Back-Table Fluorescence-Guided Imaging for Circumferential Resection Margin Evaluation Using Bevacizumab-800CW in Patients with Locally Advanced Rectal Cancer

Negative circumferential resection margins (CRM) are the cornerstone for the curative treatment of locally advanced rectal cancer (LARC). However, in up to 18.6% of patients, tumor-positive resection margins are detected on histopathology. In this proof-of-concept study, we investigated the feasibility of optical molecular imaging as a tool for evaluating the CRM directly after surgical resection to improve tumor-negative CRM rates. Methods: LARC patients treated with neoadjuvant chemoradiotherapy received an intravenous bolus injection of 4.5 mg of bevacizumab-800CW, a fluorescent tracer targeting vascular endothelial growth factor A, 2-3 d before surgery (ClinicalTrials.gov identifier: NCT01972373). First, for evaluation of the CRM status, back-table fluorescence guided imaging (FGI) of the fresh surgical resection specimens (n = 8) was performed. These results were correlated with histopathology results. Second, for determination of the sensitivity and specificity of bevacizumab-800CW for tumor detection, a mean fluorescence intensity cutoff value was determined from the formalin-fixed tissue slices (n = 42; 17 patients). Local bevacizumab-800CW accumulation was evaluated by fluorescence microscopy. Results: Back-table FGI correctly identified a tumor-positive CRM by high fluorescence intensities in 1 of 2 patients (50%) with a tumor-positive CRM. For the other patient, low fluorescence intensities were shown, although (sub)millimeter tumor deposits were present less than 1 mm from the CRM. FGI correctly identified 5 of 6 tumor-negative CRM (83%). The 1 patient with false-positive findings had a marginal negative CRM of only 1.4 mm. Receiver operating characteristic curve analysis of the fluorescence intensities of formalin-fixed tissue slices yielded an optimal mean fluorescence intensity cutoff value for tumor detection of 5,775 (sensitivity of 96.19% and specificity of 80.39%). Bevacizumab-800CW enabled a clear differentiation between tumor and normal tissue up to a microscopic level, with a tumor-to-background ratio of 4.7 +/- 2.5 (mean SD). Conclusion: In this proof-of-concept study, we showed the potential of back-table FGI for evaluating the CRM status in LARC patients. Optimization of this technique with adaptation of standard operating procedures could change perioperative decision making with regard to extending resections or applying intraoperative radiation therapy in the case of positive CRM

A Geospatial Modelling Approach Integrating Archaeobotany and Genetics to Trace the Origin and Dispersal of Domesticated Plants

Background: The study of the prehistoric origins and dispersal routes of domesticated plants is often based on the analysis of either archaeobotanical or genetic data. As more data become available, spatially explicit models of crop dispersal can be used to combine different types of evidence. Methodology/Principal Findings: We present a model in which a crop disperses through a landscape that is represented by a conductance matrix. From this matrix, we derive least-cost distances from the geographical origin of the crop and use these to predict the age of archaeological crop remains and the heterozygosity of crop populations. We use measures of the overlap and divergence of dispersal trajectories to predict genetic similarity between crop populations. The conductance matrix is constructed from environmental variables using a number of parameters. Model parameters are determined with multiple-criteria optimization, simultaneously fitting the archaeobotanical and genetic data. The consilience reached by the model is the extent to which it converges around solutions optimal for both archaeobotanical and genetic data. We apply the modelling approach to the dispersal of maize in the Americas. Conclusions/Significance: The approach makes possible the integrative inference of crop dispersal processes, whil

Short-course radiotherapy followed by chemotherapy before total mesorectal excision (TME) versus preoperative chemoradiotherapy, TME, and optional adjuvant chemotherapy in locally advanced rectal cancer (RAPIDO):a randomised, open-label, phase 3 trial

