A diagnostic prediction model for separating juvenile idiopathic arthritis and chronic musculoskeletal pain syndrome

Objective: To develop and validate a diagnostic prediction model that can distinguish between juvenile idiopathic arthritis (JIA) and chronic musculoskeletal pain syndrome (CMPS) based on patient-reported outcomes. Study design: This retrospective cohort study evaluated whether the Juvenile Arthritis Multidimensional Assessment Report (JAMAR) performs well in distinguishing JIA from CMPS. We analyzed JAMARs completed by 287 patients at their first visit to the pediatric rheumatology department of Wilhelmina Children's Hospital in Utrecht, The Netherlands. Relevant JAMAR items for predicting a diagnosis of JIA were selected in a penalized multivariable model suitable for clinical application. The model was subsequently validated with new data from the same center. Results: A total of 196 JAMARs (97 JIA, 99 CMPS) were collected in the model development data, and 91 JAMARs (48 JIA, 43 CMPS) were collected in the validation data. Variables in the prediction model that were strongest associated with a diagnosis of JIA instead of CMPS were asymmetric pain/swelling in the shoulder (OR, 2.34), difficulty with self-care (OR, 2.41), skin rash (OR, 2.07), and asymmetric/pain swelling in the knee (OR, 2.29). Calibration and discrimination (area under the receiver operating characteristic curve, 0.83; 95% CI, 0.74-0.92) of the model in the validation data were good. Conclusions: Several items from the JAMAR questionnaire can potentially distinguish JIA from CMPS in patients with corresponding symptoms. We present an easy-to-use, adjusted, and validated model to separate these 2 diagnoses early at presentation based on patient-reported outcomes to facilitate proper referral and treatment

KRAS, BRAF and PIK3CA Mutations and the Loss of PTEN Expression in Chinese Patients with Colorectal Cancer

Background: To investigate the frequency and relationship of the KRAS, BRAF and PIK3CA mutations and the loss of PTEN expression in Chinese patients with colorectal cancer (CRC). Methodology/Principal Findings: Genomic DNA was extracted from the formalin-fixed paraffin-embedded (FFPE) tissues of 69 patients with histologically confirmed CRC. Automated sequencing analysis was conducted to detect mutations in the KRAS (codons 12, 13, and 14), BRAF (codon 600) and PIK3CA (codons 542, 545 and 1047). PTEN protein expression was evaluated by immunohistochemistry on 3 mm FFPE tissue sections. Statistical analysis was carried out using SPSS 16.0 software. The frequency of KRAS, BRAF and PIK3CA mutations and loss of PTEN expression was 43.9 % (25/57), 25.4 % (15/59), 8.2 % (5/61) and 47.8 % (33/69), respectively. The most frequent mutation in KRAS, BRAF and PIK3CA was V14G (26.7 % of all mutations), V600E (40.0 % of all mutations) and V600L (40.0 % of all mutations), and H1047L (80.0 % of all mutations), respectivly. Six KRAS mutatant patients (24.0%) harbored BRAF mutations. BRAF and PIK3CA mutations were mutually exclusive. No significant correlation was observed between the four biomarkers and patients ’ characteristics. Conclusions/Significance: BRAF mutation rate is much higher in this study than in other studies, and overlap a lot with KRAS mutations. Besides, the specific types of KRAS and PIK3CA mutations in Chinese patients could be quite different from that of patients in other countries. Further studies are warranted to examine their impact on prognosis and response to targete

EGFR related mutational status and association to clinical outcome of third-line cetuximab-irinotecan in metastatic colorectal cancer

