Does oncological outcome differ between restorative and nonrestorative low anterior resection in patients with primary rectal cancer?

Aim Nonrestorative low anterior resection (n-rLAR) (also known as low Hartmann's) is performed for rectal cancer when a poor functional outcome is anticipated or there have been problems when constructing the anastomosis. Compared with restorative LAR (rLAR), little oncological outcome data are available for n-rLAR. The aim of this study was to compare oncological outcomes between rLAR and n-rLAR for primary rectal cancer. Method This was a nationwide cross-sectional comparative study including all elective sphincter-saving LAR procedures for nonmetastatic primary rectal cancer performed in 2011 in 71 Dutch hospitals. Oncological outcomes of patients undergoing rLAR and n-rLAR were collected in 2015; the data were evaluated using Kaplan-Meier survival analysis and the results compared using log-rank testing. Uni- and multivariable Cox regression analysis was used to evaluate the association between the type of LAR and oncological outcome measures. Results A total of 1197 patients were analysed, of whom 892 (75%) underwent rLAR and 305 (25%) underwent n-rLAR. The 3-year local recurrence (LR) rate was 3% after rLAR and 8% after n-rLAR (P <0.001). The 3-year disease-free survival and overall survival rates were 77% (rLAR) vs 62% (n-rLAR) (P <0.001) and 90% (rLAR) vs 75% (n-rLAR) (P <0.001), respectively. In multivariable Cox analysis, n-rLAR was independently associated with a higher risk of LR (OR = 2.95) and worse overall survival (OR = 1.72). Conclusion This nationwide study revealed that n-rLAR for rectal cancer was associated with poorer oncological outcome than r-LAR. This is probably a noncausal relationship, and might reflect technical difficulties during low pelvic dissection in a subset of those patients, with oncological implications

Planetary Nebulae in Face-On Spiral Galaxies. III. Planetary Nebula Kinematics and Disk Mass

Much of our understanding of dark matter halos comes from the assumption that the mass-to-light ratio (M/L) of spiral disks is constant. The best way to test this hypothesis is to measure the disk surface mass density directly via the kinematics of old disk stars. To this end, we have used planetary nebulae (PNe) as test particles and have measured the vertical velocity dispersion (sigma_z) throughout the disks of five nearby, low-inclination spiral galaxies: IC 342, M74 (NGC 628), M83 (NGC 5236), M94 (NGC 4736), and M101 (NGC 5457). By using HI to map galactic rotation and the epicyclic approximation to extract sigma_z from the line-of-sight dispersion, we find that, with the lone exception of M101, our disks do have a constant M/L out to ~3 optical scale lengths. However, once outside this radius, sigma_z stops declining and becomes flat with radius. Possible explanations for this behavior include an increase in the disk mass-to-light ratio, an increase in the importance of the thick disk, and heating of the thin disk by halo substructure. We also find that the disks of early type spirals have higher values of M/L and are closer to maximal than the disks of later-type spirals, and that the unseen inner halos of these systems are better fit by pseudo-isothermal laws than by NFW models.Comment: 18 pages, 15 figures, 5 tables; accepted to Ap

A Systematic Review and Meta-analysis on Omentoplasty for the Management of Abdominoperineal Defects in Patients Treated for Cancer

Objective: The objective of this systematic review and meta-analysis was to examine the effects of omentoplasty on pelviperineal morbidity following abdominoperineal resection (APR) in patients with cancer. Background: Recent studies have questioned the use of omentoplasty for the prevention of perineal wound complications. Methods: A systematic review of published literature since 2000 on the use of omentoplasty during APR for cancer was undertaken. The authors were requested to share their source patient data. Meta-analyses were conducted using a random-effects model. Results: Fourteen studies comprising 1894 patients (n ¼ 839 omentoplasty) were included. The majority had APR for rectal cancer (87%). Omentoplasty was not significantly associated with the risk of presacral abscess formation in the overall population (RR 1.11; 95% CI 0.79–1.56), nor in planned subgroup analysis (n ¼ 758) of APR with primary perineal closure for nonlocally advanced rectal cancer (RR 1.06; 95% CI 0.68–1.64). No overall differences were found for complicated perineal wound healing within 30 days (RR 1.30; 95% CI 0.92–1.82), chronic perineal sinus (RR 1.08; 95% CI 0.53–2.20), and pelviperineal complication necessitating reoperation (RR 1.06; 95% CI 0.80– 1.42) as well. An increased risk of developing a perineal hernia was found for patients submitted to omentoplasty (RR 1.85; 95% CI 1.26–2.72). Complications related to the omentoplasty were reported in 4.6% (95% CI 2.5%– 8.6%). Conclusions: This meta-analysis revealed no beneficial effect of omentoplasty on presacral abscess formation and perineal wound healing after APR, while it increases the likelihood of developing a perineal hernia. These findings do not support the routine use of omentoplasty in APR for cancer

