Cell-free DNA analysis in current cancer clinical trials: a review.

Cell-free DNA (cfDNA) analysis represents a promising method for the diagnosis, treatment selection and clinical follow-up of cancer patients. Although its general methodological feasibility and usefulness has been demonstrated, several issues related to standardisation and technical validation must be addressed for its routine clinical application in cancer. In this regard, most cfDNA clinical applications are still limited to clinical trials, proving its value in several settings. In this paper, we review the current clinical trials involving cfDNA/ctDNA analysis and highlight those where it has been useful for patient stratification, treatment follow-up or development of novel approaches for early diagnosis. Our query included clinical trials, including the terms 'cfDNA', 'ctDNA', 'liquid biopsy' AND 'cancer OR neoplasm' in the FDA and EMA public databases. We identified 1370 clinical trials (FDA = 1129, EMA = 241) involving liquid-biopsy analysis in cancer. These clinical trials show promising results for the early detection of cancer and confirm cfDNA as a tool for real-time monitoring of acquired therapy resistance, accurate disease-progression surveillance and improvement of treatment, situations that result in a better quality of life and extended overall survival for cancer patients.

Efficacy and safety of the Janus kinase 1 inhibitor PF-04965842 in patients with moderate-to-severe psoriasis: phase II, randomized, double-blind, placebo-controlled study.

BACKGROUND: PF-04965842 is an oral Janus kinase 1 inhibitor being investigated for the treatment of plaque psoriasis. OBJECTIVES: To evaluate the efficacy, safety and tolerability of PF-04965842 in patients with moderate-to-severe plaque psoriasis. METHODS: Patients in this phase II, placebo-controlled study (NCT02201524) were randomized to receive placebo, 200 mg once daily (OD), 400 mg OD or 200 mg twice daily (TD) PF-04965842 for 4 weeks. The primary endpoint was change from baseline in Psoriasis Area Severity Index (PASI) at week 4. Study enrolment was discontinued on 25 June 2015 due to changes in the sponsor's development priorities. RESULTS: Fifty-nine patients were randomized and received at least one dose of PF-04965842 or placebo. The estimated treatment effect (active -placebo PASI change from baseline) and 90% confidence interval at week 4 was -5·1 (-9·2 to -1·0), -5·6 (-9·6 to -1·6) and -10·0 (-14·2 to -5·8) for the 200 mg OD, 400 mg OD and 200 mg TD groups, respectively. At week 4, the proportion of patients achieving PASI 75 was 17% for the placebo and 200 mg OD groups, 50% for the 400 mg OD group and 60% for the 200 mg TD group. There were more abnormal laboratory test results of clinical interest (low neutrophil, reticulocyte and platelet counts) in the 200 mg TD group compared with the OD treatment groups. No serious infections or bleeding events related to neutropenia or thrombocytopenia, respectively, were reported. CONCLUSIONS: These results suggest that treatment with PF-04965842 improves symptoms and is well tolerated in patients with moderate-to-severe psoriasis.

Higher incidence of HCV in females compared to males who inject drugs: A systematic review and meta-analysis.

Women who inject drugs have been shown to have higher incidence of HIV and risk behaviours than men, but there are conflicting reports about hepatitis C virus (HCV) incidence. We systematically reviewed the literature to examine the female-to-male (F:M) HCV incidence in female and male persons who inject drugs (PWID), and also to explore the heterogeneity (i.e. methodological diversity) in these differences. We searched PubMed and EMBASE for studies published between 1989 and March 2015 for research that reported incidence of HCV infection by sex or HCV incidence F:M rate ratio. A total of 28 studies, which enrolled 9325 PWID, were included. The overall pooled HCV incidence rate (per 100 person-years observation) was 20.36 (95% CI: 13.86, 29.90) and 15.20 (95% CI: 10.52, 21.97) in females and males, respectively. F:M ratio was 1.36:1 (95% CI: 1.13, 1.64) with substantial heterogeneity (I-squared=71.6%). The F:M ratio varied by geographic location from 4.0 (95% CI: 1.80, 8.89) in China to 1.17 (95% CI: 0.95, 1.43) in the U.S. In studies which recruited participants from community settings, the F:M ratio was 1.24 (95% CI: 1.03, 1.48), which was lower than that reported in the clinical settings (1.72, 95% CI: 0.86, 3.45). The number of studies included provided sufficient statistical power to detect sex differences in this analysis. Our findings raise questions and concerns regarding sex differences with respect to the risk of HCV. Both behavioural and biological studies are needed to investigate causes and potential mechanisms as well as sex-specific prevention approaches to HCV infection.

