The recent identification of a candidate very massive 70 M(Sun) black hole is at odds with our current understanding of stellar winds and pair-instability supernovae. We investigate alternate ...explanations for this system by searching the BPASS v2.2 stellar and population synthesis models for those that match the observed properties of the system. We find binary evolution models that match the LB-1 system, at the reported Gaia distance, with more moderate black hole masses of 4 to 7 M(Sun). We also examine the suggestion that the binary motion may have led to an incorrect distance determination by Gaia. We find that the Gaia distance is accurate and that the binary system is consistent with the observation at this distance. Consequently it is highly improbable that the black hole in this system has the extreme mass originally suggested. Instead, it is more likely to be representative of the typical black hole binary population expected in our Galaxy.
ABSTRACT
DW Cnc is an intermediate polar which has previously been observed in both high and low states. Observations of the high state of DW Cnc have previously revealed a spin period at ∼38.6 min, ...however, observations from the 2018 to 2019 low state showed no evidence of the spin period. We present results from our analysis of 12 s cadence photometric data collected by Next Generation Transit Survey of DW Cnc during the high state which began in 2019. Following the previously reported suppression of the spin period signal, we identify the return of this signal during the high state, consistent with previous observations of it. We identify this as the restarting of accretion during the high state. We further identified three short outbursts lasting ∼1 d in DW Cnc with a mean recurrence time of ∼60 d and an amplitude of ∼1 mag. These are the first outbursts identified in DW Cnc since 2008. Due to the short nature of these events, we identify them not as a result of accretion instabilities but instead either from instabilities originating from the interaction of the magnetorotational instability in the accretion disc and the magnetic field generated by the white dwarf or the result of magnetic gating.
Background
Although kinase inhibitors (KIs) are generally effective, their use has a large impact on the current health care budget. Dosing strategies to reduce treatment costs are warranted. ...Boosting pharmacokinetic exposure of KIs metabolized by cytochrome P450 (CYP)3A4 with ritonavir might result in lower doses needed and subsequently reduces treatment costs. This study is a proof-of-concept study to evaluate if the dose of erlotinib can be reduced by co-administration with ritonavir.
Methods
In this open-label, cross-over study, we compared the pharmacokinetics of monotherapy erlotinib 150 mg once daily (QD) (control arm) with erlotinib 75 mg QD plus ritonavir 200 mg QD (intervention arm). Complete pharmacokinetic profiles at steady-state were taken up to 24 h after erlotinib intake for both dosing strategies.
Results
Nine patients were evaluable in this study. For the control arm, the systemic exposure over 24 h, maximum plasma concentration and minimal plasma concentration of erlotinib were 29.3 μg*h/mL (coefficient of variation (CV):58%), 1.84 μg/mL (CV:60%) and 1.00 μg/mL (CV:62%), respectively, compared with 28.9 μg*h/mL (CV:116%,
p
= 0.545), 1.68 μg/mL (CV:68%,
p
= 0.500) and 1.06 μg/mL (CV:165%,
p
= 0.150) for the intervention arm. Exposure to the metabolites of erlotinib (OSI-413 and OSI-420) was statistically significant lower following erlotinib plus ritonavir dosing. Similar results regarding safety in both dosing strategies were observed, no grade 3 or higher adverse event was reported.
Conclusions
Pharmacokinetic exposure at a dose of 75 mg erlotinib when combined with the strong CYP3A4 inhibitor ritonavir is similar to 150 mg erlotinib. Ritonavir-boosting is a promising strategy to reduce erlotinib treatment costs and provides a rationale for other expensive therapies metabolized by CYP3A4.
Several inflammatory markers have gained interest as prognostic factors for cancer. The aim of this study is to evaluate the inflammatory markers interleukin-6 (IL-6), C-reactive protein (CRP), ...neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) as predictive markers for aggressive behavior and early recurrences in primary, localized soft tissue sarcoma (STS).
115 STS patients were retrospectively reviewed. IL-6 and CRP blood levels, NLR and PLR were obtained prior to treatment. Early recurrence was defined as disease relapse (local or distant) within the first year after surgery. Cox regression analysis was used to identify prognostic factors for early recurrence.