BACKGROUND: Systemic relapses remain a major problem in locally advanced rectal cancer. Using short-course radiotherapy followed by chemotherapy and delayed surgery, the Rectal cancer And Preoperative Induction therapy followed by Dedicated Operation (RAPIDO) trial aimed to reduce distant metastases without compromising locoregional control. METHODS: In this multicentre, open-label, randomised, controlled, phase 3 trial, participants were recruited from 54 centres in the Netherlands, Sweden, Spain, Slovenia, Denmark, Norway, and the USA. Patients were eligible if they were aged 18 years or older, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1, had a biopsy-proven, newly diagnosed, primary, locally advanced rectal adenocarcinoma, which was classified as high risk on pelvic MRI (with at least one of the following criteria: clinical tumour [cT] stage cT4a or cT4b, extramural vascular invasion, clinical nodal [cN] stage cN2, involved mesorectal fascia, or enlarged lateral lymph nodes), were mentally and physically fit for chemotherapy, and could be assessed for staging within 5 weeks before randomisation. Eligible participants were randomly assigned (1:1), using a management system with a randomly varying block design (each block size randomly chosen to contain two to four allocations), stratified by centre, ECOG performance status, cT stage, and cN stage, to either the experimental or standard of care group. All investigators remained masked for the primary endpoint until a prespecified number of events was reached. Patients allocated to the experimental treatment group received short-course radiotherapy (5 × 5 Gy over a maximum of 8 days) followed by six cycles of CAPOX chemotherapy (capecitabine 1000 mg/m2 orally twice daily on days 1-14, oxaliplatin 130 mg/m2 intravenously on day 1, and a chemotherapy-free interval between days 15-21) or nine cycles of FOLFOX4 (oxaliplatin 85 mg/m2 intravenously on day 1, leucovorin [folinic acid] 200 mg/m2 intravenously on days 1 and 2, followed by bolus fluorouracil 400 mg/m2 intravenously and fluorouracil 600 mg/m2 intravenously for 22 h on days 1 and 2, and a chemotherapy-free interval between days 3-14) followed by total mesorectal excision. Choice of CAPOX or FOLFOX4 was per physician discretion or hospital policy. Patients allocated to the standard of care group received 28 daily fractions of 1·8 Gy up to 50·4 Gy or 25 fractions of 2·0 Gy up to 50·0 Gy (per physician discretion or hospital policy), with concomitant twice-daily oral capecitabine 825 mg/m2 followed by total mesorectal excision and, if stipulated by hospital policy, adjuvant chemotherapy with eight cycles of CAPOX or 12 cycles of FOLFOX4. The primary endpoint was 3-year disease-related treatment failure, defined as the first occurrence of locoregional failure, distant metastasis, new primary colorectal tumour, or treatment-related death, assessed in the intention-to-treat population. Safety was assessed by intention to treat. This study is registered with the EudraCT, 2010-023957-12, and ClinicalTrials.gov, NCT01558921, and is now complete. FINDINGS: Between June 21, 2011, and June 2, 2016, 920 patients were enrolled and randomly assigned to a treatment, of whom 912 were eligible (462 in the experimental group; 450 in the standard of care group). Median follow-up was 4·6 years (IQR 3·5-5·5). At 3 years after randomisation, the cumulative probability of disease-related treatment failure was 23·7% (95% CI 19·8-27·6) in the experimental group versus 30·4% (26·1-34·6) in the standard of care group (hazard ratio 0·75, 95% CI 0·60-0·95; p=0·019). The most common grade 3 or higher adverse event during preoperative therapy in both groups was diarrhoea (81 [18%] of 460 patients in the experimental group and 41 [9%] of 441 in the standard of care group) and neurological toxicity during adjuvant chemotherapy in the standard of care group (16 [9%] of 187 patients). Serious adverse events occurred in 177 (38%) of 460 participants in the experimental group and, in the standard of care group, in 87 (34%) of 254 patients without adjuvant chemotherapy and in 64 (34%) of 187 with adjuvant chemotherapy. Treatment-related deaths occurred in four participants in the experimental group (one cardiac arrest, one pulmonary embolism, two infectious complications) and in four participants in the standard of care group (one pulmonary embolism, one neutropenic sepsis, one aspiration, one suicide due to severe depression). INTERPRETATION: The observed decreased probability of disease-related treatment failure in the experimental group is probably indicative of the increased efficacy of preoperative chemotherapy as opposed to adjuvant chemotherapy in this setting. Therefore, the experimental treatment can be considered as a new standard of care in high-risk locally advanced rectal cancer. FUNDING: Dutch Cancer Foundation, Swedish Cancer Society, Spanish Ministry of Economy and Competitiveness, and Spanish Clinical Research Network

