Pembrolizumab versus cetuximab concurrent with radiotherapy in patients with locally advanced squamous cell carcinoma of head and neck unfit for cisplatin (GORTEC 2015-01 PembroRad): a multicenter, randomized, phase II trial.

BACKGROUND: To evaluate potential synergistic effect of pembrolizumab with radiotherapy (RT) compared with a standard-of-care (SOC) cetuximab-RT in patients with locally advanced-squamous cell carcinoma of head and neck (LA-SCCHN). PATIENTS AND METHODS: Patients with nonoperated stage III-IV SCC of oral cavity, oropharynx, hypopharynx, and larynx and unfit for receiving high-dose cisplatin were enrolled. Patients received once-daily RT up to 69.96 Gy in 33 fractions with weekly cetuximab (cetuximab-RT arm) or 200 mg Q3W pembrolizumab during RT (pembrolizumab-RT arm). The primary endpoint was locoregional control (LRC) rate 15 months after RT. To detect a difference between arms of 60%-80% in 15-month LRC, inclusion of 66 patients per arm was required to achieve a power of at least 0.85 at two-sided significance level of 0.20. RESULTS: Between May 2016 and October 2017, 133 patients were randomized to cetuximab-RT (n = 66) and pembrolizumab-RT (n = 67). Two patients (one in each arm) were not included in the analysis (a consent withdrawal and a progression before treatment start). The median age was 65 years (interquartile range 60-70 years), 92% were smokers, 60% were oropharynx (46% of oropharynx with p16+) and 75% were stage IV. Median follow-up was 25 months in both arms. The 15-month LRC rate was 59% with cetuximab-RT and 60% with pembrolizumab-RT ]odds ratio 1.05, 95% confidence interval (CI) 0.43-2.59; P = 0.91]. There was no significant difference between arms for progression-free survival (hazard ratio 0.85, 95% CI 0.55-1.32; P = 0.47) and for overall survival (hazard ratio 0.83, 95% CI 0.49-1.40; P = 0.49). Toxicity was lower in the pembrolizumab-RT arm than in the cetuximab-RT arm: 74% versus 92% patients with at least one grade ≥3 adverse events (P = 0.006), mainly due to mucositis, radiodermatitis, and rash. CONCLUSION: Compared with the SOC cetuximab-RT, pembrolizumab concomitant with RT did not improve the tumor control and survival but appeared less toxic in unfit patients with LA-SCCHN.

Search for Coherent Elastic Scattering of Solar

We report on a search for nuclear recoil signals from solar ^{8}B neutrinos elastically scattering off xenon nuclei in XENON1T data, lowering the energy threshold from 2.6 to 1.6 keV. We develop a variety of novel techniques to limit the resulting increase in backgrounds near the threshold. No significant ^{8}B neutrinolike excess is found in an exposure of 0.6 t×y. For the first time, we use the nondetection of solar neutrinos to constrain the light yield from 1-2 keV nuclear recoils in liquid xenon, as well as nonstandard neutrino-quark interactions. Finally, we improve upon world-leading constraints on dark matter-nucleus interactions for dark matter masses between 3 and 11 GeV c^{-2} by as much as an order of magnitude.

A 343 Italian cohort of patients analysed with array-comparative genomic hybridization: unsolved problems and genetic counselling difficulties.

BACKGROUND: The recent introduction of microarrays for genetic analyses has allowed higher etiological diagnostic rates in patient with intellectual disability (ID), autism spectrum disorders (ASD), epilepsy and multiple congenital anomalies (MCA), because of its resolution. This approach still results of high complexity and some limitations have been reported. In fact, it discloses several variants of unknown significance (VOUS) or incidental findings. In all cases, a massive amount of data is generated, because of this, the analysis and the interpretation is very difficult and often without a definitive conclusion. METHOD: We analysed an Italian cohort of 343 patients with ID, MCA and ASD by array-comparative genomic hybridization. The purpose of this work was to consider the proportion of the chromosomal abnormalities in such cohort and to assess the distribution of the different type of the chromosomal abnormalities concerning their pathogenic significance, their origin and their correlation to these clinical phenotypes. RESULTS: Array-comparative genomic hybridization analysis revealed 76 positive results. Abnormalities were detected in 27.8% of patients with ID, 11.1% with ASD, 10.7% with epilepsy and 19.4% with multiple congenital anomalies. The anomalies were classified in three major groups: group 1 (27 patients) with pathogenic alterations (P group); group 2 (34 patients) with VOUS potentially pathogenic (PP group); and group 3 (13 patients) with VOUS potentially benign (PB group). As expected, comparing the diagnostic groups, we observed a greater number of deletions in the P group and that all the abnormalities of the PB group were inherited. CONCLUSIONS: Our retrospective study resulted in confirming the high detection rate of microarrays. CNV classification remains a complex procedure. The difficulty in CNV classification points out the importance of the patient selection, helping the interpretation of the molecular cytogenetic results.