Analysis of resistance-associated substitutions in acute hepatitis C virus infection by deep sequencing across six genotypes and three continents.

Several direct-acting antivirals (DAAs) have been approved for the treatment of chronic hepatitis C virus (HCV) infections, opening the door to highly effective interferon-free treatment regimens. Resistance-associated substitutions (RASs) have been reported both in treatment-naïve patients and following treatment with protease (NS3), phosphoprotein (NS5A) and polymerase (NS5B) inhibitors. The prevalence of naturally occurring RASs in untreated HCV-infected individuals has mostly been analysed in those infected with genotype 1 (GT1), in the late phase of infection, and only within limited regions of the genome. Furthermore, the geographic distribution of RASs remains poorly characterized. In this study, we used next-generation sequencing to analyse full-length HCV genomes for the prevalence of RASs in acute HCV infections identified in nine international prospective cohorts. RASs were analysed in 179 participants infected with all six major HCV genotypes (GT1-GT6), and the geographic distribution of RASs was assessed in 107 GT1a and GT3a samples. While RASs were detected at varied frequencies across the three genomic regions, and between genotypes, RASs relevant to multiple DAAs in the leading IFN-free regimens were rarely detected in combination. Low-frequency RASs (<10% of the viral population) were also shown to have a GT-specific distribution. The main RASs with geographic associations were NS3 Q80K in GT1a samples and NS5B N142T in GT3a. These data provide the backdrop for prospective surveillance of RASs during DAA treatment scale-up.

Phylogenetic analysis of full-length, early infection, hepatitis C virus genomes among people with intravenous drug use: the InC3 Study.

Cross-continental phylogenetic analysis is important to understand subtle molecular differences of currently circulating hepatitis C virus (HCV) subtypes. Existence of such differences can be crucial in pursuing a universal hepatitis C vaccine. We characterized molecular epidemiology of early HCV infections identified across nine cohorts [North America (n=4), Australia (n=4) and Europe (n=1)] in the International Collaborative of Incident HIV and Hepatitis C in Injecting Cohorts (InC3 ). One hundred and ninety-two full-length HCV genomes were amplified from plasma of incident infections and subjected to next generation sequencing to establish the largest cross-continental, full-length acute HCV genomic data set available to date. Genomes from the most common subtypes (1a: n=94, 2b: n=15 and 3a: n=68) were used in phylogenetic analysis. Using full genome trees, 78 sequences (44%) were found to lie within 29 phylogenetic clusters/pairs defined on the basis of molecular similarity of consensus sequences. Of these, 26 each had exclusively Australian or North American sequences indicating a strong geographical bias for molecular similarity. On further analysis of behavioural and demographic associations, binary logistic regression analysis showed that older age and non-Caucasian ethnicity were significantly associated with clustering. HCV probably evolves in micro-epidemics within geographically isolated communities.

The unusual γ-ray burst GRB 101225A from a helium star/neutron star merger at redshift 0.33.

Long γ-ray bursts (GRBs) are the most dramatic examples of massive stellar deaths, often associated with supernovae. They release ultra-relativistic jets, which produce non-thermal emission through synchrotron radiation as they interact with the surrounding medium. Here we report observations of the unusual GRB 101225A. Its γ-ray emission was exceptionally long-lived and was followed by a bright X-ray transient with a hot thermal component and an unusual optical counterpart. During the first 10 days, the optical emission evolved as an expanding, cooling black body, after which an additional component, consistent with a faint supernova, emerged. We estimate its redshift to be z = 0.33 by fitting the spectral-energy distribution and light curve of the optical emission with a GRB-supernova template. Deep optical observations may have revealed a faint, unresolved host galaxy. Our proposed progenitor is a merger of a helium star with a neutron star that underwent a common envelope phase, expelling its hydrogen envelope. The resulting explosion created a GRB-like jet which became thermalized by interacting with the dense, previously ejected material, thus creating the observed black body, until finally the emission from the supernova dominated. An alternative explanation is a minor body falling onto a neutron star in the Galaxy.

