Induced hypertension for the treatment of acute MCA occlusion beyond the thrombolysis window: case report

BACKGROUND: A minority of stroke patients is eligible for thrombolytic therapy. Small pilot case series have hinted that elevation of incident arterial blood pressure might be associated with a favorable prognosis either in acute or subacute stroke. However, these patients were not considered for thrombolytic therapy and were not followed – up systematically. We used pharmacologically induced hypertension in a stroke patient with middle cerebral artery (MCA) occlusion ineligible for thrombolysis that was followed-up by radiological, clinical and functional outcome assessment. CASE PRESENTATION: A patient with acute embolic MCA occlusion producing a large, ischemic penumbra confirmed by perfusion CT was treated by induced hypertension with phenylephrine started within 4 h of admission. Increase in the mean arterial pressure by 20% led to a reduction of neurological deficit by 3 points on the National Institute of Stroke Scale. MRI and CT scans performed during phenylephrine infusion showed the presence of limited subcortical and cortical infarct changes that were clearly less extensive than the perfusion deficit in the brain perfusion CT at baseline, found in the absence of MCA patency. No complications due to induced hypertension therapy occurred. Moderate functional improvement up to modified Rankin scale 2 at follow up took place. CONCLUSION: Induced hypertension in acute ischemic stroke seems clinically feasible and may be beneficial in selected normo- or hypotensive stroke patients not eligible for thrombolytic recanalization therapy

Ultra-High Energy Cosmic Ray Nuclei from Individual Magnetized Sources

We investigate the dependence of composition, spectrum and angular distributions of ultra-high energy cosmic rays above 10^19 eV from individual sources on their magnetization. We find that, especially for sources within a few megaparsecs from the observer, observable spectra and composition are severely modified if the source is surrounded by fields of ~ 10^-7 Gauss on scales of a few megaparsecs. Low energy particles diffuse over larger distances during their energy loss time. This leads to considerable hardening of the spectrum up to the energy where the loss distance becomes comparable to the source distance. Magnetized sources thus have very important consequences for observations, even if cosmic rays arrive within a few degrees from the source direction. At the same time, details in spectra and chemical composition may be intrinsically unpredictable because they depend on the unknown magnetic field structure. If primaries are predominantly nuclei of atomic mass A accelerated up to a maximum energy E_max with spectra not much softer than E^-2, secondary protons from photo-disintegration can produce a conspicuous peak in the spectrum at energy ~ E_max/A. A related feature appears in the average mass dependence on energy.Comment: 15 pages, 16 ps figures, published version with minor changes, see http://stacks.iop.org/1475-7516/2004/i=08/a=01

Constrained Simulations of the Magnetic Field in the Local Universe and the Propagation of UHECRs

We use simulations of LSS formation to study the build-up of magnetic fields (MFs) in the ICM. Our basic assumption is that cosmological MFs grow in a MHD amplification process driven by structure formation out of a seed MF present at high z. Our LCDM initial conditions for the density fluctuations have been statistically constrained by the observed galaxies, based on the IRAS 1.2-Jy all-sky redshift survey. As a result, prominent galaxy clusters in our simulation coincide closely with their real counterparts. We find excellent agreement between RMs of our simulated clusters and observational data. The improved resolution compared to previous work also allows us to study the MF in large-scale filaments, sheets and voids. By tracing the propagation of UHE protons in the simulated MF we construct full-sky maps of expected deflection angles of protons with arrival energies E=1e20eV and 4e19eV, respectively. Strong deflections are only produced if UHE protons cross clusters, however covering only a small area on the sky. Multiple crossings of sheets and filaments over larger distances may give rise to noticeable deflections, depending on the model adopted for the magnetic seed field. Based on our results we argue that over a large fraction of the sky the deflections are likely to remain smaller than the present experimental angular sensitivity. Therefore, we conclude that forthcoming air shower experiments should be able to locate sources of UHE protons and shed more light on the nature of cosmological MFs.Comment: 3revised version, JCAP, accepte

Pembrolizumab Alone or With Chemotherapy for Recurrent/Metastatic Head and Neck Squamous Cell Carcinoma in KEYNOTE-048: Subgroup Analysis by Programmed Death Ligand-1 Combined Positive Score.

