Vestibular schwannomas (VS) account for approximately 85% of tumors in the cerebello-pontine angle, with a lifetime incidence of approximately 1 in 1000. Most are sporadic, with approximately 5% ...related to the tumor predisposition syndrome Neurofibromatosis Type 2 (NF2). The mainstays of management strategies are: observation, surgery, radiosurgery/radiotherapy and, for patients with NF2 and rapidly growing tumors or deteriorating neurologic function the targeted therapy bevacizumab. While morbidity and mortality rates related to treatment of VS have improved dramatically over the last decades, there are still significant improvements that could be made, in particular with regards to long-term facial nerve and hearing outcomes. Areas covered: The epidemiology and diagnosis of VS are discussed, followed by the different management strategies and outcomes of those for both sporadic and NF2 related tumors. An extensive literature review has been performed to inform this review article using PubMed and Google Scholar. Expert commentary: The future direction of VS management lies in obtaining longer-term follow-up data for patients with treated VS, and in improved understanding of cellular pathways and targeted therapies.
The North Atlantic and Europe experienced two extreme climate events in 2015: exceptionally cold ocean surface temperatures and a summer heat wave ranked in the top ten over the past 65 years. Here, ...we show that the cold ocean temperatures were the most extreme in the modern record over much of the mid-high latitude North-East Atlantic. Further, by considering surface heat loss, ocean heat content and wind driven upwelling we explain for the first time the genesis of this cold ocean anomaly. We find that it is primarily due to extreme ocean heat loss driven by atmospheric circulation changes in the preceding two winters combined with the re-emergence of cold ocean water masses. Furthermore, we reveal that a similar cold Atlantic anomaly was also present prior to the most extreme European heat waves since the 1980s indicating that it is a common factor in the development of these events. For the specific case of 2015, we show that the ocean anomaly is linked to a stationary position of the Jet Stream that favours the development of high surface temperatures over Central Europe during the heat wave. Our study calls for an urgent assessment of the impact of ocean drivers on major European summer temperature extremes in order to provide better advance warning measures of these high societal impact events.
Ovarian cancer is the fourth most common cause of cancer‐related death in women in the developed world, and one of the most heritable cancers. One of the most significant risk factors for epithelial ...ovarian cancer (EOC) is a family history of breast and/or ovarian cancer. Combined risk factors can be used in models to stratify risk of EOC, and aid in decisions regarding risk‐reduction strategies. Germline pathogenic variants in EOC susceptibility genes including those involved in homologous recombination and mismatch repair pathways are present in approximately 22% to 25% of EOC. These genes are associated with an estimated lifetime risk of EOC of 13% to 60% for BRCA1 variants and 10% to 25% for BRCA2 variants, with lower risks associated with remaining genes. Genome‐wide association studies have identified single nucleotide polymorphisms (SNPs) thought to explain an additional 6.4% of the familial risk of ovarian cancer, with 34 susceptibility loci identified to date. However, an unknown proportion of the genetic component of EOC risk remains unexplained. This review comprises an overview of individual genes and SNPs suspected to contribute to risk of EOC, and discusses use of a polygenic risk score to predict individual cancer risk more accurately.
Epithelial ovarian cancer (EOC) is one of the most heritable cancers.
Individual gene pathogenic variants are present in 22% to 25% of cases and 6.4% of additional risk is explained by single nucleotide polymorphisms.
A proportion of the genetic risk of EOC remains unexplained.
Issues remain regarding use of polygenic risk scores and how best to advise women concerned about their risk of EOC.
Immune checkpoint inhibitors (ICPI) are a tumor agnostic treatment. However, trials of their use have been site specific. Here we summarize the trial data and explore the utility of programmed ...death-ligand 1 (PD-L1) expression as a biomarker to direct their pan-cancer use.