Mass models of the Milky Way

We present a simple method for fitting parametrized mass models of the Milky Way to observational constraints. We take a Bayesian approach which allows us to take into account input from photometric and kinematic data, and expectations from theoretical modelling. This provides us with a best-fitting model, which is a suitable starting point for dynamical modelling. We also determine a probability density function on the properties of the model, which demonstrates that the mass distribution of the Galaxy remains very uncertain. For our choices of parametrization and constraints, we find disc scale lengths of 3.00 \pm 0.22 kpc and 3.29 \pm 0.56 kpc for the thin and thick discs respectively; a Solar radius of 8.29 \pm 0.16 kpc and a circular speed at the Sun of 239 \pm 5 km/s; a total stellar mass of 6.43 \pm 0.63 * 10^10 M_sun; a virial mass of 1.26 \pm 0.24 * 10^12 M_sun and a local dark matter density of 0.40 \pm 0.04 GeV/cm^3. We find some correlations between the best-fitting parameters of our models (for example, between the disk scale lengths and the Solar radius), which we discuss. The chosen disc scale-heights are shown to have little effect on the key properties of the model.Comment: 13 pages, 5 figures, 4 tables. Accepted by MNRA

The In Vitro, Ex Vivo, and In Vivo Effect of Polymer Hydrophobicity on Charge-Reversible Vectors for Self-Amplifying RNA

RNA technology has the potential to revolutionize vaccination. However, the lack of clear structure-property relationships in relevant biological models mean there is no clear consensus on the chemical motifs necessary to improve RNA delivery. In this work, we describe the synthesis of a series of copolymers based on the self-hydrolyzing charge-reversible polycation poly(dimethylaminoethyl acrylate) (pDMAEA), varying the lipophilicity of the additional co-monomers. All copolymers formed stable polyplexes, showing efficient complexation with model nucleic acids from nitrogen/phosphate (N/P) ratios of N/P = 5, with more hydrophobic complexes exhibiting slower charge reversal and disassembly compared to hydrophilic analogues. The more hydrophobic copolymers outperformed hydrophilic versions, homopolymer controls and the reference standard polymer (polyethylenimine), in transfection assays on 2D cell monolayers, albeit with significantly higher toxicities. Similarly, hydrophobic derivatives displayed up to a 4-fold higher efficacy in terms of the numbers of cells expressing green fluorescent protein (GFP+) cells in ex vivo human skin (10%) compared to free RNA (2%), attributed to transfection enrichment in epithelial cells. In contrast, in a mouse model, we observed the reverse trend in terms of RNA transfection, with no observable protein production in more hydrophobic analogues, whereas hydrophilic copolymers induced the highest transfection in vivo. Overall, our results suggest an important relationship between the vector lipophilicity and RNA transfection in vaccine settings, with polymer biocompatibility potentially a key parameter in effective in vivo protein production

Outcomes and toxicity of allogeneic hematopoietic cell transplantation in chronic myeloid leukemia patients previously treated with second-generation tyrosine kinase inhibitors : a prospective non-interventional study from the Chronic Malignancy Working Party of the EBMT

Allogeneic hematopoietic cell transplantation (allo-HCT) remains a treatment option for patients with chronic myeloid leukemia (CML) who fail to respond to tyrosine kinase inhibitors (TKIs). While imatinib seems to have no adverse impact on outcomes after transplant, little is known on the effects of prior use of second-generation TKI (2GTKI). We present the results of a prospective non-interventional study performed by the EBMT on 383 consecutive CML patients previously treated with dasatinib or nilotinib undergoing allo-HCT from 2009 to 2013. The median age was 45 years (18-68). Disease status at transplant was CP1 in 139 patients (38%), AP or >CP1 in 163 (45%), and BC in 59 (16%). The choice of 2GTKI was: 40% dasatinib, 17% nilotinib, and 43% a sequential treatment of dasatinib and nilotinib with or without bosutinib/ponatinib. With a median follow-up of 37 months (1-77), 8% of patients developed either primary or secondary graft failure, 34% acute and 60% chronic GvHD. There were no differences in post-transplant complications between the three different 2GTKI subgroups. Non-relapse mortality was 18% and 24% at 12 months and at 5 years, respectively. Relapse incidence was 36%, overall survival 56% and relapse-free survival 40% at 5 years. No differences in post-transplant outcomes were found between the three different 2GTKI subgroups. This prospective study demonstrates the feasibility of allo-HCT in patients previously treated with 2GTKI with a post-transplant complications rate comparable to that of TKI-naive or imatinib-treated patients.Peer reviewe

