Summary Background Despite its common use in cancer treatment, radiotherapy has not yet entered the era of precision medicine, and there have been no approaches to adjust dose based on biological ...differences between or within tumours. We aimed to assess whether a patient-specific molecular signature of radiation sensitivity could be used to identify the optimum radiotherapy dose. Methods We used the gene-expression-based radiation-sensitivity index and the linear quadratic model to derive the genomic-adjusted radiation dose (GARD). A high GARD value predicts for high therapeutic effect for radiotherapy; which we postulate would relate to clinical outcome. Using data from the prospective, observational Total Cancer Care (TCC) protocol, we calculated GARD for primary tumours from 20 disease sites treated using standard radiotherapy doses for each disease type. We also used multivariable Cox modelling to assess whether GARD was independently associated with clinical outcome in five clinical cohorts: Erasmus Breast Cancer Cohort (n=263); Karolinska Breast Cancer Cohort (n=77); Moffitt Lung Cancer Cohort (n=60); Moffitt Pancreas Cancer Cohort (n=40); and The Cancer Genome Atlas Glioblastoma Patient Cohort (n=98). Findings We calculated GARD for 8271 tissue samples from the TCC cohort. There was a wide range of GARD values (range 1·66–172·4) across the TCC cohort despite assignment of uniform radiotherapy doses within disease types. Median GARD values were lowest for gliomas and sarcomas and highest for cervical cancer and oropharyngeal head and neck cancer. There was a wide range of GARD values within tumour type groups. GARD independently predicted clinical outcome in breast cancer, lung cancer, glioblastoma, and pancreatic cancer. In the Erasmus Breast Cancer Cohort, 5-year distant-metastasis-free survival was longer in patients with high GARD values than in those with low GARD values (hazard ratio 2·11, 95% 1·13–3·94, p=0·018). Interpretation A GARD-based clinical model could allow the individualisation of radiotherapy dose to tumour radiosensitivity and could provide a framework to design genomically-guided clinical trials in radiation oncology. Funding None.
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The centrality determination for Au + Au collisions at 1.23
A
GeV, as measured with HADES at the GSI-SIS18, is described. In order to extract collision geometry related quantities, such as the ...average impact parameter or number of participating nucleons, a Glauber Monte Carlo approach is employed. For the application of this model to collisions at this relatively low centre-of-mass energy of
s
NN
=
2
.
42
GeV special investigations were performed. As a result a well defined procedure to determine centrality classes for ongoing analyses of heavy-ion data is established.
To assess the performance of convolutional neural networks (CNNs) for automated detection of keratoconus (KC) in standalone Scheimpflug-based dynamic corneal deformation videos.
Retrospective cohort ...study.
We retrospectively analyzed datasets with records of 734 nonconsecutive, refractive surgery candidates, and patients with unilateral or bilateral KC.
We first developed a video preprocessing pipeline to translate dynamic corneal deformation videos into 3-dimensional pseudoimage representations and then trained a CNN to directly identify KC from pseudoimages. We calculated the model's KC probability score cut-off and evaluated the performance by subjective and objective accuracy metrics using 2 independent datasets.
Area under the receiver operating characteristics curve (AUC), accuracy, specificity, sensitivity, and KC probability score.
The model accuracy on the test subset was 0.89 with AUC of 0.94. Based on the external validation dataset, the AUC and accuracy of the CNN model for detecting KC were 0.93 and 0.88, respectively.
Our deep learning-based approach was highly sensitive and specific in separating normal from keratoconic eyes using dynamic corneal deformation videos at levels that may prove useful in clinical practice.
Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.
There has been a dramatic increase in obesity in the United States. Several studies have reported conflicting results for the impact of obesity on outcomes of liver transplantation (LT). This study ...aims to assess the impact of obesity on LT and changes in body mass index (BMI) after transplantation.
All adult LTs performed at Indiana University between 2001 and 2018 were reviewed. BMIs of recipients were subdivided into 6 categories. Survival outcomes were compared across the subgroup. BMI was followed up in a cohort of patients from 2008 to 2018.
