Early predictors of outcome in comatose survivors of ventricular fibrillation and non-ventricular fibrillation cardiac arrest treated with hypothermia: a prospective study

OBJECTIVES: Current indications for therapeutic hypothermia (TH) are restricted to comatose patients with cardiac arrest (CA) due to ventricular fibrillation (VF) and without circulatory shock. Additional studies are needed to evaluate the benefit of this treatment in more heterogeneous groups of patients, including those with non-VF rhythms and/or shock and to identify early predictors of outcome in this setting. DESIGN: Prospective study, from December 2004 to October 2006. SETTING: 32-bed medico-surgical intensive care unit, university hospital. PATIENTS: Comatose patients with out-of-hospital CA. INTERVENTIONS: TH to 33 +/- 1 degrees C (external cooling, 24 hrs) was administered to patients resuscitated from CA due to VF and non-VF (including asystole or pulseless electrical activity), independently from the presence of shock. MEASUREMENTS AND MAIN RESULTS: We hypothesized that simple clinical criteria available on hospital admission (initial arrest rhythm, duration of CA, and presence of shock) might help to identify patients who eventually survive and might most benefit from TH. For this purpose, outcome was related to these predefined variables. Seventy-four patients (VF 38, non-VF 36) were included; 46% had circulatory shock. Median duration of CA (time from collapse to return of spontaneous circulation [ROSC]) was 25 mins. Overall survival was 39.2%. However, only 3.1% of patients with time to ROSC > 25 mins survived, as compared to 65.7% with time to ROSC < or = 25 mins. Using a logistic regression analysis, time from collapse to ROSC, but not initial arrest rhythm or presence of shock, independently predicted survival at hospital discharge. CONCLUSIONS: Time from collapse to ROSC is strongly associated with outcome following VF and non-VF cardiac arrest treated with therapeutic hypothermia and could therefore be helpful to identify patients who benefit most from active induced cooling.

Arterial wall dosimetry for non-Hodgkin lymphoma patients treated with radioimmunotherapy.

Tumors in non-Hodgkin lymphoma (NHL) patients are often proximal to the major blood vessels in the abdomen or neck. In external-beam radiotherapy, these tumors present a challenge because imaging resolution prevents the beam from being targeted to the tumor lesion without also irradiating the artery wall. This problem has led to potentially life-threatening delayed toxicity. Because radioimmunotherapy has resulted in long-term survival of NHL patients, we investigated whether the absorbed dose (AD) to the artery wall in radioimmunotherapy of NHL is of potential concern for delayed toxicity. SPECT resolution is not sufficient to enable dosimetric analysis of anatomic features of the thickness of the aortic wall. Therefore, we present a model of aortic wall toxicity based on data from 4 patients treated with (131)I-tositumomab. METHODS: Four NHL patients with periaortic tumors were administered pretherapeutic (131)I-tositumomab. Abdominal SPECT and whole-body planar images were obtained at 48, 72, and 144 h after tracer administration. Blood-pool activity concentrations were obtained from regions of interest drawn on the heart on the planar images. Tumor and blood activity concentrations, scaled to therapeutic administered activities-both standard and myeloablative-were input into a geometry and tracking model (GEANT, version 4) of the aorta. The simulated energy deposited in the arterial walls was collected and fitted, and the AD and biologic effective dose values to the aortic wall and tumors were obtained for standard therapeutic and hypothetical myeloablative administered activities. RESULTS: Arterial wall ADs from standard therapy were lower (0.6-3.7 Gy) than those typical from external-beam therapy, as were the tumor ADs (1.4-10.5 Gy). The ratios of tumor AD to arterial wall AD were greater for radioimmunotherapy by a factor of 1.9-4.0. For myeloablative therapy, artery wall ADs were in general less than those typical for external-beam therapy (9.4-11.4 Gy for 3 of 4 patients) but comparable for 1 patient (32.6 Gy). CONCLUSION: Blood vessel radiation dose can be estimated using the software package 3D-RD combined with GEANT modeling. The dosimetry analysis suggested that arterial wall toxicity is highly unlikely in standard dose radioimmunotherapy but should be considered a potential concern and limiting factor in myeloablative therapy.

