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Two patients with germline BRCA1 deficiency acquired genomic alterations anticipated to restore HR through increased DNA end resection loss of TP53BP1 in one patient and amplification of MRE11A in another. RAD51 foci were acquired post-resistance in all patients with genomic reversion, consistent with reconstitution of HR. All patients whose tumors demonstrated RAD51 foci post-resistance were intrinsically resistant to subsequent lines of DNA-damaging therapy. CONCLUSIONS Genomic reversion in BRCA1/2 was the most commonly observed mechanism of resistance, occurring in four of eight patients. Novel sequence alterations leading to increased DNA end resection were seen in two patients, and may be targetable for therapeutic benefit. The presence of RAD51 foci by immunohistochemistry was consistent with BRCA1/2 protein functional status from genomic data and predicted response to later DNA-damaging therapy, supporting RAD51 focus formation as a clinically useful biomarker. OBJECTIVE The aims of our study were to describe the evolution of interstitial lung disease (ILD) extent on HRCT scan in systemic sclerosis (SSc), to identify baseline prognostic factors associated with ILD evolution and to assess whether the evolution of pulmonary function tests (PFTs) correlated with this evolution. METHODS 58 SSc with ILD (SSc-ILD) patients were included. All HRCT scans and PFTs available were collected. We modelized PFTs and HRCT scans evolution using linear mixed model with random effect. RESULTS Patients underwent a median number of 3 HRCT scans (total n = 203) and 5 PFTs (total n = 329), during a mean follow-up of 5.3 ± 4.9 years. Mean SSc duration was 2.5 ± 3.1 years at the diagnosis of ILD. Mean baseline ILD extent was 32.3 ± 28.7%. We found a significant mean progression of ILD extent on serial HRCT scans of 0.92 ± 0.36% per year (p = 0.018). Male sex, diffuse cutaneous SSc (dcSSc), presence of anti-topoisomerase 1 antibodies, a higher DLCO, limited ILD and a low coarseness score at baseline in bivariate analysis, and presence of antitopoisomerase 1 antibodies and a coarseness score of 0 in multivariate analysis, were associated with faster progression of ILD extent over time There was a significant correlation between the progression of ILD extent and the decline of DLCO but only a trend for FVC. ILD extent at baseline and during follow-up was associated with survival. CONCLUSION Male sex, dcSSc, anti-topoisomerase 1 antibodies and a less severe ILD at baseline were associated with a faster progression of ILD over time. Evolution of DLCO significantly correlated with change in ILD extent on HRCT scan. Our study helps defining the profile of patients at risk of experiencing a progression of ILD on HRCT scans. BACKGROUND Clinical practice guidelines recommend screening all systemic sclerosis (SSc) patients for pulmonary arterial hypertension (PAH) with yearly echocardiograms. There is a paucity of evidence to support these guidelines. RESEARCH QUESTION Can a prediction model identify SSc patients with a very low probability of PAH and therefore not requiring annual screening echocardiogram? STUDY DESIGN AND METHODS We performed a case-control study of 925 unselected SSc subjects nested in a multi-centered, longitudinal cohort. The probability of PAH for each subject was calculated using the results of multivariate logistic regression models. A cut-off was identified for the estimated probability of PAH below which no subject developed PAH (100% sensitivity). RESULTS Study subjects were predominantly female (87.5%), with mean (SD) age 58.6 (11.7) years and disease duration of 18.2 (12.2) years. Thirty-seven subjects developed PAH during 5407.97 person-years of observation (incidence rate 0.68 per 100 person-years). Shortness of breath (SOB), diffusing capacity for carbon monoxide (DLCO) and NT-proBNP were independent predictors of PAH. All SSc-PAH cases had a probability of PAH of >1.1%. Subjects below this cut-off, none of whom had PAH, accounted for 46.2% of the study population. INTERPRETATION A simple prediction model identified subjects at very low probability of PAH who could potentially forego annual screening echocardiogram. This represents almost half of SSc subjects in a general SSc population. This study, which is the first evidence-based study for the rational use of follow-up echocardiograms in an unselected SSc cohort, requires validation. Sotuletinib The scoring system is freely available online at http//pahtool.ladydavis.ca. BACKGROUND Central sensitization, including dysfunction of descending inhibitory pain pathways, may contribute to multisite pain in patients with chronic musculoskeletal conditions. Duloxetine is a centrally acting analgesic that effectively reduces pain in patients with knee osteoarthritis. Here we assessed the efficacy of duloxetine (60 mg/day) in Japanese patients (N = 353) with pain due to knee osteoarthritis based on the number of painful body sites, determined using the Michigan Body Map. METHODS Post hoc analysis of a phase 3, randomized, placebo-controlled trial (ClinicalTrials.gov; NCT02248480). RESULTS At Week 14, the change from baseline in Brief Pain Inventory-Severity average pain score ("pain reduction") was significantly greater with duloxetine compared with placebo in patients with 3, 4, or ≥5 painful sites, but not in patients with 1 or 2 painful sites. In patients with ≥3 painful sites (57% of patients), pain reduction was significantly greater with duloxetine (n = 100) compared with placebo (n = 101) throughout the study (least squares mean change from baseline to Week 14 -2.68 vs -1.68). Greater pain reduction with duloxetine (n = 77) than placebo (n = 75) also occurred in patients with ≤2 painful sites, although the between-group difference was significant only at Week 4. CONCLUSIONS These results are consistent with duloxetine enhancing the activity of descending inhibitory pain pathways that are dysfunctional in patients with central sensitization and multisite pain. In addition, these results suggest that duloxetine may be an effective choice of analgesic for patients with knee osteoarthritis and multisite pain.
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