Among 2024 patients, 25% were in class I obesity, 9.3% were in class II obesity, and 1.1% were in class III obesity. There was no significant difference in patient and graft survival at 10-y follow-up with respect to BMI. Among 1004 patients in the subgroup, BMI of all groups except the underweight group declined in the first 3 mo postoperatively; however, the BMI of all groups except the class III obesity group returned to the pre-LT level by 2 y and reached a plateau by 5 y. In the class III obesity group, there was a significant increase in body weight at 5 y.
Class III obesity was not associated with higher mortality in our cohort. Because our cohort is small, it may be underpowered to detect a smaller difference in outcome. From our observation, obesity should not be considered a contraindication for LT. Post-LT interventions are required to prevent significant weight gain for the class III obesity group.
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The combination of a production target for secondary beams, an optimized ion optical beam line setting, in-beam detectors for minimum ionizing particles with high rate capability, and an efficient ...large acceptance spectrometer around the reaction target constitutes an experimental opportunity to study in detail hadronic interactions utilizing pion beams impinging on nucleons and nuclei. For the 0.4-2.0GeV/c pion momentum regime such a facility is located at the heavy ion synchrotron accelerator SIS18 in Darmstadt (Germany). The layout of the apparatus, performance of its components and encouraging results from a first commissioning run are presented.
The first evidence of spin alignment of vector mesons ( K*0 and ϕ ) in heavy-ion collisions at the Large Hadron Collider (LHC) is reported. The spin density matrix element ρ 00 is measured at ...midrapidity ( | y | < 0.5 ) in Pb-Pb collisions at a center-of-mass energy ( √sNN ) of 2.76 TeV with the ALICE detector. ρ 00 values are found to be less than 1/3 (1/3 implies no spin alignment) at low transverse momentum ( p T < 2 GeV / c ) for K*0 and ϕ at a level of 3 σ and 2 σ , respectively. No significant spin alignment is observed for the K0S meson ( spin = 0 ) in Pb-Pb collisions and for the vector mesons in p p collisions. The measured spin alignment is unexpectedly large but qualitatively consistent with the expectation from models which attribute it to a polarization of quarks in the presence of angular momentum in heavy-ion collisions and a subsequent hadronization by the process of recombination.
In many patients with chronic lymphocytic leukaemia requiring treatment, induction therapy with rituximab plus chemotherapy improves outcomes compared with chemotherapy alone. In this study we aimed ...to investigate the potential of rituximab maintenance therapy to prolong disease control in patients who respond to rituximab-containing induction regimens.
In this randomised, international, multicentre, open-label, phase 3 clinical trial, we enrolled patients who had achieved a complete response (CR), CR with incomplete bone marrow recovery (CRi), or partial response (PR) to first-line or second-line rituximab-containing chemoimmunotherapy and randomly assigned them in a 1:1 ratio (central block randomisation in the electronic case report form system) to either intravenous rituximab 375 mg/m(2) every 3 months, or observation alone, for 2 years. Stratification was by country, line of treatment, type of chemotherapy added to the rituximab backbone, and degree of remission following induction. The primary endpoint was progression-free survival. Efficacy analysis was done in the intention-to-treat population. This is the final, event-triggered analysis. Final analysis was triggered by the occurrence of 92 events. This trial is registered with ClinicalTrials.gov, number NCT01118234.
Between April 1, 2010, and Dec 23, 2013, 134 patients were randomised to rituximab and 129 to observation alone. Median observation times were 33·4 months (IQR 25·7-42·8) for the rituximab group and 34·0 months (25·4-41·9) for the observation group. Progression-free survival was significantly longer in the rituximab maintenance group (47·0 months, IQR 28·5-incalculable) than with observation alone (35·5 months, 95% CI 25·7-46·3; hazard ratio HR 0·50, 95% CI 0·33-0·75, p=0·00077). The incidence of grade 3-4 haematological toxicities other than neutropenia was similar in the two treatment groups. Grade 3-4 neutropenia occurred in 28 (21%) patients in the rituximab group and 14 (11%) patients in the observation group. Apart from neutropenia, the most common grade 3-4 adverse events were upper (five vs one 1% patient in the observation group) and lower (three 2% vs one 1%) respiratory tract infection, pneumonia (nine 7% vs two 2%), thrombopenia (four 3% vs four 3%), neoplasms (five 4% vs four 3%), and eye disorders (four 3% vs two 2%). The overall incidence of infections of all grades was higher among rituximab recipients (88 66% vs 65 50%).
