Minimally Invasive Surgery for Colorectal Cancer: Past, Present, and Future

A rapid progression from conventional open surgery to minimally invasive approaches in the surgical management of colorectal cancer has occurred over the last 2 decades. Initial concerns that this new approach was oncologically inferior to open surgery were ultimately refuted when several prospective randomized trials concluded that laparoscopic colectomy could achieve similar oncologic outcomes to open surgery. On the contrary, level 1 data has not yet matured regarding the oncologic safety of minimally invasive approaches for rectal cancer. We review the published literature pertaining to the evolution of minimally invasive techniques used to treat colorectal cancer surgery, including barriers to adoption, and the prospects for future advances related to innovative techniques

Detection of lensing substructure using ALMA observations of the dusty galaxy SDP.81

We study the abundance of substructure in the matter density near galaxies using ALMA Science Verification observations of the strong lensing system SDP.81. We present a method to measure the abundance of subhalos around galaxies using interferometric observations of gravitational lenses. Using simulated ALMA observations, we explore the effects of various systematics, including antenna phase errors and source priors, and show how such errors may be measured or marginalized. We apply our formalism to ALMA observations of SDP.81. We find evidence for the presence of a $M=10^{8.96\pm 0.12} M_{\odot}$ subhalo near one of the images, with a significance of $6.9\sigma$ in a joint fit to data from bands 6 and 7; the effect of the subhalo is also detected in both bands individually. We also derive constraints on the abundance of dark matter subhalos down to $M\sim 2\times 10^7 M_{\odot}$, pushing down to the mass regime of the smallest detected satellites in the Local Group, where there are significant discrepancies between the observed population of luminous galaxies and predicted dark matter subhalos. We find hints of additional substructure, warranting further study using the full SDP.81 dataset (including, for example, the spectroscopic imaging of the lensed carbon monoxide emission). We compare the results of this search to the predictions of $\Lambda$CDM halos, and find that given current uncertainties in the host halo properties of SDP.81, our measurements of substructure are consistent with theoretical expectations. Observations of larger samples of gravitational lenses with ALMA should be able to improve the constraints on the abundance of galactic substructure.Comment: 18 pages, 13 figures, Comments are welcom

Selective small molecule inhibitors of glycogen synthase kinase-3 modulate glycogen metabolism and gene transcription

AbstractBackground: Glycogen synthase kinase-3 (GSK-3) is a serine/threonine protein kinase, the activity of which is inhibited by a variety of extracellular stimuli including insulin, growth factors, cell specification factors and cell adhesion. Consequently, inhibition of GSK-3 activity has been proposed to play a role in the regulation of numerous signalling pathways that elicit pleiotropic cellular responses. This report describes the identification and characterisation of potent and selective small molecule inhibitors of GSK-3.Results: SB-216763 and SB-415286 are structurally distinct maleimides that inhibit GSK-3α in vitro, with Kis of 9 nM and 31 nM respectively, in an ATP competitive manner. These compounds inhibited GSK-3β with similar potency. However, neither compound significantly inhibited any member of a panel of 24 other protein kinases. Furthermore, treatment of cells with either compound stimulated responses characteristic of extracellular stimuli that are known to inhibit GSK-3 activity. Thus, SB-216763 and SB-415286 stimulated glycogen synthesis in human liver cells and induced expression of a β-catenin-LEF/TCF regulated reporter gene in HEK293 cells. In both cases, compound treatment was demonstrated to inhibit cellular GSK-3 activity as assessed by activation of glycogen synthase, which is a direct target of this kinase.Conclusions: SB-216763 and SB-415286 are novel, potent and selective cell permeable inhibitors of GSK-3. Therefore, these compounds represent valuable pharmacological tools with which the role of GSK-3 in cellular signalling can be further elucidated. Furthermore, development of similar compounds may be of use therapeutically in disease states associated with elevated GSK-3 activity such as non-insulin dependent diabetes mellitus and neurodegenerative disease

How Low Can We Go?: Comparing Long-term Oncologic Outcomes for APR and LAR in Very Low Rectal Cancer

