Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Ramucirumab plus docetaxel versus placebo plus docetaxel in patients with locally advanced or metastatic urothelial carcinoma after platinum-based therapy (RANGE): a randomised, double-blind, phase 3 trial

Few treatments with a distinct mechanism of action are available for patients with platinum-refractory advanced or metastatic urothelial carcinoma. We assessed the efficacy and safety of treatment with docetaxel plus either ramucirumab-a human IgG1 VEGFR-2 antagonist-or placebo in this patient population

Adenocarcinoma of the lung: an exploration of the relationships between histopathology, molecular pathology and inflammatory markers and their relationship to patient outcomes

© 2017 Dr. Timothy Dudley ClayLung cancer remains the most common cause of cancer related death worldwide, with nearly 1.4 million deaths in 2008 globally. Adenocarcinoma is the most common type of lung cancer, and its frequency compared to other histologic subtypes is increasing. The simplicity of the label “adenocarcinoma” hides its significant pathologic and clinical heterogeneity. This thesis explores a number of clinicopathologic correlates in lung adenocarcinoma specimens obtained from patients treated at St Vincent’s Hospital in Melbourne, Australia. In 2011 the International Association for the Study of Lung Cancer (IASLC), the American Thoracic Society (ATS) and the European Respiratory Society (ERS) proposed a new classification system for pulmonary adenocarcinoma. This was subsequently adopted in the 2015 edition of the World Health Organisation Classification of Tumours of the Lung, Pleura, Thymus and Heart. Multiple groups demonstrated that the new classification had prognostic significance following resection of pulmonary adenocarcinoma independent of stage. The impact of the classification in metastatic disease was not known. This thesis found that it was possible to identify the adenocarcinoma patterns of solid with mucin, papillary, micropapillary and acinar in each specimen taken from a metastatic site and semi-quantitatively assess each component. Further, the identification of a major pattern was not prognostic, but did predict for differences in survival time for patients treated with systemic therapy. The worst outcomes were observed for patients with tumours with a major solid pattern. The major solid pattern was also found to have infrequent occurrence of activating epidermal growth factor receptor (EGFR) mutations. As this is the first time that this novel finding has been reported. Validation from other groups is required. The presence of the IASLC/ATS/ERS classification as a robust new tool with clinical relevance has led to further research to define other clinicopathologic correlates. Oncogene driver mutations in genes such as EGFR and Kirsten RAS (KRAS) are critical in selection of therapy in advanced disease. This thesis examined relationships between adenocarcinoma subtype and mutation status for patients who had resected lung adenocarcinoma. Patients with solid predominant adenocarcinoma were significantly less likely to have EGFR mutations, while KRAS mutation was a frequent event in invasive mucinous adenocarcinoma. No other significant associations were found. The findings were consistent with those recently reported by other groups from centres located in predominantly Caucasian countries. EGFR inhibition and the discovery of EGFR mutations was the starting point for a major change in the approach to treatment of advanced lung adenocarcinoma, however resistant to treatment occurs. It had been suggested that upregulation of phosphorylated STAT3 (pSTAT3) via interleukin 6 (IL6) and Janus Kinase (JAK) may be linked to EGFR mutation status in the absence of treatment with EGFR tyrosine kinase inhibitors and therefore may offer a rational target to delay resistance to such therapies. In the patient cohort studied the presence of EGFR or KRAS mutation status did not enrich for activation of IL6, JAK1 or pSTAT3 as determined by immunohistochemistry. Further, there was no clinicopathologic or prognostic correlates of note found by the IL6, JAK1 or pSTAT3 activation state. The assessment of IL6, JAK1 and pSTAT3 in the same samples and by two methods to assess positivity was a unique feature of this study. In conclusion this contributes new knowledge on the relevance of pathologic subtyping in advanced lung adenocarcinoma. It confirms and consolidates recent reports oncogene mutation status and adenocarcinoma subtype following surgical resection. It examines the IL6 / JAK1 / pSTAT3 pathway in detail in resected pulmonary adenocarcinoma. Translational research that explores why adenocarcinoma subtypes have different outcomes by treatment may allow clinicians to direct therapies differently or unlock new pathways for targeting lung adenocarcinoma with therapeutic effect

Ramucirumab plus docetaxel versus placebo plus docetaxel in patients with locally advanced or metastatic urothelial carcinoma after platinum-based therapy (RANGE): overall survival and updated results of a randomised, double-blind, phase 3 trial

Background: Ramucirumab—an IgG1 vascular endothelial growth factor receptor 2 antagonist—plus docetaxel was previously reported to improve progression-free survival in platinum-refractory, advanced urothelial carcinoma. Here, we report the secondary endpoint of overall survival results for the RANGE trial. Methods: We did a randomised, double-blind, phase 3 trial in patients with advanced or metastatic urothelial carcinoma who progressed during or after platinum-based chemotherapy. Patients were enrolled from 124 investigative sites (hospitals, clinics, and academic centres) in 23 countries. Previous treatment with one immune checkpoint inhibitor was permitted. Patients were randomly assigned (1:1) using an interactive web response system to receive intravenous ramucirumab 10 mg/kg or placebo 10 mg/kg volume equivalent followed by intravenous docetaxel 75 mg/m2 (60 mg/m2 in Korea, Taiwan, and Japan) on day 1 of a 21-day cycle. Treatment continued until disease progression, unacceptable toxicity, or other discontinuation criteria were met. Randomisation was stratified by geographical region, Eastern Cooperative Oncology Group performance status at baseline, and visceral metastasis. Progression-free survival (the primary endpoint) and overall survival (a key secondary endpoint) were assessed in the intention-to-treat population. The study is registered with ClinicalTrials.gov, NCT02426125; patient enrolment is complete and the last patient on treatment is being followed up for safety issues. Findings: Between July 20, 2015, and April 4, 2017, 530 patients were randomly allocated to ramucirumab plus docetaxel (n=263) or placebo plus docetaxel (n=267) and comprised the intention-to-treat population. At database lock (March 21, 2018) for the final overall survival analysis, median follow-up was 7·4 months (IQR 3·5–13·9). In our sensitivity analysis of investigator-assessed progression-free survival at the overall survival database lock, median progression-free survival remained significantly improved with ramucirumab compared with placebo (4·1 months [95% CI 3·3–4·8] vs 2·8 months [2·6–2·9]; HR 0·696 [95% CI 0·573–0·845]; p=0·0002). Median overall survival was 9·4 months (95% CI 7·9–11·4) in the ramucirumab group versus 7·9 months (7·0–9·3) in the placebo group (stratified HR 0·887 [95% CI 0·724–1·086]; p=0·25). Grade 3 or worse treatment-related treatment-emergent adverse events in 5% or more of patients and with an incidence more than 2% higher with ramucirumab than with placebo were febrile neutropenia (24 [9%] of 258 patients in the ramucirumab group vs 16 [6%] of 265 patients in the placebo group) and neutropenia (17 [7%] of 258 vs six [2%] of 265). Serious adverse events were similar between groups (112 [43%] of 258 patients in the ramucirumab group vs 107 [40%] of 265 patients in the placebo group). Adverse events related to study treatment and leading to death occurred in eight (3%) patients in the ramucirumab group versus five (2%) patients in the placebo group. Interpretation: Additional follow-up supports that ramucirumab plus docetaxel significantly improves progression-free survival, without a significant improvement in overall survival, for patients with platinum-refractory advanced urothelial carcinoma. Clinically meaningful benefit might be restricted in an unselected population. Funding: Eli Lilly and Company