Rituximab maintenance therapy prolongs progression-free survival in patients achieving at least a PR to induction with rituximab plus chemotherapy, and the treatment is well tolerated overall. Although it is associated with an increase in infections, there is no excess in infection mortality, suggesting that remission maintenance with rituximab is an effective and safe option in the management of chronic lymphocytic leukaemia in early treatment phases.
Arbeitsgemeinschaft Medikamentöse Tumortherapie gemeinnützige GmbH (AGMT), Roche.
The first measurement at the LHC of charge-dependent directed flow (v1) relative to the spectator plane is presented for Pb-Pb collisions at √ s NN = 5.02 TeV . Results are reported for charged ...hadrons and D 0 mesons for the transverse momentum intervals p T > 0.2 GeV / c and 3 < p T < 6 GeV / c in the 5%–40% and 10%–40% centrality classes, respectively. The difference between the positively and negatively charged hadron v 1 has a positive slope as a function of pseudorapidity η , dΔv1/dη = 1.68 ± 0.49 ( stat ) ± 0.41 ( syst ) × 10−4 . The same measurement for D0 and ¯ D0 mesons yields a positive value d Δv1/dη = 4.9 ± 1.7 ( stat ) ± 0.6 ( syst ) × 10−1, which is about 3 orders of magnitude larger than the one of the charged hadrons. These measurements can provide new insights into the effects of the strong electromagnetic field and the initial tilt of matter created in noncentral heavy ion collisions on the dynamics of light (u, d, and s) and heavy (c) quarks. The large difference between the observed Δv1 of charged hadrons and D0 mesons may reflect different sensitivity of the charm and light quarks to the early time dynamics of a heavy ion collision. These observations challenge some recent theoretical calculations, which predicted a negative and an order of magnitude smaller value of d Δv1/dη for both light flavor and charmed hadrons.
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We report on the investigation of dielectron production in tagged quasi-free neutron-proton collisions by using a deuteron beam of kinetic energy 1.25GeV/u impinging on a liquid hydrogen target. ...Our measurements with HADES confirm a significant excess of
e
+
e
-
pairs above the
π
0
mass in the exclusive channel
d
p
→
n
p
e
+
e
-
(
p
s
p
e
c
t
)
as compared to the exclusive channel
p
p
e
+
e
-
measured in proton-proton collisions at the same energy. That excess points to different bremsstrahlung production mechanisms. Two models were evaluated for the role of the charged pion exchange between nucleons and double-
Δ
excitation combined with intermediate
ρ
-meson production. Differential cross sections as a function of the
e
+
e
-
invariant mass and of the angles of the virtual photon, proton and electrons provide valuable constraints and encourage further investigations on both experimental and theoretical sides.
Elderly recipients (≥70 y) account for 2.6% of all liver transplants (LTs) in the United States and have similar outcomes as younger recipients. Although the rate of elderly recipients in combined ...liver-kidney transplant (CLKT) is similar, limited data are available on how elderly recipients perform after CLKT.
We have previously shown excellent outcomes in CLKT using delayed kidney transplant (Indiana) Approach (mean kidney cold ischemia time = 53 ± 14 h). Between 2007 and 2018, 98 CLKTs were performed using the Indiana Approach at Indiana University (IU) and the data were retrospectively analyzed. Recipients were subgrouped based on their age: 18-45 (n = 16), 46-59 (n = 34), 60-69 (n = 40), and ≥70 years (n = 8).
Overall, more elderly patients received LT at IU (5.2%) when compared nationally (2.6%). The rate of elderly recipients in CLKT at IU was 8.2% (versus 2% Scientific Registry of Transplant Recipient). Recipient and donor characteristics were comparable between all age groups except recipient age and duration of dialysis. Patient survival at 1 and 3 years was similar among younger age groups, whereas patient survival was significantly lower in elderly recipients at 1 (60%) and 3 years (40%) (
= 0.0077). Control analyses (replicating Scientific Registry of Transplant Recipient's survival stratification: 18-45, 46-64, ≥65 y) showed similar patient survival in all age groups.
Although LT can be safely performed in elderly recipients, extreme caution is needed in CLKT due to the magnitude of operation.
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