A systematic review of literature, following PRISMA guidelines, was performed. Medline, Embase, Cochrane CENTRAL, NHS Health and Technology, and Web of Science were searched from their conception to June 2022 limited to the English language. The search terms and method were devised by a specialist medical librarian. Studies were limited to adults with solid cancers (excluding melanomas) treated with ICPIs. Only phase III randomized control trials (RCT) were included. The primary outcome was overall survival and secondary outcomes were progression free survival, PD-L1 expression, quality of life outcomes and adverse event data. Where present in eligible clinical trials, hazard ratios (HR), risk ratios (RR), standard error (SE) and 95% confidence intervals (CI) were extracted or calculated. Heterogeneity across studies was described with the use of an
score (Low: 25, 50%: moderate, 75% low heterogeneity). HR pools inverse variance methods were adopted by Random Effects (RE). Means were standardized across any heterogenous scale limits.
In total 46,510 participants were included in the meta-analysis. Overall, meta-analysis favored the use of ICPIs with an overall survival (OS) HR of 0.74 (95% CI 0.71 to 0.78). Lung cancers showed the most benefit in OS HR 0.72 (95% 0.66-0.78) followed by head and neck cancers HR 0.75 (95% CI 0.66-0.84) and gastroesophageal junction cancers HR 0.75 (95% CI 0.61-0.92). ICPIs seem to be efficacious at both primary presentation and recurrence OS HR 0.73 (95% CI 0.68-0.77) vs. OS HR 0.79 (95% CI 0.72 to 0.87) respectively. Interestingly, subgroup analysis comparing studies in which most cancers demonstrated PD-L1 expression vs. those studies in which a minority of cancer demonstrated PD-L1 expression reported similar effect of ICPI use on OS; oddly the data favored ICPI use in studies with a minority of PD-L1 expression. Specifically, studies with minority PD-L1 expression had an HR 0.73 (95% CI 0.68-0.78) vs. studies with majority PD-L1 expression HR 0.76 (95% CI 0.70-0.84). This was maintained even when studies exploring the same cancer site were directly compared. Subgroup analysis was performed comparing the impact on OS subdivided by the specific ICPI used. Where meta-analysis was performed, Nivolumab led to the greatest impact HR 0.70 (95% CI 0.64-0.77) with Avelumab failing to reach significance HR 0.93 (95% CI 0.80-1.06). However, overall heterogenicity was high (
= 95%). Finally, the use of ICPIs led to an improved side effect profile when compared with standard chemotherapy RR 0.85 (95% CI 0.73-0.98).
ICPIs improve survival outcomes in all cancer types. These effects are seen in the primary, recurrent, chemotherapy sensitive, chemotherapy resistant disease. These data support their use as a tumor agnostic therapy. Furthermore, they are well tolerated. However, PD-L1 as a biomarker for the targeting of ICPI use seems problematic. Other biomarkers such as mismatch repair or tumor mutational burden should be explored in randomized trials. In addition, there are still limited trials looking at ICPI use outside of lung cancer.
Abstract
Introduction
Vestibular schwannomas (VS) are histologically benign tumors arising from cranial nerve VIII. Far from a homogenous proliferation of Schwann cells, mounting evidence has ...highlighted the complex nature of the inflammatory microenvironment in these tumors.
Methods
A review of the literature pertaining to inflammation, inflammatory molecular pathways, and immune-related therapeutic targets in VS was performed. Relevant studies published up to June 2020 were identified based on a literature search in the PubMed and MEDLINE databases and the findings were synthesized into a concise narrative review of the topic.
Results
The VS microenvironment is characterized by a dense infiltrate of inflammatory cells, particularly macrophages. Significantly higher levels of immune cell infiltration are observed in growing versus static tumors, and there is a demonstrable interplay between inflammation and angiogenesis in growing VS. While further mechanistic studies are required to ascertain the exact role of inflammation in angiogenesis, tumor growth, and Schwann cell control, we are beginning to understand the key molecular pathways driving this inflammatory microenvironment, and how these processes can be monitored and targeted in vivo
.