IL-6 elevation was associated with a higher tumor grade, increased size, tumor necrosis and a higher mitotic count. NLR elevation was associated with a higher tumor grade, PLR elevation with a larger tumor size. Early recurrences were found in 24 patients (21 %). Univariable analysis revealed that tumor grade (p = 0.029), tumor size (p = 0.030, >10 cm vs < 5 cm), tumor depth (p = 0.036), necrosis on imaging (p = 0.008), mitotic count (p = 0.045, ≥20 mitoses vs 0–9 mitoses), and IL-6 level (p = 0.044) were associated with early recurrence. The factors age at diagnosis, tumor location, necrosis at pathology, (neo)adjuvant radio- or chemotherapy, resection margin, CRP level, NLR and PLR were not related to early disease recurrence.
Increased inflammatory markers in STS are associated with an aggressive phenotype. STS patients with elevation of IL-6 may be at risk for early disease recurrence.
For a nationwide real-word data study on the application of predictive mutation testing of patients with colorectal cancer (CRC) for anti-epidermal growth factor receptor (EGFR) therapy ...stratification, pathology data were collected from the Dutch Pathology Registry from October 2017 until June 2019 (N=4060) and linked with the Netherlands Cancer Registry. Mutation testing rates increased from 24% at diagnosis of stage IV disease to 60% after 20–23 months of follow-up (p<0.001). Application of anti-EGFR therapy in KRAS/NRAS wild-type patients was mainly observed from the third treatment line onwards (65% vs 17% in first/second treatment line (p<0.001)). The national average KRAS/NRAS/BRAF mutation rate was 63.9%, being similar for next-generation sequencing (NGS)-based approaches and single gene tests (64.4% vs 61.2%, p=ns). NGS-based approaches detected more additional potential biomarkers, for example, ERBB2 amplifications (p<0.05). Therefore, single gene tests are suitable to stratify patients with mCRC for anti-EGFR therapy, but NGS is superior enabling upfront identification of therapy resistance or facilitate enrolment into clinical trials.
The INT/WFC Photometric H... Survey of the Northern Galactic Plane (IPHAS) is a 1800 deg... imaging survey covering Galactic latitudes |b| < 5... and longitudes ... = 30...-215... in the r, i, and Hα ...filters using the Wide Field Camera (WFC) on the 2.5-m Isaac Newton Telescope (INT) in La Palma. We present the first quality-controlled and globally calibrated source catalogue derived from the survey, providing single-epoch photometry for 219 million unique sources across 92 per cent of the footprint. The observations were carried out between 2003 and 2012 at a median seeing of 1.1 arcsec (sampled at 0.33 arcsec pixel...) and to a mean 5... depth of 21.2 (r), 20.0 (i), and 20.3 (Hα) in the Vega magnitude system. We explain the data reduction and quality control procedures, describe and test the global re-calibration, and detail the construction of the new catalogue. We show that the new calibration is accurate to 0.03 mag (root mean square) and recommend a series of quality criteria to select accurate data from the catalogue. Finally, we demonstrate the ability of the catalogue's unique (r - Hα,...r - i) diagram to (i) characterize stellar populations and extinction regimes towards different Galactic sightlines and (ii) select and quantify Hα emission-line objects. IPHAS is the first survey to offer comprehensive CCD photometry of point sources across the Galactic plane at visible wavelengths, providing the much-needed counterpart to recent infrared surveys. (ProQuest: ... denotes formulae/symbols omitted.)
the study aims to evaluate whether high plasma trough levels of the kinase inhibitors (K.I.s) crizotinib, alectinib, osimertinib, dabrafenib, and trametinib were associated with a higher risk of ...toxicity in non-small-cell lung cancer patients.
In this retrospective cohort study, patients with non-small-cell lung cancer treated with the selected K.I.s were included if at least one plasma trough level at steady state (C min,ss ) was available. Data were extracted from electronic medical records and laboratory databases. The high group for each K.I. was defined as 10% of patients with the highest first C min,ss . The remaining patients were placed in the non-high group. The frequency of dose-limiting toxicities (DLTs), defined as adverse events leading to dose reduction, dose interruption, or permanent discontinuation, was compared between the 2 groups.
A total of 542 patients were included in the different K.I. groups. A high C min,ss of crizotinib (n = 96), alectinib (n = 105), osimertinib (n = 227), dabrafenib (n = 52), and trametinib (n = 62) correlated with a C min,ss ≥490, ≥870, ≥405, ≥150, and ≥25 ng/mL, respectively. DLTs were more common in the alectinib high group than in the alectinib non-high group (64% vs. 29%, P = 0.036). Liver toxicity was observed in 4 (36%) patients in the high group and 5 (5%) patients in the non-high group ( P = 0.007). For other K.I.s, no significant differences were observed in the frequency of DLTs between the high and non-high groups.