First Results on the Scalar WIMP-Pion Coupling, Using the XENON1T Experiment.

We present first results on the scalar coupling of weakly interacting massive particles (WIMPs) to pions from 1 t yr of exposure with the XENON1T experiment. This interaction is generated when the WIMP couples to a virtual pion exchanged between the nucleons in a nucleus. In contrast to most nonrelativistic operators, these pion-exchange currents can be coherently enhanced by the total number of nucleons and therefore may dominate in scenarios where spin-independent WIMP-nucleon interactions are suppressed. Moreover, for natural values of the couplings, they dominate over the spin-dependent channel due to their coherence in the nucleus. Using the signal model of this new WIMP-pion channel, no significant excess is found, leading to an upper limit cross section of 6.4×10^{-46} cm^{2} (90% confidence level) at 30 GeV/c^{2} WIMP mass.

Constraining the Spin-Dependent WIMP-Nucleon Cross Sections with XENON1T.

We report the first experimental results on spin-dependent elastic weakly interacting massive particle (WIMP) nucleon scattering from the XENON1T dark matter search experiment. The analysis uses the full ton year exposure of XENON1T to constrain the spin-dependent proton-only and neutron-only cases. No significant signal excess is observed, and a profile likelihood ratio analysis is used to set exclusion limits on the WIMP-nucleon interactions. This includes the most stringent constraint to date on the WIMP-neutron cross section, with a minimum of 6.3×10^{-42} cm^{2} at 30 GeV/c^{2} and 90% confidence level. The results are compared with those from collider searches and used to exclude new parameter space in an isoscalar theory with an axial-vector mediator.

Light Dark Matter Search with Ionization Signals in XENON1T.

We report constraints on light dark matter (DM) models using ionization signals in the XENON1T experiment. We mitigate backgrounds with strong event selections, rather than requiring a scintillation signal, leaving an effective exposure of (22±3) tonne day. Above ∼0.4 keV_{ee}, we observe <1 event/(tonne day keV_{ee}), which is more than 1000 times lower than in similar searches with other detectors. Despite observing a higher rate at lower energies, no DM or CEvNS detection may be claimed because we cannot model all of our backgrounds. We thus exclude new regions in the parameter spaces for DM-nucleus scattering for DM masses m_{χ} within 3-6 GeV/c^{2}, DM-electron scattering for m_{χ}>30 MeV/c^{2}, and absorption of dark photons and axionlike particles for m_{χ} within 0.186-1 keV/c^{2}.

Search for Light Dark Matter Interactions Enhanced by the Migdal Effect or Bremsstrahlung in XENON1T.

Direct dark matter detection experiments based on a liquid xenon target are leading the search for dark matter particles with masses above ∼5 GeV/c^{2}, but have limited sensitivity to lighter masses because of the small momentum transfer in dark matter-nucleus elastic scattering. However, there is an irreducible contribution from inelastic processes accompanying the elastic scattering, which leads to the excitation and ionization of the recoiling atom (the Migdal effect) or the emission of a bremsstrahlung photon. In this Letter, we report on a probe of low-mass dark matter with masses down to about 85 MeV/c^{2} by looking for electronic recoils induced by the Migdal effect and bremsstrahlung using data from the XENON1T experiment. Besides the approach of detecting both scintillation and ionization signals, we exploit an approach that uses ionization signals only, which allows for a lower detection threshold. This analysis significantly enhances the sensitivity of XENON1T to light dark matter previously beyond its reach.

A randomized trial of induction docetaxel-cisplatin-5FU followed by concomitant cisplatin-RT versus concomitant cisplatin-RT in nasopharyngeal carcinoma (GORTEC 2006-02).