Conclusion
Observational research has revealed a complex and heterogeneous tumor microenvironment in VS. The functional landscape and roles of macrophages and other immune cells in the VS inflammatory infiltrate are, however, yet to be established. The antiangiogenic drug bevacizumab has shown the efficacy of targeted molecular therapies in VS and there is hope that agents targeting another major component of the VS microenvironment, inflammation, will also find a place in their future management.
Smith-Magenis syndrome is associated with a microdeletion of the short arm of chromosome 17 with phenotypic abnormalities including dysmorphic facies, self-injurious behavior, mental and neurologic ...disturbances, and congenital cardiac defects. The majority of patients present in mid-childhood or adulthood. We describe a fetus in which the diagnosis of Smith-Magenis syndrome was made at 16 weeks of gestation following amniocentesis for increased risk for Down syndrome detected by second-trimester maternal serum screening. Ultrasound evaluation revealed multiple fetal anomalies. The pregnancy was terminated at 20 weeks of gestation. Post-mortem findings included dysmorphic facial features, tetralogy of Fallot, a thymic duct remnant, pancreatic islet cell hyperplasia, and abnormal lung fissuring. This represents the second case of prenatally diagnosed Smith-Magenis syndrome. Molecular genetic techniques in the diagnosis of the Smith-Magenis syndrome and other small deletions are becoming an important tool in the genetic evaluation of ultrasound abnormalities.
Gaia Data Release 2 Evans, D. W.; Riello, M.; De Angeli, F. ...
Astronomy and astrophysics (Berlin),
08/2018, Volume:
616
Journal Article
Peer reviewed
Open access
Aims.
We describe the photometric content of the second data release of the
Gaia
project (
Gaia
DR2) and its validation along with the quality of the data.
Methods.
The validation was mainly carried ...out using an internal analysis of the photometry. External comparisons were also made, but were limited by the precision and systematics that may be present in the external catalogues used.
Results.
In addition to the photometric quality assessment, we present the best estimates of the three photometric passbands. Various colour-colour transformations are also derived to enable the users to convert between the
Gaia
and commonly used passbands.
Conclusions.
The internal analysis of the data shows that the photometric calibrations can reach a precision as low as 2 mmag on individual CCD measurements. Other tests show that systematic effects are present in the data at the 10 mmag level.
Panels of single nucleotide polymorphisms (SNPs) stratify risk for breast cancer in women from the general population, but studies are needed assess their use in a fully comprehensive model including ...classical risk factors, mammographic density and more than 100 SNPs associated with breast cancer. A case–control study was designed (1,668 controls, 405 cases) in women aged 47–73 years attending routine screening in Manchester UK, and enrolled in a wider study to assess methods for risk assessment. Risk from classical questionnaire risk factors was assessed using the Tyrer–Cuzick model; mean percentage visual mammographic density was scored by two independent readers. DNA extracted from saliva was genotyped at selected SNPs using the OncoArray. A predefined polygenic risk score based on 143 SNPs was calculated (SNP143). The odds ratio (OR, and 95% confidence interval, CI) per interquartile range (IQ‐OR) of SNP143 was estimated unadjusted and adjusted for Tyrer–Cuzick and breast density. Secondary analysis assessed risk by oestrogen receptor (ER) status. The primary polygenic risk score was well calibrated (O/E OR 1.10, 95% CI 0.86–1.34) and accuracy was retained after adjustment for Tyrer–Cuzick risk and mammographic density (IQ‐OR unadjusted 2.12, 95% CI% 1.75–2.42; adjusted 2.06, 95% CI 1.75–2.42). SNP143 was a risk factor for ER+ and ER− breast cancer (adjusted IQ‐OR, ER+ 2.11, 95% CI 1.78–2.51; ER− 1.81, 95% CI 1.16–2.84). In conclusion, polygenic risk scores based on a large number of SNPs improve risk stratification in combination with classical risk factors and mammographic density, and SNP143 was similarly predictive for ER‐positive and ER‐negative disease.
What's new?