For alectinib, high C min,ss was correlated with a higher risk of DLT. No differences in the frequency of DLTs were observed between the high and non-high groups for crizotinib, osimertinib, dabrafenib, and trametinib.
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The anti-cancer drug pazopanib hydrochloride (PZH) has a very low aqueous solubility and a variable oral bioavailability. A new pharmaceutical formulation with an improved solubility ...may enhance the bioavailability and reduce the variability. A broad selection of polymer excipients was tested for their compatibility and solubilizing properties by conventional microscopic, thermal and spectrometric techniques. A wet milling and mixing technique was used to produce homogenous powder mixtures. The dissolution properties of the formulation were tested by a pH-switch dissolution model. The final formulation was tested in vivo in cancer patient following a dose escalation design. Of the tested mixture formulations, the one containing the co-block polymer Soluplus® in a 8:1 ratio with PZH performed best in terms of in vitro dissolution properties. The in vivo results indicated that 300 mg of the developed formulation yields similar exposure and a lower variability (379 μg/mL∗h (36.7% CV)) than previously reported values for the standard PZH formulation (Votrient®) at the approved dose of 800 mg. Furthermore, the expected plasma-Cthrough levels (27.2 μg/mL) exceeds the defined therapeutic efficacy threshold of 20 μg/mL.
Pazopanib is a multi-targeted anticancer tyrosine kinase inhibitor. This study was conducted to develop a population pharmacokinetic (popPK) model describing the complex pharmacokinetics of pazopanib ...in cancer patients.
Pharmacokinetic data were available from 96 patients from three clinical studies. A multi-compartment model including (i) a complex absorption profile, (ii) the potential non-linear dose-concentration relationship and (iii) the potential long-term decrease in exposure was developed.
A two-compartment model best described pazopanib pharmacokinetics. The absorption phase was modelled by two first-order processes: 36 % (relative standard error RSE 34 %) of the administered dose was absorbed with a relatively fast rate (0.4 h
RSE 31 %); after a lag time of 1.0 h (RSE 6 %), the remaining dose was absorbed at a slower rate (0.1 h
RSE 28 %). The relative bioavailability (rF) at a dose of 200 mg was fixed to 1. With an increasing dose, the rF was strongly reduced, which was modelled with an E
(maximum effect) model (E
was fixed to 1, the dose at half of maximum effect was estimated as 480 mg RSE 23 %). Interestingly, the plasma exposure to pazopanib also decreased over time, modelled on rF with a maximum magnitude of 50 % (RSE 27 %) and a first-order decay constant of 0.15 day
(RSE 43 %). The inter-patient and intra-patient variability on rF were estimated as 36 % (RSE 16 %) and 75 % (RSE 22 %), respectively.
A popPK model for pazopanib was developed that illustrated the complex absorption process, the non-linear dose-concentration relationship, the high inter-patient and intra-patient variability, and the first-order decay of pazopanib concentration over time. The developed popPK model can be used in clinical practice to screen covariates and guide therapeutic drug monitoring.
Mutations in KRAS result in a constitutively activated MAPK pathway. In KRAS-mutant tumours existing treatment options, e.g. MEK inhibition, have limited efficacy due to resistance through feedback ...activation of epidermal growth factor receptors (HER).
In this Phase 1 study, the pan-HER inhibitor dacomitinib was combined with the MEK1/2 inhibitor PD-0325901 in patients with KRAS-mutant colorectal, pancreatic and non-small-cell lung cancer (NSCLC). Patients received escalating oral doses of once daily dacomitinib and twice daily PD-0325901 to determine the recommended Phase 2 dose (RP2D). (Clinicaltrials.gov: NCT02039336).
Eight out of 41 evaluable patients (27 colorectal cancer, 11 NSCLC and 3 pancreatic cancer) among 8 dose levels experienced dose-limiting toxicities. The RP2D with continuous dacomitinib dosing was 15 mg of dacomitinib plus 6 mg of PD-0325901 (21 days on/7 days off), but major toxicity, including rash (85%), diarrhoea (88%) and nausea (63%), precluded long-term treatment. Therefore, other intermittent schedules were explored, which only slightly improved toxicity. Tumour regression was seen in eight patients with the longest treatment duration (median 102 days) in NSCLC.
Although preliminary signs of antitumour activity in NSCLC were seen, we do not recommend further exploration of this combination in KRAS-mutant patients due to its negative safety profile.
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