Background: Concomitant chemotherapy (CT)-radiotherapy (RT) is a standard of care in locally advanced nasopharyngeal carcinoma (NPC) and a role for induction CT is not established. Methods: Patients with locally advanced NPC, WHO type 2 or 3, were randomized to induction TPF plus concomitant cisplatin-RT or concomitant cisplatin-RT alone. The TPF regimen consisted of three cycles of Docetaxel 75 mg/m2 day 1; cisplatin 75 mg/m2 day 1; 5FU 750 mg/m2/day days 1-5. RT consisted of 70 Gy in 7 weeks plus concomitant cisplatin 40 mg/m2 weekly. Results: A total of 83 patients were included in the study. Demographics and tumour characteristics were well balanced between both arms. Most of the patients (95%) in the TPF arm received three cycles of induction CT. The rate of grade 3-4 toxicity and the compliance (NCI-CTCAE v3) during cisplatin-RT were not different between both arms. With a median follow-up of 43.1 months, the 3-year PFS rate was 73.9% in the TPF arm versus 57.2% in the reference arm [hazard ratio (HR) = 0.44; 95% confidence interval (CI): 0.20-0.97, P = 0.042]. Similarly the 3 years overall survival rate was 86.3% in the TPF arm versus 68.9% in the reference arm (HR = 0.40; 95% CI: 0.15-1.04, P = 0.05). Conclusion: In conclusion, several important aspects can be emphasized: the compliance to induction TPF was good and TPF did not compromise the tolerance of the concomitant RT-cisplatin phase. The improved PFS and overall survival rates needs to be confirmed by further trials.

Dark Matter Search Results from a One Ton-Year Exposure of XENON1T.

We report on a search for weakly interacting massive particles (WIMPs) using 278.8 days of data collected with the XENON1T experiment at LNGS. XENON1T utilizes a liquid xenon time projection chamber with a fiducial mass of (1.30±0.01) ton, resulting in a 1.0 ton yr exposure. The energy region of interest, [1.4,10.6] keV_{ee} ([4.9,40.9] keV_{nr}), exhibits an ultralow electron recoil background rate of [82_{-3}^{+5}(syst)±3(stat)] events/(ton yr keV_{ee}). No significant excess over background is found, and a profile likelihood analysis parametrized in spatial and energy dimensions excludes new parameter space for the WIMP-nucleon spin-independent elastic scatter cross section for WIMP masses above 6 GeV/c^{2}, with a minimum of 4.1×10^{-47} cm^{2} at 30 GeV/c^{2} and a 90% confidence level.

First Dark Matter Search Results from the XENON1T Experiment.

We report the first dark matter search results from XENON1T, a ∼2000-kg-target-mass dual-phase (liquid-gas) xenon time projection chamber in operation at the Laboratori Nazionali del Gran Sasso in Italy and the first ton-scale detector of this kind. The blinded search used 34.2 live days of data acquired between November 2016 and January 2017. Inside the (1042±12)-kg fiducial mass and in the [5,40] keV_{nr} energy range of interest for weakly interacting massive particle (WIMP) dark matter searches, the electronic recoil background was (1.93±0.25)×10^{-4} events/(kg×day×keV_{ee}), the lowest ever achieved in such a dark matter detector. A profile likelihood analysis shows that the data are consistent with the background-only hypothesis. We derive the most stringent exclusion limits on the spin-independent WIMP-nucleon interaction cross section for WIMP masses above 10 GeV/c^{2}, with a minimum of 7.7×10^{-47} cm^{2} for 35-GeV/c^{2} WIMPs at 90% C.L.

Search for Electronic Recoil Event Rate Modulation with 4 Years of XENON100 Data.

We report on a search for electronic recoil event rate modulation signatures in the XENON100 data accumulated over a period of 4 yr, from January 2010 to January 2014. A profile likelihood method, which incorporates the stability of the XENON100 detector and the known electronic recoil background model, is used to quantify the significance of periodicity in the time distribution of events. There is a weak modulation signature at a period of 431_{-14}^{+16} day in the low energy region of (2.0-5.8) keV in the single scatter event sample, with a global significance of 1.9σ; however, no other more significant modulation is observed. The significance of an annual modulation signature drops from 2.8σ, from a previous analysis of a subset of this data, to 1.8σ with all data combined. Single scatter events in the low energy region are thus used to exclude the DAMA/LIBRA annual modulation as being due to dark matter electron interactions via axial vector coupling at 5.7σ.

