Randomized phase III KEYNOTE-045 trial of pembrolizumab versus paclitaxel, docetaxel, or vinflunine in recurrent advanced urothelial cancer: results of >2 years of follow-up.

BackgroundNovel second-line treatments are needed for patients with advanced urothelial cancer (UC). Interim analysis of the phase III KEYNOTE-045 study showed a superior overall survival (OS) benefit of pembrolizumab, a programmed death 1 inhibitor, versus chemotherapy in patients with advanced UC that progressed on platinum-based chemotherapy. Here we report the long-term safety and efficacy outcomes of KEYNOTE-045.Patients and methodsAdult patients with histologically/cytologically confirmed UC whose disease progressed after first-line, platinum-containing chemotherapy were enrolled. Patients were randomly assigned 1 : 1 to receive pembrolizumab [200 mg every 3 weeks (Q3W)] or investigator's choice of paclitaxel (175 mg/m2 Q3W), docetaxel (75 mg/m2 Q3W), or vinflunine (320 mg/m2 Q3W). Primary end points were OS and progression-free survival (PFS) per Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST v1.1) by blinded independent central radiology review (BICR). A key secondary end point was objective response rate per RECIST v1.1 by BICR.ResultsA total of 542 patients were enrolled (pembrolizumab, n = 270; chemotherapy, n = 272). Median follow-up as of 26 October 2017 was 27.7 months. Median 1- and 2-year OS rates were higher with pembrolizumab (44.2% and 26.9%, respectively) than chemotherapy (29.8% and 14.3%, respectively). PFS rates did not differ between treatment arms; however, 1- and 2-year PFS rates were higher with pembrolizumab. The objective response rate was also higher with pembrolizumab (21.1% versus 11.0%). Median duration of response to pembrolizumab was not reached (range 1.6+ to 30.0+ months) versus chemotherapy (4.4 months; range 1.4+ to 29.9+ months). Pembrolizumab had lower rates of any grade (62.0% versus 90.6%) and grade ≥3 (16.5% versus 50.2%) treatment-related adverse events than chemotherapy.ConclusionsLong-term results (>2 years' follow-up) were consistent with those of previously reported analyses, demonstrating continued clinical benefit of pembrolizumab over chemotherapy for efficacy and safety for treatment of locally advanced/metastatic, platinum-refractory UC.Trial registrationClinicalTrials.gov: NCT02256436

The connection between superconducting phase correlations and spin excitations in YBa2_2Cu3_3O6.6_{6.6}: A magnetic field study

One of the most striking universal properties of the high-transition-temperature (high-$T_c$) superconductors is that they are all derived from the hole-doping of their insulating antiferromagnetic (AF) parent compounds. From the outset, the intimate relationship between magnetism and superconductivity in these copper-oxides has intrigued researchers. Evidence for this link comes from neutron scattering experiments that show the unambiguous presence of short-range AF correlations (excitations) in cuprate superconductors. Even so, the role of such excitations in the pairing mechanism and superconductivity is still a subject of controversy. For YBa$_2$Cu$_3$O$_{6+x}$, where $x$ controls the hole-doping level, the most prominent feature in the magnetic excitations spectra is the ``resonance''. Here we show that for underdoped YBa$_2$Cu$_3$O$_{6.6}$, where $x$ and $T_c$ are below the optimal values, modest magnetic fields suppress the resonance significantly, much more so for fields approximately perpendicular rather than parallel to the CuO$_2$ planes. Our results indicate that the resonance measures pairing and phase coherence, suggesting that magnetism plays an important role in the superconductivity of cuprates. The persistence of a field effect above $T_c$ favors mechanisms with preformed pairs in the normal state of underdoped cuprates.Comment: 12 pages, 4 figures, Nature (in press

Fission yeast Pcp1 links polo kinase-mediated mitotic entry to γ-tubulin-dependent spindle formation

The centrosomal pericentrin-related proteins play pivotal roles in various aspects of cell division; however their underlying mechanisms remain largely elusive. Here we show that fission-yeast pericentrin-like Pcp1 regulates multiple functions of the spindle pole body (SPB) through recruiting two critical factors, the γ-tubulin complex (γ-TuC) and polo kinase (Plo1). We isolated two pcp1 mutants (pcp1-15 and pcp1-18) that display similar abnormal spindles, but with remarkably different molecular defects. Both mutants exhibit defective monopolar spindle microtubules that emanate from the mother SPB. However, while pcp1-15 fails to localise the γ-TuC to the mitotic SPB, pcp1-18 is specifically defective in recruiting Plo1. Consistently Pcp1 forms a complex with both γ-TuC and Plo1 in the cell. pcp1-18 is further defective in the mitotic-specific reorganisation of the nuclear envelope (NE), leading to impairment of SPB insertion into the NE. Moreover pcp1-18, but not pcp1-15, is rescued by overproducing nuclear pore components or advancing mitotic onset. The central role for Pcp1 in orchestrating these processes provides mechanistic insight into how the centrosome regulates multiple cellular pathways