Relativistic jet activity from the tidal disruption of a star by a massive black hole.

Supermassive black holes have powerful gravitational fields with strong gradients that can destroy stars that get too close, producing a bright flare in ultraviolet and X-ray spectral regions from stellar debris that forms an accretion disk around the black hole. The aftermath of this process may have been seen several times over the past two decades in the form of sparsely sampled, slowly fading emission from distant galaxies, but the onset of the stellar disruption event has not hitherto been observed. Here we report observations of a bright X-ray flare from the extragalactic transient Swift J164449.3+573451. This source increased in brightness in the X-ray band by a factor of at least 10,000 since 1990 and by a factor of at least 100 since early 2010. We conclude that we have captured the onset of relativistic jet activity from a supermassive black hole. A companion paper comes to similar conclusions on the basis of radio observations. This event is probably due to the tidal disruption of a star falling into a supermassive black hole, but the detailed behaviour differs from current theoretical models of such events.

Public health clinic-based hepatitis C testing and linkage to care in Baltimore.

Testing and linkage to care are important determinants of hepatitis C virus (HCV) treatment effectiveness. Public health clinics serve populations at high risk of HCV. We investigated their potential to serve as sites for HCV testing, initiation of and linkage to HCV care. Cross-sectional study of patients accessing sexually transmitted infection (STI) care at the Baltimore City Health Department (BCHD) STI clinics, from June 2013 through April 2014 was conducted. Logistic regression was used to assess factors associated with HCV infection and specialist linkage to care. Between 24 June 2013 and 15 April 2014, 2681 patients were screened for HCV infection. Overall, 189 (7%) were anti-HCV positive, of whom 185 (98%) received follow-up HCV RNA testing, with 155 (84%) testing RNA positive. Of 155 RNA-positive individuals, 138 (89%) returned to the STI clinic for HCV RNA results and initial HCV care including counselling regarding transmission and harm reduction in alcohol, and 132 (85%) were referred to a specialist for HCV care. With provision of patient navigation services, 81 (52%) attended an offsite HCV specialist appointment. Alcohol use and lack of insurance coverage were associated with lower rates of specialist linkage (OR 0.4 [95% CI 0.1-0.9] and OR 0.4 [95% CI 0.1-0.9], respectively). We identified a high prevalence of HCV infection in BCHD STI clinics. With availability of patient navigation services, a large proportion of HCV-infected patients linked to off-site specialist care.

Long-term immune and virological response in HIV-infected patients receiving antiretroviral therapy.

WHAT IS KNOWN AND OBJECTIVE: The trajectory of HIV viral load and CD4 count and the occurrence of clinical events are primary considerations in the evaluation of antiretroviral therapy (ART) success or failure, yet a large number of studies do not describe these events from the point of therapy initiation. This study aims to describe the virological and immune response to ART and factors associated with immune and virological success in outpatients from a HIV/AIDS clinic in southern Brazil from therapy initiation. METHODS: Longitudinal observational with ambidirectional data collection study with adult patients followed for at least 12 months after enrolment. Outcomes include (i) favourable immune response, defined as CD4 count ≥200 cells/mm³; and (ii) virological success, defined as viral load below the limit of detection (50 copies/mL). RESULTS: The study included 332 patients, mostly men (63%), whose mean age was 40 (±10) years and with median family income of BR$ 490·00 per month (IQR: 350-875). Before starting ART, 43% of patients had indications of stable immune status (CD4 count ≥200 cells/mm³); the median CD4 count was 179 cells/mm³ (IQR: 93·5, 267) and increased to 379·5 cells/mm³ (IQR: 236·5, 591·3). The proportion of patients with CD4 count ≥200 cells/mm³ increased from 76% to 83%, and with undetectable viral load (UVL) increased from 51·7% to 73%. Factors associated with immune success at the end of study follow-up were as follows: female gender, pretreatment CD4 count ≥200 cells/mm³, previous UVL (measured when started prospective follow-up) and treatment with three drugs compared with ≥4. Factors associated with virological success were as follows: UVL (measured when started prospective follow-up) and use of three drugs compared with ≥4. WHAT IS NEW AND CONCLUSIONS: Results of this study show that a large proportion (73%) of patients have rapid and successful immune and virological responses to ART and that factors which predict this response include starting ART early, whereas viral load is low and CD4 count is high, with fewer drugs. These results further support the ongoing need for ongoing programmes to increase early HIV testing, early linkage to and treatment with ART, and increased viral suppression.

