Despite the completion of numerous phase II studies, a standard of care treatment has yet to be defined for metastatic uveal melanoma (mUM). To determine benchmarks of progression free survival (PFS) ...and overall survival (OS), we carried out a meta-analysis using individual patient level trial data.
Individual patient variables and survival outcomes were requested from 29 trials published from 2000 to 2016. Univariable and multivariable analysis were carried out for prognostic factors. The variability between trial arms and between therapeutic agents on PFS and OS was investigated.
OS data were available for 912 patients. The median PFS was 3.3months (95% CI 2.9–3.6) and 6-month PFS rate was 27% (95% CI 24–30). Univariable analysis showed male sex, elevated (i.e. > versus ≤ upper limit of normal) lactate dehydrogenase (LDH), elevated alkaline phosphatase (ALP) and diameter of the largest liver metastasis (≥3cm versus <3cm) to be substantially associated with shorter PFS. Multivariable analysis showed male sex, elevated LDH and elevated ALP were substantially associated with shorter PFS. The most substantial factors associated with 6-month PFS rate, on both univariable and multivariable analysis were elevated LDH and ALP. The median OS was 10.2months (95% CI 9.5–11.0) and 1year OS was 43% (95% CI 40–47). The most substantial prognostic factors for shorter OS by univariable and multivariable analysis were elevated LDH and elevated ALP. Patients treated with liver directed treatments had statistically significant longer PFS and OS.
Benchmarks of 6-month PFS and 1-year OS rates were determined accounting for prognostic factors. These may be used to facilitate future trial design and stratification in mUM.
Lymph node density (LND) has previously been reported to reliably predict recurrence risk and survival in oral cavity squamous cell carcinoma (OSCC). This multicenter international study was designed ...to validate the concept of LND in OSCC.
The study included 4254 patients diagnosed as having OSCC. The median follow-up was 41 months. Five-year overall survival (OS), disease-specific survival (DSS), disease-free survival (DFS), locoregional control and distant metastasis rates were calculated using the Kaplan-Meier method. Lymph node density (number of positive lymph nodes/total number of excised lymph nodes) was subjected to multivariate analysis.
The OS was 49% for patients with LND0.07 compared with 35% for patients with LND>0.07 (P<0.001). Similarly, the DSS was 60% for patients with LND0.07 compared with 41% for those with LND>0.07 (P<0.001). Lymph node density reliably stratified patients according to their risk of failure within the individual N subgroups (P=0.03). A modified TNM staging system based on LND ratio was consistently superior to the traditional system in estimating survival measures.
This multi-institutional study validates the reliability and applicability of LND as a predictor of outcomes in OSCC. Lymph node density can potentially assist in identifying patients with poor outcomes and therefore for whom more aggressive adjuvant treatment is needed.
Highlights • Effect of explicitly different cognitive tasks on dual-task walking was assessed. • Prioritization of cognitive task is altered with the type of cognitive task. • Walking speed has an ...impact on cognitive task performance while dual-task walking. • Slow walking decreases cognitive cost of dual-task walking.
Immunotherapy induces durable responses in a subset of patients with cancer. High tumor mutational burden (TMB) may be a response biomarker for PD-1/PD-L1 blockade in tumors such as melanoma and ...non-small cell lung cancer (NSCLC). Our aim was to examine the relationship between TMB and outcome in diverse cancers treated with various immunotherapies. We reviewed data on 1,638 patients who had undergone comprehensive genomic profiling and had TMB assessment. Immunotherapy-treated patients (
= 151) were analyzed for response rate (RR), progression-free survival (PFS), and overall survival (OS). Higher TMB was independently associated with better outcome parameters (multivariable analysis). The RR for patients with high (≥20 mutations/mb) versus low to intermediate TMB was 22/38 (58%) versus 23/113 (20%;
= 0.0001); median PFS, 12.8 months vs. 3.3 months (
≤ 0.0001); median OS, not reached versus 16.3 months (
= 0.0036). Results were similar when anti-PD-1/PD-L1 monotherapy was analyzed (
= 102 patients), with a linear correlation between higher TMB and favorable outcome parameters; the median TMB for responders versus nonresponders treated with anti-PD-1/PD-L1 monotherapy was 18.0 versus 5.0 mutations/mb (
< 0.0001). Interestingly, anti-CTLA4/anti-PD-1/PD-L1 combinations versus anti-PD-1/PD-L1 monotherapy was selected as a factor independent of TMB for predicting better RR (77% vs. 21%;
= 0.004) and PFS (
= 0.024). Higher TMB predicts favorable outcome to PD-1/PD-L1 blockade across diverse tumors. Benefit from dual checkpoint blockade did not show a similarly strong dependence on TMB.