Cmr1/WDR76 defines a nuclear genotoxic stress body linking genome integrity and protein quality control

DNA replication stress is a source of genomic instability. Here we identify ​changed mutation rate 1 (​Cmr1) as a factor involved in the response to DNA replication stress in Saccharomyces cerevisiae and show that ​Cmr1—together with ​Mrc1/​Claspin, ​Pph3, the chaperonin containing ​TCP1 (CCT) and 25 other proteins—define a novel intranuclear quality control compartment (INQ) that sequesters misfolded, ubiquitylated and sumoylated proteins in response to genotoxic stress. The diversity of proteins that localize to INQ indicates that other biological processes such as cell cycle progression, chromatin and mitotic spindle organization may also be regulated through INQ. Similar to ​Cmr1, its human orthologue ​WDR76 responds to proteasome inhibition and DNA damage by relocalizing to nuclear foci and physically associating with CCT, suggesting an evolutionarily conserved biological function. We propose that ​Cmr1/​WDR76 plays a role in the recovery from genotoxic stress through regulation of the turnover of sumoylated and phosphorylated proteins

Successful Outcomes with Oral Fluoroquinolones Combined with Rifampicin in the Treatment of Mycobacterium ulcerans: An Observational Cohort Study

Buruli ulcer is a necrotizing infection of skin and subcutaneous tissue caused by Mycobacterium ulcerans and is the third most common mycobacterial disease worldwide (after tuberculosis and leprosy). In recent years its treatment has radically changed, evolving from a predominantly surgically to a predominantly medically treated disease. The World Health Organization now recommends combined streptomycin and rifampicin antibiotic treatment as first-line therapy for Mycobacterium ulcerans infections. However, alternatives are needed where recommended antibiotics are not tolerated or accepted by patients, contraindicated, or not accessible nor affordable. This study describes the use of antibiotics, including oral fluoroquinolones, in the treatment of Mycobacterium ulcerans in south-eastern Australia. It demonstrates that antibiotics combined with surgery are highly effective in the treatment of Mycobacterium ulcerans. In addition, oral fluoroquinolone-containing antibiotic combinations are shown to be as effective and well tolerated as other recommended antibiotic combinations. Fluoroquinolone antibiotics therefore offer the potential to provide an alternative oral antibiotic to be combined with rifampicin for Mycobacterium ulcerans treatment, allowing more accessible and acceptable, less toxic, and less expensive treatment regimens to be available, especially in resource-limited settings where the disease burden is greatest

Impact of the "Tobacco control law" on exposure to environmental tobacco smoke in Spain

<p>Abstract</p> <p>Background</p> <p>The initial evaluations of the introduction of legislation that regulates smoking in enclosed public places in European countries, describe an important effect in the control of exposure to environmental tobacco smoke. However, the evidence is still limited. The objective of this study is to estimate the short-term effects of the comprehensive "Tobacco control law" introduced in Spain on January 2006, which includes a total ban of smoking in workplaces and a partial limitation of smoking in bars and restaurants.</p> <p>Methods</p> <p>Cross-sectional, population-based study. The self-reported exposure to environmental tobacco smoke at home, at work, in bars and restaurants of the population aged 18 to 64 years in the Madrid Region during a period prior to the law (October and November 2005; n = 1750) was compared to that of the period immediately after the law came into force (January-July 2006; n = 1252). Adjusted odds ratios (OR) were calculated using logistic regression models.</p> <p>Results</p> <p>Passive exposure to tobacco smoke at home has hardly changed. However, at indoor workplaces there has been a considerable reduction: after the law came into force the OR for daily exposure > 0–3 hours versus non-exposure was 0.11 (95% CI: 0.07 to 0.17) and for more than 3 hours, 0.12 (95% CI: 0.09 to 0.18). For fairly high exposure in bars and restaurants versus non-exposure, the OR in the former was 0.30 (95% CI: 0.20 to 0.44) and in the latter was 0.24 (95% CI: 0.18 to 0.32); for very high exposure versus non-exposure they were 0.16 (95% CI: 0.10 to 0.24) and 0.11 (95% CI: 0.07 to 0.19), respectively. These results were similar for the smoking and non-smoking populations.</p> <p>Conclusion</p> <p>A considerable reduction in exposure to environmental tobacco smoke in the workplace and, to a lesser extent, in bars and restaurants, is related to the implementation of the "Tobacco control law". Although only initial figures, these results already demonstrate the effectiveness of strategies that establish control measures to guarantee smoke-free places.</p