Cytokines and hs-CRP levels in individuals treated with aspirin for cardiovascular prevention: a population-based study (CoLaus Study)

Backgrounds: Pro-inflammatory cytokines and high-sensitive C-reactive protein (hs-CRP) are associated with increased risk for cardiovascular disease. Low-dose aspirin for cardiovascular (CV) prevention is reported to have anti-inflammatory effects. The aim of this study was to determine the association between cytokines and hs-CRP levels and low-dose aspirin use for CV prevention in a population-based cohort (CoLaus Study). Methods and Results: Blood samples were assessed in 6,085 participants (3,201 women) aged 35-75 years. Medications' use and indications were recorded. Among aspirin users (n=1'034; 17%), overall low-dose (351; 5.8%) and low-dose for CV prevention (324; 5.3%) users were specifically selected for analysis. IL-1beta, IL-6 and TNF-alpha were assessed by a multiplex particle-based flow cytometric assay and hs-CRP by an immunometric assay. Cytokines and hs-CRP were presented in quartiles. Multivariate analysis adjusting for sex, age, smoking status, body mass index, concomitant use of various immunomodulatory drugs, diabetes mellitus showed no association between cytokines and hs-CRP levels and low-dose aspirin use for CV prevention either comparing the topmost vs. the three other quartiles (OR 95% CI, 0.84 (0.59 - 1.18), 1.03 (0.78 - 1.32), 1.10 (0.83 - 1.46), 1.00 (0.67 - 1.69) for IL-1beta, IL-6, TNF-alpha and hs-CRP, respectively), or comparing the topmost quartile vs. the first one (OR 95% CI, 0.87 (0.60 - 1.26), 1.19 (0.79 - 1.79), 1.26 (0.86 - 1.84), 1.06 (0.67 - 1.69)). Conclusions: Low-dose aspirin use for cardiovascular prevention does not seem to impact plasma cytokine and hs-CRP levels in a population-based cohort.

Long duration response to levodopa in advanced Parkinson's disease patients treated with subthalamic deep brain stimulation

Résumé La levodopa (LD) est le traitement antiparkinsonien le plus efficace et le plus répandu. Son effet est composé d'une réponse de courte (quelques heures) et de longue durée (jours à semaines). La persistance de cette dernière dans les phases avancées de la maladie de Parkinson est controversée, et sa mesure directe n'a jamais été faite en raison des risques liés à un sevrage complet de LD. La stimulation du noyau sous-thalamique est un nouveau traitement neurochirurgical de la maladie de Parkinson, indiqué dans les formes avancées, qui permet l'arrêt complet du traitement médicamenteux chez certains patients. Nous avons étudié 30 patients qui ont bénéficié d'une telle stimulation, et les avons évalués avant l'intervention sans médicaments, et à 6 mois postopératoires, sans médicaments et sans stimulation. Chez 19 patients, la médication a pu être complètement arrêtée, alors qu'elle a dû être réintroduite chez les 11 patients restants. Au cours des 6 mois qui ont suivi l'intervention, le parkinsonisme s'est aggravé de façon significative dans le groupe sans LD, et non dans le groupe avec LD. Cette différence d'évolution s'explique par la perte de l'effet à long terme de la LD dans le groupe chez qui ce médicament a pu être arrêté. En comparant cette aggravation à la magnitude de l'effet à court terme, la réponse de longue durée correspond environ à 80 pourcent de la réponse de courte durée, et elle lui est inversement corrélée. Parmi les signes cardinaux de la maladie, la réponse de longue durée affecte surtout la bradycinésie et la rigidité, mais pas le tremblement ni la composante axiale. La comparaison du parkinsonisme avec traitement (stimulation et LD si applicable) ne montre aucune différence d'évolution entre les 2 groupes, suggérant que la stimulation compense tant la réponse de courte que de longue durée. Notre travail montre que la réponse de longue durée à la LD demeure significative chez les patients parkinsoniens après plus de 15 ans d'évolution, et suggère que la stimulation du noyau sous-thalamique compense les réponses de courte et de longue durée. Abstract Background: Long duration response to levodopa is supposed to decrease with Parkinson's disease (PD) progression, but direct observation of this response in advanced PD has never been performed. Objective: To study the long duration response to levodopa in advanced PD patients treated with subthalamic deep-brain stimulation. Design and settings: We studied 30 consecutive PD patients who underwent subthalamic deep-brain stimulation. One group had no antiparkinsonian treatment since surgery (no levodopa), while medical treatment had to be reinitiated in the other group (levodopa). Main outcome measures: motor Unified Parkinson's Disease Rating Scale (UPDRS). Results: In comparison with preoperative assessment, evaluation six months postoperatively with stimulation turned off for three hours found a worsening of the motor part of UPDRS in the no-levodopa group. This worsening being absent in the levodopa group, it most probably reflected the loss of the long duration response to levodopa in the no-levodopa group. Stimulation turned on, postoperative motor UPDRS in both groups were similar to preoperative on medication scores, suggesting that subthalamic deep-brain stimulation compensated for both the short and long duration responses to levodopa. Conclusions: Our results suggest that the long duration response to levodopa remains significant even in advanced PD, and that subthalamic deep-brain stimulation compensates for both the short and the long duration resposes to levodopa.