PURPOSE: The phase III KEYNOTE-048 (ClinicalTrials.gov identifier: NCT02358031) trial of pembrolizumab in recurrent or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) included planned efficacy analyses in the total population and in participants with programmed death ligand-1 (PD-L1) combined positive score (CPS) ≥ 1 and CPS ≥ 20. To further characterize the predictive value of PD-L1 expression on outcome, we conducted efficacy analyses in the PD-L1 CPS < 1 and CPS 1-19 subgroups in KEYNOTE-048. METHODS: Participants with R/M HNSCC and no prior systemic therapy for R/M disease were randomly assigned 1:1:1 to pembrolizumab, pembrolizumab-chemotherapy, or cetuximab-chemotherapy. Post hoc efficacy analyses of the PD-L1 CPS < 1 and CPS 1-19 subgroups were performed. RESULTS: Of 882 participants enrolled, 128 had PD-L1 CPS < 1 and 373 had CPS 1-19. For pembrolizumab versus cetuximab-chemotherapy, the median overall survival was 7.9 versus 11.3 months in the PD-L1 CPS < 1 subgroup (hazard ratio [HR], 1.51 [95% CI, 0.96 to 2.37]) and 10.8 versus 10.1 months in the CPS 1-19 subgroup (HR, 0.86 [95% CI, 0.66 to 1.12]). For pembrolizumab-chemotherapy versus cetuximab-chemotherapy, the median overall survival was 11.3 versus 10.7 months in the PD-L1 CPS < 1 subgroup (HR, 1.21 [95% CI, 0.76 to 1.94]) and 12.7 versus 9.9 months in the CPS 1-19 subgroup (HR, 0.71 [95% CI, 0.54 to 0.94]). CONCLUSION: Increased efficacy of pembrolizumab or pembrolizumab-chemotherapy was observed with increasing PD-L1 expression. PD-L1 CPS < 1 subgroup analysis was limited by small participant numbers. Results from the PD-L1 CPS 1-19 subgroup support previous findings of treatment benefit with pembrolizumab monotherapy and pembrolizumab-chemotherapy in patients with PD-L1 CPS ≥ 1 tumors. Although PD-L1 expression is informative, exploration of additional predictive biomarkers is needed for low PD-L1-expressing HNSCC

Pembrolizumab With or Without Chemotherapy in Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma: Updated Results of the Phase III KEYNOTE-048 Study.

PURPOSE: Pembrolizumab and pembrolizumab-chemotherapy demonstrated efficacy in recurrent/metastatic head and neck squamous cell carcinoma in KEYNOTE-048. Post hoc analysis of long-term efficacy and progression-free survival on next-line therapy (PFS2) is presented. METHODS: Patients were randomly assigned (1:1:1) to pembrolizumab, pembrolizumab-chemotherapy, or cetuximab-chemotherapy. Efficacy was evaluated in programmed death ligand 1 (PD-L1) combined positive score (CPS) ≥ 20, CPS ≥ 1, and total populations, with no multiplicity or alpha adjustment. RESULTS: The median study follow-up was 45.0 months (interquartile range, 41.0-49.2; n = 882). At data cutoff (February 18, 2020), overall survival improved with pembrolizumab in the PD-L1 CPS ≥ 20 (hazard ratio [HR], 0.61; 95% CI, 0.46 to 0.81) and CPS ≥ 1 populations (HR, 0.74; 95% CI, 0.61 to 0.89) and was noninferior in the total population (HR, 0.81; 95% CI, 0.68 to 0.97). Overall survival improved with pembrolizumab-chemotherapy in the PD-L1 CPS ≥ 20 (HR, 0.62; 95% CI, 0.46 to 0.84), CPS ≥ 1 (HR, 0.64; 95% CI, 0.53 to 0.78), and total (HR, 0.71; 95% CI, 0.59 to 0.85) populations. The objective response rate on second-course pembrolizumab was 27.3% (3 of 11). PFS2 improved with pembrolizumab in the PD-L1 CPS ≥ 20 (HR, 0.64; 95% CI, 0.48 to 0.84) and CPS ≥ 1 (HR, 0.79; 95% CI, 0.66 to 0.95) populations and with pembrolizumab-chemotherapy in the PD-L1 CPS ≥ 20 (HR, 0.64; 95% CI, 0.48 to 0.86), CPS ≥ 1 (HR, 0.66; 95% CI, 0.55 to 0.81), and total (HR, 0.73; 95% CI, 0.61 to 0.88) populations. PFS2 was similar after pembrolizumab and longer after pembrolizumab-chemotherapy on next-line taxanes and shorter after pembrolizumab and similar after pembrolizumab-chemotherapy on next-line nontaxanes. CONCLUSION: With a 4-year follow-up, first-line pembrolizumab and pembrolizumab-chemotherapy continued to demonstrate survival benefit versus cetuximab-chemotherapy in recurrent/metastatic head and neck squamous cell carcinoma. Patients responded well to subsequent treatment after pembrolizumab-based therapy