Panels of single nucleotide polymorphisms (SNPs) stratify risk for breast cancer in women from the general population, but studies are needed to assess their use in a fully‐comprehensive model including classical questionnaire risk factors, mammographic density, and more than 100 SNPs associated with breast cancer. In this study, the predictive ability of a predefined panel of 143 SNPs was assessed after adjustment for questionnaire risk factors and mammography density using women from a U.K. cohort. The panel showed substantial improvement in risk stratification in combination with classical risk factors and mammographic density, for both oestrogen receptor‐positive and negative breast cancer.
Gaia Data Release 2 Riello, M.; De Angeli, F.; Evans, D. W. ...
Astronomy and astrophysics (Berlin),
08/2018, Volume:
616
Journal Article
Peer reviewed
Open access
Context.
The second
Gaia
data release is based on 22 months of mission data with an average of 0.9 billion individual CCD observations per day. A data volume of this size and granularity requires a ...robust and reliable but still flexible system to achieve the demanding accuracy and precision constraints that
Gaia
is capable of delivering.
Aims.
We aim to describe the input data, the treatment of blue photometer/red photometer (BP/RP) low-resolution spectra required to produce the integrated
G
BP
and
G
RP
fluxes, the process used to establish the internal
Gaia
photometric system, and finally, the generation of the mean source photometry from the calibrated epoch data for
Gaia
DR2.
Methods.
The internal
Gaia
photometric system was initialised using an iterative process that is solely based on
Gaia
data. A set of calibrations was derived for the entire
Gaia
DR2 baseline and then used to produce the final mean source photometry. The photometric catalogue contains 2.5 billion sources comprised of three different grades depending on the availability of colour information and the procedure used to calibrate them: 1.5 billion gold, 144 million silver, and 0.9 billion bronze. These figures reflect the results of the photometric processing; the content of the data release will be different due to the validation and data quality filters applied during the catalogue preparation. The photometric processing pipeline, PhotPipe, implements all the processing and calibration workflows in terms of Map/Reduce jobs based on the Hadoop platform. This is the first example of a processing system for a large astrophysical survey project to make use of these technologies.
Results.
The improvements in the generation of the integrated
G
–band fluxes, in the attitude modelling, in the cross-matching, and and in the identification of spurious detections led to a much cleaner input stream for the photometric processing. This, combined with the improvements in the definition of the internal photometric system and calibration flow, produced high-quality photometry. Hadoop proved to be an excellent platform choice for the implementation of PhotPipe in terms of overall performance, scalability, downtime, and manpower required for operations and maintenance.
Observational studies suggest that higher birth weight (BW) is associated with increased risk of breast cancer in adult life. We conducted a two-sample Mendelian randomisation (MR) study to assess ...whether this association is causal. Sixty independent single nucleotide polymorphisms (SNPs) known to be associated at P < 5 × 10-8 with BW were used to construct (1) a 41-SNP instrumental variable (IV) for univariable MR after removing SNPs with pleiotropic associations with other breast cancer risk factors and (2) a 49-SNP IV for multivariable MR after filtering SNPs for data availability. BW predicted by the 41-SNP IV was not associated with overall breast cancer risk in inverse-variance weighted (IVW) univariable MR analysis of genetic association data from 122,977 breast cancer cases and 105,974 controls (odds ratio = 0.86 per 500 g higher BW; 95 % confidence interval 0.73–1.01). Sensitivity analyses using four alternative methods and three alternative IVs, including an IV with 59 of the 60 BW-associated SNPs, yielded similar results. Multivariable MR adjusting for the effects of the 49-SNP IV on birth length, adult height, adult body mass index, age at menarche, and age at menopause using IVW and MR-Egger methods provided estimates consistent with univariable analyses. Results were also similar when all analyses were repeated after restricting to estrogen receptor-positive or-negative breast cancer cases. Point estimates of the odds ratios from most analyses performed indicated an inverse relationship between genetically-predicted BW and breast cancer, but we are unable to rule out an association between the non-genetically-determined component of BW and breast cancer. Thus, geneticallypredicted higher BW was not associated with an increased risk of breast cancer in adult life in our MR study.
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