Screening for Genomic Rearrangements in Families with Breast and Ovarian Cancer Identifies BRCA1 Mutations Previously Missed by Conformation-Sensitive Gel Electrophoresis or Sequencing

The frequency of genomic rearrangements in BRCA1 was assessed in 42 American families with breast and ovarian cancer who were seeking genetic testing and who were subsequently found to be negative for BRCA1 and BRCA2 coding-region mutations. An affected individual from each family was tested by PCR for the exon 13 duplication (Puget et al. 1999a) and by Southern blot analysis for novel genomic rearrangements. The exon 13 duplication was detected in one family, and four families had other genomic rearrangements. A total of 5 (11.9%) of the 42 families with breast/ovarian cancer who did not have BRCA1 and BRCA2 coding-region mutations had mutations in BRCA1 that were missed by conformation-sensitive gel electrophoresis or sequencing. Four of five families with BRCA1 genomic rearrangements included at least one individual with both breast and ovarian cancer; therefore, 4 (30.8%) of 13 families with a case of multiple primary breast and ovarian cancer had a genomic rearrangement in BRCA1. Families with genomic rearrangements had prior probabilities of having a BRCA1 mutation, ranging from 33% to 97% (mean 70%) (Couch et al. 1997). In contrast, in families without rearrangements, prior probabilities of having a BRCA1 mutation ranged from 7% to 92% (mean 37%). Thus, the prior probability of detecting a BRCA1 mutation may be a useful predictor when considering the use of Southern blot analysis for families with breast/ovarian cancer who do not have detectable coding-region mutations

Serious adverse events in patients with idiopathic pulmonary fibrosis in the placebo arms of 6 clinical trials

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a fatal interstitial lung disease characterized by irreversible loss of lung function and an unpredictable course of disease progression. METHODS: The safety data for patients with IPF who received placebo in 6 clinical trials were pooled to examine the categories and frequencies of serious adverse events (SAEs) in this population. RESULTS: In 1082 patients with IPF who received placebo, 673 SAEs were reported. Of these, 93 SAEs resulted in death (8.6% of patients). Respiratory-related conditions were the most frequently reported SAE (225 events, 16.33 per 100 patient-exposure years [PEY]), followed by infections and infestations (136 events, 9.87 per 100 PEY) and cardiac disorders (79 events, 5.73 per 100 PEY); these categories also had the most fatal outcomes (60, 10, and 10 deaths, respectively). The most frequently reported fatal respiratory-related SAEs were IPF and respiratory failure (38 and 11 patients, respectively), and the most frequently reported fatal infections and infestations and cardiac disorders were pneumonia (5 patients) and myocardial infarction (3 patients), respectively. CONCLUSIONS: This pooled analysis has value as a comparator for safety in future studies of IPF and provides insights in the natural evolution of both IPF and common comorbidities.status: publishe

An Open-Label, Phase II Study of the Safety of Pirfenidone in Patients with Idiopathic Pulmonary Fibrosis (PIPF-002)

<p></p><p><b>Article full text</b></p> <p><br></p> <p>The full text of this article can be found here<b>.</b> <a href="https://link.springer.com/article/10.1007/s41030-018-0053-y">https://link.springer.com/article/10.1007/s41030-018-0053-y</a></p><p></p><p></p><p> </p><p><br></p> <p><b>Provide enhanced content for this article</b></p> <p><br></p> <p>If you are an author of this publication and would like to provide additional enhanced content for your article then please contact <a href="http://www.medengine.com/Redeem/”mailto:[email protected]”"><b>[email protected]</b></a>.</p> <p><br></p> <p>The journal offers a range of additional features designed to increase visibility and readership. All features will be thoroughly peer reviewed to ensure the content is of the highest scientific standard and all features are marked as ‘peer reviewed’ to ensure readers are aware that the content has been reviewed to the same level as the articles they are being presented alongside. Moreover, all sponsorship and disclosure information is included to provide complete transparency and adherence to good publication practices. This ensures that however the content is reached the reader has a full understanding of its origin. No fees are charged for hosting additional open access content.</p> <p><br></p> <p>Other enhanced features include, but are not limited to:</p> <p><br></p> <p>• Slide decks</p> <p>• Videos and animations</p> <p>• Audio abstracts</p> <p>• Audio slides</p><br><p></p

Long-term evaluation of the safety and efficacy of recombinant human pentraxin-2 (rhPTX-2) in patients with idiopathic pulmonary fibrosis (IPF): an open-label extension study