Management of very low rectal cancer is one of the most challenging issues faced by colorectal surgeons. For tumors in the mid and upper rectum, procedures can be done to resect the cancer while maintaining continence, a major determinant of post-operative quality of life. In the low rectum, however, to optimize oncologic outcomes, many surgeons feel compelled to pursue abdominoperineal (APR) over low anterior resection (LAR), a sphincter-preserving procedure. It was hypothesized that after robust adjustment, procedure choice will not be associated with a difference in disease-free survival in the resection of tumors in the low rectum. To analyze this, the US Rectal Cancer Collaborative Database, a comprehensive, multi-center dataset obtained from six institutions between 2010 and 2016, was queried. Patients undergoing TME resection for Stage I-III very low rectal cancers (involvement) were selected for this study. Patients were categorized by procedure- LAR vs APR. Primary outcome was five-year disease-free survival. Secondary outcomes included overall survival, recurrence, length of stay, and complications. An adjusted analysis was performed to account for all known potential confounders. 431 patients with very low rectal cancer treated by either APR or LAR were identified. 154 (35.7%) underwent APR. The overall recurrence rate was 19.6%. Median follow-up time was 42.5 months. An analysis adjusted for age, gender, BMI, ASA class, and pathologic stage observed no difference in disease free survival between operative types (HR=0.90, 95% CI [0.53-1.52], p=0.70). Similarly, secondary outcomes demonstrated no significant difference between operation types, including length of stay (Beta: 0.04, Std. error = 0.25, p = 0.54), overall survival (HR=1.29, 95% CI [0.71-2.32], p=0.39), or complications (OR = 1.53, 95% CI [0.94 - 2.50], p=0.09). In this analysis, no significant difference in disease-free survival or overall survival was observed between patients undergoing APR or LAR for very low rectal cancer. This comprehensive study supports the treatment of very low rectal cancer, less than 5cm from the anorectal ring with no sphincter involvement, by either abdominal perineal or low anterior resection. Further studies may focus on patient-reported and quality of life outcomes which may influence decision-making

Mass Calibration and Cosmological Analysis of the SPT-SZ Galaxy Cluster Sample Using Velocity Dispersion σv\sigma_v and X-ray YXY_\textrm{X} Measurements

We present a velocity dispersion-based mass calibration of the South Pole Telescope Sunyaev-Zel'dovich effect survey (SPT-SZ) galaxy cluster sample. Using a homogeneously selected sample of 100 cluster candidates from 720 deg2 of the survey along with 63 velocity dispersion ($\sigma_v$) and 16 X-ray Yx measurements of sample clusters, we simultaneously calibrate the mass-observable relation and constrain cosmological parameters. The calibrations using $\sigma_v$ and Yx are consistent at the $0.6\sigma$ level, with the $\sigma_v$ calibration preferring ~16% higher masses. We use the full cluster dataset to measure $\sigma_8(\Omega_ m/0.27)^{0.3}=0.809\pm0.036$. The SPT cluster abundance is lower than preferred by either the WMAP9 or Planck+WMAP9 polarization (WP) data, but assuming the sum of the neutrino masses is $\sum m_\nu=0.06$ eV, we find the datasets to be consistent at the 1.0$\sigma$ level for WMAP9 and 1.5$\sigma$ for Planck+WP. Allowing for larger $\sum m_\nu$ further reconciles the results. When we combine the cluster and Planck+WP datasets with BAO and SNIa, the preferred cluster masses are $1.9\sigma$ higher than the Yx calibration and $0.8\sigma$ higher than the $\sigma_v$ calibration. Given the scale of these shifts (~44% and ~23% in mass, respectively), we execute a goodness of fit test; it reveals no tension, indicating that the best-fit model provides an adequate description of the data. Using the multi-probe dataset, we measure $\Omega_ m=0.299\pm0.009$ and $\sigma_8=0.829\pm0.011$. Within a $\nu$CDM model we find $\sum m_\nu = 0.148\pm0.081$ eV. We present a consistency test of the cosmic growth rate. Allowing both the growth index $\gamma$ and the dark energy equation of state parameter $w$ to vary, we find $\gamma=0.73\pm0.28$ and $w=-1.007\pm0.065$, demonstrating that the expansion and the growth histories are consistent with a LCDM model ($\gamma=0.55; \,w=-1$).Comment: Accepted by ApJ (v2 is accepted version); 17 pages, 6 figure

Enteral lactoferrin supplementation for very preterm infants: a randomised placebo-controlled trial