Management of Lung Nodules and Lung Cancer Screening During the COVID-19 Pandemic: CHEST Expert Panel Report

Background: The risks from potential exposure to coronavirus disease 2019 (COVID-19), and resource reallocation that has occurred to combat the pandemic, have altered the balance of benefits and harms that informed current (pre-COVID-19) guideline recommendations for lung cancer screening and lung nodule evaluation. Consensus statements were developed to guide clinicians managing lung cancer screening programs and patients with lung nodules during the COVID-19 pandemic. / Methods: An expert panel of 24 members, including pulmonologists (n = 17), thoracic radiologists (n = 5), and thoracic surgeons (n = 2), was formed. The panel was provided with an overview of current evidence, summarized by recent guidelines related to lung cancer screening and lung nodule evaluation. The panel was convened by video teleconference to discuss and then vote on statements related to 12 common clinical scenarios. A predefined threshold of 70% of panel members voting agree or strongly agree was used to determine if there was a consensus for each statement. Items that may influence decisions were listed as notes to be considered for each scenario. / Results: Twelve statements related to baseline and annual lung cancer screening (n = 2), surveillance of a previously detected lung nodule (n = 5), evaluation of intermediate and high-risk lung nodules (n = 4), and management of clinical stage I non–small-cell lung cancer (n = 1) were developed and modified. All 12 statements were confirmed as consensus statements according to the voting results. The consensus statements provide guidance about situations in which it was believed to be appropriate to delay screening, defer surveillance imaging of lung nodules, and minimize nonurgent interventions during the evaluation of lung nodules and stage I non–small-cell lung cancer. / Conclusions: There was consensus that during the COVID-19 pandemic, it is appropriate to defer enrollment in lung cancer screening and modify the evaluation of lung nodules due to the added risks from potential exposure and the need for resource reallocation. There are multiple local, regional, and patient-related factors that should be considered when applying these statements to individual patient care

Dynamics of Lamin-A Processing Following Precursor Accumulation

Lamin A (LaA) is a component of the nuclear lamina, an intermediate filament meshwork that underlies the inner nuclear membrane (INM) of the nuclear envelope (NE). Newly synthesized prelamin A (PreA) undergoes extensive processing involving C-terminal farnesylation followed by proteolysis yielding non-farnesylated mature lamin A. Different inhibitors of these processing events are currently used therapeutically. Hutchinson-Gilford Progeria Syndrome (HGPS) is most commonly caused by mutations leading to an accumulation of a farnesylated LaA isoform, prompting a clinical trial using farnesyltransferase inhibitors (FTI) to reduce this modification. At therapeutic levels, HIV protease inhibitors (PI) can unexpectedly inhibit the final processing step in PreA maturation. We have examined the dynamics of LaA processing and associated cellular effects during PI or FTI treatment and following inhibitor washout. While PI reversibility was rapid, with respect to both LaA maturation and associated cellular phenotype, recovery from FTI treatment was more gradual. FTI reversibility is influenced by both cell type and rate of proliferation. These results suggest a less static lamin network than has previously been observed

A retrospective analysis of clinical outcome of patients with chemo-refractory metastatic breast cancer treated in a single institution phase I unit

BACKGROUND AND METHODS: Novel approaches to treat chemo-refractory metastatic breast cancer (MBC) are currently under investigation. This retrospective series reviews the outcome of 70 MBC patients who have participated in 30 phase I trials at the Royal Marsden Hospital from 2002 to 2009. RESULTS: The median treatment lines before phase I trial entry for MBC was 5 (range: 1-12 lines). The overall response rate was 11.4% (95% CI: 4.0-18.9%) and the clinical benefit rate at 4 months was 20% (95% CI: 10.6-29.3). The median time to progression was 7.0 weeks (95% CI: 6.4-7.5) and median overall survival was 8.7 months (95% CI: 7.6-9.8) from start of first phase I treatment. No patients discontinued trial because of treatment-related toxicities. Abnormal lactate dehydrogenase, serum albumin <35 mg per 100 ml, >or=5 previous treatment lines, liver metastases and Eastern Cooperative Group performance status >or=2 at study entry were significantly associated with poor overall survival in multivariate analysis. CONCLUSION: This retrospective analysis provides evidence that patients with MBC tolerate phase I clinical trials and a significant proportion of patients with chemo-refractory disease, particularly those with triple-negative or Her2-positive breast cancer, may benefit from treatment