Background: Recombinant human pentraxin-2 (rhPTX-2) significantly decreased decline in percent predicted forced vital capacity (FVC) and stabilized 6-min walk distance (6MWD) in patients with idiopathic pulmonary fibrosis (IPF) during the 28-week, placebo-controlled, randomized period of the Phase II PRM-151–202 study. Interim (76-week) data from the open-label extension (OLE) demonstrated sustained safety and efficacy with rhPTX-2 treatment. Here, we present the entire long-term OLE safety and efficacy data to 128 weeks. Methods: Patients who completed the randomized PRM-151–202 study period were eligible for the OLE, during which all patients received rhPTX-2, having started rhPTX-2 (i.e., crossed from placebo) or continued rhPTX-2 after Week 28. rhPTX-2 was administered in 28-week cycles, with 10 mg/kg intravenous infusions (60 min) on Days 1, 3, and 5 in the first week of each cycle, then one infusion every 4 weeks up to Week 128. The OLE primary objective was to assess the long-term safety and tolerability of rhPTX-2. Other outcomes included FVC, 6MWD, and patient-reported outcomes (descriptive analysis). Results: All 111 patients who completed the randomized period entered the OLE (n = 37 started rhPTX-2; n = 74 continued rhPTX-2); 57 (51.4%) completed to Week 128. The treatment-emergent adverse event (TEAE) profile was consistent with the randomized period, with the majority of TEAEs graded mild or moderate. Serious TEAEs occurred in 47 patients (42.3%), most frequently IPF (n = 11; 9.9%), pneumonia (n = 7; 6.3%), and acute respiratory failure (n = 3; 2.7%). Three patients underwent lung transplantation. Most serious TEAEs (and all 14 fatal events) were considered unrelated to rhPTX-2 treatment. For patients starting vs continuing rhPTX-2, mean (95% confidence interval) changes from baseline to Week 128 were, respectively, − 6.2% (− 7.7; − 4.6) and − 5.7% (− 8.0; − 3.3) for percent predicted FVC and − 36.3 m (− 65.8; − 6.9) and − 28.9 m (− 54.3; − 3.6) for 6MWD; however, conclusions were limited by patient numbers at Week 128. Conclusions: Long-term treatment (up to 128 weeks) with rhPTX-2 was well tolerated in patients with IPF, with no new safety signals emerging in the OLE. The limited efficacy data over 128 weeks may suggest a trend towards a treatment effect. Trial registration NCT02550873; EudraCT 2014-004782-24

Effect of Recombinant Human Pentraxin 2 vs Placebo on Change in Forced Vital Capacity in Patients With Idiopathic Pulmonary Fibrosis: A Randomized Clinical Trial

IMPORTANCE: Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic lung disease with poor prognosis. Approved therapies do not halt disease progression. OBJECTIVE: To determine the effect of recombinant human pentraxin 2 vs placebo on change from baseline to week 28 in mean forced vital capacity (FVC) percentage of predicted value. DESIGN, SETTING, AND PARTICIPANTS: Phase 2, randomized, double-blind, placebo-controlled trial conducted at 18 sites in 7 countries of eligible patients with IPF (N\u2009=\u2009117; aged 40-80 years; FVC 6550% and 6490% predicted; ratio of forced expiratory volume in the first second/FVC >0.70; diffusing capacity for carbon monoxide [Dlco] 6525% and 6490% predicted; and distance of 65150 m on the 6-minute walk test). Study period was August 2015-May 2017. INTERVENTIONS: Patients were randomized to receive either recombinant human pentraxin 2 (10 mg/kg intravenous every 4 weeks, n\u2009=\u200977) or placebo (n\u2009=\u200939) for 24 weeks, and stratified by concurrent IPF treatment status. MAIN OUTCOMES AND MEASURES: The primary end point was the least-squares mean change in FVC percentage of predicted value from baseline to week 28 (minimal clinically important difference, decline of 2%-6%). Secondary end points included mean change in lung volumes (total, normal, and interstitial lung abnormalities) on high-resolution computed tomography (HRCT) and 6-minute walk distance (minimal clinically important difference, 24-45 m). RESULTS: Of 117 randomized patients, 116 received at least 1 dose of study drug (mean age, 68.6 years; 81.0% men; mean time since IPF diagnosis, 3.8 years), and 111 (95.7%) completed the study. The least-squares mean change in FVC percentage of predicted value from baseline to week 28 in patients treated with recombinant human pentraxin 2 was -2.5 vs -4.8 for those in the placebo group (difference, +2.3 [90% CI, 1.1 to 3.5]; P\u2009=\u2009.001). No significant treatment differences were observed in total lung volume (difference, 93.5 mL [90% CI, -27.7 to 214.7]), quantitative parenchymal features on HRCT (normal lung volume difference, -1.2% [90% CI, -4.4 to 1.9]; interstitial lung abnormalities difference, 1.1% [90% CI, -2.2 to 4.3]), or measurement of Dlco (difference, -0.4 [90% CI, -2.6 to 1.7]). The change in 6-minute walk distance was -0.5 m for patients treated with recombinant human pentraxin 2 vs -31.8 m for those in the placebo group (difference, +31.3 m [90% CI, 17.4 to 45.1]; P < .001). The most common adverse events in the recombinant human pentraxin 2 vs placebo group were cough (18% vs 5%), fatigue (17% vs 10%), and nasopharyngitis (16% vs 23%). CONCLUSIONS AND RELEVANCE: In this preliminary study, recombinant human pentraxin 2 vs placebo resulted in a slower decline in lung function over 28 weeks for patients with idiopathic pulmonary fibrosis. Further research should more fully assess efficacy and safety. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT02550873