Late term tolerance in head neck cancer patients irradiated in the IMRT era

BACKGROUND: The aim was to quantify severe transient and persisting late term effects in our single institution head neck cancer (HNC) cohort treated with curatively intended intensity modulated radiation therapy (IMRT). Hypothesis was if a 2-year follow up (FU) is sufficient to estimate the long term tolerance in HNC irradiated in the IMRT era. METHODS: Between 01/2002-8/2012, 707/1211 (58%) consecutively treated IMRT patients met the inclusion criteria of a FU time >12 months and loco-regional disease control (LRC). 45% presented with loco-regionally advanced disease; 55% were referred for curative definitive IMRT (66Gy-72Gy in 30--35 fractions), 45% underwent postoperative IMRT (60-66Gy in 30--33 fractions). Systemic concomitant therapy was administered in 85%. Highly consistent treatment procedures were performed with respect to contouring processes, dose constraints, radiation schedules, and the use of systemic therapy. Grade 3/4 late term effects were prospectively assessed and analyzed with respect to subgroups at particular risk for specific late effects. RESULTS: Mean/median FU of the cohort was 41/35 months (15--124). 13% of the patients (92/707) experienced any grade 3/4 late effects (101 events in 92/707 patients), 81% in the first 12 months after radiation. 4% of all developed persisting late grade 3/4 effects (25 events in 25/707 patients). CONCLUSIONS: IMRT led to a high late term tolerance in loco-regionally disease free HNC patients. The onset of any G3/4 effects showed a plateau at 2 years. The question of the cervical vessel tolerance in disease free long time survivors is still open and currently under evaluation at our institution

Comparison of the Full Outline of UnResponsiveness and Glasgow Liege Scale/Glasgow Coma Scale in an Intensive Care Unit Population.

peer reviewedBACKGROUND: The Full Outline of UnResponsiveness (FOUR) has been proposed as an alternative for the Glasgow Coma Scale (GCS)/Glasgow Liege Scale (GLS) in the evaluation of consciousness in severely brain-damaged patients. We compared the FOUR and GLS/GCS in intensive care unit patients who were admitted in a comatose state. METHODS: FOUR and GLS evaluations were performed in randomized order in 176 acutely (<1 month) brain-damaged patients. GLS scores were transformed in GCS scores by removing the GLS brainstem component. Inter-rater agreement was assessed in 20% of the studied population (N = 35). A logistic regression analysis adjusted for age, and etiology was performed to assess the link between the studied scores and the outcome 3 months after injury (N = 136). RESULTS: GLS/GCS verbal component was scored 1 in 146 patients, among these 131 were intubated. We found that the inter-rater reliability was good for the FOUR score, the GLS/GCS. FOUR, GLS/GCS total scores predicted functional outcome with and without adjustment for age and etiology. 71 patients were considered as being in a vegetative/unresponsive state based on the GLS/GCS. The FOUR score identified 8 of these 71 patients as being minimally conscious given that these patients showed visual pursuit. CONCLUSIONS: The FOUR score is a valid tool with good inter-rater reliability that is comparable to the GLS/GCS in predicting outcome. It offers the advantage to be performable in intubated patients and to identify non-verbal signs of consciousness by assessing visual pursuit, and hence minimal signs of consciousness (11% in this study), not assessed by GLS/GCS scales