<p>Abstract</p> <p>Background</p> <p>As supplement to <it>KRAS </it>mutational analysis<it>, BRAF and PIK3CA </it>mutations as well as expression of PTEN may account for additional non-responders to anti-EGFR-MoAbs treatment. The aim of the present study was to investigate the utility as biomarkers of these mutations in a uniform cohort of patients with metastatic colorectal cancer treated with third-line cetuximab/irinotecan.</p> <p>Methods</p> <p>One-hundred-and-seven patients were prospectively included in the study. Mutational analyses of <it>KRAS, BRAF </it>and <it>PIK3CA </it>were performed on DNA from confirmed malignant tissue using commercially available kits. Loss of PTEN and EGFR was assessed by immunohistochemistry.</p> <p>Results</p> <p>DNA was available in 94 patients. The frequency of KRAS, <it>BRAF </it>and <it>PIK3CA </it>mutations were 44%, 3% and 14%, respectively. All were non-responders. EGF receptor status by IHC and loss of PTEN failed to show any clinical importance. <it>KRAS </it>and <it>BRAF </it>were mutually exclusive. Supplementing <it>KRAS </it>analysis with <it>BRAF </it>and <it>PIK3CA </it>indentified additional 11% of non-responders. Patient with any mutation had a high risk of early progression, whereas triple-negative status implied a response rate (RR) of 41% (p < 0.001), a disease control (DC) rate of 73% (p < 001), and a significantly higher PFS of 7.7(5.1-8.6 95%CI) versus 2.3 months (2.1-3.695%CI) (p < 0.000).</p> <p>Conclusion</p> <p>Triple-negative status implied a clear benefit from treatment, and we suggest that patient selection for third-line combination therapy with cetuximab/irinotecan could be based on triple mutational testing.</p

Real-world comparison of the effects of etanercept and adalimumab on well-being in non-systemic juvenile idiopathic arthritis: a propensity score matched cohort study

Background: Etanercept (ETN) and adalimumab (ADA) are considered equally efective biologicals in the treat‑ ment of arthritis in juvenile idiopathic arthritis (JIA) but no studies have compared their impact on patient-reported well-being. The objective of this study was to determine whether ETN and ADA have a diferential efect on patientreported well-being in non-systemic JIA using real-world data. Methods: Biological-naive patients without a history of uveitis were selected from the international Pharmachild registry. Patients starting ETN were matched to patients starting ADA based on propensity score and outcomes were collected at time of therapy initiation and 3–12 months afterwards. Primary outcome at follow-up was the improve‑ ment in Juvenile Arthritis Multidimensional Assessment Report (JAMAR) visual analogue scale (VAS) well-being score from baseline. Secondary outcomes at follow-up were decrease in active joint count, adverse events and uveitis events. Outcomes were analyzed using linear and logistic mixed efects models. Results: Out of 158 eligible patients, 45 ETN starters and 45 ADA starters could be propensity score matched result‑ ing in similar VAS well-being scores at baseline. At follow-up, the median improvement in VAS well-being was 2 (inter‑ quartile range (IQR): 0.0 – 4.0) and scores were signifcantly better (P=0.01) for ETN starters (median 0.0, IQR: 0.0 – 1.0) compared to ADA starters (median 1.0, IQR: 0.0 – 3.5). The estimated mean diference in VAS well-being improvement from baseline for ETN versus ADA was 0.89 (95% CI: -0.01 – 1.78; P=0.06). The estimated mean diference in active joint count decrease was -0.36 (95% CI: -1.02 – 0.30; P=0.28) and odds ratio for adverse events was 0.48 (95% CI: 0.16 –1.44; P=0.19). One uveitis event was observed in the ETN group. Conclusions: Both ETN and ADA improve well-being in non-systemic JIA. Our data might indicate a trend towards a slightly stronger efect for ETN, but larger studies are needed to confrm this given the lack of statistical signifcance

The human epidermal growth factor receptor (EGFR) gene in European patients with advanced colorectal cancer harbors infrequent mutations in its tyrosine kinase domain

ABSTRACT: BACKGROUND: The epidermal growth factor receptor (EGFR), a member of the ErbB family of receptors, is a transmembrane tyrosine kinase (TK) activated by the binding of extracellular ligands of the EGF-family and involved in triggering the MAPK signaling pathway, which leads to cell proliferation. Mutations in the EGFR tyrosine kinase domain are frequent in non-small-cell lung cancer (NSCLC). However, to date, only very few, mainly non-European, studies have reported rare EGFR mutations in colorectal cancer (CRC). METHODS: We screened 236 clinical tumor samples from European patients with advanced CRC by direct DNA sequencing to detect potential, as yet unknown mutations, in the EGFR gene exons 18 to 21, mainly covering the EGFR TK catalytic domain. RESULTS: EGFR sequences showed somatic missense mutations in exons 18 and 20 at a frequency of 2.1% and 0.4% respectively. Somatic SNPs were also found in exons 20 and 21 at a frequency of about 3.1% and 0.4% respectively. Of these mutations, four have not yet been described elsewhere. CONCLUSIONS: These mutation frequencies are higher than in a similarly sized population characterized by Barber and colleagues, but still too low to account for a major role played by the EGFR gene in CRC.Peer reviewe

