern European countries since 2014. Survival from IPF diagnosis until death was estimated, accounting for lefttruncation. The Cox proportional hazards regression model was used to estimate adjusted hazard ratios (HR) of death for prognostic factors, using restricted cubic splines to fit continuous factors. Results: The cohort included 1620 patients (mean age at diagnosis 67.6 years, 71% male, 63% smoking history), including 75% enrolled within 6 months of diagnosis. Median survival was 4.5 years, with 45% surviving 5 years post-diagnosis. Compared with GAP stage I, mortality was higher with GAP stages II (HR 2.9; 95% CI: 2.3-3.7) and III (HR 4.0; 95% CI: 2.8-5.7) while, with redefined cutoffs , the corresponding HRs were 2.7 (95% CI: 1.8-4.0) and 5.8 (95% CI: 4.0-8.3) respectively. Mortality was higher with concurrent pulmonary hypertension (HR 2.0; 95% CI: 1.5-2.9) and lung cancer (HR 2.6; 95% CI: 1.3-4.9). Conclusions: EMPIRE, one of the largest long-term registries of patients with IPF, provides a more accurate confirmation of prognostic factors and co-morbidities on longer term five-year mortality. It also suggests that some fine-tuning of the indices for mortality may provide a more accurate long-term prognostic profile for these patients.
BackgroundAspirin-exacerbated respiratory disease (AERD) is a distinct eosinophilic phenotype of severe asthma with accompanying chronic rhinosinusitis, nasal polyposis, and hypersensitivity to aspirin. Urinary 3-bromotyrosine (uBrTyr) is a noninvasive marker of eosinophil-catalyzed protein oxidation. The lack of in vitro diagnostic test makes the diagnosis of AERD difficult. We aimed to determine uBrTyr levels in patients with AERD (n = 240) and aspirin-tolerant asthma (ATA) (n = 226) and to assess whether its addition to urinary leukotriene E4 (uLTE4) levels and blood eosinophilia can improve the prediction of AERD diagnosis.MethodsClinical data, spirometry and blood eosinophilis were evaluated. UBrTyr and uLTE4 levels were measured in urine by HPLC and ELISA, respectively.ResultsBoth groups of asthmatics (AERD, n = 240; ATA, n = 226) had significantly higher uBrTyr, uLTE4 levels, and blood eosinophils than healthy controls (HC) (n = 71) (p < 0.05). ULTE4 levels and blood eosinophils were significantly higher in AERD as compared to ATA (p = 0.004, p < 0.0001, respectively). whereas uBrTyr levels were not significantly different between both asthma phenotypes (p = 0.34). Asthmatics with high levels of uBrTyr (> 0.101 ng/mg Cr), uLTE4 levels (> 800 pg/mg Cr) and blood eosinophils (> 300 cells/ul) were 7 times more likely to have AERD.. However, uBrTyr did not increase the benefit for predicting AERD when uLTE4 and blood eosinophils were already taken into account (p = 0.57).ConclusionUBrTyr levels are elevated both in AERD and ATA as compared to HC, but they could not differentiate between these asthma phenotypes suggesting a similar eosinophilic activation. The addition of uBrTyr to elevated uLTE4 levels and blood eosinophils did not statistically enhance the prediction of AERD diagnosis.
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