Predicting prognosis using molecular profiling in estrogen receptor-positive breast cancer treated with tamoxifen.

Background: Estrogen receptor positive (ER+) breast cancers (BC) are heterogeneous with regard to their clinical behavior and response to therapies. The ER is currently the best predictor of response to the anti-estrogen agent tamoxifen, yet up to 30-40% of ER+ BC will relapse despite tamoxifen treatment. New prognostic biomarkers and further biological understanding of tamoxifen resistance are required. We used gene expression profiling to develop an outcome-based predictor using a training set of 255 ER+ BC samples from women treated with adjuvant tamoxifen monotherapy. We used clusters of highly correlated genes to develop our predictor to facilitate both signature stability and biological interpretation. Independent validation was performed using 362 tamoxifen-treated ER+ BC samples obtained from multiple institutions and treated with tamoxifen only in the adjuvant and metastatic settings.Results: We developed a gene classifier consisting of 181 genes belonging to 13 biological clusters. In the independent set of adjuvantly-treated samples, it was able to define two distinct prognostic groups (HR 2.01 95% CI: 1.29-3.13; p = 0.002). Six of the 13 gene clusters represented pathways involved in cell cycle and proliferation. In 112 metastatic breast cancer patients treated with tamoxifen, one of the classifier components suggesting a cellular inflammatory mechanism was significantly predictive of response.Conclusion: We have developed a gene classifier that can predict clinical outcome in tamoxifen-treated ER+ BC patients. Whilst our study emphasizes the important role of proliferation genes in prognosis, our approach proposes other genes and pathways that may elucidate further mechanisms that influence clinical outcome and prediction of response to tamoxifen.

Recurrent Macular Edema in Central Retinal Vein Occlusion Treated with Intravitreal Ranibizumab using a Modified Treat and Extend Regimen.

Background: The aim of this study was to evaluate the stability over time of the individually defined interval of intravitreal ranibizumab injection (IVR) for the treatment of recurrent macular edema (ME) in central retinal vein occlusion (CRVO). Patients and Methods: A case series of treatment naïve patients followed in the Jules Gonin Eye Hospital for macular edema due to central retinal vein occlusion is presented. Patients were treated monthly with IVR until complete absence of fluid on qualitative SD-OCT with a minimum of 5 monthly IVR. Thereafter, they were followed according to a modified treat and extend regimen (mTER). Results: Twelve eyes (12 patients) with ME due to CRVO were included. The mean follow-up period was 31.3 months. Analysis showed that best corrected visual acuity (BCVA), central macular thickness and qualitative spectral domain optical coherence tomography (SD-OCT) showed comparable results under monthly interval, after titration of an individualized interval and when performed in a series. 78 % of treating intervals were within ± 2 weeks of the first individually adjusted interval. The mean first defined interval was 4.3 weeks and the mean interval over time was 5.5 weeks (p = 0.003). There was a trend towards longer interval over time. Conclusion: The adjusted interval of retreatment of patients with ME due to CRVO showed a high stability with a trend toward longer duration over time. An mTER regimen seems to be valuable to follow patients with ME with good stabilization of VA.

Long-Term Follow-Up of Choroidal Neovascularization in Pathological Myopia Treated with Intravitreal Ranibizumab.

Background: The purpose of this contribution is to report our functional results on the efficacy of intravitreal ranibizumab for submacular choroidal neovessels (CNV) in high myopia, and to compare the roles of optical coherence tomography (OCT), fluorescein angiography and visual acuity changes in the treatment decision prior to each injection. Patients and Methods: This is a retrospective study performed in Jules Gonin Eye Hospital. It included all patients with myopic CNV treated with intravitreal ranibizumab injections with a minimum follow-up of 24 months. After an induction dosing from 1 to 3 injections, the follow-up was based on a pro re nata regimen. Ophthalmic evaluation, best corrected visual acuity, and OCT were done at each visit, and fluorescein angiography at baseline and if neovascular activity was suspected. Retreatment criteria included metamorphopsia, visual loss of ≥ 5 ETDRS letters, any fluid on OCT and/or leakage on fluorescein angiography. Results: 24 eyes were included in the study. Mean follow-up was 49 months. Mean visual acuity improved significantly from 62.8 ± 13.8 letters at baseline to 72.8 ± 12.9 letters at last follow-up visit (p = 0.001). The mean number of injections was 2.2 in the first year and below 1 for the following years. The sensitivities of fluorescein angiography, SD OCT, and visual acuity loss ≥ 5 letters were 62.6 %, 51.4 %, and 40 %, respectively. The fluorescein angiography showed a significantly higher sensitivity in treatment decision than OCT (p = 0.007). Conclusion: Our study has shown that ranibizumab injections provide a significant long-term visual benefit in myopic CNV with a small number of injections. Fluorescein angiography has a preponderant role in the treatment decision of active myopic CNV.

