Summary Renal-cell carcinoma is considered to be a radioresistant tumour, but this notion might be wrong. If given in a few (even single) fractions, but at a high fraction dose, stereotactic body ...radiotherapy becomes increasingly important in the management of renal-cell carcinoma, both in primary settings and in treatment of oligometastatic disease. There is an established biological rationale for the radiosensitivity of renal-cell carcinoma to stereotactic body radiotherapy based on the ceramide pathway, which is activated only when a high dose per fraction is given. Apart from the direct effect of stereotactic body radiotherapy on renal-cell carcinoma, stereotactic body radiotherapy can also induce an abscopal effect. This effect, caused by immunological processes, might be enhanced when targeted drugs and stereotactic body radiotherapy are combined. Therefore, rigorous, prospective randomised trials involving a multidisciplinary scientific panel are needed urgently.
Summary Background Ipilimumab is a fully human monoclonal antibody that binds cytotoxic T-lymphocyte antigen 4 to enhance antitumour immunity. Our aim was to assess the use of ipilimumab after ...radiotherapy in patients with metastatic castration-resistant prostate cancer that progressed after docetaxel chemotherapy. Methods We did a multicentre, randomised, double-blind, phase 3 trial in which men with at least one bone metastasis from castration-resistant prostate cancer that had progressed after docetaxel treatment were randomly assigned in a 1:1 ratio to receive bone-directed radiotherapy (8 Gy in one fraction) followed by either ipilimumab 10 mg/kg or placebo every 3 weeks for up to four doses. Non-progressing patients could continue to receive ipilimumab at 10 mg/kg or placebo as maintenance therapy every 3 months until disease progression, unacceptable toxic effect, or death. Patients were randomly assigned to either treatment group via a minimisation algorithm, and stratified by Eastern Cooperative Oncology Group performance status, alkaline phosphatase concentration, haemoglobin concentration, and investigator site. Patients and investigators were masked to treatment allocation. The primary endpoint was overall survival, assessed in the intention-to-treat population. This trial is registered with ClinicalTrials.gov , number NCT00861614. Findings From May 26, 2009, to Feb 15, 2012, 799 patients were randomly assigned (399 to ipilimumab and 400 to placebo), all of whom were included in the intention-to-treat analysis. Median overall survival was 11·2 months (95% CI 9·5–12·7) with ipilimumab and 10·0 months (8·3–11·0) with placebo (hazard ratio HR 0·85, 0·72–1·00; p=0·053). However, the assessment of the proportional hazards assumption showed that it was violated (p=0·0031). A piecewise hazard model showed that the HR changed over time: the HR for 0–5 months was 1·46 (95% CI 1·10–1·95), for 5–12 months was 0·65 (0·50–0·85), and beyond 12 months was 0·60 (0·43–0·86). The most common grade 3–4 adverse events were immune-related, occurring in 101 (26%) patients in the ipilimumab group and 11 (3%) of patients in the placebo group. The most frequent grade 3–4 adverse events included diarrhoea (64 16% of 393 patients in the ipilimumab group vs seven 2% of 396 in the placebo group), fatigue (40 11% vs 35 9%), anaemia (40 10% vs 43 11%), and colitis (18 5% vs 0). Four (1%) deaths occurred because of toxic effects of the study drug, all in the ipilimumab group. Interpretation Although there was no significant difference between the ipilimumab group and the placebo group in terms of overall survival in the primary analysis, there were signs of activity with the drug that warrant further investigation. Funding Bristol-Myers Squibb.
To propose a random forest normal tissue complication probability (RF-NTCP) model to predict late rectal toxicity following prostate cancer radiation therapy, and to compare its performance to that ...of classic NTCP models.
Clinical data and dose-volume histograms (DVH) were collected from 261 patients who received 3-dimensional conformal radiation therapy for prostate cancer with at least 5 years of follow-up. The series was split 1000 times into training and validation cohorts. A RF was trained to predict the risk of 5-year overall rectal toxicity and bleeding. Parameters of the Lyman-Kutcher-Burman (LKB) model were identified and a logistic regression model was fit. The performance of all the models was assessed by computing the area under the receiving operating characteristic curve (AUC).
The 5-year grade ≥2 overall rectal toxicity and grade ≥1 and grade ≥2 rectal bleeding rates were 16%, 25%, and 10%, respectively. Predictive capabilities were obtained using the RF-NTCP model for all 3 toxicity endpoints, including both the training and validation cohorts. The age and use of anticoagulants were found to be predictors of rectal bleeding. The AUC for RF-NTCP ranged from 0.66 to 0.76, depending on the toxicity endpoint. The AUC values for the LKB-NTCP were statistically significantly inferior, ranging from 0.62 to 0.69.
The RF-NTCP model may be a useful new tool in predicting late rectal toxicity, including variables other than DVH, and thus appears as a strong competitor to classic NTCP models.