Methotrexate therapy associated with a reduced rate of new-onset uveitis in patients with biological-naïve juvenile idiopathic arthritis

OBJECTIVE: To study the effect of methotrexate (MTX) therapy on new-onset uveitis in patients with biological-naïve juvenile idiopathic arthritis (JIA). METHODS: In this matched case-control study, we compared MTX exposure between cases with JIA-associated chronic uveitis (JIA-U) and patients with JIA and without JIA-U at the time of matching (controls). Data were collected from electronic health records of the University Medical Centre Utrecht, the Netherlands. Cases with JIA-U were matched 1:1 to JIA control patients based on JIA diagnosis date, age at JIA diagnosis, JIA subtype, antinuclear antibodies status and disease duration. The effect of MTX on JIA-U onset was analysed using a multivariable time-varying Cox regression analysis. RESULTS: Ninety-two patients with JIA were included and characteristics were similar between cases with JIA-U (n=46) and controls (n=46). Both ever-use of MTX and exposure years were lower in cases with JIA-U than in controls. Cases with JIA-U significantly more often discontinued MTX treatment (p=0.03) and out of those who did, 50% afterwards developed uveitis within 1 year. On adjusted analysis, MTX was associated with a significantly reduced new-onset uveitis rate (HR: 0.35; 95% CI: 0.17 to 0.75). No different effect was observed between a low (<10 mg/m2/week) and standard MTX dose (≥10 mg/m2/week). CONCLUSION: This study demonstrates an independent protective effect of MTX on new-onset uveitis in patients with biological-naïve JIA. Clinicians might consider early initiation of MTX in patients at high uveitis risk. We advocate more frequent ophthalmologic screening in the first 6-12 months after MTX discontinuation

A gene expression predictor of response to EGFR-targeted therapy stratifies progression-free survival to cetuximab in KRAS wild-type metastatic colorectal cancer

<p>Abstract</p> <p>Background</p> <p>The anti-EGFR monoclonal antibody cetuximab is used in metastatic colorectal cancer (CRC), and predicting responsive patients garners great interest, due to the high cost of therapy. Mutations in the KRAS gene occur in ~40% of CRC and are a negative predictor of response to cetuximab. However, many KRAS-wildtype patients do not benefit from cetuximab. We previously published a gene expression predictor of sensitivity to erlotinib, an EGFR inhibitor. The purpose of this study was to determine if this predictor could identify KRAS-wildtype CRC patients who will benefit from cetuximab therapy.</p> <p>Methods</p> <p>Microarray data from 80 metastatic CRC patients subsequently treated with cetuximab were extracted from the study by Khambata-Ford et al. The study included KRAS status, response, and PFS for each patient. The gene expression data were scaled and analyzed using our predictive model. An improved predictive model of response was identified by removing features in the 180-gene predictor that introduced noise.</p> <p>Results</p> <p>Forty-three of eighty patients were identified as harboring wildtype-KRAS. When the model was applied to these patients, the predicted-sensitive group had significantly longer PFS than the predicted-resistant group (median 88 days vs. 56 days; mean 117 days vs. 63 days, respectively, p = 0.008). Kaplan-Meier curves were also significantly improved in the predicted-sensitive group (p = 0.0059, HR = 0.4109. The model was simplified to 26 of the original 180 genes and this further improved stratification of PFS (median 147 days vs. 56.5 days in the predicted sensitive and resistant groups, respectively, p < 0.0001). However, the simplified model will require further external validation, as features were selected based on their correlation to PFS in this dataset.</p> <p>Conclusion</p> <p>Our model of sensitivity to EGFR inhibition stratified PFS following cetuximab in KRAS-wildtype CRC patients. This study represents the first true external validation of a molecular predictor of response to cetuximab in KRAS-WT metastatic CRC. Our model may hold clinical utility for identifying patients responsive to cetuximab and may therefore minimize toxicity and cost while maximizing benefit.</p