Fluence plays a critical role on the subsequent distribution of chemotherapy and tumor growth delay in murine mesothelioma xenografts pre-treated by photodynamic therapy.

BACKGROUND: The pre-conditioning of tumor vessels by low-dose photodynamic therapy (L-PDT) was shown to enhance the distribution of chemotherapy in different tumor types. However, how light dose affects drug distribution and tumor response is unknown. Here we determined the effect of L-PDT fluence on vascular transport in human mesothelioma xenografts. The best L-PDT conditions regarding drug transport were then combined with Lipoplatin(®) to determine tumor response. in vivo. Lasers Surg. Med. 47:323-330, 2015. © 2015 Wiley Periodicals, Inc. METHODS: Nude mice bearing dorsal skinfold chambers were implanted with H-Meso1 cells. Tumors were treated by Visudyne(®) -mediated photodynamic therapy with 100 mW/cm(2) fluence rate and a variable fluence (5, 10, 30, and 50 J/cm(2) ). FITC-Dextran (FITC-D) distribution was assessed in real time in tumor and normal tissues. Tumor response was then determined with best L-PDT conditions combined to Lipoplatin(®) and compared to controls in luciferase expressing H-Meso1 tumors by size and whole body bioluminescence assessment (n = 7/group). RESULTS: Tumor uptake of FITC-D following L-PDT was significantly enhanced by 10-fold in the 10 J/cm(2) but not in the 5, 30, and 50 J/cm(2) groups compared to controls. Normal surrounding tissue uptake of FITC-D following L-PDT was significantly enhanced in the 30 J/cm(2) and 50 J/cm(2) groups compared to controls. Altogether, the FITC-D tumor to normal tissue ratio was significantly higher in the 10 J/cm(2) group compared others. Tumor growth was significantly delayed in animals treated by 10 J/cm2-L-PDT combined to Lipoplatin(®) compared to controls. CONCLUSIONS: Fluence of L-PDT is critical for the optimal distribution and effect of subsequently administered chemotherapy. These findings have an importance for the clinical translation of the vascular L-PDT concept in the clinics. Lasers Surg. Med. 47:323-330, 2015.

Refractory intraretinal or subretinal fluid in neovascular age-related macular degeneration treated with intravitreal ranizubimab: Functional and Structural Outcome.

PURPOSE: To investigate the visual acuity results of eyes with neovascular age-related macular degeneration and refractory fluid despite monthly treatment with ranibizumab, and to investigate differences between refractory subretinal fluid and intraretinal cystic changes. METHODS: Retrospective chart review of consecutive treatment-refractory neovascular age-related macular degeneration, defined as persistent intraretinal or subretinal fluid despite monthly ranibizumab injections during 12 months or more. Data were evaluated for baseline characteristics, type and location of the refractory fluid, mean visual acuity change, number of injections, and the time point of first complete disappearance of all fluid on spectral domain optical coherence tomography. RESULTS: Seventy-six eyes (74 patients, mean age, 76.8 years) were identified. The mean follow-up was 33.6 months (range, 12-73 months). The mean number of injections was 11.4 in the first year and 27.7 over follow-up. The refractory fluid was located subfoveally in 61.8%. In 27 eyes (35.5%), the fluid resolved after a mean of 21.8 months (range, 13-49 months). Mean visual acuity increased by 9.0, 7.9, and 7.9 letters by Month 12, Month 24, and Month 36, respectively. Subgroup analysis revealed a higher risk for fibrosis (odds ratio, 3.30) or atrophy (odds ratio, 3.34) in patients with refractory cysts as compared with refractory subretinal fluid. Furthermore, refractory cysts showed a higher risk for a 10-letter visual acuity loss (P = 0.018). CONCLUSION: Fluid refractory to monthly treatment with ranibizumab for neovascular age-related macular degeneration still allowed for well-maintained visual improvement, even in subfoveal location. Late fluid resolution may occur. However, refractory cysts were associated with poorer anatomical and functional outcome than subretinal fluid.

Quantitative proteomics of heat-treated human cells show an across-the-board mild depletion of housekeeping proteins to massively accumulate few HSPs.