Objective To investigate the clinical manifestations at diagnosis and during follow-up in patients with 22q11.2 deletion syndrome to better define the natural history of the disease. Study design A ...retrospective and prospective multicenter study was conducted with 228 patients in the context of the Italian Network for Primary Immunodeficiencies. Clinical diagnosis was confirmed by cytogenetic or molecular analysis. Results The cohort consisted of 112 males and 116 females; median age at diagnosis was 4 months (range 0 to 36 years 10 months). The diagnosis was made before 2 years of age in 71% of patients, predominantly related to the presence of heart anomalies and neonatal hypocalcemia. In patients diagnosed after 2 years of age, clinical features such as speech and language impairment, developmental delay, minor cardiac defects, recurrent infections, and facial features were the main elements leading to diagnosis. During follow-up (available for 172 patients), the frequency of autoimmune manifestations ( P = .015) and speech disorders ( P = .002) increased. After a median follow-up of 43 months, the survival probability was 0.92 at 15 years from diagnosis. Conclusions Our data show a delay in the diagnosis of 22q11.2 deletion syndrome with noncardiac symptoms. This study provides guidelines for pediatricians and specialists for early identification of cases that can be confirmed by genetic testing, which would permit the provision of appropriate clinical management.
Two-particle angular correlations are measured in high-multiplicity proton-proton collisions at $ \sqrt{s} $ = 13 TeV by the ALICE Collaboration. The yields of particle pairs at short-(∆η ∼ 0) and ...long-range (1.6 < |∆η| < 1.8) in pseudorapidity are extracted on the near-side (∆φ ∼ 0). They are reported as a function of transverse momentum (p$_{T}$) in the range 1 < p$_{T}$< 4 GeV/c. Furthermore, the event-scale dependence is studied for the first time by requiring the presence of high-p$_{T}$ leading particles or jets for varying p$_{T}$ thresholds. The results demonstrate that the long-range “ridge” yield, possibly related to the collective behavior of the system, is present in events with high-p$_{T}$ processes as well. The magnitudes of the short- and long-range yields are found to grow with the event scale. The results are compared to EPOS LHC and PYTHIA 8 calculations, with and without string-shoving interactions. It is found that while both models describe the qualitative trends in the data, calculations from EPOS LHC show a better quantitative agreement for the p$_{T}$ dependency, while overestimating the event-scale dependency.graphic not available: see fulltext
The coherent photoproduction of $\rm{J/\psi}$ and $\rm{\psi'}$ mesons was measured in ultra-peripheral Pb-Pb collisions at a center-of-mass energy $\sqrt{s_{\mathrm{NN}}}~=~5.02$ TeV with the ALICE ...detector. Charmonia are detected in the central rapidity region for events where the hadronic interactions are strongly suppressed. The $\rm{J/\psi}$ is reconstructed using the dilepton ($l^{+} l^{-}$) and proton-antiproton decay channels, while for the $\rm{\psi'}$, the dilepton and the $l^{+} l^{-} \pi^{+} \pi^{-}$ decay channels are studied. The analysis is based on an event sample corresponding to an integrated luminosity of about 233 ${\mu b}^{-1}$. The results are compared with theoretical models for coherent $\rm{J/\psi}$ and $\rm{\psi'}$ photoproduction. The coherent cross section is found to be in a good agreement with models incorporating moderate nuclear gluon shadowing of about 0.65 at a Bjorken-$x$ of around $6\times 10^{-4}$, such as the EPS09 parametrization, however none of the models is able to fully describe the rapidity dependence of the coherent $\rm{J/\psi}$ cross section including ALICE measurements at forward rapidity. The ratio of $\rm{\psi'}$ to $\rm{J/\psi}$ coherent photoproduction cross sections was also measured and found to be consistent with the one for photoproduction off protons.
The jet radial structure and particle transverse momentum ($p_{\rm T}$) composition within jets are presented in centrality-selected Pb–Pb collisions at $\sqrt{s_{\rm NN}}$ = 2.76 TeV. Track-based ...jets, which are also called charged jets, were reconstructed with a resolution parameter of R=0.3 at midrapidity $|\eta_{\rm ch jet}|$ < 0.6 for transverse momenta $p_{\rm T, ch jet}$ = 30 –120 GeV/c . Jet–hadron correlations in relative azimuth and pseudorapidity space ( Δφ,Δη ) are measured to study the distribution of the associated particles around the jet axis for different $p_{\rm T, assoc}$-ranges between 1 and 20 GeV/ c . The data in Pb–Pb collisions are compared to reference distributions for pp collisions, obtained using embedded PYTHIA simulations. The number of high-$p_{\rm T}$ associate particles (4 < $p_{\rm T, assoc}$ < 20 GeV/c) in Pb–Pb collisions is found to be suppressed compared to the reference by 30 to 10%, depending on centrality. The radial particle distribution relative to the jet axis shows a moderate modification in Pb–Pb collisions with respect to PYTHIA. High-$p_{\rm T}$ associate particles are slightly more collimated in Pb–Pb collisions compared to the reference, while low-$p_{\rm T}$ associate particles tend to be broadened. The results, which are presented for the first time down to $p_{\rm T, ch jet}$ = 30 GeV/c in Pb–Pb collisions, are compatible with both previous jet–hadron-related measurements from the CMS Collaboration and jet shape measurements from the ALICE Collaboration at higher $p_{\rm T}$, and add further support for the established picture of in-medium parton energy loss.
PDF