Predicted Impact of COVID-19 on Neglected Tropical Disease Programs and the Opportunity for Innovation

Due to the COVID-19 pandemic, many key neglected tropical disease (NTD) activities have been postponed. This hindrance comes at a time when the NTDs are progressing towards their ambitious goals for 2030. Mathematical modelling on several NTDs, namely gambiense sleeping sickness, lymphatic filariasis, onchocerciasis, schistosomiasis, soil-transmitted helminthiases (STH), trachoma, and visceral leishmaniasis, shows that the impact of this disruption will vary across the diseases. Programs face a risk of resurgence, which will be fastest in high-transmission areas. Furthermore, of the mass drug administration diseases, schistosomiasis, STH, and trachoma are likely to encounter faster resurgence. The case-finding diseases (gambiense sleeping sickness and visceral leishmaniasis) are likely to have fewer cases being detected but may face an increasing underlying rate of new infections. However, once programs are able to resume, there are ways to mitigate the impact and accelerate progress towards the 2030 goals.</p

Polygenic risk scores and breast and epithelial ovarian cancer risks for carriers of BRCA1 and BRCA2 pathogenic variants

Purpose We assessed the associations between population-based polygenic risk scores (PRS) for breast (BC) or epithelial ovarian cancer (EOC) with cancer risks forBRCA1andBRCA2pathogenic variant carriers. Methods Retrospective cohort data on 18,935BRCA1and 12,339BRCA2female pathogenic variant carriers of European ancestry were available. Three versions of a 313 single-nucleotide polymorphism (SNP) BC PRS were evaluated based on whether they predict overall, estrogen receptor (ER)-negative, or ER-positive BC, and two PRS for overall or high-grade serous EOC. Associations were validated in a prospective cohort. Results The ER-negative PRS showed the strongest association with BC risk forBRCA1carriers (hazard ratio [HR] per standard deviation = 1.29 [95% CI 1.25-1.33],P = 3x10(-72)). ForBRCA2, the strongest association was with overall BC PRS (HR = 1.31 [95% CI 1.27-1.36],P = 7x10(-50)). HR estimates decreased significantly with age and there was evidence for differences in associations by predicted variant effects on protein expression. The HR estimates were smaller than general population estimates. The high-grade serous PRS yielded the strongest associations with EOC risk forBRCA1(HR = 1.32 [95% CI 1.25-1.40],P = 3x10(-22)) andBRCA2(HR = 1.44 [95% CI 1.30-1.60],P = 4x10(-12)) carriers. The associations in the prospective cohort were similar. Conclusion Population-based PRS are strongly associated with BC and EOC risks forBRCA1/2carriers and predict substantial absolute risk differences for women at PRS distribution extremes.Peer reviewe

Copy number variants as modifiers of breast cancer risk for BRCA1/BRCA2 pathogenic variant carriers

The risk of germline copy number variants (CNVs) in BRCA1 and BRCA2 pathogenic variant carriers in breast cancer is assessed, with CNVs overlapping SULT1A1 decreasing breast cancer risk in BRCA1 carriers.The contribution of germline copy number variants (CNVs) to risk of developing cancer in individuals with pathogenic BRCA1 or BRCA2 variants remains relatively unknown. We conducted the largest genome-wide analysis of CNVs in 15,342 BRCA1 and 10,740 BRCA2 pathogenic variant carriers. We used these results to prioritise a candidate breast cancer risk-modifier gene for laboratory analysis and biological validation. Notably, the HR for deletions in BRCA1 suggested an elevated breast cancer risk estimate (hazard ratio (HR) = 1.21), 95% confidence interval (95% CI = 1.09-1.35) compared with non-CNV pathogenic variants. In contrast, deletions overlapping SULT1A1 suggested a decreased breast cancer risk (HR = 0.73, 95% CI 0.59-0.91) in BRCA1 pathogenic variant carriers. Functional analyses of SULT1A1 showed that reduced mRNA expression in pathogenic BRCA1 variant cells was associated with reduced cellular proliferation and reduced DNA damage after treatment with DNA damaging agents. These data provide evidence that deleterious variants in BRCA1 plus SULT1A1 deletions contribute to variable breast cancer risk in BRCA1 carriers.Peer reviewe