Background Infections acquired in hospital are an important cause of morbidity and mortality in very preterm infants. Several small trials have suggested that supplementing the enteral diet of very preterm infants with lactoferrin, an antimicrobial protein processed from cow's milk, prevents infections and associated complications. The aim of this large randomised controlled trial was to collect data to enhance the validity and applicability of the evidence from previous trials to inform practice. Methods In this randomised placebo-controlled trial, we recruited very preterm infants born before 32 weeks' gestation in 37 UK hospitals and younger than 72 h at randomisation. Exclusion criteria were presence of a severe congenital anomaly, anticipated enteral fasting for longer than 14 days, or no realistic prospect of survival. Eligible infants were randomly assigned (1:1) to receive either enteral bovine lactoferrin (150 mg/kg per day; maximum 300 mg/day; lactoferrin group) or sucrose (same dose; control group) once daily until 34 weeks' postmenstrual age. Web-based randomisation minimised for recruitment site, gestation (completed weeks), sex, and single versus multifetal pregnancy. Parents, caregivers, and outcome assessors were unaware of group assignment. The primary outcome was microbiologically confirmed or clinically suspected late-onset infection (occurring >72 h after birth), which was assessed in all participants for whom primary outcome data was available by calculating the relative risk ratio with 95% CI between the two groups. The trial is registered with the International Standard Randomised Controlled Trial Number 88261002. Findings We recruited 2203 participants between May 7, 2014, and Sept 28, 2017, of whom 1099 were assigned to the lactoferrin group and 1104 to the control group. Four infants had consent withdrawn or unconfirmed, leaving 1098 infants in the lactoferrin group and 1101 in the sucrose group. Primary outcome data for 2182 infants (1093 [99·5%] of 1098 in the lactoferrin group and 1089 [99·0] of 1101 in the control group) were available for inclusion in the modified intention-to-treat analyses. 316 (29%) of 1093 infants in the intervention group acquired a late-onset infection versus 334 (31%) of 1089 in the control group. The risk ratio adjusted for minimisation factors was 0·95 (95% CI 0·86–1·04; p=0·233). During the trial there were 16 serious adverse events for infants in the lactoferrin group and 10 for infants in the control group. Two events in the lactoferrin group (one case of blood in stool and one death after intestinal perforation) were assessed as being possibly related to the trial intervention. Interpretation Enteral supplementation with bovine lactoferrin does not reduce the risk of late-onset infection in very preterm infants. These data do not support its routine use to prevent late-onset infection and associated morbidity or mortality in very preterm infants. Funding UK National Institute for Health Research Health Technology Assessment programme (10/57/49)

Analysis of Sunyaev-Zel'dovich Effect Mass-Observable Relations using South Pole Telescope Observations of an X-ray Selected Sample of Low Mass Galaxy Clusters and Groups

(Abridged) We use 95, 150, and 220GHz observations from the SPT to examine the SZE signatures of a sample of 46 X-ray selected groups and clusters drawn from ~6 deg^2 of the XMM-BCS. These systems extend to redshift z=1.02, have characteristic masses ~3x lower than clusters detected directly in the SPT data and probe the SZE signal to the lowest X-ray luminosities (>10^42 erg s^-1) yet. We develop an analysis tool that combines the SZE information for the full ensemble of X-ray-selected clusters. Using X-ray luminosity as a mass proxy, we extract selection-bias corrected constraints on the SZE significance- and Y_500-mass relations. The SZE significance- mass relation is in good agreement with an extrapolation of the relation obtained from high mass clusters. However, the fit to the Y_500-mass relation at low masses, while in good agreement with the extrapolation from high mass SPT clusters, is in tension at 2.8 sigma with the constraints from the Planck sample. We examine the tension with the Planck relation, discussing sample differences and biases that could contribute. We also present an analysis of the radio galaxy point source population in this ensemble of X-ray selected systems. We find 18 of our systems have 843 MHz SUMSS sources within 2 arcmin of the X-ray centre, and three of these are also detected at significance >4 by SPT. Of these three, two are associated with the group brightest cluster galaxies, and the third is likely an unassociated quasar candidate. We examine the impact of these point sources on our SZE scaling relation analyses and find no evidence of biases. We also examine the impact of dusty galaxies using constraints from the 220 GHz data. The stacked sample provides 2.8$\sigma$ significant evidence of dusty galaxy flux, which would correspond to an average underestimate of the SPT Y_500 signal that is (17+-9) per cent in this sample of low mass systems.Comment: 15 pages, 7 figure