Search for Event Rate Modulation in XENON100 Electronic Recoil Data.

We have searched for periodic variations of the electronic recoil event rate in the (2-6) keV energy range recorded between February 2011 and March 2012 with the XENON100 detector, adding up to 224.6 live days in total. Following a detailed study to establish the stability of the detector and its background contributions during this run, we performed an unbinned profile likelihood analysis to identify any periodicity up to 500 days. We find a global significance of less than 1σ for all periods, suggesting no statistically significant modulation in the data. While the local significance for an annual modulation is 2.8σ, the analysis of a multiple-scatter control sample and the phase of the modulation disfavor a dark matter interpretation. The DAMA/LIBRA annual modulation interpreted as a dark matter signature with axial-vector coupling of weakly interacting massive particles to electrons is excluded at 4.8σ.

Limits on spin-dependent WIMP-nucleon cross sections from 225 live days of XENON100 data.

We present new experimental constraints on the elastic, spin-dependent WIMP-nucleon cross section using recent data from the XENON100 experiment, operated in the Laboratori Nazionali del Gran Sasso in Italy. An analysis of 224.6 live days×34 kg of exposure acquired during 2011 and 2012 revealed no excess signal due to axial-vector WIMP interactions with 129Xe and 131Xe nuclei. This leads to the most stringent upper limits on WIMP-neutron cross sections for WIMP masses above 6 GeV/c², with a minimum cross section of 3.5×10(-40) cm² at a WIMP mass of 45 GeV/c², at 90% confidence level.

A new case of pure partial 7q duplication.

We report on an 18-month-old boy conceived by assisted reproduction technology with developmental delay, hypotonia, microcephaly, frontal bossing, a mild convergent squint, malformed ears, and a short neck. Karyotype analysis revealed a de novo 7q21.1q22.3 duplication characterized by array comparative genomic hybridization (array-CGH) as a segment of 18.69 Mb. Duplications of the long arm of chromosome 7 are uncommon. There are 18 reported cases of different 7q segments with a pure duplication with no additional deletion of other chromosomes. As a consequence, duplications of chromosome 7q have been classified in 4 groups on the basis of the involved region. The present case is included in group 3 which involves interstitial duplications of different sizes. In the literature, only one case with an apparently smaller duplication of the same region has been described. Despite this, the phenotype is different. Moreover, the 2 patients share some phenotypic features, such as psychomotor delay, hypotonia, frontal bossing, short neck, and strabismus. However, the absence of physical characterization in most of the reported cases could justify the lacking phenotype-genotype correlation in patients with partial 7q duplication. Further studies using recent molecular approaches such as array-CGH might permit a more clinically useful grouping of 7q duplications.

Dark matter results from 225 live days of XENON100 data.

We report on a search for particle dark matter with the XENON100 experiment, operated at the Laboratori Nazionali del Gran Sasso for 13 months during 2011 and 2012. XENON100 features an ultralow electromagnetic background of (5.3 ± 0.6) × 10(-3) events/(keV(ee) × kg × day) in the energy region of interest. A blind analysis of 224.6 live days × 34 kg exposure has yielded no evidence for dark matter interactions. The two candidate events observed in the predefined nuclear recoil energy range of 6.6-30.5 keV(nr) are consistent with the background expectation of (1.0 ± 0.2) events. A profile likelihood analysis using a 6.6-43.3 keV(nr) energy range sets the most stringent limit on the spin-independent elastic weakly interacting massive particle-nucleon scattering cross section for weakly interacting massive particle masses above 8 GeV/c(2), with a minimum of 2 × 10(-45) cm(2) at 55 GeV/c(2) and 90% confidence level.

Histosurgical mapping of endoscopic endonasal surgery of sinonasal tumours to improve radiotherapy guidance.