High proportion of extrapulmonary tuberculosis in a low prevalence setting: a retrospective cohort study.

OBJECTIVES: The proportion of extrapulmonary tuberculosis (EPTB) cases in the United States (US) has been rising due to a slower rate of decline in EPTB compared to pulmonary tuberculosis (PTB). The purpose of this study was to characterise the clinical and treatment differences between EPTB and PTB patients, and identify patient factors associated with EPTB. STUDY DESIGN: We performed a retrospective cohort study of active tuberculosis (TB) cases treated at the Baltimore City Health Department between 2008 and 2013. METHODS: We categorised patients as having 'only PTB' (infection in the lung parenchyma), 'EPTB/PTB' (infection in the lung and an additional site), and 'only EPTB' (infection not involving the lung). Pearson's chi-squared tests were used to evaluate categorical variables and compare clinical and demographic differences between only PTB, only EPTB, and EPTB/PTB patients. Student t-tests and one-way analysis of variance tests were utilised to assess continuous variables and to compare treatment differences. RESULTS: One hundred and sixty-three patients were treated for TB; 39.3% had some form of EPTB (either EPTB/PTB or only EPTB). There was no difference found between EPTB, PTB, and EPTB/PTB patients with respect to HIV status, gender, race, foreign-born status, or mean age. Patients with only EPTB were less likely than patients with some form of PTB (only PTB or EPTB/PTB) to present with cough (30.4% vs 61.5%; P < 0.001), night sweats (10.9% vs 39.3%; P < 0.001), and weight loss (28.3% vs 47.9%; P = 0.023). Patients with some form of EPTB were also more likely to be hospitalised postdiagnosis compared to patients with only PTB (39.1% vs 20.2%; P = 0.009), and to have longer mean durations of treatment (37.9 weeks [SD = 11.1] vs 31.8 weeks [SD = 8.1]; P < 0.001). CONCLUSIONS: EPTB patients present with atypical symptoms, undergo prolonged treatment, and experience increased hospitalisations. In order to improve diagnostic algorithms and treatment modalities, EPTB must be further characterised.

Perception of Mattering and Suicide Ideation in the Australian Working Population: Evidence from a Cross-Sectional Survey.

Thoughts about suicide are a risk factor for suicide deaths and attempts and are associated with a range of mental health outcomes. While there is considerable knowledge about risk factors for suicide ideation, there is little known about protective factors. The current study sought to understand the role of perceived mattering to others as a protective factor for suicide in a working sample of Australians using a cross-sectional research design. Logistic regression analysis indicated that people with a higher perception that they mattered had lower odds of suicide ideation than those with lower reported mattering, after controlling for psychological distress, demographic and relationship variables. These results indicate the importance of further research and intervention studies on mattering as a lever for reducing suicidality. Understanding more about protective factors for suicide ideation is important as this may prevent future adverse mental health and behavioural outcomes.

Factors associated with hepatitis C virus RNA levels in early chronic infection: the InC3 study.