Phycodnavirus Potassium Ion Channel Proteins Question the Virus Molecular Piracy Hypothesis

Phycodnaviruses are large dsDNA, algal-infecting viruses that encode many genes with homologs in prokaryotes and eukaryotes. Among the viral gene products are the smallest proteins known to form functional K+ channels. To determine if these viral K+ channels are the product of molecular piracy from their hosts, we compared the sequences of the K+ channel pore modules from seven phycodnaviruses to the K+ channels from Chlorella variabilis and Ectocarpus siliculosus, whose genomes have recently been sequenced. C. variabilis is the host for two of the viruses PBCV-1 and NY-2A and E. siliculosus is the host for the virus EsV-1. Systematic phylogenetic analyses consistently indicate that the viral K+ channels are not related to any lineage of the host channel homologs and that they are more closely related to each other than to their host homologs. A consensus sequence of the viral channels resembles a protein of unknown function from a proteobacterium. However, the bacterial protein lacks the consensus motif of all K+ channels and it does not form a functional channel in yeast, suggesting that the viral channels did not come from a proteobacterium. Collectively, our results indicate that the viruses did not acquire their K+ channel-encoding genes from their current algal hosts by gene transfer; thus alternative explanations are required. One possibility is that the viral genes arose from ancient organisms, which served as their hosts before the viruses developed their current host specificity. Alternatively the viral proteins could be the origin of K+ channels in algae and perhaps even all cellular organisms

The strengths and limitations of routine staging before treatment with abdominal CT in colorectal cancer

<p>Abstract</p> <p>Background</p> <p>Advanced colorectal cancer (CRC), either locally advanced, metastasized (mCRC) or both, is present in a relevant proportion of patients. The chances on curation of advanced CRC are continuously improving with modern multi-modality treatment options. For incurable CRC the focus lies on palliation of symptoms, which is not necessarily a resection of the primary tumor. Both situations motivate adequate staging before treatment in CRC. This prospective observational study evaluates the outcomes after the introduction of routine staging with abdominal CT before treatment.</p> <p>Methods</p> <p>In a prospective observational study of 612 consecutive patients (2007-2009), the ability of abdominal CT to find liver metastases (LM), peritoneal carcinomatosis (PC) and T4 stage in colon cancer (CC) was analysed.</p> <p>Results</p> <p>Advanced CRC was present in 58% of patients, mCRC in 31%. The ability to find LM was excellent (99%), cT4 stage CC good (86%) and PC poor (33%). In the group of surgical patients with emergency presentations, the incidences of both mCRC (51%) and locally advanced colon cancer (LACC) (69%) were higher than in the elective group (20% and 26% respectively). Staging tended to be omitted more often in the emergency group (35% versus 12% in elective surgery).</p> <p>Conclusions</p> <p>The strengths of staging with abdominal CT are to find LM and LACC, however it fails in diagnosing PC. On grounds of the incidence of advanced CRC, staging is warranted in patients with emergency presentations as well.</p

Fermi Large Area Telescope observations of the Vela-X Pulsar Wind Nebula

We report on gamma-ray observations in the off-pulse window of the Vela pulsar PSR B0833-45, using 11 months of survey data from the Fermi Large Area Telescope (LAT). This pulsar is located in the 8 degree diameter Vela supernova remnant, which contains several regions of non-thermal emission detected in the radio, X-ray and gamma-ray bands. The gamma-ray emission detected by the LAT lies within one of these regions, the 2*3 degrees area south of the pulsar known as Vela-X. The LAT flux is signicantly spatially extended with a best-fit radius of 0.88 +/- 0.12 degrees for an assumed radially symmetric uniform disk. The 200 MeV to 20 GeV LAT spectrum of this source is well described by a power-law with a spectral index of 2.41 +/- 0.09 +/- 0.15 and integral flux above 100 MeV of (4.73 +/- 0.63 +/- 1.32) * 10^{-7} cm^{-2} s^{-1}. The first errors represent the statistical error on the fit parameters, while the second ones are the systematic uncertainties. Detailed morphological and spectral analyses give strong constraints on the energetics and magnetic field of the pulsar wind nebula (PWN) system and favor a scenario with two distinct electron populations.Comment: 21 pages, 5 figures, accepted for publication in Astrophysical Journa