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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the etiologic agent for the 2019 coronavirus disease (COVID-19) pandemic, has caused a public health emergency. The need for additional ...research in viral pathogenesis is essential as the number of cases and deaths rise. Understanding the virus and its ability to cause disease has been the main focus of current literature; however, there is much unknown. Studies have revealed new findings related to the full transmission potential of SARS-CoV-2 and its subsequent ability to cause infection by different means. The virus is hypothesized to be of increased virulence compared with previous coronavirus that caused epidemics, in part due to its overall structural integrity and resilience to inactivation. To date, many studies have discussed that the rationale behind its transmission potential is that viral RNA has unexpectedly been detected in multiple bodily fluids, with some samples having remained positive for extended periods of time. Additionally, the receptor by which the virus gains cellular entry, ACE2, has been found to be expressed in different human body systems, thereby potentiating its infection in those locations. In this evidence-based comprehensive review, we discuss various potential routes of transmission of SARS-CoV-2—respiratory/droplet, indirect, fecal-oral, vertical, sexual, and ocular. Understanding these different routes is important as they pertain to clinical practice, especially in taking preventative measures to mitigate the spread of SARS-CoV-2.
The maintenance of cardiovascular homeostasis is highly dependent on tightly controlled interactions between the heart and the kidneys. Therefore, it is not surprising that a dysfunction in one organ ...affects the other. This interlinking relationship is aptly demonstrated in the cardiorenal syndrome. The characteristics of the cardiorenal syndrome state include alterations in neurohumoral drive, autonomic reflexes, and fluid balance. The evidence suggests that several factors contribute to these alterations. These may include peripheral and central nervous system abnormalities. However, accumulating evidence from animals with experimental models of congestive heart failure and renal dysfunction as well as humans with the cardiorenal syndrome suggests that alterations in neural pathways, from and to the kidneys and the heart, including the central nervous system are involved in regulating sympathetic outflow and may be critically important in the alterations in neurohumoral drive, autonomic reflexes, and fluid balance commonly observed in the cardiorenal syndrome. This review focuses on studies implicating neural pathways, particularly the afferent and efferent signals from the heart and the kidneys integrating at the level of the paraventricular nucleus in the hypothalamus to alter neurohumoral drive, autonomic pathways, and fluid balance. Further, it explores the potential mechanisms of action for the known beneficial use of various medications or potential novel therapeutic manipulations for the treatment of the cardiorenal syndrome. A comprehensive understanding of these mechanisms will enhance our ability to treat cardiorenal conditions and their cardiovascular complications more efficaciously and thoroughly.
Tin-doped antimony selenide ((Sn
x
Sb
1
-
x
)
2
Se
3
) crystals were grown by direct vapour transport to overcome the challenges posed by the high intrinsic electrical resistivity of Sb
2
Se
3
. ...Energy dispersive analysis of x-ray and scanning electron microscopy were performed to determine elemental chemical composition and morphology of the grown crystals. The powder x-ray diffraction spectra revealed that the (Sn
x
Sb
1
-
x
)
2
Se
3
crystals possess an orthorhombic crystal lattice structure. Furthermore, all microstructural parameters were evaluated. The Raman spectra of the grown crystals revealed the structure of Sb
2
Se
3
to be unaltered during Sn doping. The value of the optical band gap of (Sn
x
Sb
1
-
x
)
2
Se
3
crystals decreased from 1.20 eV to 0.97 eV as the doping concentration of Sn increased from x = 0.00, 0.10, 0.15, 0.20. Moreover, the decomposition kinetic parameters were evaluated using several kinetic models. The electrical, trap-depth and photoresponse parameters were studied in different samples with variations of temperature and illumination intensity. The exceptional performance of the (Sn
x
Sb
1
-
x
)
2
Se
3
crystals suggests that they hold promising potential for applications in highly efficient photoelectric and solar devices.
This paper examines the different channels through which academic researchers interact with industry and the factors that influence the researchers’ engagement in a variety of interactions. This ...study is based on a large scale survey of UK academic researchers. The results show that university researchers interact with industry using a wide variety of channels, and engage more frequently in the majority of the channels examined – such as
consultancy & contract research, joint research, or training – as compared to patenting or spin-out activities. In explaining the variety and frequency of interactions, we find that individual characteristics of researchers have a stronger impact than the characteristics of their departments or universities. Finally, we argue that by paying greater attention to the broad range of knowledge transfer mechanisms (in addition to patenting and spin-outs), policy initiatives could contribute to building the researchers’ skills necessary to integrate the worlds of scientific research and application.
Recent genomic studies have identified novel recurrent somatic mutations in patients with myeloid malignancies, including myeloproliferative neoplasms (MPNs), myelodysplastic syndrome (MDS) and acute ...myeloid leukaemia (AML). In some cases these mutations occur in genes with known roles in regulating chromatin and/or methylation states in haematopoietic progenitors, and in other cases genetic and functional studies have elucidated a role for specific mutations in altering epigenetic patterning in myeloid malignancies. In this Review we discuss recent genetic and functional data implicating mutations in epigenetic modifiers, including tet methylcytosine dioxygenase 2 (TET2), isocitrate dehydrogenase 1 (IDH1), IDH2, additional sex combs-like 1 (ASXL1), enhancer of zeste homologue 2 (EZH2) and DNA methyltransferase 3A (DNMT3A), in the pathogenesis of MPN, MDS and AML, and discuss how this knowledge is leading to novel clinical, biological and therapeutic insights.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
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