PURPOSE: Endoscopic endonasal surgery (EES) is becoming a standard for most malignant sinonasal tumours. Margin analysis after piecemeal resection is complex and optimally relies on accurate histosurgical mapping. Postoperative radiotherapy may be adapted based on margin assessment mapping to reduce the dose to some sinonasal subvolumes. We assessed the use of histosurgical mapping by radiation oncologists (RO). MATERIAL AND METHODS: A French practice survey was performed across 29 ENT expert RO (2 did not answer) regarding integration of information on EES, as well as quality of operative and pathology reportsto refine radiotherapy planning after EES. This was assessed through an electronic questionnaire. RESULTS: EES was ubiquitously performed in France. Operative and pathology reports yielded accurate description of EES samples according to 66.7% of interviewed RO. Accuracy of margin assessment was however insufficient according to more than 40.0% of RO. Additional margins/biopsies of the operative bed were available in 55.2% (16/29) of the centres. In the absence of additional margins, quality of resection after EES was considered as microscopically incomplete in 48.3% or dubious in 48.3% of RO. As performed, histosurgical mapping allowed radiotherapy dose and volumes adaptation according to 26.3% of RO only. CONCLUSIONS: Standardized histosurgical mapping with margin and additional margin analysis could be more systematic. Advantages of accurate EES reporting could be dose painting radiotherapy to further decrease morbidity in sinonasal tumours.

Material radiopurity control in the XENONnT experiment.

The selection of low-radioactive construction materials is of the utmost importance for rare-event searches and thus critical to the XENONnT experiment. Results of an extensive radioassay program are reported, in which material samples have been screened with gamma-ray spectroscopy, mass spectrometry, and 222 Rn emanation measurements. Furthermore, the cleanliness procedures applied to remove or mitigate surface contamination of detector materials are described. Screening results, used as inputs for a XENONnT Monte Carlo simulation, predict a reduction of materials background ( ∼ 17%) with respect to its predecessor XENON1T. Through radon emanation measurements, the expected 222 Rn activity concentration in XENONnT is determined to be 4.2 ( - 0.7 + 0.5 )  µ Bq/kg, a factor three lower with respect to XENON1T. This radon concentration will be further suppressed by means of the novel radon distillation system.

222 Rn emanation measurements for the XENON1T experiment.

The selection of low-radioactive construction materials is of utmost importance for the success of low-energy rare event search experiments. Besides radioactive contaminants in the bulk, the emanation of radioactive radon atoms from material surfaces attains increasing relevance in the effort to further reduce the background of such experiments. In this work, we present the 222 Rn emanation measurements performed for the XENON1T dark matter experiment. Together with the bulk impurity screening campaign, the results enabled us to select the radio-purest construction materials, targeting a 222 Rn activity concentration of 10 µ Bq / kg in 3.2 t of xenon. The knowledge of the distribution of the 222 Rn sources allowed us to selectively eliminate problematic components in the course of the experiment. The predictions from the emanation measurements were compared to data of the 222 Rn activity concentration in XENON1T. The final 222 Rn activity concentration of ( 4.5 ± 0.1 ) µ Bq / kg in the target of XENON1T is the lowest ever achieved in a xenon dark matter experiment.

[Interest of a sterilised anti-burning gel in radiation dermatitis: results of a comparative study]. / Intérêt d'un gel stérile anti-brûlure dans les radiodermites : résultats d'une étude comparative.

Trial objectives were to assess effectiveness and tolerance of sterilized Avène thermal spring water anti burning gel (ATSW gel) in prevention of radiation dermatitis in adults irradiated (6 weeks) for breast (n=61) or head and neck (n=8) cancer. Patients included in this open labelled, 2 parallel groups, multicentric study, were randomly assigned to apply five times daily for ten weeks either the Avène spring water gel (n=35) or trolamine cream (n=34). The median of emergence of the first objective radiation dermatitis signs was 31 days in the ATSW gel group and 29 days in the control group (p=0,924). The median incidence for pruritus in patients of the ETA gel group was 46 days versus 27 days (p=0,028) and 44 days versus 24 days for pain (p=0,426). Global efficacy was <> in 46,7 % of patients of the ETA gel group versus 17,2 % (p=0,029) and tolerance was <> in 65,5 % of the ETA gel group versus 40,7 % (p=0,107). No radionecrosis was observed. In conclusion, the efficacy of the Avène spring water gel was similar to the control product in prophylaxis of radiation dermatitis. Tolerance was better and the pruritus was significantly more delayed in patients who applied the Avène spring water gel than in controls.