Classic semiquantitative proteomic methods have shown that all organisms respond to a mild heat shock by an apparent massive accumulation of a small set of proteins, named heat-shock proteins (HSPs) and a concomitant slowing down in the synthesis of the other proteins. Yet unexplained, the increased levels of HSP messenger RNAs (mRNAs) may exceed 100 times the ensuing relative levels of HSP proteins. We used here high-throughput quantitative proteomics and targeted mRNA quantification to estimate in human cell cultures the mass and copy numbers of the most abundant proteins that become significantly accumulated, depleted, or unchanged during and following 4 h at 41 °C, which we define as mild heat shock. This treatment caused a minor across-the-board mass loss in many housekeeping proteins, which was matched by a mass gain in a few HSPs, predominantly cytosolic HSPCs (HSP90s) and HSPA8 (HSC70). As the mRNAs of the heat-depleted proteins were not significantly degraded and less ribosomes were recruited by excess new HSP mRNAs, the mild depletion of the many housekeeping proteins during heat shock was attributed to their slower replenishment. This differential protein expression pattern was reproduced by isothermal treatments with Hsp90 inhibitors. Unexpectedly, heat-treated cells accumulated 55 times more new molecules of HSPA8 (HSC70) than of the acknowledged heat-inducible isoform HSPA1A (HSP70), implying that when expressed as net copy number differences, rather than as mere "fold change" ratios, new biologically relevant information can be extracted from quantitative proteomic data. Raw data are available via ProteomeXchange with identifier PXD001666.

Comparison between Radiographic (2-dimensional and 3-dimensional) and Histologic Findings of Periapical Lesions Treated with Apical Surgery.

INTRODUCTION: The aim of this study was to evaluate the concordance of 2- and 3-dimensional radiography and histopathology in the diagnosis of periapical lesions. METHODS: Patients were consecutively enrolled in this study provided that preoperative periapical radiography (PR) and cone-beam computed tomographic imaging of the tooth to be treated with apical surgery were performed. The periapical lesional tissue was histologically analyzed by 2 blinded examiners. The final histologic diagnosis was compared with the radiographic assessments of 4 blinded observers. The initial study material included 62 teeth in the same number of patients. RESULTS: Four lesions had to be excluded during processing, resulting in a final number of 58 evaluated cases (31 women and 27 men, mean age = 55 years). The final histologic diagnosis of the periapical lesions included 55 granulomas (94.8%) and 3 cysts (5.2%). Histologic analysis of the tissue samples from the apical lesions exhibited an almost perfect agreement between the 2 experienced investigators with an overall agreement of 94.83% (kappa = 0.8011). Radiographic assessment overestimated cysts by 28.4% (cone-beam computed tomographic imaging) and 20.7% (periapical radiography), respectively. Comparing the correlation of the radiographic diagnosis of 4 observers with the final histologic diagnosis, 2-dimensional (kappa = 0.104) and 3-dimensional imaging (kappa = 0.111) provided only minimum agreement. CONCLUSIONS: To establish a final diagnosis of an apical radiolucency, the tissue specimen should be evaluated histologically and specified as a granuloma (with/without epithelium) or a cyst. Analysis of 2-dimensional and 3-dimensional radiographic images alike results only in a tentative diagnosis that should be confirmed with biopsy.

Refractory subretinal fluid in patients with neovascular age-related macular degeneration treated with intravitreal ranibizumab: visual acuity outcome.

PURPOSE: To investigate the functional outcome of eyes with neovascular AMD (nAMD) and subretinal fluid (SRF) refractory to treatment with ranibizumab. METHODS: Retrospective chart review of consecutive treatment-refractory SRF in nAMD despite monthly ranibizumab injections during 12 months or more. Data were evaluated for baseline characteristics, location of the refractory SRF, mean visual acuity (VA) change, number of injections, and timepoint of first complete disappearance of SRF. RESULTS: Forty-five eyes in 44 patients (mean age of 76 years) were included. The mean follow-up was 32.4 months (range 12-73 months). The mean number of injections was 11.6 in the first year and 27.5 over follow-up. The refractory SRF was located subfoveally in 66.7 %. In 12 eyes (26.7 %), complete absorption of SRF was found after a mean of 22.6 months (range, 13-41 months). Mean VA increased by 10.4, 8.2, and 8.6 letters by month 12, 24, and 36, respectively. CONCLUSIONS: Neovascular AMD with SRF refractory to monthly retreatment with ranibizumab may still allow good and maintained visual improvement, even if the fluid is located subfoveally. SRF may progressively absorb under continuous monthly treatment. The necessity to treat refractory SRF with monthly injections could be questioned and would need future investigations.