Detection of 16 Gamma-Ray Pulsars Through Blind Frequency Searches Using the Fermi LAT

Pulsars are rapidly-rotating, highly-magnetized neutron stars emitting radiation across the electromagnetic spectrum. Although there are more than 1800 known radio pulsars, until recently, only seven were observed to pulse in gamma rays and these were all discovered at other wavelengths. The Fermi Large Area Telescope makes it possible to pinpoint neutron stars through their gamma-ray pulsations. We report the detection of 16 gamma-ray pulsars in blind frequency searches using the LAT. Most of these pulsars are coincident with previously unidentified gamma-ray sources, and many are associated with supernova remnants. Direct detection of gamma-ray pulsars enables studies of emission mechanisms, population statistics and the energetics of pulsar wind nebulae and supernova remnants.Comment: Corresponding authors: Michael Dormody, Paul S. Ray, Pablo M. Saz Parkinson, Marcus Ziegle

Fermi-LAT Search for Pulsar Wind Nebulae around gamma-ray Pulsars

The high sensitivity of the Fermi-LAT (Large Area Telescope) offers the first opportunity to study faint and extended GeV sources such as pulsar wind nebulae (PWNe). After one year of observation the LAT detected and identified three pulsar wind nebulae: the Crab Nebula, Vela-X and the PWN inside MSH 15-52. In the meantime, the list of LAT detected pulsars increased steadily. These pulsars are characterized by high energy loss rates from ~3 \times 10^{33} erg s$^{-1}$ to 5 \times 10$^{38}$ erg s$^{-1}$ and are therefore likely to power a PWN. This paper summarizes the search for PWNe in the off-pulse windows of 54 LAT-detected pulsars using 16 months of survey observations. Ten sources show significant emission, seven of these likely being of magnetospheric origin. The detection of significant emission in the off-pulse interval offers new constraints on the gamma-ray emitting regions in pulsar magnetospheres. The three other sources with significant emission are the Crab Nebula, Vela-X and a new pulsar wind nebula candidate associated with the LAT pulsar PSR J1023-5746, coincident with the TeV source HESS J1023-575. We further explore the association between the H.E.S.S. and the Fermi source by modeling its spectral energy distribution. Flux upper limits derived for the 44 remaining sources are used to provide new constraints on famous PWNe that have been detected at keV and/or TeV energies.Comment: Accepted for publication in Astrophysical Journal, 42 pages, 17 figure

Fermi LAT observations of the Geminga pulsar

We report on the \textit{Fermi}-LAT observations of the Geminga pulsar, the second brightest non-variable GeV source in the $\gamma$-ray sky and the first example of a radio-quiet $\gamma$-ray pulsar. The observations cover one year, from the launch of the $Fermi$ satellite through 2009 June 15. A data sample of over 60,000 photons enabled us to build a timing solution based solely on $\gamma$ rays. Timing analysis shows two prominent peaks, separated by $\Delta \phi$ = 0.497 $\pm$ 0.004 in phase, which narrow with increasing energy. Pulsed $\gamma$ rays are observed beyond 18 GeV, precluding emission below 2.7 stellar radii because of magnetic absorption. The phase-averaged spectrum was fitted with a power law with exponential cut-off of spectral index $\Gamma$ = (1.30 $\pm$ 0.01 $\pm$ 0.04), cut-off energy $E_{0}$ = (2.46 $\pm$ 0.04 $\pm$ 0.17) GeV and an integral photon flux above 0.1 GeV of (4.14 $\pm$ 0.02 $\pm$ 0.32) $\times$ 10$^{-6}$ cm$^{-2}$ s$^{-1}$. The first uncertainties are statistical and the second are systematic. The phase-resolved spectroscopy shows a clear evolution of the spectral parameters, with the spectral index reaching a minimum value just before the leading peak and the cut-off energy having maxima around the peaks. Phase-resolved spectroscopy reveals that pulsar emission is present at all rotational phases. The spectral shape, broad pulse profile, and maximum photon energy favor the outer magnetospheric emission scenarios.Comment: 32 pages, 12 figures, 3 tables. Accepted for publication in The Astrophysical Journal. Corresponding authors: Denis Dumora ([email protected]), Fabio Gargano ([email protected]), Massimiliano Razzano ([email protected]