Improved understanding of natural history of hepatitis C virus (HCV) RNA levels in chronic infection provides enhanced insights into immunopathogenesis of HCV and has implications for the clinical management of chronic HCV infection. This study assessed factors associated with HCV RNA levels during early chronic infection in a population with well-defined early chronic HCV infection. Data were from an international collaboration of nine prospective cohorts studying acute HCV infection (InC(3) study). Individuals with persistent HCV and detectable HCV RNA during early chronic infection (one year [±4 months] postinfection) were included. Distribution of HCV RNA levels during early chronic infection was compared by selected host and virological factors. A total of 308 individuals were included. Median HCV RNA levels were significantly higher among males (vs females; 5.15 vs 4.74 log IU/mL; P < 0.01) and among individuals with HIV co-infection (vs no HIV; 5.89 vs 4.86; P = 0.02). In adjusted logistic regression, male sex (vs female, adjusted odds ratio [AOR]: 1.93; 95%CI: 1.01, 3.69), interferon lambda 4 (IFNL4) rs12979860 CC genotype (vs TT/CT; AOR: 2.48; 95%CI: 1.42, 4.35), HIV co-infection (vs no HIV; AOR: 3.27; 95%CI: 1.35, 7.93) and HCV genotype G2 (vs G3; AOR: 5.40; 95%CI: 1.63, 17.84) were independently associated with high HCV RNA levels (>5.6 log IU/mL = 400 000 IU/mL). In conclusion, this study demonstrated that IFNL4 rs12979860 CC genotype, male sex, HIV co-infection and HCV genotype G2 are associated with high HCV RNA levels in early chronic infection. These factors exert their role as early as one year following infection.

Response to treatment following recently acquired hepatitis C virus infection in a multicentre collaborative cohort.

Pegylated interferon therapy is highly effective in recently acquired HCV. The optimal timing of treatment, regimen and influence of host factors remains unclear. We aimed to measure sustained virological response (SVR) during recent HCV infection and identify predictors of response. Data were from five prospective cohorts of high-risk individuals in Australia, Canada, Germany and the United States. Individuals with acute or early chronic HCV who commenced pegylated interferon therapy were included. The main outcome was SVR, and predictors were assessed using logistic regression. Among 516 with documented recent HCV infection, 237 were treated (pegylated interferon n = 161; pegylated interferon/ribavirin n = 76) (30% female, median age 35 years, 56% ever injected drugs, median duration of infection 6.2 months). Sixteen per cent (n = 38) were HIV/HCV co-infected. SVR among those with HCV mono-infection was 64% by intention to treat; SVR was 68% among HCV/HIV co-infection. Independent predictors of SVR in HCV mono-infection were duration of HCV infection (the odds of SVR declined by 8% per month of infection, aOR 0.92, 95% CI 0.85-0.99, P = 0.033), IFNL4 genotype (adjusted OR 2.27, 95% CI 1.13-4.56, P = 0.021), baseline HCV RNA <400 000 IU/mL (aOR 2.06, 95% CI 1.03-4.12, P = 0.041) and age ≥40 years (vs <30: aOR 2.92, 95% CI 1.31-6.49, P = 0.009), with no difference by drug regimen, HCV genotype, symptomatic infection or gender. The effect of infection duration on odds of SVR was greater among genotype-1 infection. Interferon-based HCV treatment is highly effective in recent HCV infection. Duration of infection, IFNL4 genotype and baseline HCV RNA levels can predict virological response and may inform clinical decision-making.

A gamma-ray burst at a redshift of z approximately 8.2.

Long-duration gamma-ray bursts (GRBs) are thought to result from the explosions of certain massive stars, and some are bright enough that they should be observable out to redshifts of z > 20 using current technology. Hitherto, the highest redshift measured for any object was z = 6.96, for a Lyman-alpha emitting galaxy. Here we report that GRB 090423 lies at a redshift of z approximately 8.2, implying that massive stars were being produced and dying as GRBs approximately 630 Myr after the Big Bang. The burst also pinpoints the location of its host galaxy.

NEOCENT: a randomised feasibility and translational study comparing neoadjuvant endocrine therapy with chemotherapy in ER-rich postmenopausal primary breast cancer.