Enteral lactoferrin supplementation for very preterm infants: a randomised placebo-controlled trial

Background Infections acquired in hospital are an important cause of morbidity and mortality in very preterm infants. Several small trials have suggested that supplementing the enteral diet of very preterm infants with lactoferrin, an antimicrobial protein processed from cow's milk, prevents infections and associated complications. The aim of this large randomised controlled trial was to collect data to enhance the validity and applicability of the evidence from previous trials to inform practice. Methods In this randomised placebo-controlled trial, we recruited very preterm infants born before 32 weeks' gestation in 37 UK hospitals and younger than 72 h at randomisation. Exclusion criteria were presence of a severe congenital anomaly, anticipated enteral fasting for longer than 14 days, or no realistic prospect of survival. Eligible infants were randomly assigned (1:1) to receive either enteral bovine lactoferrin (150 mg/kg per day; maximum 300 mg/day; lactoferrin group) or sucrose (same dose; control group) once daily until 34 weeks' postmenstrual age. Web-based randomisation minimised for recruitment site, gestation (completed weeks), sex, and single versus multifetal pregnancy. Parents, caregivers, and outcome assessors were unaware of group assignment. The primary outcome was microbiologically confirmed or clinically suspected late-onset infection (occurring >72 h after birth), which was assessed in all participants for whom primary outcome data was available by calculating the relative risk ratio with 95% CI between the two groups. The trial is registered with the International Standard Randomised Controlled Trial Number 88261002. Findings We recruited 2203 participants between May 7, 2014, and Sept 28, 2017, of whom 1099 were assigned to the lactoferrin group and 1104 to the control group. Four infants had consent withdrawn or unconfirmed, leaving 1098 infants in the lactoferrin group and 1101 in the sucrose group. Primary outcome data for 2182 infants (1093 [99·5%] of 1098 in the lactoferrin group and 1089 [99·0] of 1101 in the control group) were available for inclusion in the modified intention-to-treat analyses. 316 (29%) of 1093 infants in the intervention group acquired a late-onset infection versus 334 (31%) of 1089 in the control group. The risk ratio adjusted for minimisation factors was 0·95 (95% CI 0·86–1·04; p=0·233). During the trial there were 16 serious adverse events for infants in the lactoferrin group and 10 for infants in the control group. Two events in the lactoferrin group (one case of blood in stool and one death after intestinal perforation) were assessed as being possibly related to the trial intervention. Interpretation Enteral supplementation with bovine lactoferrin does not reduce the risk of late-onset infection in very preterm infants. These data do not support its routine use to prevent late-onset infection and associated morbidity or mortality in very preterm infants. Funding UK National Institute for Health Research Health Technology Assessment programme (10/57/49)

The Redshift Evolution of the Mean Temperature, Pressure, and Entropy Profiles in 80 SPT-Selected Galaxy Clusters

(Abridged) We present the results of an X-ray analysis of 80 galaxy clusters selected in the 2500 deg^2 South Pole Telescope survey and observed with the Chandra X-ray Observatory. We divide the full sample into subsamples of ~20 clusters based on redshift and central density, performing an X-ray fit to all clusters in a subsample simultaneously, assuming self-similarity of the temperature profile. This approach allows us to constrain the shape of the temperature profile over 0<r<1.5R500, which would be impossible on a per-cluster basis, since the observations of individual clusters have, on average, 2000 X-ray counts. The results presented here represent the first constraints on the evolution of the average temperature profile from z=0 to z=1.2. We find that high-z (0.6<z<1.2) clusters are slightly (~40%) cooler both in the inner (rR500) regions than their low-z (0.3<z<0.6) counterparts. Combining the average temperature profile with measured gas density profiles from our earlier work, we infer the average pressure and entropy profiles for each subsample. Overall, our observed pressure profiles agree well with earlier lower-redshift measurements, suggesting minimal redshift evolution in the pressure profile outside of the core. We find no measurable redshift evolution in the entropy profile at rR500 in our high-z subsample. This flattening is consistent with a temperature bias due to the enhanced (~3x) rate at which group-mass (~2 keV) halos, which would go undetected at our survey depth, are accreting onto the cluster at z~1. This work demonstrates a powerful method for inferring spatially-resolved cluster properties in the case where individual cluster signal-to-noise is low, but the number of observed clusters is high.Comment: 17 pages, 13 figures, submitted to ApJ. Updated following referee repor