Neoadjuvant endocrine therapy is an alternative to chemotherapy for women with oestrogen receptor (ER)-positive early breast cancer (BC). We aimed to assess feasibility of recruiting patients to a study comparing chemotherapy versus endocrine therapy in postmenopausal women with ER-rich primary BC, and response as well as translational endpoints were assessed. Patients requiring neoadjuvant therapy were randomised to chemotherapy: 6 × 3-weekly cycles FE100C or endocrine therapy: letrozole 2.5 mg, daily for 18-23 weeks. Primary endpoints were recruitment feasibility and tissue collection. Secondary endpoints included clinical, radiological and pathological response rates, quality of life and translational endpoints. 63/80 patients approached were eligible, of those 44 (70, 95% CI 57-81) were randomised. 12 (54.5, 95% CI 32.2-75.6) chemotherapy patients showed radiological objective response compared with 13 (59.1, 95% CI 36.4-79.3) letrozole patients. Compared with baseline, mean Ki-67 levels fell in both groups at days 2-4 and at surgery [fold change: 0.24 (95% CI 0.12-0.51) and 0.24; (95% CI 0.15-0.37), respectively]. Plasma total cfDNA levels rose from baseline to week 8 [fold change: chemotherapy 2.10 (95% CI 1.47-3.00), letrozole 1.47(95% CI 0.98-2.20)], and were maintained at surgery in the chemotherapy group [chemotherapy 2.63; 95% CI 1.56-4.41), letrozole 0.95 (95% CI 0.71-1.26)]. An increase in plasma let-7a miRNA was seen at surgery for patients with objective radiological response to chemotherapy. Recruitment and tissue collection endpoints were met; however, a larger trial was deemed unfeasible due to slow accrual. Both regimens were equally efficacious. Dynamic changes were seen in Ki-67 and circulating biomarkers in both groups with increases in cfDNA and let-7a miRNA persisting until surgery for chemotherapy patients.

Evidence for topologically protected surface states and a superconducting phase in [Tl4](Tl(1-x)Sn(x))Te3 using photoemission, specific heat, and magnetization measurements, and density functional theory.

We report the discovery of surface states in the perovskite superconductor [Tl4]TlTe3 (Tl5Te3) and its nonsuperconducting tin-doped derivative [Tl4](Tl0.4Sn0.6)Te3 as observed by angle-resolved photoemission spectroscopy. Density functional theory calculations predict that the surface states are protected by a Z2 topology of the bulk band structure. Specific heat and magnetization measurements show that Tl5Te3 has a superconducting volume fraction in excess of 95%. Thus Tl5Te3 is an ideal material in which to study the interplay of bulk band topology and superconductivity.

Broadband observations of the naked-eye gamma-ray burst GRB 080319B.

Long-duration gamma-ray bursts (GRBs) release copious amounts of energy across the entire electromagnetic spectrum, and so provide a window into the process of black hole formation from the collapse of massive stars. Previous early optical observations of even the most exceptional GRBs (990123 and 030329) lacked both the temporal resolution to probe the optical flash in detail and the accuracy needed to trace the transition from the prompt emission within the outflow to external shocks caused by interaction with the progenitor environment. Here we report observations of the extraordinarily bright prompt optical and gamma-ray emission of GRB 080319B that provide diagnostics within seconds of its formation, followed by broadband observations of the afterglow decay that continued for weeks. We show that the prompt emission stems from a single physical region, implying an extremely relativistic outflow that propagates within the narrow inner core of a two-component jet.

An extremely luminous X-ray outburst at the birth of a supernova.

Massive stars end their short lives in spectacular explosions--supernovae--that synthesize new elements and drive galaxy evolution. Historically, supernovae were discovered mainly through their 'delayed' optical light (some days after the burst of neutrinos that marks the actual event), preventing observations in the first moments following the explosion. As a result, the progenitors of some supernovae and the events leading up to their violent demise remain intensely debated. Here we report the serendipitous discovery of a supernova at the time of the explosion, marked by an extremely luminous X-ray outburst. We attribute the outburst to the 'break-out' of the supernova shock wave from the progenitor star, and show that the inferred rate of such events agrees with that of all core-collapse supernovae. We predict that future wide-field X-ray surveys will catch each year hundreds of supernovae in the act of exploding.